IL323616A - Bifunctional compounds for degrading braf via ubiquitin proteosome pathway - Google Patents

Description

Attorney Docket No .: 121843.002NU - 3200 PCT BIFUNCTIONAL COMPOUNDS FOR DEGRADING BRAF VIA UBIQUITIN PROTEOSOME PATHWAY CROSS REFERENCE [ 0001 ] This patent application claims the benefit of United States Provisional Patent Application No. 63 / 462,918 , filed April 28 , 2023 , the contents of which are incorporated herein by reference in their entirety for all purposes . FIELD [ 0002 ] This disclosure provides novel bifunctional compounds for proteolytically degrading targeted serine / threonine - protein kinase B - Raf ( BRAF ) and methods for treating diseases modulated by BRAF .

BACKGROUND [ 0003 ] Serine / threonine - protein kinase B - Raf ( BRAF ) participates in cellular signalling related to cell growth . BRAF provides a promising target for therapies for treating several inflammatory , autoimmune , and proliferative diseases and disorders .

SUMMARY [ 0004 ] Provided herein are compounds capable of binding , inhibiting , and / or degrading BRAF . The compounds are useful for the treatment or prevention of inflammatory , autoimmune , and proliferative diseases and disorders in a subject in need thereof . In certain embodiments , the compounds described herein include a BRAF hook bound to a linker further bound to a ubiquitin ligase harness . [ 0005 ] In one aspect , provided herein are compounds according to Formula ( I ) : wherein O = S - RHN -R1b R1a- X4 . X( I ) ¹R is alkyl , aryl , amino , alkylamino , dialkylamino , cycloalkyl , or heterocycloalkyl , each unsubstituted or substituted with one or more halogen or hydroxyl ; a¹R is halogen ; - 1 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT R1b is hydrogen , haloalkyl , or halogen ; ²R is hydrogen , alkyl , cycloalkyl , haloalkyl , or - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM ; ¹X is carbon or nitrogen ; X2 is carbon or nitrogen ; ³X is sulfur , nitrogen , oxygen , or carbon ; the bonds among ¹X , ²X , and ³X comprise single and double bonds , and the ring containing X1 , X2 , and ³X is aromatic ; X4 is carbon or nitrogen ; X5 is hydrogen or 4R³RN- ; ³R is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl ; R4 is hydrogen , alkyl , cycloalkyl , or - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM wherein ¹rA is arylene or heteroarylene , each unsubstituted or substituted with one or more alkyl or one or more halogen ; ¹Z is a bond or -CH2- ; n is zero or one ; Z is absent , -C ( O ) - , -O- , C1-10 alkylene , C1-10 alkylene - C ( Me ) ( Me ) - , three- to six - membered cycloalkylene , three to six - membered cycloalkylene - C1-10 alkylene , heterocycloalkylene , or -C ( Me ) ( Me ) - ; ¹yC is absent or heterocycloalkylene , unsubstituted or substituted with one or more alkyl or one or more halogen ; ³Z is absent , C1-10 alkylene , or -C ( O ) - ; L is a linker according to -L1 - L2 - ³L - -ªL or -LA - ³L - ²L - -¹L , wherein ¹L- is absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -C1-8 alkylene- , -C2-8 alkynylene- , -C6-10 aryl- , -C4-10 heteroaryl- , -¹Q- , or -²Q- ; each -²L- , -³L- , and -L- is independently , absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -0- , - ( CH2CH2 - O ) 1-8- , -C1-8 alkylene- , -C6-10 aryl- , -C4-10 heteroaryl- , -¹Q- , -²Q- , or -³Q- ; -C2-alkynylene- , each R10 is independently , hydrogen or methyl ; -2- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT each ¹¹R is , independently , hydrogen , methyl , aryl , or heteroaryl ; each ¹Q- is a three- to seven - membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl , hydroxyl , or halogen ; each -²Q- is a five- to thirteen - membered bicyclic heterocycloalkylene comprising at least one nitrogen , wherein the five- to thirteen - membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring ; each -Q3- is a three- to six - membered cycloalkylene ; UBM is a ubiquitin ligase binding moiety ; wherein at least one of ²R or R4 is - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM ; or a stereoisomer and / or pharmaceutical salt thereof . [ 0006 ] In one aspect , provided herein are compounds according to Formula ( I ) : O = 5 - RHN R1a- R1b ( I ) wherein ¹R is alkyl , aryl , amino , alkylamino , dialkylamino , cycloalkyl , or heterocycloalkyl , each unsubstituted or substituted with a halogen or hydroxyl ; a¹R is halogen ; R1b is hydrogen or halogen ; ²R is hydrogen , alkyl , cycloalkyl , haloalkyl , or - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM ; ¹X is carbon or nitrogen ; X2 is carbon or nitrogen ; ³X is sulfur , nitrogen , oxygen , or carbon ; the bonds among ¹X , ²X , and ³X comprise single and double bonds , and the ring containing X1 , X2 , and ³X is aromatic ; X4 is carbon or nitrogen ; X5 is hydrogen or R³RN- + ; - 3 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ³R is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl ; R4 is hydrogen , alkyl , cycloalkyl , or - [ ¹rA - Z1 ] n - ²Z - ¹yC - ³Z - L - UBM wherein ¹rA is arylene or heteroarylene , each unsubstituted or substituted with one or more alkyl or one or more halogen ; ¹Z is a bond or -CH2- ; n is zero or one . Z is absent , -C ( O ) - , -O- , C1-10 alkylene , C1-10 alkylene - C ( Me ) ( Me ) - , three- to six - membered cycloalkylene , three- to six - membered cycloalkylene - C1-10 alkylene , heterocycloalkylene , or -C ( Me ) ( Me ) - ; ¹yC is absent or heterocycloalkylene , unsubstituted or substituted with alkyl ; ³Z is absent , C1-10 alkylene , or -C ( O ) - ; L is a linker according to -L1 - L2 - ³L - -ªL or -L * ³L- - ²L - -¹L , wherein ₁L- is absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -C1-8 alkylene- , -C2-8 alkynylene- , -C6-10 aryl- , -C4-10 heteroaryl- , -¹Q- , or -²Q- ; each -²L- , -³L- , and -L- is independently , absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -O- , - ( CH2CH2-0 ) 1-8- , -C1-8 alkylene- , -C2-8 alkynylene- , -C6-10 aryl- , -C4-10 heteroaryl- , -¹Q- , -²Q- , or -³Q- ; each R10 is independently , hydrogen or methyl ; each ¹¹R is , independently , hydrogen , methyl , aryl , or heteroaryl ; each ¹Q- is a three- to seven - membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl , hydroxyl , or halogen ; each -²Q- is a five- to thirteen - membered bicyclic heterocycloalkylene comprising at least one nitrogen , wherein the five- to thirteen - membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring ; each -Q3- is a three- to six - membered cycloalkylene ; UBM is a ubiquitin ligase binding moiety ; wherein at least one of ²R or R4 is - [ ¹rA - ¹Z ] ²Z- - ¹yC - ³Z - L - UBM ; or a stereoisomer and / or pharmaceutical salt thereof . [ 0007 ] The compounds of Formula ( 1 ) comprise a BRAF hook . The BRAF hook is a moiety capable of binding BRAF in vitro , in vivo , and / or in a cell . Useful BRAF hooks are described herein . The ubiquitin ligase harness is a moiety capable of harnessing a ubiquitin ligase in vitro , - 4 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT in vivo , and / or in a cell . In certain embodiments , the ubiquitin ligase is an E3 ligase . Useful ubiquitin ligase harnesses are described herein . The compounds of Formula ( I ) further comprise a linker . The linker is any moiety capable of covalently binding the harness and the hook while permitting each to bind or harness its target . By harnessing a ubiquitin ligase and binding BRAF , the compounds of Formula ( I ) are capable of targeting BRAF for degradation under the appropriate conditions , for instance in a cell . Degrading BRAF provides a mechanism useful for treating inflammatory , autoimmune , and proliferative diseases and disorders in subjects in need thereof . [ 0008 ] In another aspect , provided herein are compounds of Formula ( II ) : wherein O = S - ¹R HN -R1b R1a- N RX X ( II ) ¹R is alkyl , aryl , amino , alkylamino , dialkylamino , cycloalkyl , or heterocycloalkyl , each unsubstituted or substituted with a halogen or hydroxyl ; a¹R is halogen ; R1b is hydrogen or halogen ; ²R is - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM wherein ¹rA is arylene or heteroarylene , each unsubstituted or substituted with one or more alkyl or one or more halogen ; ¹Z is a bond or -CH2- ; n is zero or one ; Z is absent , -C ( O ) - , -O- , C1-10 alkylene , C1-10 alkylene - C ( Me ) ( Me ) - , three- to six - membered cycloalkylene , three- to six - membered cycloalkylene - C1-10 alkylene , heterocycloalkylene , or -C ( Me ) ( Me ) - ; ¹yC is absent or heterocycloalkylene , unsubstituted or substituted with alkyl ; ³Z is absent , C1-10 alkylene , or -C ( O ) - ; L is a linker according to -L1 - L2 - ³L - L- or -L4 - ³L - ²L - -¹L , wherein - 5 - 1100573566 5 AMERICAS oxygen ; Attorney Docket No .: 121843.002NU - 3200 PCT ¹L- is absent , -N ( ¹R ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -C1-8 alkylene- , -C2-8 alkynylene- , -C6-10 aryl- , -C4-10 heteroaryl- , -¹Q- , or -²Q- ; each -²L- , -³L- , and -L- is independently , absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -O- , - ( CH2CH2 - O ) 1-8- , -C1-8 alkylene- , -C2-8 alkynylene- , -C6-10 aryl- , -C4-10 heteroaryl- , -¹Q- , -²Q- , or -³Q- ; each R10 is independently , hydrogen or methyl ; each ¹¹R is , independently , hydrogen , methyl , aryl , or heteroaryl ; each ¹Q- is a three- to seven - membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl , hydroxyl , or halogen ; each -²Q- is a five- to thirteen - membered bicyclic heterocycloalkylene comprising at least one nitrogen , wherein the five- to thirteen - membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring ; each -Q3- is a three- to six - membered cycloalkylene ; UBM is a ubiquitin ligase binding moiety ; ¹X is nitrogen or oxygen ; ³X is sulfur when ¹X is nitrogen ; oxygen when ₁X is nitrogen ; or nitrogen when ¹X is the bonds among X1 and ³X comprise single and double bonds , and the ring containing X1 and ³X is aromatic ; X4 is carbon or nitrogen ; X5 is hydrogen or 4R³RN- ; ³R is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl ; R4 is hydrogen , alkyl , or cycloalkyl ; or a stereoisomer and / or pharmaceutical salt thereof . [ 0009 ] As described in more detail elsewhere herein , one side of the molecules of Formual I or II is a ubiquitin ligase harness . The other side of the molecules is a BRAF hook . The middle portion of the molecules is a linker . [ 00010 ] In another aspect , provided herein are pharmaceutical compositions . The pharmaceutical compositions comprise the compounds of Formula ( I ) and / or ( II ) along with one or more pharmaceutically acceptable carriers , diluents , and / or excipients . - 6 - 1100573566 5 AMERICAS [ 00011 ] Attorney Docket No .: 121843.002NU - 3200 PCT In another aspect , provided herein are methods of treating a disease or disorder in a subject in need thereof comprising the step of administering to the subject a therapeutically effective amount of the compound of Formula ( I ) and / or ( II ) , or pharmaceutical compositions thereof to the subject . In certain embodiments , provided herein are the compounds and compositions of Formula ( I ) and / or ( II ) for use in therapy . In certain embodiments , provided herein are the compounds and compositions of Formula ( I ) and / or ( II ) for use in the treatment or prevention of inflammatory , autoimmune , or proliferative diseases and disorders . In certain embodiments , provided herein are the uses of the compounds and compositions of Formula ( I ) and / or ( II ) for the manufacture of medicaments . In certain embodiments , provided herein are the uses of the compounds and compositions of Formula ( I ) and / or ( II ) for the manufacture of medicaments for the treatment or prevention of inflammatory , autoimmune , or proliferative diseases and disorders . In certain embodiments , the disease or disorder is an autoimmune disease or disorder . In certain embodiments , the disease or disorder is a proliferative disease or disorder , for instance , a T - cell lymphoma . In certain embodiments , the disease or disorder is cancer . In certain embodiments , the compounds or compositions of Formula ( I ) and / or ( II ) are for use in the treatment of cancer . -7- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT DETAILED DESCRIPTION Definitions [ 00012 ] For purposes herein , the chemical elements are identified in accordance with the Periodic Table of the Elements , CAS version , Handbook of Chemistry and Physics , 75th Ed . Additionally , general principles of organic chemistry are described in " Organic Chemistry , " Thomas Sorrell , University Science Books , Sausalito : 1999 , and " March's Advanced Organic Chemistry , " 5th Ed . , Ed .: Smith , M.B. and March , J. , John Wiley & Sons , New York : 2001 , the entire contents of which are hereby incorporated herein by reference . [ 00013 ] As described herein , " protecting group " refers to a moiety or functionality that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction . Standard protecting groups are provided in Wuts and Greene : " Greene's Protective Groups in Organic Synthesis , " 4th Ed , Wuts , P.G.M. and Greene , T.W. , Wiley - Interscience , New York : 2006 . [ 00014 ] As described herein , compounds herein optionally may be substituted with one or more substituents , such as those illustrated generally herein , or as exemplified by particular classes , subclasses , and / or species of this description . [ 00015 ] [ 00016 ] As used herein , the term " hydroxyl " or " hydroxy " refers to an -OH moiety .

As used herein , the term " aliphatic " encompasses the terms alkyl , alkenyl , and alkynyl , each of which are optionally substituted as set forth below . [ 00017 ] As used herein , an " alkyl " group refers to a saturated aliphatic hydrocarbon group containing one to twelve ( e.g. , one to eight , one to six , or one to four ) carbon atoms . An alkyl group can be straight or branched . Examples of alkyl groups include , but are not limited to , methyl , ethyl , propyl , isopropyl , butyl , isobutyl , sec - butyl , tert - butyl , n - pentyl , n - heptyl , or - ethylhexyl . An alkyl group can be substituted ( i.e. , optionally substituted ) with one or more substituents such as halo , phospho , cycloaliphatic ( e.g. , cycloalkyl or cycloalkenyl ) , heterocycloaliphatic ( e.g. , heterocycloalkyl or heterocycloalkenyl ) , aryl , heteroaryl , alkoxy , aroyl , heteroaroyl , acyl ( e.g. , ( aliphatic ) carbonyl , ( cycloaliphatic ) carbonyl , ( heterocycloaliphatic ) carbonyl ) , nitro , cyano , amido ( e.g. , ( cycloalkylalkyl ) carbonylamino , arylcarbonylamino , aralkylcarbonylamino , ( heterocycloalkyl ) carbonylamino , ( heterocycloalkylalkyl ) carbonylamino , heteroaralkylcarbonylamino , alkylaminocarbonyl , or heteroarylcarbonylamino , cycloalkylaminocarbonyl , heterocycloalkylaminocarbonyl , arylaminocarbonyl , or heteroarylaminocarbonyl ) , amino - 8 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( e.g. , aliphaticamino , cycloaliphaticamino , or heterocycloaliphaticamino ) , sulfonyl ( e.g. , aliphatic - SO2- , cycloaliphatic - SO2- , or aryl - SO2- ) , sulfinyl , sulfanyl , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , carboxy , carbamoyl , cycloaliphaticoxy , heterocycloaliphaticoxy , aryloxy , heteroaryloxy , aralkyloxy , heteroarylalkoxy , alkoxycarbonyl , alkylcarbonyloxy , or hydroxy . Without limitation , some examples of substituted alkyls include carboxyalkyl ( such as HOOC - alkyl , alkoxycarbonylalkyl , and alkylcarbonyloxyalkyl ) , cyanoalkyl , hydroxyalkyl , alkoxyalkyl , acylalkyl , aralkyl , ( alkoxyaryl ) alkyl , ( sulfonylamino ) alkyl ( such as ( alkyl - SO2- amino ) alkyl ) , aminoalkyl , amidoalkyl , ( cycloaliphatic ) alkyl , or haloalkyl . [ 00018 ] As used herein , an " alkenyl " group refers to an aliphatic carbon group that contains two to eight ( e.g. , two to four or two to six ) carbon atoms and at least one double bond . Like an alkyl group , an alkenyl group can be straight or branched . Examples of an alkenyl group include , but are not limited to , allyl , 1- or 2 - isopropenyl , 2 - butenyl , and 2 - hexenyl . An alkenyl group can be optionally substituted with one or more substituents such as halo , phospho , cycloaliphatic ( e.g. , cycloalkyl or cycloalkenyl ) , heterocycloaliphatic ( e.g. , heterocycloalkyl or heterocycloalkenyl ) , aryl , heteroaryl , alkoxy , aroyl , heteroaroyl , acyl ( e.g. , ( aliphatic ) carbonyl , ( cycloaliphatic ) carbonyl , or ( heterocycloaliphatic ) carbonyl ) , nitro , cyano , amido ( e.g. , ( cycloalkylalkyl ) carbonylamino , arylcarbonylamino , aralkylcarbonylamino , ( heterocycloalkyl ) carbonylamino , heteroarylcarbonylamino , cycloalkylaminocarbonyl , ( heterocycloalkylalkyl ) carbonylamino , heteroaralkylcarbonylamino , alkylaminocarbonyl , heterocycloalkylaminocarbonyl , arylaminocarbonyl , or heteroarylaminocarbonyl ) , amino ( e.g. , aliphaticamino , cycloaliphaticamino , heterocycloaliphaticamino , or aliphaticsulfonylamino ) , sulfonyl ( e.g. , ( e.g. , alkyl - SO2- , cycloaliphatic - SO2- , or aryl - SO2- ) , sulfinyl , sulfanyl , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , carboxy , carbamoyl , cycloaliphaticoxy , heterocycloaliphaticoxy , aryloxy , heteroaryloxy , aralkyloxy , heteroaralkoxy , alkoxycarbonyl , alkylcarbonyloxy , or hydroxy . Without limitation , some examples of substituted alkenyls include cyanoalkenyl , alkoxyalkenyl , acylalkenyl , hydroxyalkenyl , aralkenyl , ( alkoxyaryl ) alkenyl , ( sulfonylamino ) alkenyl ( such as ( alkyl - SO2 - amino ) alkenyl ) , aminoalkenyl , amidoalkenyl , ( cycloaliphatic ) alkenyl , or haloalkenyl . [ 00019 ] As used herein , an " alkynyl " group refers to an aliphatic carbon group that contains two to eight ( e.g. , two to four or two to six ) carbon atoms and has at least one triple bond . An alkynyl group can be straight or branched . Examples of an alkynyl group include , but are not limited to , propargyl and butynyl . An alkynyl group can be optionally substituted -9- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT with one or more substituents such as aroyl , heteroaroyl , alkoxy , cycloalkyloxy , heterocycloalkyloxy , aryloxy , heteroaryloxy , aralkyloxy , nitro , carboxy , cyano , halo , hydroxy , sulfo , mercapto , sulfanyl ( e.g. , aliphaticsulfanyl or cycloaliphaticsulfanyl ) , sulfinyl ( e.g. , aliphaticsulfinyl or cycloaliphaticsulfinyl ) , sulfonyl ( e.g. , aliphatic - SO2- , aliphaticamino - SO2- , or cycloaliphatic - SO2- ) , amido ( e.g. , aminocarbonyl , alkylaminocarbonyl , alkylcarbonylamino , cycloalkylaminocarbonyl , cycloalkylcarbonylamino , arylaminocarbonyl , aralkylcarbonylamino , ( heterocycloalkyl ) carbonylamino , heterocycloalkylaminocarbonyl , arylcarbonylamino , ( cycloalkylalkyl ) carbonylamino , heteroaralkylcarbonylamino , heteroarylcarbonylamino , or heteroarylaminocarbonyl ) , urea , thiourea , sulfamoyl , sulfamide , alkoxycarbonyl , alkylcarbonyloxy , cycloaliphatic , heterocycloaliphatic , aryl , heteroaryl , acyl ( e.g. , ( cycloaliphatic ) carbonyl or ( heterocycloaliphatic ) carbonyl ) , amino ( e.g. , aliphaticamino ) , sulfoxy , oxo , carboxy , carbamoyl , ( cycloaliphatic ) oxy , ( heterocycloaliphatic ) oxy , or ( heteroaryl ) alkoxy . [ 00020 ] As used herein , an " amido " group encompasses both " aminocarbonyl " and " carbonylamino . " These terms when used alone or in connection with another group refer to an amido group such as -N ( R ) -C ( O ) -RY or -C ( O ) -N ( R ) 2 when used terminally , and -C ( O ) -N ( R ) - or -N ( R ) -C ( O ) - when used internally , wherein RX and RY can be aliphatic , cycloaliphatic , aryl , araliphatic , heterocycloaliphatic , heteroaryl , or heteroaraliphatic . Examples of amido groups include alkylamido ( such as alkylcarbonylamino or alkylaminocarbonyl ) , ( heterocycloaliphatic ) amido , ( heteroaralkyl ) amido , ( heteroaryl ) amido , ( heterocycloalkyl ) alkylamido , arylamido , aralkylamido , ( cycloalkyl ) alkylamido , cycloalkylamido . [ 00021 ] or As used herein , an " amino " group refers to -NRRY wherein each of RX and R ¥ is independently hydrogen ( H or -H ) , aliphatic , cycloaliphatic , ( cycloaliphatic ) aliphatic , aryl , araliphatic , heterocycloaliphatic , ( heterocycloaliphatic ) aliphatic , heteroaryl , carboxy , sulfanyl , sulfinyl , sulfonyl , ( ( cycloaliphatic ) aliphatic ) carbonyl , ( heterocycloaliphatic ) carbonyl , ( aliphatic ) carbonyl , ( cycloaliphatic ) carbonyl , arylcarbonyl , ( araliphatic ) carbonyl , ( ( heterocycloaliphatic ) aliphatic ) carbonyl , ( heteroaryl ) carbonyl , or ( heteroaraliphatic ) carbonyl , each of which being defined elsewhere herein and being optionally substituted . Examples of amino groups include alkylamino , dialkylamino , or arylamino . When the term " amino " is not the terminal group ( e.g. , - 10 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT alkylcarbonylamino ) , it is represented by -NRX- , where RX has the same meaning as defined above . aryl ; [ 00022 ] As used herein , an " aryl " group used alone or as part of a larger moiety as in " aralkyl , " " aralkoxy , " or " aryloxyalkyl " refers to monocyclic ( e.g. , phenyl ) ; bicyclic ( e.g. , indenyl , naphthalenyl , tetrahydronaphthyl , or tetrahydroindenyl ) ; and tricyclic ( e.g. , fluorenyl tetrahydrofluorenyl , tetrahydroanthracenyl , or anthracenyl ) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic . The bicyclic and tricyclic groups include benzofused ( e.g. , 2- or 3- membered , or bi- or tricyclic carbocyclic ) rings . For example , a benzofused group includes phenyl fused with two or more C4-8 carbocyclic moieties . An aryl is optionally substituted with one or more substituents including aliphatic ( e.g. , alkyl , alkenyl , or alkynyl ) ; cycloaliphatic ; ( cycloaliphatic ) aliphatic ; heterocycloaliphatic ; ( heterocycloaliphatic ) aliphatic ; heteroaryl ; alkoxy ; ( cycloaliphatic ) oxy ; ( heterocycloaliphatic ) oxy ; aryloxy ; heteroaryloxy ; ( araliphatic ) oxy ; ( heteroaraliphatic ) oxy ; aroyl ; heteroaroyl ; amino ; oxo ( i.e. , on a non - aromatic carbon within a carbocyclic ring of a benzofused bicyclic or tricyclic aryl ) ; nitro ; carboxy ; amido ; acyl ( aliphatic ) carbonyl ; ( cycloaliphatic ) carbonyl ; ( ( cycloaliphatic ) aliphatic ) carbonyl ; ( araliphatic ) carbonyl ; ( heterocycloaliphatic ) carbonyl ; ( ( heterocycloaliphatic ) aliphatic ) carbonyl ; or ( heteroaraliphatic ) carbonyl ) ; sulfonyl ( e.g. , aliphatic - SO2- or amino - -₂OS ) ; sulfinyl ( e.g. , aliphatic - S ( O ) - or cycloaliphatic - S ( O ) - ) ; sulfanyl ( e.g. , aliphatic - S- ) ; cyano ; halo ; hydroxy ; mercapto ; sulfoxy ; urea ; thiourea ; sulfamoyl ; sulfamide ; or carbamoyl . Alternatively , an aryl can be unsubstituted . As used herein , an " arylene " is a divalent version of " aryl . " ( e.g. , ﻭﻭ [ 00023 ] Non - limiting examples of substituted aryls include haloaryl ( e.g. , mono- , di- ( such as p , m - dihaloaryl ) , and ( tri - halo ) aryl ) ; ( carboxy ) aryl ( e.g. , ( alkoxycarbonyl ) aryl , ( ( aralkyl ) carbonyloxy ) aryl , and ( alkoxycarbonyl ) aryl ) ; ( amido ) aryl ( e.g. , ( aminocarbonyl ) aryl , ( ( ( alkylamino ) alkyl ) aminocarbonyl ) aryl , ( alkylcarbonyl ) aminoaryl , ( arylaminocarbonyl ) aryl , and ( ( ( heteroaryl ) amino ) carbonyl ) aryl ) ; aminoaryl ( e.g. , ( ( alkylsulfonyl ) amino ) aryl or ( cyanoalkyl ) aryl ; ( alkoxy ) aryl ; ( sulfamoyl ) aryl ( e.g. , ( alkylsulfonyl ) aryl ; ( ( dialkyl ) amino ) aryl ) ; ( aminosulfonyl ) aryl ) ; ( cyano ) aryl ; ( hydroxyalkyl ) aryl ; ( ( alkoxy ) alkyl ) aryl ; ( hydroxy ) aryl , ( ( carboxy ) alkyl ) aryl ; ( ( ( dialkyl ) amino ) alkyl ) aryl ; ( nitroalkyl ) aryl ; ( ( ( alkylsulfonyl ) amino ) alkyl ) aryl ; ( ( heterocycloaliphatic ) carbonyl ) aryl ; ( ( alkylsulfonyl ) alkyl ) aryl ; ( cyanoalkyl ) aryl ; ( hydroxyalkyl ) aryl ; ( alkylcarbonyl ) aryl ; - 11 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT alkylaryl ; ( trihaloalkyl ) aryl ; p - amino - m - alkoxycarbonylaryl ; p - amino - m - cyanoaryl ; p - halo - m- aminoaryl ; or ( m- ( heterocycloaliphatic ) -o- ( alkyl ) ) aryl . [ 00024 ] As used herein , an " araliphatic " such as an " aralkyl " group refers to an aliphatic group ( e.g. , a C1-4 alkyl group ) that is substituted with an aryl group . " Aliphatic , " " alkyl , " and " aryl " are defined elsewhere herein . An example of an araliphatic such as an aralkyl group is benzyl . [ 00025 ] As used herein , an " aralkyl " group refers to an alkyl group ( e.g. , a C1-4 alkyl group ) that is substituted with an aryl group . Both " alkyl " and " aryl " have been defined above . An example of an aralkyl group is benzyl . An aralkyl is optionally substituted with one or more substituents such as aliphatic ( e.g. , alkyl , alkenyl , or alkynyl , including carboxyalkyl , hydroxyalkyl , or haloalkyl such as trifluoromethyl ) , cycloaliphatic ( e.g. , cycloalkyl or cycloalkenyl ) , ( cycloalkyl ) alkyl , heterocycloalkyl , ( heterocycloalkyl ) alkyl , aryl , heteroaryl , alkoxy , cycloalkyloxy , heterocycloalkyloxy , aryloxy , heteroaryloxy , aralkyloxy , heteroaralkyloxy , aroyl , heteroaroyl , nitro , carboxy , alkoxycarbonyl , alkylcarbonyloxy , amido aminocarbonyl , alkylcarbonylamino , cycloalkylcarbonylamino , arylcarbonylamino , ( e.g. , ( cycloalkylalkyl ) carbonylamino , ( heterocycloalkyl ) carbonylamino , aralkylcarbonylamino , ( heterocycloalkylalkyl ) carbonylamino , heteroarylcarbonylamino , or heteroaralkylcarbonylamino ) , cyano , halo , hydroxy , acyl , mercapto , alkylsulfanyl , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , or carbamoyl . [ 00026 ] As used herein , a " bicyclic ring system " includes 6- to 12 - membered ( e.g. , 8- to 12- or 9- , 10- , or 11 - membered ) structures that form two rings , wherein the two rings have at least one atom in common ( e.g. , two atoms in common ) . Bicyclic ring systems include bicycloaliphatics ( e.g. , bicycloalkyl or bicycloalkenyl ) , bicycloheteroaliphatics , bicyclic aryls , and bicyclic heteroaryls . [ 00027 ] As used herein , a " cycloaliphatic " group encompasses a " ❞lyklaolcyc group and a " cycloalkenyl " group , each of which are optionally substituted as set forth below . [ 00028 ] As used herein , a " cycloalkyl " group refers to a saturated carbocyclic mono- or bicyclic ( fused , bridged , or spiro ) ring of three to ten ( e.g. , five to ten ) carbon atoms . Examples of cycloalkyl groups include cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cycloheptyl , adamantyl , norbornyl , cubyl , octahydro - indenyl , decahydro - naphthyl , bicyclo [ 3.2.1 ] octyl , bicyclo [ 2.2.2 ] octyl , bicyclo [ 3.3.1 ] nonyl , bicyclo [ 3.3.2 ] decyl , bicyclo [ 2.2.2 ] octyl , adamantyl , spiro [ 3.3 ] heptanyl , or ( ( aminocarbonyl ) cycloalkyl ) cycloalkyl . - 12 - 1100573566 5 AMERICAS ﻭ Attorney Docket No .: 121843.002NU - 3200 PCT [ 00029 ] A " cycloalkenyl " group , as used herein , refers to a non - aromatic carbocyclic ring of three to ten ( e.g. , four to eight ) carbon atoms having one or more double bonds . include cyclopentenyl , 1,4 - cyclohexa - di - enyl , hexahydro - indenyl , octahydro - naphthyl , cyclohexenyl , Examples of cycloalkenyl groups cycloheptenyl , cyclooctenyl , bicyclo [ 2.2.2 ] octenyl , or bicyclo [ 3.3.1 ] nonenyl . [ 00030 ] A " cycloalkyl " or " cycloalkenyl " group can be optionally substituted with one or more substituents such as phospho , aliphatic ( e.g. , alkyl , alkenyl , or alkynyl ) , cycloaliphatic , ( cycloaliphatic ) aliphatic , heterocycloaliphatic , ( heterocycloaliphatic ) aliphatic , aryl , heteroaryl , alkoxy , ( cycloaliphatic ) oxy , ( heterocycloaliphatic ) oxy , aryloxy , heteroaryloxy , ( araliphatic ) oxy , ( heteroaraliphatic ) oxy , aroyl , heteroaroyl , amino , amido ( e.g. , ( aliphatic ) carbonylamino , ( cycloaliphatic ) carbonylamino , ( ( cycloaliphatic ) aliphatic ) carbonylamino , ( aryl ) carbonylamino , ( araliphatic ) carbonylamino , ( heterocycloaliphatic ) carbonylamino , ( ( heterocycloaliphatic ) aliphatic ) carbonylamino , ( heteroaryl ) carbonylamino , or ( heteroaraliphatic ) carbonylamino ) , nitro , carboxy ( e.g. , HOOC- alkoxycarbonyl , or alkylcarbonyloxy ) , acyl ( e.g. , ( cycloaliphatic ) carbonyl , ( ( cycloaliphatic ) aliphatic ) carbonyl , ( araliphatic ) carbonyl , ( heterocycloaliphatic ) carbonyl , ( ( heterocycloaliphatic ) aliphatic ) carbonyl , or ( heteroaraliphatic ) carbonyl , cyano , halo , hydroxy , mercapto , sulfonyl ( e.g. , alkyl - SO2- and aryl - SO2- ) , sulfinyl ( e.g. , alkyl - S ( O ) - ) , sulfanyl ( e.g. , alkyl - S- ) , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , or carbamoyl . [ 00031 ] As used herein , the term " heterocycloaliphatic " encompasses heterocycloalkyl groups and heterocycloalkenyl groups , each of which being optionally substituted as set forth below . [ 00032 ] As used herein , a " heterocycloalkyl " or divalent " heterocycloalklene " group refers to a 3- to 15 - membered mono- or bicylic ( e.g. , 5- to 10 - membered mono- or bicyclic ) saturated ring structure ( e.g. , fused , bridged , or spiro ) , in which one or more of the ring atoms is a heteroatom ( e.g. , nitrogen ( N ) , oxygen ( O ) , sulfur ( S ) , or combinations thereof ) . Non- limiting examples of a heterocycloalkyl ( or a divalent heterocycloalkylene ) group include piperidyl or piperidinyl , piperazyl or piperazinyl , tetrahydropyranyl , tetrahydrofuryl or tetrahydrofuranyl , 1,4 - dioxolanyl , 1,4 - dithianyl , 1,3 - dioxolanyl , 1,3 - diazepanyl , 1,4- diazepanyl , oxazolidyl or oxazolidinyl , isoxazolidyl or isoxazolidinyl , morpholinyl , thiomorpholinyl , octahydrobenzofuryl or octahydrobenzofuranyl , octahydrochromenyl , octahydrothiochromenyl , octahydroindolyl or octahydroindolinyl , octahydropyrindinyl or - 13 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT octahydro - 1H - cyclopenta [ x ] pyridine where x is h or C , decahydroquinolinyl , octahydrobenzo [ b ] thiopheneyl , 2 - oxa - bicyclo [ 2.2.2 ] octyl , 1 - aza - bicyclo [ 2.2.2 ] octyl , 3 - aza- bicyclo [ 3.2.1 ] octyl , 3,8 - diazabicyclo [ 3.2.1 ] octyl , decahydro - 2,7 - naphthyridine , 2.8- diazaspiro [ 4.5 ] decane , 2 - azaspiro [ 3.3 ] heptane , 2 - azaspiro [ 3.5 ] nonane , azaspiro [ 5.5 ] undecane , 2,7 - diazaspiro [ 3.5 ] nonane , octahydropyrrolo [ 3,4 - c ] pyrrole , octahydro - 1H - pyrrolo [ 3,4 - b ] pyridine , 2,5 - diazabicyclo [ 2.2.1 ] heptane , 3- 1 - oxa - 8- azaspiro [ 4.5 ] decane , and 2,6 - dioxa - tricyclo [ 3.3.1.03,7 ] nonyl . A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form , for example , tetrahydroisoquinoline , that could be categorized as a heteroaryl as defined elsewhere herein . [ 00033 ] A " heterocycloalkenyl " group , as used herein , refers to a mono- or bicylic ( e.g. , 5- to 10 - membered mono- or bicyclic ) non - aromatic ring structure having one or more double bonds , and wherein one or more of the ring atoms is a heteroatom ( e.g. , nitrogen ( N ) , oxygen ( O ) , or sulfur ( S ) ) . Monocyclic and bicyclic heterocycloalkenyls are numbered according to standard chemical nomenclature . [ 00034 ] A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phospho , aliphatic ( e.g. , alkyl , alkenyl , or alkynyl ) , cycloaliphatic , ( cycloaliphatic ) aliphatic , heterocycloaliphatic , ( heterocycloaliphatic ) aliphatic , aryl , heteroaryl , alkoxy , ( cycloaliphatic ) oxy , ( heterocycloaliphatic ) oxy , aryloxy , heteroaryloxy , ( araliphatic ) oxy , ( heteroaraliphatic ) oxy , aroyl , heteroaroyl , amino , amido ( e.g. , ( cycloaliphatic ) carbonylamino , ( ( cycloaliphatic ) aliphatic ) carbonylamino , ( aryl ) carbonylamino , ( araliphatic ) carbonylamino , ( aliphatic ) carbonylamino , ( ( heterocycloaliphatic ) aliphatic ) carbonylamino , carboxy ( heterocycloaliphatic ) carbonylamino , ( heteroaryl ) carbonylamino , or ( heteroaraliphatic ) carbonylamino , nitro , ( e.g. , HOOC- , alkoxycarbonyl , or alkylcarbonyloxy ) , acyl ( e.g. , ( cycloaliphatic ) carbonyl , ( ( cycloaliphatic ) aliphatic ) carbonyl , ( araliphatic ) carbonyl , ( heterocycloaliphatic ) carbonyl , ( ( heterocycloaliphatic ) aliphatic ) carbonyl , or ( heteroaraliphatic ) carbonyl ) , nitro , cyano , halo , hydroxy , mercapto , sulfonyl ( e.g. , alkylsulfonyl or arylsulfonyl ) , sulfinyl ( e.g. , alkylsulfinyl ) , sulfanyl ( e.g. , alkylsulfanyl ) , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , or carbamoyl . [ 00035 ] A " heteroaryl " group , as used herein , refers to a monocyclic , bicyclic , or tricyclic ring system having four to fifteen ring atoms wherein one or more of the ring atoms . is a heteroatom ( e.g. , N , O , S , or combinations thereof ) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is - 14 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT aromatic . A heteroaryl group includes a benzofused ring system having two to three rings . For example , a benzofused group includes one or two 4- to 8 - membered heterocycloaliphatic moieties ( e.g. , indolizyl , indolyl , isoindolyl , isoindolinyl - 1,3 - dione , isoindolinyl - 1 - one , 3H- indolyl , indolinyl , benzo [ b ] furyl , benzo [ b ] thiopheneyl , quinolinyl , or isoquinolinyl ) . Some examples of heteroaryl are pyridyl , 1H - indazolyl , furyl or furanyl , pyrrolyl , thienyl , thiazolyl , oxazolyl , imidazolyl , tetrazolyl , benzofuryl or benzofuranyl , isoquinolinyl , 1 - oxoisoquinolin- ( 1H ) -yl , benzthiazolyl , xanthene , thioxanthene , phenothiazine , dihydroindole , benzo [ 1,3 ] dioxole , benzo [ b ] furyl , benzo [ b ] thiopheneyl , indazolyl , benzimidazolyl , 3 - methyl- - oxo - 2,3 - dihydro - 1H - benzo [ d ] imidazol - 1 - yl , benzthiazolyl , puryl or purinyl , cinnolyl , quinolyl , quinazolyl , phthalazyl , quinazolyl , quinoxalyl , isoquinolyl , 4H - quinolizyl , benzo- 1,2,5 - thiadiazolyl , or 1,8 - naphthyridyl . Other examples of heteroaryls include 1,2,3,4- tetrahydroisoquinoline and 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazine . As used herein , " heteroarylene " is a divalent version of " heteroaryl . " [ 00036 ] Without limitation , monocyclic heteroaryls include furyl , thiophene - yl , 2H- pyrrolyl , oxazolyl , thiazolyl , imidazolyl , pyrazolyl , isoxazolyl , isothiazolyl , 1,3,4 - thiadiazolyl , pyridyl , pyridazyl , pyrimidyl , pyrazolyl , pyrazyl , or 1,3,5 - triazyl . Monocyclic heteroaryls are numbered according to standard chemical nomenclature . [ 00037 ] Without limitation , bicyclic heteroaryls include indolizyl , indolyl , isoindolyl , 3H - indolyl , indolinyl , benzo [ b ] furyl , benzo [ b ] thiopheneyl , quinolinyl , isoquinolinyl , indazolyl , benzimidazyl , benzthiazolyl , purinyl , 4H - quinolizyl , quinolyl , isoquinolyl , cinnolyl , phthalazyl , quinazolyl , quinoxalyl , 1,8 - naphthyridyl , or pteridyl . Bicyclic heteroaryls are numbered according to standard chemical nomenclature . [ 00038 ] A heteroaryl is optionally substituted with one or more substituents such as aliphatic ( e.g. , alkyl , alkenyl , or alkynyl ) ; cycloaliphatic ; ( cycloaliphatic ) aliphatic ; heterocycloaliphatic ; ( heterocycloaliphatic ) aliphatic ; aryl ; heteroaryl ; alkoxy ; ( cycloaliphatic ) oxy ; ( heterocycloaliphatic ) oxy ; aryloxy ; heteroaryloxy ; ( araliphatic ) oxy ; ( heteroaraliphatic ) oxy ; aroyl ; heteroaroyl ; amino ; oxo ( on a non - aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl ) ; carboxy ; amido ; acyl ( e.g. , ( aliphatic ) carbonyl ; ( cycloaliphatic ) carbonyl ; ( araliphatic ) carbonyl ; ( ( cycloaliphatic ) aliphatic ) carbonyl ; ( heterocycloaliphatic ) carbonyl ; ( ( heterocycloaliphatic ) aliphatic ) carbonyl ; or ( heteroaraliphatic ) carbonyl ) ; sulfonyl ( e.g. , aliphaticsulfonyl or aminosulfonyl ) ; sulfinyl ( e.g. , aliphaticsulfinyl ) ; sulfanyl ( e.g. , - 15 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT aliphaticsulfanyl ) ; nitro ; cyano ; halo ; hydroxy ; mercapto ; sulfoxy ; urea ; thiourea ; sulfamoyl ; sulfamide ; or carbamoyl . Alternatively , a heteroaryl can be unsubstituted . [ 00039 ] Non - limiting examples of substituted heteroaryls include ( halo ) heteroaryl ( e.g. , mono- and di- ( halo ) heteroaryl ) ; ( carboxy ) heteroaryl ( e.g. , ( alkoxycarbonyl ) heteroaryl ) ; cyanoheteroaryl ; aminoheteroaryl ( e.g. , ( ( alkylsulfonyl ) amino ) heteroaryl and ( ( dialkyl ) amino ) heteroaryl ) ; ( amido ) heteroaryl ( e.g. , aminocarbonylheteroaryl , ( ( alkylcarbonyl ) amino ) heteroaryl , ( ( ( ( alkyl ) amino ) alkyl ) aminocarbonyl ) heteroaryl , ( ( ( heteroaryl ) amino ) carbonyl ) heteroaryl , ( ( heterocycloaliphatic ) carbonyl ) heteroaryl , ( ( alkylcarbonyl ) amino ) heteroaryl ) ; ( cyanoalkyl ) heteroaryl ; and ( alkoxy ) heteroaryl ; ( alkoxyalkyl ) heteroaryl ; ( sulfamoyl ) heteroaryl ( e.g. , ( aminosulfonyl ) heteroaryl ) ; ( sulfonyl ) heteroaryl ( e.g. , ( alkylsulfonyl ) heteroaryl ) ; ( hydroxy ) heteroaryl ; ( ( carboxy ) alkyl ) heteroaryl ; ( ( ( dialkyl ) amino ) alkyl ) heteroaryl ; ( hydroxyalkyl ) heteroaryl ; ( heterocycloaliphatic ) heteroaryl ; ( cycloaliphatic ) heteroaryl ; ( nitroalkyl ) heteroaryl ; ( ( ( alkylsulfonyl ) amino ) alkyl ) heteroaryl ; ( ( alkylsulfonyl ) alkyl ) heteroaryl ; ( cyanoalkyl ) heteroaryl ; ( acyl ) heteroaryl ( e.g. , ( alkylcarbonyl ) heteroaryl ) ; ( alkyl ) heteroaryl ; or ( haloalkyl ) heteroaryl ( e.g. , trihaloalkylheteroaryl ) . [ 00040 ] As used herein , a " heteroaraliphatic " ( such as a heteroaralkyl group ) refers to an aliphatic group ( e.g. , a C1-4 alkyl group ) that is substituted with a heteroaryl group . " Aliphatic , " " alkyl , " and " heteroaryl " have been defined above . [ 00041 ] As used herein , a " heteroaralkyl " group refers to an alkyl group ( e.g. , a C1-alkyl group ) that is substituted with a heteroaryl group . Both " alkyl " and " heteroaryl " have been defined above . A heteroaralkyl is optionally substituted with one or more substituents such as alkyl ( including carboxyalkyl , hydroxyalkyl , and haloalkyl such as trifluoromethyl ) , alkenyl , alkynyl , cycloalkyl , ( cycloalkyl ) alkyl , heterocycloalkyl , ( heterocycloalkyl ) alkyl , aryl , heteroaryl , alkoxy , cycloalkyloxy , heterocycloalkyloxy , aryloxy , heteroaryloxy , aralkyloxy , heteroaralkyloxy , aroyl , heteroaroyl , nitro , carboxy , alkoxycarbonyl , alkylcarbonyloxy , aminocarbonyl , alkylcarbonylamino , cycloalkylcarbonylamino , ( cycloalkylalkyl ) carbonylamino , ( heterocycloalkyl ) carbonylamino , arylcarbonylamino , aralkylcarbonylamino , ( heterocycloalkylalkyl ) carbonylamino , heteroarylcarbonylamino , heteroaralkylcarbonylamino , cyano , halo , hydroxy , acyl , mercapto , alkylsulfanyl , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , or carbamoyl . - 16 - 1100573566 5 AMERICAS [ 00042 ] Attorney Docket No .: 121843.002NU - 3200 PCT As used herein , " cyclic moiety " and " cyclic group " refer to mono- , bi- , and tri- cyclic ring systems including cycloaliphatic , heterocycloaliphatic , aryl , or heteroaryl , each of which has been previously defined . [ 00043 ] As used herein , a " bridged bicyclic ring system " refers to a bicyclic heterocyclicalipahtic ( or heterocycloaliphatic ) ring system or bicyclic cycloaliphatic ring system in which the rings are bridged . Examples of bridged bicyclic ring systems include , but are not limited to , adamantanyl , norbornanyl , bicyclo [ 3.2.1 ] octyl , bicyclo [ 2.2.2 ] octyl , bicyclo [ 3.3.1 ] nonyl , bicyclo [ 3.3.2 ] decyl , 2 - oxabicyclo [ 2.2.2 ] octyl , 1 - azabicyclo [ 2.2.2 ] octyl , - azabicyclo [ 3.2.1 ] octyl , and 2,6 - dioxa - tricyclo [ 3.3.1.03,7 ] nonyl . A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl ( including carboxyalkyl , hydroxyalkyl , and haloalkyl such as trifluoromethyl ) , alkenyl , alkynyl , cycloalkyl , ( cycloalkyl ) alkyl , heterocycloalkyl , ( heterocycloalkyl ) alkyl , aryl , heteroaryl , alkoxy , cycloalkyloxy , heterocycloalkyloxy , aryloxy , heteroaryloxy , aralkyloxy , heteroaralkyloxy , aroyl , heteroaroyl , nitro , carboxy , alkoxycarbonyl , alkylcarbonyloxy , aminocarbonyl , alkylcarbonylamino , cycloalkylcarbonylamino , ( cycloalkylalkyl ) carbonylamino , ( heterocycloalkyl ) carbonylamino , arylcarbonylamino , aralkylcarbonylamino , ( heterocycloalkylalkyl ) carbonylamino , heteroarylcarbonylamino , heteroaralkylcarbonylamino , cyano , halo , hydroxy , acyl , mercapto , alkylsulfanyl , sulfoxy , urea , thiourea , sulfamoyl , sulfamide , oxo , or carbamoyl . [ 00044 ] As used herein , an " acyl " group refers to a RX - C ( O ) - ( such as alkyl - C ( O ) - , also referred to as " alkylcarbonyl " ) where RX and " alkyl " have been defined previously . Acetyl and pivaloyl are examples of acyl groups . [ 00045 ] As used herein , an " aroyl " or " heteroaroyl " refers to an aryl - C ( O ) - or a heteroaryl - C ( O ) - . The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined herein . For example , aroyl includes benzoyl . [ 00046 ] As used herein , an " alkoxy " group refers to an alkyl - O- group where " alkyl " has been defined previously herein . [ 00047 ] As used herein , a " carbamoyl " group refers to a group having the formula -O- CO - NRRY or -NRX - CO - O - RZ , wherein RX and RY have been defined above and RZ can be aliphatic , aryl , araliphatic , heterocycloaliphatic , heteroaryl , or heteroaraliphatic . [ 00048 ] As used herein , a " carboxy " group refers to -COOH , when used as a terminal group ; or -OC ( O ) - , or -C ( O ) O- when used as an internal group . - 17 - 1100573566 5 AMERICAS [ 00049 ] Attorney Docket No .: 121843.002NU - 3200 PCT As used herein , an " ester " refers to -COORX when used as a terminal group ; or -COORX- when used as an internal group , wherein RX has been defined above . As used herein , an " alkoxycarbonyl , " which is encompassed by the term ester , used alone or in connection with another group refers to a group such as alkyl - O - C ( O ) - ( i.e. , a carbonate ester ) . [ 00050 ] [ 00051 ] As used herein , a " formate " refers to -OC ( O ) H .

As used herein , an " acetate " refers to -OC ( O ) RX , wherein RX has been defined above . In one embodiment , acetate is -OC ( O ) Me [ 00052 ] As used herein , a " haloaliphatic " group refers to an aliphatic group substituted with one to three halogen atoms . For instance , haloalkyl includes -CF3 . [ 00053 ] [ 00054 ] As used herein , a " mercapto " or " sulfhydryl " group refers to -SH .

As used herein , a " sulfo " group refers to -SO3H , or -SO3RX when used terminally or -S ( O ) 3- when used internally . In one embodiment , -SO3H is a sulfonic acid . In one embodiment , RXSO3 " is a sulfonate . [ 00055 ] As used herein , a " sulfamide " group refers to the formula -NRX - S ( O ) 2 - NRYRZ when used terminally and -NRX - S ( O ) 2 - NRY- when used internally , wherein R , RY , and RZ have been defined above . [ 00056 ] As used herein , a " sulfamoyl " group refers to the formula -S ( O ) 2 - NRYRZ wherein RY and RZ have been defined above . In one embodiment , -O - S ( O ) 2 - NRYRZ is a sulfamate . [ 00057 ] As used herein , a " sulfonamide " group refers to the formula RZ - S ( O ) 2 - NRRY or -NRX - S ( O ) 2 - RZ when used terminally ; or -S ( O ) 2 - NRX- , or -NRX - S ( O ) 2- when used internally , wherein RX , RY , and RZ are defined above . [ 00058 ] As used herein a " sulfide " group refers to -S - RX when used terminally and -S- when used internally , wherein RX has been defined above . Examples of sulfanyls include aliphatic - S- , cycloaliphatic - S- , aryl - S- , or the like . [ 00059 ] As used herein a " sulfinyl " group refers to -S ( O ) -RX when used terminally and -S ( O ) - when used internally , wherein RX has been defined above . Examples of sulfinyl groups include aliphatic - S ( O ) - , aryl - S ( O ) - , ( cycloaliphatic ( aliphatic ) ) - S ( O ) - , cycloalkyl - S ( O ) - , heterocycloaliphatic - S ( O ) - , heteroaryl - S ( O ) - , and / or the like . - 18 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 00060 ] As used herein , a " sulfonyl " group refers to -S ( O ) 2 - RX when used terminally and -S ( O ) 2- when used internally , wherein RX has been defined above . Examples of sulfonyl groups include cycloaliphatic - S ( O ) 2- , aliphatic - S ( O ) 2- , aryl - S ( O ) 2- , heterocycloaliphatic - S ( O ) 2- , ( cycloaliphatic ( aliphatic ) ) - S ( O ) 2- , heteroaryl - S ( O ) 2- , ( cycloaliphatic ( amido ( aliphatic ) ) ) - S ( O ) 2- , and / or the like . [ 00061 ] As used herein , a " sulfinate " group refers to -O - S ( O ) -RX , or -S ( O ) -O - RX , when used terminally and -O - S ( O ) - or -S ( O ) -O- when used internally , where RX has been defined above . [ 00062 ] As used herein , a " halogen " or " halo " group refers to fluorine ( F ) , chlorine ( Cl ) , bromine ( Br ) , or iodine ( I ) . [ 00063 ] As used herein , an " alkoxyalkyl " refers to an alkyl group modified with an alkoxy group , such as alkyl - O - alkyl- or ethers , wherein alkyl has been defined above . [ 00064 ] [ 00065 ] As used herein , the term " phospho " refers to phosphinates , phosphonates , phosphine oxides , phosphoramidates , phosphinic amides , and phosphonamidates . Examples of phosphinates , phosphonates , phosphine oxides , phosphoramidates , phosphinic amides , and phosphonamidates include -P ( O ) ( ³R ) 2 , ( ³R ) 2P ( O ) ³RO , and RP - PO ( ³RO ) 2 , wherein RP is aliphatic , alkoxy , aryloxy , heteroaryloxy , ( cycloaliphatic ) oxy , ( heterocycloaliphatic ) oxy , aryl , heteroaryl , cycloaliphatic , or amino .

As used herein , a " carbonyl " or " oxo " refers to -C ( O ) - or = 0 . [ 00066 ] As used herein , an " aminoalkyl " refers to the formula ( RX ) 2N - alkyl- where RX has been defined above . [ 00067 ] [ 00068 ] As used herein , a " cyanoalkyl " refers to the formula ( NC ) -alkyl- .

As used herein , a " urea " group refers to the formula -NRX - CO - NRYRZ and a " thiourea " refers to the formula -NRX - CS - ²RYRN each when used terminally and -NRX - CO- NRY- or -NRX - CS - NRY- each when used internally , wherein RX , RY , and RZ have been defined above . [ 00069 ] As used herein , a " guanidine " group refers to the formula -N = C ( N ( YR³R ) ) ( N ( R * R ¥ ) ) or ³RN- - C ( = ³RN ) NR * R ¥ wherein RX and RY have been defined above . - 19 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 00070 ] As used herein , the term " amidino " group refers to the formula -C ( NRX ) NRXRY wherein RX and RY have been defined above . [ 00071 ] As used herein , the term " vicinal " generally refers to the placement of substituents on a group that includes two or more carbon atoms , wherein the substituents are attached to adjacent carbon atoms . [ 00072 ] As used herein , the term " geminal " generally refers to the placement of substituents on the same carbon atom . [ 00073 ] As used herein , an " aliphatic chain " refers to a branched or straight aliphatic group ( e.g. , alkyl groups , alkenyl groups , or alkynyl groups ) . A straight aliphatic chain has the structure - [ CH2 ] v- , where v is one to twelve . A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups . A branched aliphatic chain has the structure - [ CQQ ] v- , where each Q is independently a hydrogen ( H or -H ) or an aliphatic group ; however , Q shall be an aliphatic group in at least one instance . The term aliphatic chain includes alkyl chains , alkenyl chains , and alkynyl chains , where alkyl , alkenyl , and alkynyl are defined above . [ 00074 ] The phrase " optionally substituted " is used interchangeably herein with the phrase " substituted or unsubstituted . " As described herein , compounds herein can optionally be substituted with one or more substituents , as illustrated generally above , or as exemplified by particular classes , subclasses , and species within this description . As described herein , the variables R , X , L , and Z , and other variables contained in Formula ( I ) or ( II ) described herein encompass specific groups , for example , alkyl and aryl . Unless otherwise noted , each of the specific groups within the variables R , X , L , and Z , and other variables contained therein can be optionally substituted with one or more substituents described herein . Each substituent of a specific group is further optionally substituted with one to three halo , cyano , oxo , alkoxy , hydroxy , amino , nitro , aryl , cycloaliphatic , heterocycloaliphatic , heteroaryl , haloalkyl , and / or alkyl . For instance , an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three halo , cyano , oxo , alkoxy , hydroxy , amino , nitro , aryl , haloalkyl , and alkyl . As an additional example , the cycloalkyl portion of a ( cycloalkyl ) carbonylamino can be optionally substituted with one to three halo , cyano , alkoxy , hydroxy , nitro , haloalkyl , and alkyl . When two alkoxy groups are bound to the same atom or adjacent atoms , the two alkoxy groups can form a ring together with the atom ( s ) to which they are bound . - 20 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 00075 ] As used herein , the term " substituted , " whether preceded by the term " optionally " or not , refers generally to the replacement of one or more hydrogen atoms in a given chemical structure with the radical of a specified substituent . Specific substituents are defined above and described below within the compounds and examples thereof . Unless otherwise indicated , an optionally substituted group can have a substituent at each substitutable position of the group , and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group , the substituent can be either the same or different at every position . A ring substituent , such as a heterocycloalkyl , can be bound to another ring , such as a cycloalkyl , to form a spiro - bicyclic ring system , for example , both rings share one common atom . Non - limiting examples of spiro heterocycloalkyls include HN NH NH 2,8 - diazaspiro [ 4.5 ] decane HN☑ HN ✓ NH 2,7 - diazaspiro [ 3.5 ] nonane HN HN NH 3,9 - diazaspiro [ 5.5 ] undecane 3 - azaspiro [ 5.5 ] undecane and and 2 - oxa - 6 - azaspiro [ 3.4 ] octane Spiro compounds depicted with overlapping rings indicate that the spirocyclic rings can bond at any vertex . For instance , in the www . spiro group ring . [ 00076 ] , the two rings can bond at any of the three available vertex atoms in either As one of ordinary skill in the art will recognize , combinations of substituents envisioned by this description are those combinations that result in the formation of stable or chemically feasible compounds . [ 00077 ] As used herein , the phrase " stable or chemically feasible " refers to compounds that are not substantially altered when subjected to conditions to allow for their production , detection , recovery , purification , and / or use for one or more of the purposes disclosed herein . In some embodiments , a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ° C or less , in the absence of moisture or other chemically reactive conditions , for at least a week . - 21 - 1100573566 5 AMERICAS [ 00078 ] Attorney Docket No .: 121843.002NU - 3200 PCT As used herein , an " effective amount " is defined as the amount required to confer a therapeutic effect on the treated subject or patient , and is typically determined based on age , surface area , weight , and / or condition of the subject or patient . The interrelationship between dosages for animals and humans ( based on milligrams per meter squared of body surface ) is described by Freireich et al . , Cancer Chemother . Rep . , 50 : 219 ( 1966 ) . Body surface area may be approximately determined from height and weight of the subject or patient . See , e.g. , Scientific Tables , Geigy Pharmaceuticals , Ardsley , New York , 537 ( 1970 ) . As used herein , " patient " refers to an animal , alternatively a mammal , including a human . [ 00079 ] The terms " pharmaceutical formulation " and " pharmaceutical composition " refer to preparations that are in such form as to permit the biological activity of the active ingredient to be effective , and that contain no additional components that are unacceptably toxic to an individual or subject to which the formulation or composition would be administered . Such formulations or compositions may be sterile . [ 00080 ] The term " excipients " as used herein includes pharmaceutically acceptable excipients , carriers , vehicles , or stabilizers that are nontoxic to the subject , cell , or mammal being exposed thereto at the dosages and concentrations employed . In certain embodiments , the physiologically acceptable excipient is an aqueous pH buffered solution . [ 00081 ] The terms " treating " or " treatment " of a disease refer to executing a protocol , which may include administering one or more therapeutic agent to a subject and / or an individual ( human or otherwise ) , in an effort to obtain beneficial or desired results in the subject or individual , including clinical results . In certain embodiments , beneficial or desired clinical results include , but are not limited to , alleviation or amelioration of one or more symptoms , diminishment of extent of disease , stabilized ( i.e. , not worsening ) state of disease , preventing spread of disease , delay or slowing of disease progression , amelioration or palliation of the disease state , and remission ( whether partial or total ) . In certain embodiments , " treatment " can also mean prolonging survival as compared to expected survival of an individual not receiving treatment . In certain embodiments , " treating " and " treatment " may occur by administration of one dose of a therapeutic agent or therapeutic agents , or may occur upon administration of a series of doses of a therapeutic agent or therapeutic agents . In certain embodiments , " treating " or " treatment " does not require complete alleviation of signs or symptoms , and does not require a cure . In certain embodiments , " treatment " can also refer to clinical intervention , such as administering one or more therapeutic agents to a subject and / or an individual , designed to alter - 22 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT the natural course of the subject , individual , or cell being treated ( i.e. , to alter the course of the individual or cell that would occur in the absence of the clinical intervention ) . In certain embodiments , the term " therapeutic agent " can refer to a compound or drug that induces the proteolytic degradation of BRAF or compositions thereof . [ 00082 ] The term " individual , " " patient , " or " subject " refers to a mammal . In certain embodiments , a " mammal " for purposes of treatment includes humans ; non - human primates ; domestic and farm animals ; and zoo , sports , or pet animals , such as dogs , horses , rabbits , cattle , pigs , hamsters , gerbils , mice , ferrets , rats , cats , etc. In some embodiments , the individual or subject is human . [ 00083 ] As used herein , the term " about " means within ± 10 % of a stated value . For example , a dose that is about 100 mg / kg provides that the dose can be 90 mg / kg to 110 mg / kg . By way of further example , an amount of an additional therapeutic agent ranging from about % to about 100 % provides that the amount of additional therapeutic agent ranges from 45- % to 90-110 % . A person of skill in the art will appreciate the scope and application of the term " about " when used to describe other stated values disclosed herein . [ 00084 ] Unless otherwise stated , structures depicted herein also are meant to include all isomeric ( e.g. , enantiomeric , diastereomeric , and geometric ( or conformational ) ) forms of the chemical structure ; for example , the ( R ) - and ( S ) - configurations for each asymmetric center , ( Z ) and ( E ) - double bond isomers , and syn- / cis- and anti- / trans - conformational isomers . Therefore , single stereochemical isomers as well as enantiomeric , diastereomeric , and geometric ( or conformational ) mixtures of the present compounds are within the scope of the description . Alternatively , as used herein , " enantiomeric excess ( ee ) " refers to a dimensionless mol ratio describing the purity of chiral substances that contain , for example , a single stereogenic center . For instance , an enantiomeric excess of zero would indicate a racemic ( e.g. , 50:50 mixture of enantiomers , or no excess of one enantiomer over the other ) . By way of further example , an enantiomeric excess of ninety - nine would indicate a nearly stereopure enantiomeric compound ( i.e. , large excess of one enantiomer over the other ) . The percentage enantiomeric excess , % ee ( [ ( R ) -compound ] - [ ( S ) -compound ] ) / ( [ ( R ) -compound ] + [ ( S ) - compound ] ) x 100 , where the ( R ) -compound > ( S ) -compound ; or % ee = ( [ ( S ) -compound ] - [ ( R ) -compound ] ) / ( [ ( S ) -compound ] + [ ( R ) -compound ] ) x 100 , where the ( S ) -compound > ( R ) - compound . Also as used herein , " diastereomeric excess ( de ) " refers to a dimensionless mol ratio describing the purity of chiral substances that contain more than one stereogenic center . = - 23 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT For example , a diastereomeric excess of zero would indicate an equimolar mixture of diastereoisomers . By way of further example , diastereomeric excess of ninety - nine would indicate a nearly stereopure diastereomeric compound ( i.e. , large excess of one diastereomer over the other ) . Diastereomeric excess may be calculated via a similar method to ee . As would be appreciated by a person of skill , de is usually reported as percent de ( % de ) . % de may be calculated in a similar manner to % ee . [ 00085 ] In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de greater than zero . For example , in certain embodments , the compounds or inhibitors described herein have an ee , de , % ee , or % de of ten . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de of twenty - five . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de of fifty . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de of seventy - five . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de of ninety - nine . [ 00086 ] In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de range from ninety to one hundred . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de range from ninety - five to one hundred . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de range from ninety - seven to one hundred . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de range from ninety - eight to one hundred . In certain embodiments , the compounds or inhibitors described herein have an ee , de , % ee , or % de range from ninety - nine to one hundred . [ 00087 ] In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is nine . In one embodiment of a compound - 24 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT or inhibitor described herein , the ee , de , % ee , or % de is ten . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eleven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twelve . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirteen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fourteen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifteen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixteen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventeen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighteen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is nineteen . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty- three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is twenty - nine . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty- two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is thirty - nine . In one - 25 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty- one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is forty - nine . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty- one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is fifty - nine . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty- one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is sixty - nine . In one - 26 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy- eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is seventy - nine . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty- six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - eight . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is eighty - nine . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - one . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - two . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety- three . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - four . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - five . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - six . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - seven . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is ninety - eight . In one embodiment of a compound - 27- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT or inhibitor described herein , the ee , de , % ee , or % de is ninety - nine . In one embodiment of a compound or inhibitor described herein , the ee , de , % ee , or % de is one hundred . In certain embodiments , compounds or inhibitors described within Table 1 herein have an ee , de , % ee , or % de as described within this paragraph . In certain embodiments , compounds or inhibitors described in the Examples and / or Biological Examples have an ee , de , % ee , or % de as described within this paragraph . Unless otherwise stated , all tautomeric forms of the compounds of this description are within the scope of this description . Additionally , unless otherwise stated , structures depicted herein also are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms . For example , compounds having the present structures except for the replacement of hydrogen by deuterium or tritium , or the replacement of a carbon by a 13C- or 14C - enriched carbon are within the scope of this description . Such compounds are useful , for example , as analytical tools or probes in biological assays , or as therapeutic agents . [ 00088 ] As used herein , the term " & 1 " means that a compound including the " & 1 " notation at a particular chemical element or atom ( e.g. , carbon ) within the compound was prepared as a mixture of two stereoisomers at the noted chemical element or atom ( e.g. , a diastereomeric mixture having a de or % de as described above ) . [ 00089 ] Chemical structures and nomenclature are derived from ChemDraw , version 21.0 , Cambridge , MA . [ 00090 ] It is noted that the use of the descriptors " first , " " second , " " third , " or the like is used to differentiate separate elements ( e.g. , solvents , reaction steps , processes , reagents , or the like ) and may or may not refer to the relative order or relative chronology of the elements described .

Compounds [ 00091 ] In one embodiment , provided is a compound of Formula ( I ) 0 = HN -R1b R1a- R N +( I ) 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Lis a linker according to as described above . In certain embodiments , ¹L— - ²L - ³L - ªL - ³L - L - L7- or -L7 - L6 - ³L - ªL - ³L - ²L - -¹L , wherein -¹L- is absent , -N ( º¹R ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -C1-8 alkylene- , -C2-8 alkynylene- , -C6 - C10 aryl- , -C4 - C 10 heteroaryl- , ¹Q , or ²Q ; each -²L- , –³L- , —ªL− , and -5L— is independently , absent , -N ( º¹R ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -O- , - ( CH2 - CH2 - O ) 1-8- , -C1-8 alkylene- , -C2-8 alkynylene- , -C6 - C10 aryl- , -C4 - C10 heteroaryl- , ¹Q , ²Q , or ³Q ; and each -L- and -L7- is independently , absent , -N ( R10 ) - , -C ( º¹R ) 2- , -C ( O ) - , -C ( O ) -N ( º¹R ) - , -N ( R10 ) -C ( O ) - , or -C ( ¹¹R ) 2 - C ( O ) -N ( º¹R ) - . [ 00092 ] In certain embodiments , b¹R is hydrogen . In certain embodiments , b¹R is halogen . In certain embodiments , ¹X is nitrogen ; ²X is carbon , ³X is sulfur ; and X4 is carbon or nitrogen . In one embodiment , ¹R is alkyl ; ª¹R is fluoro ; ²R is - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM ; n is zero ; ²Z is absent ; and ¹yC is an unsubstituted heterocycloalkylene . In one embodiment , ³Z is -C ( O ) . In one embodiment , ¹L is ¹Q . In one embodiment , ²L is -C ( O ) . In one embodiment , ³L is ¹Q ; and L4 is absent . In one embodiment , ¹R is -CH2CH2CH3 . [ 00093 ] In certain embodiments , ¹X is carbon or nitrogen ; ²X is nitrogen , and ³X is carbon or nitrogen . In one embodiment , ¹X is carbon ; ²X is nitrogen , and ³X is nitrogen . In one embodiment , ¹R is alkyl ; a¹R is fluoro ; ²R is - [ ¹rA - ¹Z ] n - Z2 - ¹yC - ³Z - L - UBM ; ¹rA is ¹Z is a bond ; n is one ; ²Z and ³Z are absent ; and ¹yC is an unsubstituted heterocycloalkylene . In one embodiment , X4 is carbon and X5 is hydrogen . In one embodiment , ¹L is -C ( ¹¹R ) 2- . In one embodiment , R11 hydrogen . In one embodiment , ²L is ¹Q ; and ³L and L4 are absent . In one embodiment , ¹R is -CH2CH2CH3 . [ 00094 ] In certain embodiments , ¹X is nitrogen ; ²X is carbon , ³X is sulfur ; and X4 is nitrogen . In one embodiment , ¹R is alkyl ; a¹R is fluoro ; ²R is alkyl ; n is zero ; ²Z is absent ; and ¹yC is an unsubstituted heterocycloalkylene . In one embodiment , ³Z is absent , -CH2- or -C ( O ) - . In one embodiment , ¹L is ¹Q , -C ( ¹¹R ) 2- , or -CH2CH2CH2CH2CH2- , or ³Q . In one embodiment , ²L is absent , ¹Q , ²Q , -C ( ¹¹R ) 2- , -C ( O ) - , or -O- . In one embodiment , ³L is absent , ¹Q , or -CH2CH2CH2- ; and L4 is absent . In one embodiment , ¹R is -CH2CH2CH3 . [ 00095 ] In certain embodiments , UBM binds an E3 ubiquitin ligase . In one embodiment , UBM binds SCFB - TRCP , VHL , MDM2 , IAP , or CRBN . [ 00096 ] In certain embodiments , UBM binds VHL . In one embodiment , UBM binds VHL and has the following chemical formula - 29 - 1100573566 5 AMERICAS ĄZ- N - R -NH Attorney Docket No .: 121843.002NU - 3200 PCT R8 wherein designates attachment to L ; Z4 is a bond , -CH2- , -C ( O ) - , -C ( O ) N ( ²¹R ) - , or -N ( ²¹R ) - , wherein R12 is hydrogen or methyl ; X6 is C - H or nitrogen ; R8 is alkyl , alkenyl , alkylene , alkynyl , aryl , cycloalkyl , heterocycloalkyl , heteroaryl , -S ( O ) ( ³¹R ) , or -S ( O ) 2 ( ³¹R ) ; wherein ³¹R is hydrogen , hydroxyl , alkyl , alkenyl , alkynyl , aryl , heterocycle , or heteroaryl , wherein each alkyl , alkenyl , alkylene , alkynyl , aryl , cycloalkyl , heterocycloalkyl , and heteroaryl is unsubstituted or substituted ; R ' is hydrogen , unsubstituted or substituted C1-8 alkyl , or ¹AA- - ²AA - R14 wherein each ¹AA and ²AA is an amino acid residue , and R14 is hydrogen or methyl . In one embodiment , UBM binds VHL and has the following chemical formula { -5z— A ' RN- wherein designates attachment to L ; Z5 is a bond , -CH2- , -C ( O ) - , -C ( O ) N ( ²¹R ) - , -N ( ²¹R ) - , or -O- , wherein ²¹R is hydrogen or methyl ; A is phenyl or C4 - heteroaryl ; X7 is -CH2 , ²¹RN- , oxygen , or sulfur , wherein ²¹R is hydrogen or methyl ; p is zero or one ; R15 is unsubstituted or substituted C1-8 alkyl , ¹AA- - ²AA - R14 , wherein each ¹AA and ²AA is an amino acid residue , and R14 is hydrogen or methyl . In one embodiment , UBM binds VHL and has the following chemical formula X9 R R16 wherein designates attachment to L ; Z6 is a bond , -CH2- , -C ( O ) - , -C ( O ) N ( ²¹R ) - , or N ( ²¹R ) , wherein R12 is hydrogen or methyl ; W is X Z Z' N ' , Ror - 30 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ' N ' to R18 wherein , Zdesignates attachment to X8 , wherein designates attachment to X , and wherein , designates attachment to Z6 ; X8 is carbon or nitrogen ; ⁹X is C - H or -CH2- ; R16 is hydrogen , -OH , halogen , -NH2 , -C1-3 alkyl , -C2-6 alkenyl , -C2-alkynyl , -C1-3 alkoxy , -C1-3 thioalkyl , -C1-3 alkylamine , -C6-10 aryl , cycloalkyl , heterocycloalkyl , or heteroaryl ; 7¹R is -C ( O ) N ( H ) -C6-10 aralkyl , -C ( O ) CH ( t - butyl ) -N ( H ) -C3-cycloalkyl , -C ( O ) -CH ( t - butyl ) -N ( H ) C ( O ) -C3 - C6 cycloalkyl , - N , ZH ' N ' R N N CN , or ¹AA- - ²AA - R14 , wherein each ¹AA and ²AA is an N amino acid residue and R14 is hydrogen or methyl ; and R18 is halogen or S- [ 00097 ] In certain embodiments , UBM binds CRBN . In one embodiment , UBM binds CRBN and has the following chemical formula NH NH X6 X or wherein - 31 - 1100573566 5 AMERICAS ﻭ Attorney Docket No .: 121843.002NU - 3200 PCT X6 absent or ³RN ; X7 absent or -C ( O ) - ; and X8 is arylene or heteroarylene . In one embodiment , NH NH ﺲﺧ UBM binds CRBN and is selected from the group consisting of " w NH NH NH NH NH NH .N . ' N ' .N . wherein " NH NH ﻭ M NH NH NH NH .NH , M N , N N- w , .NH ( ⁹X ) m " NH .N . and , NH X is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM binds CRBN and is NH - ( ³X ) m wherein X ' is absent or halogen ; and m is one , two , three , or four .

In one embodiment , UBM binds CRBN and is m NH ( ⁹X ) m wherein X9 is absent . In one 1100573566 5 AMERICAS embodiment , UBM binds CRBN and is one embodiment , UBM binds CRBN and is In one embodiment , UBM binds CRBN and is ` NH NH Attorney Docket No .: 121843.002NU - 3200 PCT wherein X is halogen ; and m is one . In - ( ⁹X ) m wherein X ' is halogen ; and m is two . three . In one embodiment , UBM binds CRBN and is NH - ( ⁹X ) m wherein X is halogen ; and m is NH ( ⁹X ) m wherein X9 is halogen ; and NH m is four . In one embodiment , UBM binds CRBN and is In one embodiment , UBM - 33 - 1100573566 5 AMERICAS NH Attorney Docket No .: 121843.002NU - 3200 PCT NH ' N ' binds CRBN and is In one embodiment , UBM binds CRBN and is . In NH one embodiment , UBM binds CRBN and is M In one embodiment , UBM binds .N .

NH NH .N .

N CRBN and is In one embodiment , UBM binds CRBN and is In one embodiment , UBM binds CRBN and is w NH NH wherein X is absent or halogen ; and .NH m is one , two , three , or four . In one embodiment , UBM binds CRBN and is ( ⁹X ) m NH - 34 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT NH NH wherein X is absent . In one embodiment , UBM binds CRBN and is ( ⁹X ) m wherein ﺱﻯ NH .NH ( ⁹x ) m X is halogen ; and m is one . In one embodiment , UBM binds CRBN and is wherein X is halogen ; and m is two . In one embodiment , UBM binds CRBN and is NH NH CRBN and is M wherein X is halogen ; and m is three . In one embodiment , UBM binds NH NH binds CRBN and is wherein X ' is halogen ; and m is four . In one embodiment , UBM NH .NH In one embodiment , UBM binds CRBN and is - 35 - 1100573566 5 AMERICAS NH NH Attorney Docket No .: 121843.002NU - 3200 PCT In one embodiment , UBM binds CRBN and is NH M NH NH In one N embodiment , UBM binds CRBN and is In one embodiment , UBM binds CRBN NH .N .

NH and is In one embodiment , UBM binds CRBN and is [ 00098 ] In one embodiment , provided is a compound of Formula ( II ) O = S - ¹R HN -R1b R1a- ²R X5 ( II ) as described above . In certain embodiments , L is a linker according to ¹L- - ²L - ³L - L4 - L5 - L - L7- or -L ' - L - ³L - ªL - ³L - ²L - -¹L , wherein -¹L- is absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -C1-8 alkylene- , -C2-8 alkynylene- , -C6 - C10 aryl- , -C4 - C 10 heteroaryl- , ¹Q , or ²Q ; each -²L- , –³L- , —ªL− , and -5L— is independently , absent , -N ( R10 ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -O- , - ( CH2 - CH2 - O ) 1-8- , -C1-8 alkylene- , -C2-8 alkynylene- , -C6 - C10 aryl- , -C4 - C10 heteroaryl- , ¹Q , - 36 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ²Q , or ³Q ; and each -L6- and -L7- is independently , absent , -N ( R10 ) - , -C ( º¹R ) 2- , -C ( O ) - , -C ( O ) -N ( º¹R ) - , -N ( R10 ) -C ( O ) - , or -C ( ¹¹R ) 2 - C ( O ) -N ( º¹R ) - . [ 00099 ] In certain embodiments , b¹R is hydrogen . In certain embodiments , ¹R is halogen . In certain embodiments , ¹X is nitrogen ; ³X is oxygen ; and X4 is carbon or nitrogen . In certain embodiments , ¹X is oxygen ; ³X is nitrogen ; and X4 is carbon or nitrogen . [ 000100 ] In certain embodiments , X1 is nitrogen ; ³X is sulfur ; and X4 is carbon or nitrogen . In one embodiment , ¹R is alkyl ; a¹R is fluoro ; ²R is - [ ¹rA - ¹Z ] n - ²Z - ¹yC - ³Z - L - UBM ; n is zero ; ²Z is absent ; and ¹yC is an unsubstituted heterocycloalkylene . In one embodiment , ³Z is -C ( O ) . In one embodiment , ¹L is ¹Q . In one embodiment , ²L is -C ( O ) . In one embodiment , 3³L is Q1 and L4 is absent . In one embodiment , ¹R is -CH2CH2CH3 . [ 000101 ] In certain embodiments , UBM binds an E3 ubiquitin ligase . In one embodiment , UBM binds u0000FCS - TRCP , VHL , MDM2 , IAP , or CRBN . [ 000102 ] In certain embodiments , UBM binds VHL . In one embodiment , UBM binds VHL and has the following chemical formula { ªz— N - R -NH ³R wherein 1 } designates attachment to L ; Z + is a bond , -CH2- , -C ( O ) - , -C ( O ) N ( ²¹R ) - , or -N ( ²¹R ) - , wherein ²¹R is hydrogen or methyl ; X6 is C - H or nitrogen ; R8 is alkyl , alkenyl , alkylene , alkynyl , aryl , cycloalkyl , heterocycloalkyl , heteroaryl , -S ( O ) ( ³¹R ) , or -S ( O ) 2 ( ³¹R ) ; wherein ³¹R is hydrogen , hydroxyl , alkyl , alkenyl , alkynyl , aryl , heterocycle , or heteroaryl , wherein each alkyl , alkenyl , alkylene , alkynyl , aryl , cycloalkyl , heterocycloalkyl , and heteroaryl is unsubstituted or substituted ; ⁹R is hydrogen , unsubstituted or substituted C1-8 alkyl , or ¹AA- - ²AA - R14 wherein each ¹AA and ²AA is an amino acid residue , and R14 is hydrogen or methyl . In one embodiment , UBM binds VHL and has the following chemical formula RN N. -Z5 . A -Xwherein - 37 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT designates attachment to L ; Z5 is a bond , -CH2- , -C ( O ) - , -C ( O ) N ( ²¹R ) - , -N ( ²¹R ) - , or -O- , wherein ²¹R is hydrogen or methyl ; A is phenyl or C4 - heteroaryl ; X7 is ₂HC- , ²¹RN- , oxygen , or sulfur , wherein R12 is hydrogen or methyl ; p is zero or one ; R15 is unsubstituted or substituted C1-8 alkyl , ¹AA- - ²AA - R14 , wherein each ¹AA and ²AA is an amino acid residue , and R14 is hydrogen or methyl . In one embodiment , UBM binds VHL and has the following chemical formula L ɓz- — W- to to R R16 wherein designates attachment to L ; Z6 is a bond , -CH2- , -C ( O ) - , -C ( O ) N ( ²¹R ) - , or N ( ²¹R ) , wherein to R12 is hydrogen or methyl ; W is Z ﻢﺤﻣﺩ N to Z , Z ' N ' Ror R18 wherein , attachment to X , and wherein , Zdesignates attachment to X8 , wherein designates designates attachment to Z6 ; X8 is carbon or nitrogen ; X is C - H or -CH2- ; R16 is hydrogen , -OH , halogen , -NH2 , -C1-3 alkyl , -C2-6 alkenyl , -C2-alkynyl , -C1-3 alkoxy , -C1-3 thioalkyl , -C1-3 alkylamine , -C6-10 aryl , cycloalkyl , heterocycloalkyl , or heteroaryl ; R17 is -C ( O ) N ( H ) -C6-10 aralkyl , -C ( O ) CH ( t - butyl ) -N ( H ) -C3-cycloalkyl , -C ( O ) -CH ( t - butyl ) -N ( H ) C ( O ) -C3 - C6 cycloalkyl , X' N ' Rﻭ IZ .N . F - 38- 1100573566 5 AMERICAS , O - N , CN Attorney Docket No .: 121843.002NU - 3200 PCT , or ¹AA- - ²AA - R14 , wherein each ¹AA and ²AA is an N amino acid residue and R14 is hydrogen or methyl ; and R18 is halogen or S- [ 000103 ] In certain embodiments , UBM binds CRBN . In one embodiment , UBM binds CRBN and has the following chemical formula NH ' N ' NH w or to wherein X6 is absent or ³RN ; X7 is absent or -C ( O ) - ; and X8 is arylene or heteroarylene . In one NH embodiment , UBM binds CRBN and is selected from the group consisting of - ( ⁹X ) m NH " m ' N ' NH " NH ' N ' N. ﻭ www NH NH NH NH ﻭ N .N . NH , 1100573566 5 AMERICAS NH Attorney Docket No .: 121843.002NU - 3200 PCT NH NH NH NH NH NH ' N ' NH .N .

NH י ﻭ and m wherein X9 is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM NH - ( ⁹X ) m binds CRBN and is wherein X is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM binds CRBN and is one embodiment , UBM binds CRBN and is NH NH - ( ⁹X ) m wherein X ' is absent . In - ( ⁹X ) m wherein X is halogen ; and m is NH - ( ⁹X ) m one . In one embodiment , UBM binds CRBN and is wherein X9 is halogen ; and - 40 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT m is two . In one embodiment , UBM binds CRBN and is NH halogen ; and m is three . In one embodiment , UBM binds CRBN and is M NH X is halogen ; and m is four . In one embodiment , UBM binds CRBN and is NH N wherein X9 is · ( ⁹X ) m wherein NH . In one embodiment , UBM binds CRBN and is In one embodiment , UBM binds NH NH CRBN and is In one embodiment , UBM binds CRBN and is M In one - 41 - 1100573566 5 AMERICAS N NH Attorney Docket No .: 121843.002NU - 3200 PCT embodiment , UBM binds CRBN and is In one embodiment , UBM binds CRBN NH NH NH N ww and is In one embodiment , UBM binds CRBN and is wherein X is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM binds ( ⁹X ) m M NH .NH CRBN and is ( ⁹X ) m wherein X is absent . In one embodiment , UBM binds CRBN and is w NH NH ( ⁹X ) m wherein X ' is halogen ; and m is one . In one embodiment , UBM binds CRBN and is NH NH wherein X ' is halogen ; and m is two . In one embodiment , - 42 - 1100573566 5 AMERICAS UBM binds CRBN and is CNH NH Attorney Docket No .: 121843.002NU - 3200 PCT wherein X ' is halogen ; and m is three . In one NH NH embodiment , UBM binds CRBN and is ( ⁹X ) m wherein X is halogen ; and m is four . In one embodiment , UBM binds CRBN and is NH NH NH NH . In one embodiment , UBM binds CRBN and is In one embodiment , UBM binds CRBN and is M NH NH NH N In one embodiment , UBM binds CRBN and is In one - 43 - 1100573566 5 AMERICAS NH Attorney Docket No .: 121843.002NU - 3200 PCT embodiment , UBM binds CRBN and is In one embodiment , UBM binds CRBN N NH [ 000104 ] and is In certain embodiments of the compounds of Formula ( I ) or Formula ( II ) , L includes at least one -¹Q- ; at least one -Q2- ; at least one -³Q- ; at least one -C ( ¹¹R ) 2- ; or at least one C1-8 alkylene- . In one embodiment , L is selected from the group consisting of a . -¹Q- ; b . C. ¹Q- - C ( O ) -¹Q- ; -C ( ¹¹R ) 2 - -¹Q ; d . ¹Q- - C ( ¹¹R ) 2 - -¹Q ; e . -C ( ¹¹R ) 2 - O- ; f . ³Q- - 0- ; g . -C ( ¹¹R ) 2 - ¹Q - -¹Q ; h . ¹Q- - -¹Q ; i . -C ( ¹¹R ) 2 - -²Q ; j . k . . m . n . . p . q .

-C1-8 alkylene- ; -C ( ¹¹R ) 2 - ¹Q - C1-8 alkylene- ; ³Q- - C ( ¹¹R ) 2- ; -C ( ¹¹R ) 2- ; -²Q- ; ¹Q- - C ( O ) -C ( ¹¹R ) 2- ; ¹Q- - C ( O ) ³Q- - 0- ; ¹Q- - C ( O ) -C ( ¹¹R ) 2 - -¹Q ; - 44 - 1100573566 5 AMERICAS r . S. ¹Q- - C ( ¹¹R ) 2 - ³Q - 0- ; and ¹Q- - C ( ¹¹R ) 2- Attorney Docket No .: 121843.002NU - 3200 PCT In one embodiment , L is -¹Q- . In one embodiment , L is ¹Q- - C ( O ) -¹Q- . In one embodiment , L is -C ( ¹¹R ) 2 - ¹Q . In one embodiment , L is ¹Q- - C ( ¹¹R ) 2 - -¹Q . In one embodiment , L is -C ( ¹¹R ) 2 - O- . In one embodiment , L is -Q3-0- . In one embodiment , L is -C ( ¹¹R ) 2 - ¹Q - -¹Q . In one embodiment , L is ¹Q- - -¹Q . In one embodiment , L is -C ( ¹¹R ) 2 - -²Q . In one embodiment , L is -C1-8 alkylene- . In one embodiment , L is -C ( 1¹¹R ) 2 - ¹Q - C1-8 alkylene- . In one embodiment , L is ³Q- - C ( ¹¹R ) 2- . In one embodiment , L is -C ( ¹¹R ) 2- . In one embodiment , L is -²Q- . In one embodiment , L is ¹Q- - C ( O ) -C ( ¹¹R ) 2- . In one embodiment , L is ¹Q- - C ( O ) ³Q- - O- . In one embodiment , L is ¹Q- - C ( O ) -C ( ¹¹R ) 2 - -¹Q . In one embodiment , L is ¹Q- - C ( ¹¹R ) 2 - Q3-0- . In one embodiment , L is ¹Q- - C ( ¹¹R ) 2- . In certain embodiments , -¹Q- is ww ²n R N. or wherein R19 is hydrogen , hydroxyl , halogen , or unsubstituted alkyl , ¹n is one or two , ²n is one or two , and ³n is one or two . In one embodiment , -¹Q- is selected from the group consisting of ww N. ww .N . m Mw | ' N ' R , and M , wherein R19 is hydrogen , hydroxyl , fluoro , or methyl . In M N one embodiment , -¹Q- is Mw In one embodiment , -¹Q- is .N . ww ﺓ R wherein R19 is hydrogen , hydroxyl , fluoro , or methyl . In one embodiment , -¹Q- is ww In one embodiment , -¹Q- is ww " N ' n www.In certain embodiments , -²Q- is nww , wherein n4 is one or two , n5 is one or two , - 45 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT M | .N .

N and no is one or two . In one embodiment , -²Q- is selected from the group consisting of w ww and ww .N . M In one embodiment , -²Q- is w In one embodiment , -²Q- is w In certain ww embodiments , -³Q- is ww wherein n is one or two , and ³n is one or two . In one , embodiment , -³Q- is selected from the group consisting of ww $ ﺕھ ﮦﻮﺘﻳ ww ww , m , and ww In one embodiment , -³Q- is M In one embodiment , -³Q- is w In one www embodiment , -³Q- is In one embodiment , -³Q- is In certain embodiments , each ¹¹R is , independently , hydrogen or methyl . In certain embodiments , both R11 are hydrogen ; one ¹¹R is hydrogen and one ¹¹R is methyl ; or both ¹¹R are methyl . In certain embodiments , -C1-alkylene- is -CH2CH2- , selected -CH2CH2CH2- , from group consisting of -CH2- , the -CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2CH2CH2- , and In one embodiment , -CH2CH2CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2CH2CH2CH2- . -C1-8 alkylene- is -CH2- . In one embodiment , -C1-8 alkylene- is -CH2CH2- . In one embodiment , -C1-8 alkylene- is -CH2CH2CH2- . In one embodiment , -C1-8 alkylene- is -CH2CH2CH2CH2- . In - 46 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT one embodiment , -C1-8 alkylene- is -CH2CH2CH2CH2CH2- . In one embodiment , -C1-8 alkylene- is -CH2CH2CH2CH2CH2CH2- . -CH2CH2CH2CH2CH2CH2CH2- .

In one embodiment , In one -C1-8 alkylene- embodiment , -C1-8 alkylene- is is -CH2CH2CH2CH2CH2CH2CH2CH2- . In certain embodiments , the linker L is selected from ww Z Z ' N ' UBM N. ﻭ ³Z m .N M ' N ' UBM , ³Z ³Z ' N ' UBM N ³Z Z UBM , , ³Z UBM ' N ' , R ³Z N m MW UBM , UBM ' N ' ww UBM ﻭ w M UBM N N.

' N ' ﻭ ﻭ Z N.

' N ' ww UBM ³Z ³Z N UBM ww , F Mw .N .

UBM N ' ﻭ ﻭ ww Z UBM ﻭ UBM N N ﻭ M UBM ﻭ M UBM , UBM ﻭ N UBM , w UBM , Z r f f f f c l UBM UBM , ﻭ UBM N , UBM , N UBM ﻭ UBM ﻭ UBM ﻭ 1100573566 5 AMERICAS ³Z ` N ' _OH w UBM H R ﻭ Attorney Docket No .: 121843.002 ww ³Z NU - 3200 PCT Zw M ³Z N.

HO M ww ³Z F ' N ' UBM , .N . ' N ' w UBM ³Z N ww ' N ' UBM UBM , , ﻭ M UBM ww ' N ' ww UBM UBM indicates attachment to ³Z , and ³Z & N ﻭ ³Z UBM ﻭ N M UBM .N . www Z ' N ' ﻭ ' N ' ww UBM , ' N ' UBM UBM and , wherein , indicates attachment to UBM . In one embodiment , UBM ww the linker L is UBM wherein indicates attachment to ³Z , and indicates attachment to UBM . In one embodiment , the linker L is indicates attachment to ³Z , and UBM N.

N www UBM wherein indicates attachment to UBM . In one embodiment , the - 48 - 1100573566 5 AMERICAS ³Z Attorney Docket No .: 121843.002NU - 3200 PCT UBM linker L is UBM wherein indicates attachment to ³Z , and indicates attachment N ww to UBM . In one embodiment , the linker L is UBM wherein indicates attachment to UBM ³Z , and indicates attachment to UBM . In one embodiment , the linker L is ﻭ ³Z N.

' N ' ww UBM UBM wherein indicates attachment to ³Z , and indicates attachment to ³Z ' N ' w UBM . In one embodiment , the linker L is UBM wherein indicates UBM attachment to ³Z , and indicates attachment to UBM . In one embodiment , the linker L is Z UBM UBM wherein indicates attachment to ³Z , and indicates attachment to UBM . 49 . 1100573566 5 AMERICAS In one embodiment , the linker L is .N .

' N ' Attorney Docket No .: 121843.002NU - 3200 PCT M UBM wherein R indicates attachment to ³Z , and ³Z N UBM vvv indicates attachment to UBM . In one embodiment , the linker L is UBM wherein UBM indicates attachment to ³Z , and indicates attachment to UBM . In one embodiment , the ﻭ ³Z Ő UBM linker L is UBM wherein indicates attachment to ³Z , and indicates attachment to , ³Z UBM . In one embodiment , the linker Lis UBM ww UBM wherein indicates attachment to ³Z , and indicates attachment to UBM . In one embodiment , the linker L is UBM indicates attachment to ³Z , and ﺵﺩ www UBM wherein indicates attachment to UBM . In one embodiment , - 50 - 1100573566 5 AMERICAS Z Attorney Docket No .: 121843.002NU - 3200 PCT the linker L is UBM wherein indicates attachment to ³Z , and ﻭ ³Z ww www UBM indicates attachment to UBM . In one embodiment , the linker L is UBM wherein indicates UBM attachment to ³Z , and indicates attachment to UBM . In one embodiment , the linker L is ﻭ ³Z ww N UBM wherein ﻞﻠﻫ UBM indicates attachment to ³Z , and indicates attachment to UBM . In UBM one embodiment , the linker L is UBM } wherein indicates attachment to ³Z , and - 51 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 indicates attachment to UBM . In one embodiment , the linker L is UBM indicates attachment to ³Z , and w N NU - 3200 PCT w UBM wherein R indicates attachment to UBM . In one embodiment , the UBM UBM linker L is wherein indicates attachment to ³Z , and indicates , ³Z F ד . attachment to UBM . In one embodiment , the linker L is UBM indicates attachment to ³Z , and ³Z .N .

N www UBM wherein R indicates attachment to UBM . In one embodiment , the ww linker Lis UBM wherein indicates attachment to ³Z , and ﻭ UBM ww indicates attachment -52- 1100573566 5 AMERICAS www .N ³Z $ Attorney Docket No .: 121843.002NU - 3200 PCT to UBM . In one embodiment , the linker L is ww UBM wherein indicates attachment to ³Z , ³Z and UBM N indicates attachment to UBM . In one embodiment , the linker L is UBM UBM wherein indicates attachment to ³Z , and ﻭ indicates attachment to UBM . In one ³Z embodiment , the linker L is UBM wherein ww ﻞﻫ indicates attachment to ³Z , and www ' N ' UBM ww indicates attachment to UBM . In one embodiment , the linker L is UBM wherein UBM indicates attachment to ³Z , and indicates attachment to UBM . In one embodiment , the , ³Z linker L is UBM wherein ﻞﻣ indicates attachment to ³Z , and UBM indicates attachment to UBM UBM . In one embodiment , the linker L is wherein indicates attachment to ³Z , and - 53 - 1100573566 5 AMERICAS ww Attorney Docket No .: 121843.002NU - 3200 PCT UBM indicates attachment to UBM . In one embodiment , the linker L is 3 ﺝ Z OH ww UBM wherein UBM indicates attachment to ³Z , and indicates attachment to UBM . In one embodiment , ³Z ww UBM the linker L is UBM wherein indicates attachment to ³Z , and indicates Zww F N M attachment to UBM . In one embodiment , the linker L is UBM wherein indicates UBM attachment to ³Z , and indicates attachment to UBM . In one embodiment , the linker L is ³Z ' N ' UBM w UBM wherein indicates attachment to ³Z , and indicates attachment to UBM . In -54- 1100573566 5 AMERICAS N.

Attorney Docket No .: 121843.002NU - 3200 PCT one embodiment , the linker L is UBM wherein indicates attachment to ³Z , and www HO UBM M indicates attachment to UBM . In one embodiment , the linker L is UBM wherein UBM indicates attachment to ³Z , and indicates attachment to UBM . In one embodiment , Zww the linker L is UBM wherein R indicates attachment to ³3Z , and Z attachment to UBM . In one embodiment , the linker L is N UBM indicates UBM wherein indicates 1100573566 5 AMERICAS UBM attachment to ³Z , and ZM N ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT indicates attachment to UBM . In one embodiment , the linker L is UBM ww UBM wherein indicates attachment to ³Z , and indicates attachment to UBM .

' N ' N ww In one embodiment , the linker L is UBM wherein indicates attachment to ³Z , and ﻭ ³Z N.

' N ' UBM ww UBM indicates attachment to UBM . In one embodiment , the linker L is UBM wherein indicates attachment to ³Z , and indicates attachment to UBM . In one ﻭ - 56 - 1100573566 5 AMERICAS Z Attorney Docket No .: 121843.002NU - 3200 PCT UBM UBM embodiment , the linker L is indicates attachment to UBM . wherein indicates attachment to ³Z , and [ 000105 ] consisting In certain embodiments , the compound of Formula ( I ) is selected from the group of ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , and ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide . In certain embodiments , the compond of Formula ( I ) is selected from the group consisting of ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 4- ( 3- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3- dioxoisoindolin - 4 - yl ) propyl ) piperazin - 1 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) - - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 18,4r ) -4 - ( ( 6- ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) -yl ) methyl ) cyclohexane - 1- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - - 57 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1,3 - dioxoisoindolin - 5 - yl ) piperazin - 1 - yl ) acetyl ) -4 - methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) -4- methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1- ( 2- ( 6- ( 2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) -yl ) acetyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - 1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperazin - 1 - yl ) acetyl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 2- ( 1- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperidin - 4- yl ) azetidine - 3 - carbonyl ) piperidin - 4 - yl ) propan - 2 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1 - ( ( 1R , 4r ) -4- ( 3 - ( ( R ) -2,6- dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) methyl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 3 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) -2 - fluorophenyl ) - - hydroxypiperidin - 4 - yl ) acetyl ) azetidin - 3 - yl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 4 - yl ) acetyl ) piperidin - 4- - 58 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( S ) -N- ( 3- ( 5- ( 2- yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , aminopyrimidin - 4 - yl ) -2- ( 4- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - ( ( ( 18,4r ) -4 - ( ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) oxy ) cyclohexyl ) methyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4- ( 9- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) -3 - azaspiro [ 5.5 ] undecane - 3 - carbonyl ) piperidin - 1- yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2 - ( ( S ) - 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) -3 - azaspiro [ 5.5 ] undecan- - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) acetyl ) azetidin - 3- yl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- ( methylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1 - ( ( ( 18,4r ) -4- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenoxy ) cyclohexyl ) methyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- - 59 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) piperidine - 4 - carbonyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 4- yl ) acetyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin- - yl ) ethyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 2- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperazin - 1 - yl ) acetyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 1'- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( isopropylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperazin - 1 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1 - ( ( 1R , 4r ) -4- ( 4 - ( ( R ) -2,6- dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) methyl ) piperidin - 4- - 60 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 2- ( 6- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - oxoisoindolin - 5 - yl ) hexanoyl ) -2- azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( 2 - ( ( ( R ) -1 - hydroxypropan - 2 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) thiazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , rac- ( 3R ) -3- { 6- [ 4- ( 4- { 4- [ 5- ( 2 - aminopyrimidin- - yl ) -4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ,, rac- ( 3R ) -3- { 6- [ 4- ( 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -5- { 2 - [ ( propan - 2- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1- carbonyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 1- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1- oxoisoindolin - 5 - yl ) piperidin - 4 - yl ) methyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -4- methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperidine - 4 - carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ) -5- ( 2- ( methylamino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 3- ( 6- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - oxoisoindolin - 5 - yl ) hexanoyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) acetyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- - 61 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( methylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin- - yl ) acetyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( isopropylamino ) pyrimidin - 4 - yl ) thiazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- ( cyclopropylamino ) pyrimidin - 4- yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2 - ( ( R ) -1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) phenyl ) pyrrolidin - 3 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -2- azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) acetyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - 1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 1- ( 1- ( 2,6- dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - benzo [ d ] imidazol - 4 - yl ) piperidine - 4- carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( methylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperidin - 4 - yl ) azetidine - 3- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 2- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperidin - 4 - yl ) azetidine - 3 - carbonyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 1- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - benzo [ d ] imidazol - 4 - yl ) piperidin- - yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - - 62 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7- diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ) propan - 2 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , and ( R ) -4 - ( ( 4- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro- 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidin - 1 - yl ) methyl ) -N- ( 2,6 - dioxopiperidin - 3- yl ) benzamide . In certain embodiments , the compound of Formula ( I ) is selected from the group consisting of ( R ) -4- ( 4 - ( ( 6 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) -2 - azaspiro [ 3.3 ] heptan - 2 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6- dioxopiperidin - 3 - yl ) benzamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 2 - ( ( S ) -1- ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4'- bipiperidin ] -4 - yl ) acetyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 1- ( 1- ( 2,6- dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - benzo [ d ] imidazol - 4 - yl ) piperidine - 4- carbonyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 1- ( 1- ( 2- ( 2,6- dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperidin - 4 - yl ) azetidine - 3 - carbonyl ) -2- azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3- dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 6- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - oxoisoindolin - 5 - yl ) hexanoyl ) -2- azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2 - ( ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 2- ( 4- ( 3- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 4- yl ) propyl ) piperazin - 1 - yl ) acetyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 1 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) -4 - fluoropiperidine - 4 - carbonyl ) -2- - 63 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2 - ( ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 ' - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 7- ( 2- ( 4- ( 4 - ( ( 2,6 - dioxopiperidin - 3- yl ) amino ) phenyl ) piperidin - 1 - yl ) acetyl ) -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 7- ( ( ( 1S , 4r ) -4- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenoxy ) cyclohexyl ) methyl ) -7- azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 7 - ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1 - oxo - 1,2- dihydroisoquinolin - 6 - yl ) piperidin - 4 - yl ) methyl ) -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin- - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 7- ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) -7 - azaspiro [ 3.5 ] nonan - 2- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , and ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 7- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperazin- - yl ) acetyl ) -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide . In certain embodiments , the compound of Formula ( I ) is selected from the group consisting of ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 3 - yl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2 - ( ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3- dioxoisoindolin - 5 - yl ) oxy ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2 - ( ( 2- ( 2,6- dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) oxy ) acetyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2- ( 4- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperazin - 1- yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2 - ( ( S ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -4- ( 4 - ( ( 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) phenyl ) piperidin - 1- - 64 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) benzamide , ( R ) -5- ( 4 - ( ( 4- ( 4 - ( ( 4- ( 2- ( tert- butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2- yl ) amino ) phenyl ) piperidin - 1 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3- yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1 - ( ( ( 18,4r ) -4 - ( ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) oxy ) cyclohexyl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2- ( ( S ) -1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3 - yl ) acetyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2 - ( ( R ) -1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3- yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2 - ( ( S ) -1- ( 1 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3- dihydro - 1H - benzo [ d ] imidazol - 5 - yl ) pyrrolidin - 3 - yl ) acetyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 1- ( 1- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3 - dihydro- 1H - benzo [ d ] imidazol - 4 - yl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) azetidine - 3 - carbonyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2- ( 2- ( 2- ( 2,6- - 65 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7- yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 6- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -3- oxoisoindolin - 5 - yl ) hexanoyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 2- ( 4- ( 2- ( 2,6- dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperazin - 1 - yl ) acetyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -5- ( 4 - ( ( 4 - ( ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2- yl ) amino ) methyl ) piperidin - 1 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3- yl ) picolinamide , ( S ) -5- ( 4 - ( ( 4- ( 1 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -2 - methylpropan - 2- yl ) piperidin - 1 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) methyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) -2 - methylpropyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , 5- ( 4 - ( ( ( R ) -3 - ( ( ( 4- ( 2- ( tert - butyl ) -4- ( 2- fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) methyl ) pyrrolidin - 1- yl ) methyl ) piperidin - 1 - yl ) -N - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) - 5- ( 2 - ( ( ( 1r , 4r ) -4 - ( ( 4 - ( ( 1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) methyl ) cyclohexyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( ( 1s , 4s ) -4- ( 4- ( 1- ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperazin - 1- yl ) cyclohexyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( ( 1r , 4r ) -4- ( 4- ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidine - 4 - carbonyl ) piperazin - 1 - yl ) cyclohexyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( ( 1r , 4r ) -4- ( 4 - ( ( 1- ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) cyclohexyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( ( 1s , 4s ) -4- ( 4 - ( ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) cyclohexyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( 3R ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- - 66 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione , ( 3S ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- ylmethyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione , rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert- butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl } amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione , rac- ( 3S ) -3- ( 2 - { [ ( 1r , 4r ) -4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } cyclohexyl ] methyl } -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) piperidine - 2,6 - dione , rac- ( 3S ) -3- ( 2 - { [ ( 1r , 4r ) -4- { 4- [ 6 - ( { 4- [ 2 - tert- butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } cyclohexyl ] methyl } -1,2,3,4- tetrahydroisoquinolin - 7 - yl ) piperidine - 2,6 - dione , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 2- ( 4- ( 4- ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 1 - yl ) acetyl ) -1,2,3,4 - tetrahydroisoquinolin- - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4- ( 6- ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2- yl ) amino ) -1,2,3,4 - tetrahydroisoquinoline - 2 - carbonyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3- yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin- - yl ) pyrrolidine - 3 - carbonyl ) -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 2- ( 4- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperazin - 1 - yl ) acetyl ) -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( 2- ( 6- ( 2,6 - dioxopiperidin - 3 - yl ) -3,4- dihydroisoquinolin - 2 ( 1H ) -yl ) acetyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert- butyl ) -5- ( 2 - ( ( 1 - ( ( 1 - ( ( 1S , 4r ) -4- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1- carbonyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1 - ( ( 1S , 4r ) -4 - ( ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) oxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) methyl ) -1H- pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) - N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( 2- ( 4- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin- - yl ) acetyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4- ( 4 - ( ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- -67- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -1H - pyrazol - 1- yl ) methyl ) piperidine - 1 - carbonyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine- - carbonyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( 2- ( 4- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperazin - 1 - yl ) acetyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert- butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( 2 - ( ( S ) -1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3- yl ) acetyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( 2 - ( ( R ) -1- ( 4 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3 - yl ) acetyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert- butyl ) -5- ( 2 - ( ( 1- ( 1 - ( ( 1S , 4r ) -4- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1- carbonyl ) piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1- ( 1 - ( ( 1S , 4r ) -4 - ( ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) oxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) -1H - pyrazol - 4- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1- ( 1- ( 2- ( 4- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 1- yl ) acetyl ) piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4- ( 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -1H - pyrazol - 1 - yl ) piperidine- - carbonyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1- ( 1 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine - 3- carbonyl ) piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1- ( 1- ( 2 - ( ( S ) -1- ( 4 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3 - yl ) acetyl ) piperidin - 4 - yl ) -1H - pyrazol - 4- yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1- ( 2- ( 6- ( 2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) - yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1- ( 2- ( 4- ( 4 - ( ( 2,6 - dioxopiperidin - 3- yl ) amino ) phenyl ) piperidin - 1 - yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1 - ( ( R ) -1- ( 5 - ( ( S ) - 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ) piperidin - 4- - 68 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2- ( 6- ( 2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) - yl ) acetyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 1- ( 3- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( 1S , 4r ) -4- ( 4 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1 - carbonyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( 18,4r ) -4 - ( ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) oxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2- ( 4- ( 4- ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 1 - yl ) acetyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4- ( 4- ( 3 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) phenoxy ) piperidine - 1 - carbonyl ) piperidin - 1 - yl ) -N- ( 2,6- dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( R ) -1- ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2- ( 4- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperazin- - yl ) acetyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2 - ( ( S ) -1- ( 4 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3 - yl ) acetyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2 - ( ( R ) -1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenyl ) pyrrolidin - 3- yl ) acetyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- - 69 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -3- fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( 2S , 4R ) -1 - ( ( S ) -2- ( 5- ( 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) phenyl ) piperidin - 1 - yl ) -5- oxopentanamido ) -3,3 - dimethylbutanoyl ) -4 - hydroxy - N - ( ( S ) -1- ( 4- ( 4 - methylthiazol - 5- yl ) phenyl ) ethyl ) pyrrolidine - 2 - carboxamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2 - ( ( 1- ( 2- ( 2,6- dioxopiperidin - 3 - yl ) -1 - oxo - 1,2 - dihydroisoquinolin - 6 - yl ) piperidin - 4 - yl ) methyl ) -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1 - ( ( ( 1S , 4r ) -4- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) phenoxy ) cyclohexyl ) methyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1 - oxo - 1,2 - dihydroisoquinolin - 6 - yl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4 - ( ( 4 - ( ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -1H - pyrazol - 1- yl ) methyl ) piperidin - 1 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1 - ( ( 1- ( 2 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1- ( 1- ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1 - oxo - 1,2 - dihydroisoquinolin - 6 - yl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4 - ( ( 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -1H - pyrazol - 1 - yl ) piperidin - 1- yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2- ( ( 1- ( 1- ( 2 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin- - yl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 1- ( 1- ( 2 - ( ( S ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1- ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1 - oxo - 1,2 - dihydroisoquinolin - 6 - yl ) piperidin - 4- - 70 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1- ( 2 - ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1- ( 2 - ( ( S ) -1- ( 5 - ( ( S ) - 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidin- - yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( ( 18,4r ) -4- ( 4 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) phenoxy ) cyclohexyl ) methyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1 - oxo - 1,2- dihydroisoquinolin - 6 - yl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2- ( ( R ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1- ( 2 - ( ( S ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) pyrrolidin - 3 - yl ) ethyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidin - 4 - yl ) methyl ) piperidin - 4- yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4 - ( ( 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) -1H - pyrazol - 1 - yl ) piperidin - 1 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6- dioxopiperidin - 3 - yl ) picolinamide , ( R ) -5- ( 4 - ( ( 4 - ( ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -1H - pyrazol - 1- yl ) methyl ) piperidin - 1 - yl ) methyl ) piperidin - 1 - yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4- carbonyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) -2- methylthiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4- yl ) -2 - methylthiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - ( ( 5- ( 4 - ( ( 1- - 71 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) pyridin - 2- yl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) - N- ( 3- ( 5- ( 2 - ( ( 5- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) pyridin - 2 - yl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - ( ( 5- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) pyridin - 2 - yl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , rac- ( 3R ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) pyridin - 3 - yl ] piperidine - 2,6- dione , ( S ) -N- ( 3- ( 5- ( 2 - ( ( 4- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( R ) -1- ( 5 - ( ( R ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ) piperazin - 1 - yl ) -3- fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) - N- ( 3- ( 5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( R ) -1- ( 5 - ( ( R ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ) piperazin - 1 - yl ) -3- fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , rac- ( 38 ) -3- [ 6- ( 3- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } azetidin - 1- yl ) pyridin - 3 - yl ] piperidine - 2,6 - dione , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 2- ( 1- ( 4 - ( ( 2,6- dioxopiperidin - 3 - yl ) amino ) -2 - fluorophenyl ) -4 - hydroxypiperidin - 4 - yl ) acetyl ) piperazin - 1 - yl ) - - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 2- ( 6- ( 2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin- ( 1H ) -yl ) acetyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- - 72 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( 18,4r ) -4 - ( ( 5 - ( ( S ) -2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) oxy ) cyclohexane - 1 - carbonyl ) piperazin - 1 - yl ) -3- fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) - N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) acetyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 4- yl ) acetyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -3- fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) - N- ( 3- ( 5- ( 2 - ( ( 4- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 4- yl ) acetyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl } methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione , rac- ( 3S ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } -4- methylpiperidin - 1 - yl ) pyridin - 3 - yl ] piperidine - 2,6 - dione , ( 3R ) -3- ( 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] piperazin - 1 - yl } methyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione , rac- ( 3S ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2- methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin- - yl ) pyridin - 3 - yl ] piperidine - 2,6 - dione , rac- ( 3R ) -3- { 6- [ 4- ( 2- { 4- [ 6 - ( { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) -2 - oxoethyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine- - carbonyl ) piperazin - 1 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1- ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , rac- ( 3S ) -3- [ 4- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert- - 73 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) phenyl ] piperidine - 2,6 - dione , ( R ) -N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- ylmethyl ) -4 - methylpiperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione , rac- ( 38 ) -3- ( 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5- yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) -4 - fluoropiperidin - 1- yl ] phenylpiperidine - 2,6 - dione , ( S ) -N- ( 3- ( 5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin- - yl ) -4 - methylpiperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) amino ) pyrimidin - 4 - yl ) -2- methylthiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - ( ( 4- ( 4 - ( ( 1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) -4 - fluoropiperidin - 4 - yl ) methyl ) piperazin - 1- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) -2 - methylthiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , rac- ( 3R ) -3- { 6- [ 6 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 2 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione , ( 3R ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione , rac- ( 3R ) -3- [ 2- ( 2- { 4- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] piperazin - 1 - yl ) -2- oxoethyl ) -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ] piperidine - 2,6 - dione , and ( 3R ) -3- { 6- [ 4 - ( { 4- [ 6- ( { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5- yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione . In certain embodiments , the compound of Formula ( I ) is selected from the group consisting of ( S ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , and ( S ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin- - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide . In certain embodiments , the compound of Formula ( I ) is - 74 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT selected from the group consisting of ( R ) -N- ( 3- ( 1- ( 4- ( 4- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidine - 4 - carbonyl ) piperazine - 1 - carbonyl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazine - 1 - carbonyl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidine - 4 - carbonyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 1- ( 4 - ( ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) oxy ) phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 1- ( 4- ( 4- ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazine - 1 - carbonyl ) phenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin- - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - fluorophenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4 - yl ) methyl ) piperidin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) - N- ( 3- ( 1- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , yl ) methyl ) piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- ( S ) -N- ( 3- ( 1- ( 6- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 1- ( 4- ( 4- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) piperazine - 1 - carbonyl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4- ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 6- ( 4- ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) pyridin - 3- - 75 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 1- ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 1- ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 4- ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 1- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4- carbonyl ) piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 1- ( 4- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - fluorophenyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , and ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin- - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide . [ 000106 ] In certain embodiments , the compound of Formula ( II ) is selected from the group consisting of ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , and ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- - 76 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( pyridin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide . In certain embodiments , the compound of Formula ( II ) is selected from the group consisting of ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 4- ( 3- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoi soindolin - 4- yl ) propyl ) piperazin - 1 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 18,4r ) -4 - ( ( 6- ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) -yl ) methyl ) cyclohexane - 1- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - 1,3 - dioxoisoindolin - 5 - yl ) piperazin - 1 - yl ) acetyl ) -4 - methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) -4- methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1- ( 2- ( 6- ( 2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) -yl ) acetyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - 1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperazin - 1 - yl ) acetyl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 2- ( 1- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperidin - 4- yl ) azetidine - 3 - carbonyl ) piperidin - 4 - yl ) propan - 2 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1 - ( ( 1R , 4r ) -4- ( 3 - ( ( R ) -2,6- dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) methyl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- - 77 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) -2- ( 3 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) -2 - fluorophenyl ) - - hydroxypiperidin - 4 - yl ) acetyl ) azetidin - 3 - yl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 4 - yl ) acetyl ) piperidin - 4- yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 4- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - ( ( ( 18,4r ) -4 - ( ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) oxy ) cyclohexyl ) methyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -5- ( 4- ( 9- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) -3 - azaspiro [ 5.5 ] undecane - 3 - carbonyl ) piperidin - 1- yl ) -N- ( 2,6 - dioxopiperidin - 3 - yl ) picolinamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2 - ( ( S ) -1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidin - 3 - yl ) ethyl ) -3 - azaspiro [ 5.5 ] undecan - 9- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) - 2- ( 1- ( 1- ( 2- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) acetyl ) azetidin - 3- yl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- - 78 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( methylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 2- ( 1 ' - ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyridin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1 - ( ( ( 18,4r ) -4- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) phenoxy ) cyclohexyl ) methyl ) piperidin - 4- yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperidine - 4 - carbonyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 2- ( 1- ( 4 - ( ( 2,6 - dioxopiperidin - 3 - yl ) amino ) phenyl ) piperidin - 4- yl ) acetyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin- - yl ) ethyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 2- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperazin - 1 - yl ) acetyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) piperazin - 1 - yl ) phenyl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 1'- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ) -3- - 79 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4- yl ) methyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3- yl ) phenyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( isopropylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 4- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperazin - 1 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1 - ( ( 1R , 4r ) -4- ( 4 - ( ( R ) -2,6- dioxopiperidin - 3 - yl ) phenoxy ) cyclohexane - 1 - carbonyl ) piperidin - 4 - yl ) methyl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 2- ( 6- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - oxoisoindolin - 5 - yl ) hexanoyl ) -2- azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( 2 - ( ( ( R ) -1 - hydroxypropan - 2 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) thiazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , rac- ( 35 ) -3- { 6- [ 4- ( 4- { 4- [ 5- ( 2 - aminopyrimidin- - yl ) -4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione , rac- ( 3S ) -3- { 6- [ 4- ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -5- { 2 - [ ( propan - 2- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1- carbonyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 1- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - ( ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1- oxoisoindolin - 5 - yl ) piperidin - 4 - yl ) methyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -4- methylpiperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 3- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- - 80 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) piperidine - 4 - carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide , ( R ) -N- ( 3- ( 2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) - 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ) -5- ( 2- ( methylamino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 3- ( 6- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - oxoisoindolin - 5 - yl ) hexanoyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) acetyl ) -4 - methylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( methylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin- - yl ) acetyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( isopropylamino ) pyrimidin - 4 - yl ) thiazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2- ( cyclopropylamino ) pyrimidin - 4- yl ) -2- ( 1- ( 1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 2- ( 1- ( 1- ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4- carbonyl ) piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2 - ( ( R ) -1- ( 4 - ( ( S ) -2,6 - dioxopiperidin - 3- yl ) phenyl ) pyrrolidin - 3 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -2- azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 1 - ( ( 1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) acetyl ) piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - 1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 1- ( 1- ( 2,6- dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - benzo [ d ] imidazol - 4 - yl ) piperidine - 4- carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 2- ( 1- ( 1 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidin - 4 - yl ) methyl ) piperidine - 4- - 81 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 carbonyl ) piperidin - 4 - yl ) -5- ( 2- ( methylamino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2- NU - 3200 PCT fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) piperidin - 4 - yl ) azetidine - 3- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 2- ( 1- ( 1- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5- yl ) piperidin - 4 - yl ) azetidine - 3 - carbonyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , ( S ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( 1 - ( ( 1- ( 1- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - benzo [ d ] imidazol - 4 - yl ) piperidin- - yl ) methyl ) piperidine - 4 - carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide . ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) - 1,3 - dioxoisoindolin - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) -3 - azaspiro [ 5.5 ] undecan - 9- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide , ( R ) -N- ( 3- ( 5- ( 2 - aminopyrimidin - 4- yl ) -2- ( 2- ( 1- ( 2- ( 2- ( 2- ( 2,6 - dioxopiperidin - 3 - yl ) -1,3 - dioxoisoindolin - 5 - yl ) -2,7- diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ) propan - 2 - yl ) thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide , and ( R ) -4 - ( ( 4- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro- 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidin - 1 - yl ) methyl ) -N- ( 2,6 - dioxopiperidin - 3- yl ) benzamide . [ 000107 ] In certain embodiments of Formula ( I ) , ¹X is carbon ; ²X is nitrogen , ³X is nitrogen ; X4 is carbon ; and X5 is hydrogen . In certain embodiments of Formula ( I ) , ¹R is alkyl , dialkylamino , cycloalkyl , or heterocycloalkyl each unsubstituted or substituted with one or more halogen ; a¹R is halogen ; R1b is hydrogen , haloalkyl or halogen ; ²R is - [ ¹rA - Z1 ] n - Z2 - -¹yC ³Z - L - UBM ; ¹rA is arylene or heteroarylene , each unsubstituted or substituted with one or more halogen ; ¹Z is a bond ; n is one ; ²Z is absent ; ¹yC is absent or heterocycloalkylene , unsubstituted or substituted with one or more alkyl or one or more halogen ; ³Z is absent or C1-10 alkylene ; L is a linker according to ¹L- - ²L - ³L - –ªL or 4L– - ³L - ²L - -¹L , wherein -¹L- is -¹Q- or ²Q- ; each -²L- , -³L- , and -L- is independently , absent , -C1-8 alkylene- , or -¹Q- ; each -¹Q- is a three- to seven - membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl or halogen ; each -²Q- is a five- to thirteen - membered bicyclic heterocycloalkylene comprising at least one nitrogen , wherein the five- to thirteen - membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring ; and UBM is a ubiquitin ligase binding moiety ; or a stereoisomer and / or pharmaceutical salt thereof . -82- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000108 ] In certain embodiments of Formula ( I ) , ¹R is selected from the group consisting of propyl , ethylmethylamino , sec - butyl , w F " 9 י w F ﻩ ﻩﺮﻫﺮﻫ and , N. ﻭ N , , , , In one embodiment , ¹R is propyl . In one embodiment , ¹R is ethylmethylamino . In one embodiment , ¹R is sec - butyl . In one embodiment , ¹R is In one embodiment , ¹R is In one embodiment , ¹R is In one embodiment , ¹R is In one embodiment , ¹R is In one embodiment , ¹R is In one embodiment , ¹R is In one embodiment , ¹R is ﺢﻣﺩ N- D N. In one embodiment , ¹R is In one embodiment , ¹R is In one N. N embodiment , ¹R is In one embodiment , ¹R is In one embodiment , F F N ¹R is In one embodiment , ¹R is In one embodiment , ¹R is F S In one LL F F embodiment , ¹R is F ﻪﻣﺎﻧ is N. In one embodiment , ¹R is In one embodiment , ¹R - 83 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000109 ] In certain embodiments of Formula ( I ) , a¹R is chloro or fluoro ; and b¹R is hydrogen , chloro , fluoro , or haloalkyl . In certain embodiments of Formula ( I ) , ¹rA is arylene or heteroarylene unsubstituted or substituted with one or two halogen . In certain embodiments of Formula ( I ) , UBM binds an E3 ubiquitin ligase . In certain embodiments of Formula ( I ) , UBM binds u0000FCS - TRCP , VHL , MDM2 , IAP , or CRBN . In certain embodiments of Formula ( I ) , UBM binds CRBN . In certain embodiments of Formula ( I ) , UBM binds CRBN and has NH NH ' N ' the following chemical formula X or wherein X6 absent or ³RN ; X7 absent ﻭ or -C ( O ) - ; and X8 is arylene or heteroarylene . In certain embodiments of Formula ( I ) , UBM binds CRBN and is selected from the group consisting of NH NH NH ' N ' ( m⁹X , NH NH NH NH N. ' N ' .N . N.

NH NH M NH NH NH NH ww NH N N- M , NH NH .N .

NH w NH , , , and wherein X is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM binds CRBN - 84 - 1100573566 5 AMERICAS and is NH Attorney Docket No .: 121843.002NU - 3200 PCT ( ⁹X ) m wherein X9 is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM binds CRBN and is embodiment , UBM binds CRBN and is one embodiment , UBM binds CRBN and is M ﺵﺮﻣا NH In one embodiment , UBM binds CRBN and is NH - ( ⁹X ) m NH ( m⁹X wherein X is absent . In one wherein X is halogen ; and m is one . In - ( m⁹x wherein X is halogen ; and m is two .

NH · ( ⁹X ) m wherein X is halogen ; and m is - 85 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT NH three . In one embodiment , UBM binds CRBN and is ( ³X ) m NH wherein X9 is halogen ; and m is four . In one embodiment , UBM binds CRBN and is . In one embodiment , UBM ' N ' NH NH ' N ' binds CRBN and is . In one embodiment , UBM binds CRBN and is . In NH one embodiment , UBM binds CRBN and is In one embodiment , UBM binds N NH .N .

CNH CRBN and is www In one embodiment , UBM binds CRBN and is In one - 86 - 1100573566 5 AMERICAS embodiment , UBM binds CRBN and is .NH NH Attorney Docket No .: 121843.002NU - 3200 PCT wherein X is absent or halogen ; and m is one , two , three , or four . In one embodiment , UBM binds CRBN and is NH wherein X ' is absent . In one embodiment , UBM binds CRBN and is ( ³X ) m NH .NH NH wherein NH NH X is halogen ; and m is one . In one embodiment , UBM binds CRBN and is ( ³X ) m wherein X is halogen ; and m is two . In one embodiment , UBM binds CRBN and is NH NH wherein X is halogen ; and m is three . In one embodiment , UBM binds - 87 - 1100573566 5 AMERICAS NH NH Attorney Docket No .: 121843.002NU - 3200 PCT CRBN and is ( m³X wherein X ' is halogen ; and m is four . In one embodiment , UBM binds CRBN and is NH .NH NH In one embodiment , UBM binds CRBN and is m NH In one embodiment , UBM binds CRBN and is NH NH NH In one embodiment , UBM binds CRBN and is . In one embodiment , UBM binds CRBN NH .N .

NH and is In one embodiment , UBM binds CRBN and is [ 000110 ] In certain embodiments of Formula ( I ) , the compound is selected from the group consisting of ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,4 - dioxotetrahydropyrimidin - 1 ( 2H ) - - 88 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- yl ) -2 - fluorophenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ; ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ; rac- ( R ) - N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide ; rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide ; rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide ; N- ( 5 - chloro - 3- ( 1- ( 4 - ( ( R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) -3 - methylpiperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide ; ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) - - fluorophenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2,5 - difluorophenyl ) cyclopentanesulfonamide ; rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) cyclopentanesulfonamide ; rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) cyclopentanesulfonamide ; ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) cyclopentanesulfonamide ; ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4- yl ) methyl ) -1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide ; ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) - - fluorophenyl ) piperidin - 4 - yl ) methyl ) -1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) - - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1- yl ] phenyl - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; N- [ 5- chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- - 89 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4- [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1- yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; N- [ 5- chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4- [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl ) -4 - fluoropiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin- - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- ( 3- ( 1- ( 4 - ( ( R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- -90- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; chloro - 3- [ 1- ( 4-4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- NU - 3200 PCT ( 3R ) -N- { 5- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1- sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 7- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl ) -7 - azaspiro [ 3.5 ] nonan - 2- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide ; N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - 2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide ; N- [ 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan- - yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - 2,5 - difluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- { 3- [ 1- ( 4- [ 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- -91- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -3- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1- yl ] phenylpiperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) piperidine - 2,6 - dione ; 1- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) -1,3 - diazinane - 2,4 - dione ; rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3- yl ) piperidine - 2,6 - dione ; ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1- yl ] phenylpiperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione ; ( 3R ) -3- ( 4- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) piperidine - 2,6- dione ; 1- ( 4- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) phenyl ) - 1,3 - diazinane - 2,4 - dione ; rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin- - ylpiperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione ; 1- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) -1,3 - diazinane- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- 2,4 - dione ; fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1- yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) - - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1- yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1- sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4- [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1- yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1- sulfonamide ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- -92- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) - - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1- yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5- [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1- yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1- sulfonamide : ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl } methyl ) -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) - - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; ( RS ) -N- ( 5 - chloro- 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) butane - 2 - sulfonamide ; ( 2R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- rac- yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] butane- - sulfonamide ; rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) butane - 2 - sulfonamide ; ( 2RS ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ] -2 - fluorophenylbutane - 2 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5- [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide ; rac - N- { 5- -93- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoroazetidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl - 3 - fluoroazetidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) - 2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) - 2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl - 3 - fluoroazetidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide ; N- [ 5- chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- ylmethyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide ; N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide ; rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1- sulfonamide ; N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenylpyrrolidine - 1 - sulfonamide ; rac - N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro- 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -1,4 - diazepan - 1 - yl } -2 - fluorophenyl ) - - 94- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenylpyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -1,4 - diazepan - 1- yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2- fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- N- [ 5- fluorophenyl ] pyrrolidine - 1 - sulfonamide ; rac - N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) - 2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 6- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 6- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro- 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- [ 5- ( difluoromethyl ) -3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; rac - N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- -95- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin- - yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3- diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5- chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5- [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1- sulfonamide ; ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4- [ 4- ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl ) methyl ) piperazin - 1- yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoroazetidine - 1- sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide ; N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo- 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] -2 - fluorophenyl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; ( 3R ) -N- [ 5 - chloro- 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl ) methyl ) piperazin- - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3- fluoropyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } cyclopentanesulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- - 96 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } cyclopentanesulfonamide ; N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } cyclopentanesulfonamide ; ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ] phenylpiperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione ; rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) -3- ( pyridin- - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine- 2,6 - dione ; ( 3R ) -3- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- N- [ 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- yl } phenyl ) piperidine - 2,6 - dione ; pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] -3- fluorophenylpiperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione ; ( 3S ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] -2 - fluorophenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine- 2,6 - dione ; rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 4- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperazin - 1- yl ) methyl ) piperidin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide ; N- ( 5 - chloro - 3- ( 1- ( 4 - ( ( 3R , 5R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin- - yl ) piperidin - 4 - yl ) methyl ) -3,5 - dimethylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide ; N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5- [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2- yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; N- { 5- chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -2,3 - difluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro- 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2,5 - difluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ; rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -3,5 - difluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- - 97 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ; and N- [ 5 - chloro- 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl ) methyl ) piperazin- - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] cyclopentanesulfonamide .

Linkers [ 000111 ] L is a linker according ﻭ to In Formula ( I ) or ( II ) , L is a linker . The linker can be any linker suitable for linking the right and left portions of a molecule or Formula herein . In certain embodiments , the linker does not interfere with the harness or hook functions of a molecule or Formula herein .

In certain embodiments , the linker provides useful solubility , flexibility , and / or distance between the portions of a molecule or Formula herein . In certain embodiments , L is a linker according to ¹L- - ²L - ³L - ªL - ³L - L6 - -²L or -L7 - L - ³L - ªL - ³L - ²L - ¹L . In certain embodiments , L is a linker according to -L1 - ²L - ³L - L4 - L5 - L6- or -L - ³L - ³L - ³L - ²L - ¹L . In certain embodiments , L is a linker according to ¹L- - ²L - ³L - L4 - –5L or ³L– - L4 - ³L - ²L - ¹L . In certain embodiments , ¹L- - ²L - ³L - -²L or -L4 - ³L - ²L - ¹L . In certain embodiments , L is a linker according to ¹L- - -²L -³L or ³L- - ²L - -¹L . In certain embodiments , L is a linker according to -L1 - -²L or ²L- - -¹L . In certain embodiments , L is a linker according to -¹L- , -²L− , -³L− , —ªL− , –³L— , –6L− , –7L− , or other combinations as would be appreciated by a person of skill in the art . For example , in certain embodiments , L is a linker according to ¹L- - ³L - —6L , L— ' - ³L - -¹L , or ¹L- - ³L - L6 - -²L . Each group Lx is described in detail below . In certain embodiments , the linker L comprises at least one heterocyclic group . In certain embodiments , the linker L comprises one heterocyclic group . In certain embodiments , the linker L comprises two heterocyclic groups . In certain embodiments , the linker L comprises three heterocyclic groups . In certain embodiments , the linker L comprises at least one spiro bicyclic heterocycloalkylene group . In certain embodiments , the linker L comprises one spiro bicyclic heterocycloalkylene group . In certain embodiments , the linker L comprises two spiro bicyclic heterocycloalkylene groups . In certain embodiments , the linker L comprises three spiro bicyclic heterocycloalkylene groups . In certain embodiments , the linker L comprises at least one heterocycloalkylene group and at least one spiro bicyclic heterocycloalkylene . The remaining groups of or within the linker are selected for chemical compatibility with adjacent groups , as will be recognized by those of skill in the art . - 98 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000112 ] In certain embodiments , L is a linker according to -L1 - L2 - L3 - L4 - L5 - L6 - L7- . In certain embodiments , L is a linker according to -L7 - L6 - L3 - L4 - ³L - ²L - -¹L In certain embodiments , -¹L- is absent , -N ( º¹R ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -C1-8 alkylene- , -C2-8 alkynylene- , -C6 - C10 aryl- , -heteroaryl- , -C4 - C 10 heteroaryl- , -¹Q- , or -²Q- ; each -²L- , —³L- , —ªL— , and -5L— is independently , absent , -N ( º¹R ) - , -C ( ¹¹R ) 2- , -C ( O ) - , -O- , - ( CH2 - CH2 - O ) 1-8- , C1-8 alkylene- , -C2-8 alkynylene- , -C6 - C10 aryl- , substituted -C6 - C10 aryl- , -heteroaryl- , -C4 - C10 heteroaryl- , -¹Q- , -²Q- , or -³Q- ; each -L6- and –7L- is independently , absent , -N ( º¹R ) - , -C ( º¹R ) 2- , -C ( O ) - , -C ( O ) -N ( º¹R ) - , -N ( R10 ) -C ( O ) - , -heteroaryl- , -C4 - C10 heteroaryl- , or -C ( ¹¹R ) 2 - C ( O ) -N ( º¹R ) - . In certain embodiments , L comprises at least one -Q1- . In certain embodiments , L comprises one -¹Q- . In certain embodiments , L comprises two -¹Q- . In certain embodiments , L comprises three - -¹Q . In certain embodiments , L comprises at least one -²Q- . In certain embodiments , L comprises one -Q2- . In certain embodiments , L comprises two -²Q- . In certain embodiments , L comprises three -²Q- . In certain embodiments , L comprises at least one -¹Q- and at least one -²Q- . In certain embodiments , L comprises one -¹Q- and one -²Q- . - [ 000113 ] In certain embodiments , each -¹Q- is an unsubstituted or substituted three- to seven - membered heterocycloalkylene comprising at least one nitrogen ; each -²Q- is a five- to thirteen - membered bicyclic heterocycloalkylene comprising at least one nitrogen , wherein the five- to thirteen - membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring ; each -³Q- is a three- to six - membered cycloalkylene ; each R10 is hydrogen or methyl ; and each ¹¹R is independently , hydrogen , methyl , aryl , substituted aryl , or heteroaryl . In certain embodiments , R10 is hydrogen . In certain embodiments , R10 is methyl . In certain embodiments , one ¹¹R is hydrogen . In certain embodiments , both ¹¹R are hydrogen . In certain embodiments , one R11 is methyl . In certain embodiments , one ¹¹R is hydrogen and the other is methyl . In certain embodiments , both ¹¹R are methyl . In certain embodiments , one ¹¹R is aryl . In certain embodiments , one R11 is hydrogen or methyl and the other is aryl . In certain embodiments , both R11 are aryl . In certain embodiments , R11 is a substituted aryl . In certain embodiments , one ¹¹R is heteroaryl . In certain embodiments , one ¹¹R is hydrogen or methyl and the other is heteroaryl . In certain embodiments , both ¹¹R are heteroaryl . [ 000114 ] In certain embodiments of Formula ( I ) or ( II ) , L comprises at least one -¹Q- ww N ²n ﻭ wherein ¹n is one or two , and ²n is one or two . according to ww - 99 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT In certain embodiments of Formula ( I ) or ( II ) , L comprises at least one -¹Q- . [ 000115 ] [ 000116 ] In certain embodiments of Formula ( I ) or ( II ) , L is selected from ¹Q- - N ( Me ) -CH2 - ¹Q - C ( O ) — ; -N ( Me ) ¹Q- - CH2 - ¹Q - C ( O ) — ; ²Q- - CH2 - ¹Q - C ( O ) - ; ¹Q- - CH2 - ¹Q - C ( O ) - ; ¹Q- - ¹Q - C ( O ) - ; ¹Q- - CH2 - N ( Me ) ¹Q- - C ( O ) — ; ¹Q- - CH2 - ¹Q - CH2 - C ( O ) -N ( Me ) - ; ¹Q- - CH2 - -¹Q ; ¹Q- - CH2 - -²Q ; ¹Q- - CH2 - CH2 - -¹Q ; ¹Q- - CH2 - CH2 - -²Q ; ¹Q- - C ( O ) -¹Q- ; ¹Q- - C ( O ) -²Q- ; ¹Q- - CH2 - ¹Q - N ( Me ) -C ( O ) — ; -CH2 - CH2 - CH2 - CH2 - ¹Q - C ( O ) — ; ¹Q- - C ( O ) - ; ¹Q- - C ( O ) ¹Q- - CH ( C6H5 ) - ; -C = ₂HCC - ¹Q - C ( O ) - ; ¹Q- - CH2 - ¹Q - NH - C ( O ) — ; -CH2 - CH2 - CH2 - ¹Q - C ( O ) - ; ¹Q- - CH2 - ¹Q - C ( Me ) -C ( O ) -N ( Me ) - ; -CH2 - -¹Q ; ¹Q- - C ( O ) ¹Q- - CH2- ; N− ( H ) - ( CH2 ) 5 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -N ( H ) - ( CH2 ) 2 - O- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -¹Q- ( CH2 ) 3 - C ( O ) ¹Q- - CH ( C6H5 ) - ; ²Q- - C ( O ) ¹Q- - CH ( C6H5 ) - ; ²Q- - CH2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -²Q- ( CH2 ) 3 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -²Q— ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 6 - ¹Q - CH ( C6H5 ) ; - 100 - 1100573566 5 AMERICAS ¹Q— - ¹Q - C ( O ) ¹Q- - CH ( C6H5 ) — ; ¹Q- - CH2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -¹Q- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; Attorney Docket No .: 121843.002NU - 3200 PCT - ( CH2 ) 3 - C ( O ) ¹Q- - CH ( C6H5 ) — ; − ( CH2 ) 4 - C ( O ) ¹Q- - CH ( C6H5 ) — ; − ( CH2 ) 5 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 6 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 3 - ¹Q - CH2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; − ( CH2 ) 3 - O - ³Q - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 3 - O- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 3 - O- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( pyrid - 2 - yl ) — ; - ( CH2 ) 4 - ¹Q - CH ( C6H5 ) - ; - ( CH2 ) 5 - ¹Q - CH ( C6H5 ) - ; - ( CH2 ) 6 - ¹Q - CH ( pyrid - 2 - yl ) - ; - ( CH2 ) 7 - ¹Q - CH ( C6H5 ) - ; − ( CH2 ) 7 - ¹Q - CH ( Me ) -C ( O ) -N ( Me ) - ; -N ( H ) - ( CH2 ) 2 - O- ( CH2 ) 2 - ¹Q - CH ( Me ) -C ( O ) -N ( Me ) - ; - ( CH2 ) 3 - O- ( CH2 ) 2 - C ( O ) -¹Q- CH ( Me ) -C ( O ) -N ( Me ) - ; -N ( H ) - ( CH2 ) 2 - O- ( CH2 ) 2 - ¹Q - CH ( C6H5 ) — ; -N ( H ) - ( CH2 ) 2- [ O- ( CH2 ) 2 ] 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -N ( H ) - ( CH2 ) 2- [ 0- ( CH2 ) 2 ] 3 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -N ( H ) - ( CH2 ) 2- [ O- ( CH2 ) 2 ] 4 - C ( O ) ¹Q- - CH ( C6H5 ) — ; N− ( H ) - ( CH2 ) 2- [ O- ( CH2 ) 2 ] 5 - C ( O ) ¹Q- - CH ( C6H5 ) — ; N− ( H ) - ( CH2 ) 2- [ O- ( CH2 ) 2 ] 6 - C ( O ) ¹Q- - CH ( C6H5 ) — ; N− ( H ) - ( CH2 ) 2- [ O- ( CH2 ) 2 ] 7 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -N ( H ) - ( CH2 ) 2- [ O- ( CH2 ) 2 ] 8 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -N ( H ) ³Q- - 0- ( CH2 ) 2 - CH2- ; -N ( H ) - ( CH2 ) 3 - –¹Q ( CH2 ) —2 ; C– ( O ) N ( H ) [ ( CH2 ) 3 – O ] –3 ( CH2 ) -NH- ; -C ( O ) -N ( H ) - [ ( CH2 ) 3 - O ] –3 ( CH2 ) 2- ; ¹Q— – C ( O ) – [ ( CH2 ) 2 − O ] –3 ( CH2 ) 2 – –HN ; -¹Q- ( CH2 ) 3 - O - CH2- ; ¹Q- - C ( O ) - ( C6H6 ) -CH2- ; - 101 - 1100573566 5 AMERICAS -¹Q- ( 2 - pyridyl ) -O – –₂HC , ﻭ or Attorney Docket No .: 121843.002NU - 3200 PCT -N ( H ) ³Q- - X- ( 2 - pyridyl ) -0- , -NH -X- or -N ( H ) -Q3 - X- ( 4 - pyridyl ) - , or -NH -X- -N ( H ) - ( CH2 ) 2 - ³Q - X- ( 2 - pyridyl ) O– – –2HC , H .N . , or -NH -NH -CH = C- ( CH2 ) 2 - -¹Q ; -¹Q- ; -C ( O ) - ( CH2 - CH2 - O ) - ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -N ( H ) -C ( O ) - ( CH2 - CH2 - O ) 4- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; N− ( H ) -C ( O ) – ( CH2 - CH2 - O ) 5- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 - CH2-0 ) 5- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 - CH2 - O ) - ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 - CH2 - O ) 4- ( CH2 ) 2 – C ( O ) ¹Q— – CH ( C6H5 ) — ; - ( CH2 ) 4 - ¹Q - CH ( C6H5 ) - ; - ( CH2 ) 3 - ¹Q - CH ( C6H5 ) — ; - ( CH2 ) 6 - ¹Q - CH ( C6H5 ) — ; - ( CH2 ) 5 - ¹Q - CH ( C6H5 ) - ; - ( CH2 - CH2-0 ) - ( CH2 ) 2 - ¹Q - CH ( C6H5 ) - ; -C ( O ) - ( CH2 - CH2 - O ) 4- ( CH2 ) 2 - ¹Q - CH ( C6H5 ) — ; -C ( O ) - ( CH2 - CH2 - O ) 5- ( CH2 ) 2 - C ( O ) ¹Q— – CH ( C6H5 ) - ; -C ( O ) - ( CH2 - CH2 - O ) 6- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -C ( O ) - ( CH2 - CH2 - O ) 3- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; - ( CH2 ) 5 - C ( O ) ¹Q- - CH ( C6H5 ) - ; - ( CH2 - CH2 - O ) 3- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; N X. .N .

-NH or , - 102 - 1100573566 5 AMERICAS - ( CH2 ) 7 - C ( O ) ¹Q- - CH ( C6H5 ) — ; -C ( O ) -pyrimidine - ¹Q - C ( O ) ¹Q- - CH ( C6H5 ) — or -C ( O ) - ( CH2 ) -Q1-3 - pyridyl - C ( O ) ¹Q— - CH ( C6H5 ) - , -CH ( C6H5 ) — ; -C ( O ) -2 - pyridyl - ¹Q - CH2 - C ( O ) ¹Q- - CH ( C6H5 ) , .N . Q1 - CH ( C6H5 ) — -C ( O ) - ( CH2 ) ¹Q- - CH2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -C ( O ) - ( CH2 ) 2 - -¹Q ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; C– ( O ) – ( CH2 ) 9 – C ( O ) ¹Q– - CH ( C6H5 ) — ; -C ( O ) - ( CH2 ) 7 - C ( O ) ¹Q- - CH ( C6H5 ) - ; Attorney Docket No .: 121843.002NU - 3200 PCT N ' N 21 - CH ( C6H5 ) — ; .N .

¹Q - CH ( C 6 H 5 ) — , or ﻭ 1Q1 - CH ( C6H5 ) — or , -C ( O ) - ( CH2 ) 5 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -C ( O ) - ( CH2 - CH2 - O ) 2- ( CH2 ) 2 - C ( O ) ¹Q- - CH ( C6H5 ) - ; -C ( O ) -2 - pyridyl - ¹Q - C ( O ) ¹Q- - CH ( C6H5 ) — , -QCH3 ( C6H5 ) — -CH2 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 3 - C ( O ) ¹Q- - CH ( C6H5 ) — ; - ( CH2 ) 4 - C ( O ) ¹Q- - CH ( C6H5 ) - ; and CH3 ( C6H5 ) — or , - 103 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ¹Q- - 4 - pyridyl - ¹Q — CH ( C6H5 ) — , -Q ' . In some embodiments , X is oxygen or sulfur .

Q1 - CH ( C6H5 ) — ﻭ -Q1 - CH ( C6H5 ) — - or -Q [ 000117 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- selected from the group consisting of N , OH ﻭ and , www ( I ) or Formula ( II ) , L comprises at least one -¹Q- as N , N , In certain embodiments of Formula -☑ In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- as In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- as In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- as In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- as OH In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- as In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -¹Q- as - 104 - 1100573566 5 AMERICAS ﻭ Attorney Docket No .: 121843.002NU - 3200 PCT [ 000118 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one N n-²Q- according to m ﻭ wherein ³n is one or two . [ 000119 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one .N . -²Q- according to [ 000120 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one n -²Q- according to no ahum wherein ¹n is one or two , ³n is one or two , and ºn is one or two . , [ 000121 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one H -²Q- according to [ 000122 ] or In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -²Q- according to wherein n8 is one or two . [ 000123 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -²Q- according to N [ 000124 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one ntal n -²Q- according to n18 is three and n19 is two .

-N , wherein n18 and n19 is two , or n18 is two and n19 is three , or - 105 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000125 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -N . -²Q- according to [ 000126 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one n -²Q- according to nﻭ wherein ²²n is zero to two ; n23 is zero to two , and n24 is one or two , or wherein ²²n is two and each n23 and n24 is one ; or n22 is two and each n23 and n24 is two . [ 000127 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -²Q- according to [ 000128 ] N N- ﻭ DO or In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -²Q- according to [ 000129 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one ww ²n -³Q- according to ww wherein ¹n is one or two , and ²n is one or two . , [ 000130 ] In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one www wwwwww -³Q- selected from the group consisting of , wh and , In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at least one -³Q- as least In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at one - 106 - 1100573566 5 AMERICAS -³Q- as www least one -³Q- as Attorney Docket No .: 121843.002NU - 3200 PCT In certain embodiments of Formula ( I ) or Formula ( II ) , L comprises at comprises at least one -³Q- as In certain embodiments of Formula ( I ) or Formula ( II ) , L Pharmaceutical Compositions [ 000131 ] The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier , diluent , adjuvant , or vehicle . In one embodiment , this disclosure provides a pharmaceutical composition comprising one or more compounds described herein , and a pharmaceutically acceptable carrier , diluent , adjuvant , or vehicle . In one embodiment , this disclosure provides a pharmaceutical composition comprising an effective amount of one or more compounds of this disclosure , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier , diluent , adjuvant , or vehicle . Pharmaceutically acceptable carriers include , for example , pharmaceutical diluents , excipients , or carriers suitably selected with respect to the intended form of administration , and consistent with conventional pharmaceutical practices . [ 000132 ] According to another embodiment , this description provides a composition comprising one or more compounds herein , or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier , adjuvant , or vehicle . Pharmaceutical compositions of this description comprise a therapeutically effective amount of one or more compounds of Formula ( I ) or ( II ) , wherein a " therapeutically effective amount " is an amount that is ( a ) effective to measurably degrade BRAF ( or reduce the amount of BRAF ) in a biological sample or in a patient ; or ( b ) effective in treating and / or ameliorating a disease or disorder that is mediated by BRAF . [ 000133 ] It will also be appreciated that certain compounds of this disclosure can exist in free form ( e.g. , a neutral compound ) for treatment , or where appropriate , as a pharmaceutically acceptable derivative ( e.g. , a salt ) thereof . According to this disclosure , a pharmaceutically acceptable derivative includes , but is not limited to , pharmaceutically acceptable prodrugs , salts , esters , salts of such esters , or any other adduct / educt or derivative that upon - 107 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT administration to a patient in need is capable of providing , directly or indirectly , one or more compounds as otherwise described herein , or a metabolite , or residue thereof . [ 000134 ] As used herein , the term " pharmaceutically acceptable salt " refers to those salts that are , within the scope of sound medical practice or judgment , suitable for use in contact with cells , tissues , and / or the tissues of humans and lower animals without undue toxicity , irritation , allergic response , and the like . [ 000135 ] Pharmaceutically acceptable salts are well known in the art . For example , S. M. Berge et al . describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977 , 66 , 1-19 , incorporated herein by reference . Pharmaceutically acceptable salts of the compounds of this description include those derived from suitable inorganic and organic acids and bases . Examples of pharmaceutically acceptable , nontoxic acid addition salts include salts of an amino group formed with inorganic acids such as hydrochloric acid , hydrobromic acid , phosphoric acid , sulfuric acid , and perchloric acid ; or with organic acids such as acetic acid , oxalic acid , maleic acid , tartaric acid , citric acid , succinic acid , or malonic acid ; or by using other methods used in the art such as ion exchange . Other pharmaceutically acceptable salts include adipate , alginate , ascorbate , aspartate , benzenesulfonate , benzoate , bisulfate , borate , butyrate , camphorate , camphorsulfonate , citrate , cyclopentanepropionate , digluconate , dodecylsulfate , ethanesulfonate , formate , fumarate , glucoheptonate , glycerophosphate , gluconate , hemisulfate , heptanoate , hexanoate , hydroiodide , 2 - hydroxy - ethanesulfonate , lactobionate , lactate , laurate , lauryl sulfate , malate , maleate , malonate , methanesulfonate , 2- naphthalenesulfonate , nicotinate , nitrate , oleate , oxalate , palmitate , pamoate , pectinate , persulfate , 3 - phenylpropionate , phosphate , picrate , pivalate , propionate , stearate , succinate , sulfate , tartrate , thiocyanate , p - toluenesulfonate , undecanoate , and valerate salts , and the like . Salts derived from appropriate bases include alkali metal , alkaline earth metal , ammonium ( NH4 ) , and N ( C1-4 alkyl ) 4 salts . This description also envisions the quaternization of any basic nitrogen - containing groups of the compounds disclosed herein . Water or oil - soluble or dispersable products may be obtained by such quaternization . Representative alkali or alkaline earth metal salts include sodium , lithium , potassium , calcium , magnesium , and the like . Further pharmaceutically acceptable salts include , when appropriate , nontoxic ammonium , quaternary ammonium , and amine cations formed using counterions such as halide , hydroxide , carboxylate , sulfate , phosphate , nitrate , lower alkyl sulfonate , and aryl sulfonate . - 108 - 1100573566 5 AMERICAS [ 000136 ] Attorney Docket No .: 121843.002NU - 3200 PCT A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds described herein . The pharmaceutically acceptable carriers should be biocompatible , for example , non - toxic , non - inflammatory , non- immunogenic , and / or devoid of other undesired reactions or side - effects upon administration to a subject . Standard pharmaceutical formulation techniques can be employed . [ 000137 ] The pharmaceutically acceptable carrier , adjuvant , or vehicle , as used herein , includes any and all solvents , diluents , or other liquid vehicle , dispersion , or suspension aids , surface active agents , isotonic agents , thickening or emulsifying agents , preservatives , solid binders , lubricants , and the like , as suited to the particular dosage form desired . Remington's Pharmaceutical Sciences , Sixteenth Edition , E. W. Martin ( Mack Publishing Co. , Easton , Pa . , 1980 ) discloses various carriers used in formulating pharmaceutically acceptable compositions , and known techniques for the preparation thereof . Except insofar as any conventional carrier medium is incompatible with the compounds described herein , such as by producing any undesirable biological effect , or otherwise interacting in a deleterious manner with any other component ( s ) of the pharmaceutically acceptable composition , the use of such conventional carrier medium is contemplated to be within the scope of this description . As used herein , the phrase " side effects " encompasses unwanted and adverse effects of a therapy ( e.g. , a prophylactic or therapeutic agent ) . Side effects are usually unwanted , but unwanted effects are not necessarily adverse or unbeneficial . An adverse effect from a therapy ( e.g. , prophylactic or therapeutic agent ) might be harmful , uncomfortable , or risky . Side effects include , but are not limited to , fever , chills , lethargy , gastrointestinal toxicities ( including gastric and intestinal ulcerations and erosions ) , nausea , vomiting , neurotoxicities , nephrotoxicities or renal toxicities ( including such conditions as papillary necrosis and chronic interstitial nephritis ) , hepatic toxicities ( including elevated serum liver enzyme levels ) , myelotoxicities ( including leukopenia , myelosuppression , thrombocytopenia , and anemia ) , dry mouth , metallic taste , prolongation of gestation , weakness , somnolence , pain ( including muscle pain , bone pain , and headache ) , hair loss , asthenia , dizziness , extra - pyramidal symptoms , akathisia , cardiovascular disturbances , and sexual dysfunction . [ 000138 ] Some examples of materials that can serve as pharmaceutically acceptable carriers include , but are not limited to , ion exchangers , alumina , aluminum stearate , lecithin , serum proteins ( such as human serum albumin ) , buffer substances ( such as Tween 80 , phosphates , glycine , sorbic acid , or potassium sorbate ) , partial glyceride mixtures of saturated vegetable fatty acids , water , salts or electrolytes ( such as protamine sulfate , disodium hydrogen - 109 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT phosphate , potassium hydrogen phosphate , sodium chloride , or zinc salts ) , colloidal silica , magnesium trisilicate , polyvinyl pyrrolidone , polyacrylates , waxes , polyethylene- polyoxypropylene - block polymers , methylcellulose , hydroxypropyl methylcellulose , wool fat , sugars such as lactose , glucose , and sucrose ; starches such as corn starch and potato starch ; cellulose and its derivatives such as sodium carboxymethyl cellulose , ethyl cellulose , and cellulose acetate ; powdered tragacanth ; malt ; gelatin ; talc ; excipients such as cocoa butter and suppository waxes ; oils such as peanut oil , cottonseed oil , safflower oil , sesame oil , olive oil , corn oil , and soybean oil ; glycols such as propylene glycol or polyethylene glycol ; esters such as ethyl oleate and ethyl laurate ; agar ; buffering agents such as magnesium hydroxide and aluminum hydroxide ; alginic acid ; pyrogen - free water ; isotonic saline ; Ringer's solution ; ethyl alcohol , and phosphate buffer solutions , as well as other non - toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate , as well as coloring agents , releasing agents , coating agents , sweetening , flavoring , and perfuming agents . Preservatives and antioxidants can also be present in the composition , according to the judgment of the formulator . [ 000139 ] As used herein , the term " measurably degrade " means a measurable reduction in ( a ) BRAF activity , between a sample comprising one or more compounds of this description and BRAF versus an equivalent sample comprising BRAF in the absence of said compound ( s ) ; or ( b ) the concentration of BRAF in a sample over time .

Administration [ 000140 ] The compositions of this disclosure may be administered orally , parenterally , via inhalation spray , topically , rectally , nasally , buccally , vaginally , or via an implanted reservoir . As used herein , the term " parenteral " includes subcutaneous , intravenous , intramuscular , intra - articular , intra - synovial , intrasternal , intrathecal , intraocular , intrahepatic , intralesional , and intracranial injection or infusion techniques . Compositions can be administered orally , intraperitoneally , or intravenously . Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension . These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents . The sterile injectable preparation may also be a sterile injectable solution or suspension in a non - toxic parenterally - acceptable diluent or solvent , for example , as a solution in 1,3 - butanediol . Among the acceptable vehicles and solvents that may be employed are water , Ringer's solution , and isotonic sodium chloride solution . In addition , sterile , fixed oils are conventionally employed as a solvent or suspending medium . - 110 - 1100573566 5 AMERICAS [ 000141 ] Attorney Docket No .: 121843.002NU - 3200 PCT For this purpose , any bland fixed oil may be employed including synthetic mono- or di - glycerides . Fatty acids , such as oleic acid and its glyceride derivatives , are useful in the preparation of injectables , as are natural pharmaceutically acceptable oils , such as olive oil or castor oil , especially in their polyoxyethylated versions . These oil solutions or suspensions may also contain a long - chain alcohol diluent or dispersant , such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions . Other commonly used surfactants , such as Tweens , Spans , and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid , liquid , or other dosage forms may also be used for the purposes of formulation . [ 000142 ] The pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including , but not limited to , capsules , tablets , aqueous suspensions , or solutions . In the case of tablets for oral use , carriers commonly used include lactose and corn starch . Lubricating agents , such as magnesium stearate , are also typically added . For oral administration in a capsule form , useful diluents include lactose and dried cornstarch . When aqueous suspensions are required for oral use , the active ingredient is combined with emulsifying and suspending agents . If desired , certain sweetening , flavoring , or coloring agents may also be added . [ 000143 ] Alternatively , the pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration . These can be prepared by mixing the agent with a suitable non - irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vaginal cavity to release the drug . Such materials include cocoa butter , polyethylene glycol , or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound . [ 000144 ] The pharmaceutically acceptable compositions of this disclosure may also be administered topically , especially when the target of treatment includes areas or organs readily accessible by topical application , including diseases of the eye , skin , or lower intestinal tract . Suitable topical formulations are readily prepared for each of these areas or organs . - 111 - 1100573566 5 AMERICAS [ 000145 ] Attorney Docket No .: 121843.002NU - 3200 PCT Topical application for the lower intestinal tract can be via a rectal suppository formulation ( see above ) or in a suitable enema formulation . Topically - transdermal patches may also be used . [ 000146 ] For topical applications , the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers . Carriers for topical administration of the compounds of this disclosure include , but are not limited to , mineral oil , liquid petrolatum , white petrolatum , propylene glycol , polyoxyethylene , polyoxypropylene compound , emulsifying wax , and water . Alternatively , the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers . Suitable carriers include , but are not limited to , mineral oil , sorbitan monostearate , polysorbate 60 , cetyl esters wax , cetearyl alcohol , 2 - octyldodecanol , benzyl alcohol , and water . [ 000147 ] For ophthalmic use , the pharmaceutically acceptable compositions may be formulated , for example , as micronized suspensions in isotonic , pH adjusted sterile saline or other aqueous solution , or as solutions in isotonic , pH adjusted sterile saline or other aqueous solution , either with or without a preservative such as benzylalkonium chloride . Alternatively , for ophthalmic uses , the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum . The pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation . Such compositions are prepared according to techniques well - known in the art of pharmaceutical formulation and may be prepared as solutions in saline , employing benzyl alcohol or other suitable preservatives , absorption promoters to enhance bioavailability , fluorocarbons , and / or other conventional solubilizing or dispersing agents . [ 000148 ] In certain embodiments , the compositions of this disclosure are administered orally . The pharmaceutically acceptable compositions of this description may be orally administered in any orally acceptable dosage form including , but not limited to , capsules , tablets , aqueous suspensions , or solutions . In the case of tablets for oral use , carriers commonly used include lactose and corn starch . Lubricating agents , such as magnesium stearate , are also typically added . For oral administration in a capsule form , useful diluents include lactose and dried cornstarch . When aqueous suspensions are required for oral use , the active ingredient is -112- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT combined with emulsifying and suspending agents . If desired , certain sweetening , flavoring , or coloring agents may also be added . [ 000149 ] Liquid dosage forms for oral administration include , but are not limited to , pharmaceutically acceptable emulsions , microemulsions , solutions , suspensions , syrups , and elixirs . In addition to the biologically active compounds herein , the liquid dosage forms may contain inert diluents commonly used in the art , for example , water or other solvents , solubilizing agents and emulsifiers such as ethyl alcohol , isopropyl alcohol , ethyl carbonate , ethyl acetate , benzyl alcohol , benzyl benzoate , propylene glycol , 1,3 - butylene glycol , dimethylformamide , oils ( in particular , cottonseed , groundnut , corn , germ , olive , castor , and sesame oils ) , glycerol , tetrahydrofurfuryl alcohol , polyethylene glycols and fatty acid esters of sorbitan , and mixtures thereof . Besides inert diluents , the oral compositions can also include adjuvants such as wetting agents , emulsifying and suspending agents , sweetening , flavoring , and perfuming agents . [ 000150 ] Solid dosage forms for oral administration include capsules , tablets , pills , powders , and granules . In such solid dosage forms , the biologically active compound ( s ) described herein are mixed with at least one inert , pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate , and / or a ) fillers or extenders such as starches , lactose , sucrose , glucose , mannitol , and silicic acid ; b ) binders such as carboxymethylcellulose , alginates , gelatin , polyvinylpyrrolidinone , sucrose , and acacia ; c ) humectants such as glycerol ; d ) disintegrating agents such as agar - agar , calcium carbonate , potato or tapioca starch , alginic acid , certain silicates , and sodium carbonate ; e ) solution retarding agents such as paraffin ; f ) absorption accelerators such as quaternary ammonium compounds ; g ) wetting agents , for example , cetyl alcohol and glycerol monostearate ; h ) absorbents such as kaolin and bentonite clay ; and i ) lubricants such as talc , calcium stearate , magnesium stearate , solid polyethylene glycols , sodium lauryl sulfate , and mixtures thereof . In the case of capsules , tablets , and pills , the dosage form may also comprise buffering agents . [ 000151 ] Solid compositions of a similar type may also be employed as fillers in soft and hard - filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like . The solid dosage forms of tablets , dragees , capsules , pills , and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art . Solid dosage forms optionally may contain opacifying agents . These solid dosage forms can also be of a - 113 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT composition such that they release the active ingredient ( s ) only , for example , in a certain part of the intestinal tract , optionally in a delayed manner . Examples of embedding compositions that can be used include polymeric substances and waxes . Solid compositions of a similar type may also be employed as fillers in soft and hard - filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like . [ 000152 ] The active compounds herein can also be in micro - encapsulated form with one or more excipients as noted above . The solid dosage forms of tablets , dragees , capsules , pills , and granules can be prepared with coatings and shells such as enteric coatings , release controlling coatings , and other coatings well known in the pharmaceutical formulating art . In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose , lactose , or starch . Such dosage forms may also comprise , as is normal practice , additional substances other than inert diluents , for example , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose . In the case of capsules , tablets , and pills , the dosage forms may also comprise buffering agents . They may optionally contain opacifying agents and can also be of a composition such that they release the active ingredient ( s ) only , for example , in a certain part of the intestinal tract , optionally in a delayed manner . Examples of embedding compositions that can be used include polymeric substances and waxes . [ 000153 ] The compounds of the description are formulated in dosage unit form for ease of administration and uniformity of dosage . As used herein , the phrase " dosage unit form " refers to a physically discrete unit of agent appropriate for the subject , cell , tissue , or patient to be treated . It will be understood , however , that the total daily usage of the compounds , and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment . The specific effective dose level for any particular subject , cell , tissue , patient , or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder ; the activity of the specific compound ( s ) employed ; the specific composition ( s ) employed ; the age , body weight , general health , sex , and diet of the subject , cell , tissue , and / or patient ; the time of administration , route of administration , and rate of excretion of the specific compound ( s ) employed ; the duration of the treatment ; drugs used in combination or coincidental with the specific compound ( s ) employed , and like factors well known in the medical arts . - 114 - 1100573566 5 AMERICAS [ 000154 ] Attorney Docket No .: 121843.002NU - 3200 PCT The amount of the compounds of this disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the subject , cell , tissue , and / or host treated , the particular mode of administration , and other factors . The compositions should be formulated so that a dosage of between 0.01 -100 mg / kg body weight / day of the compound ( s ) or inhibitor ( s ) can be administered to a subject , cell , tissue , and / or patient receiving these compositions . [ 000155 ] Depending upon the particular condition or disease to be treated or prevented , additional therapeutic agents , which are normally administered to treat or prevent that condition , may also be present in the compositions of this disclosure . As used herein , additional therapeutic agents that are normally administered to treat or prevent a particular disease , or condition , are known as " appropriate for the disease , or condition , being treated . " [ 000156 ] The compound or composition can be administered concurrently with , prior to , or subsequent to , one or more additional therapeutically active agents . In general , each agent will be administered at a dose and / or on a time schedule determined for that agent . It will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different composition . The particular combination to employ in a regimen will take into account compatibility of the compounds described herein with the additional therapeutically active agent and / or the desired therapeutic effect to be achieved . In general , it is expected that additional therapeutically active agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually . In some embodiments , the levels utilized in combination will be lower than those utilized individually . Additional therapeutically active agents include , but are not limited to , small organic molecules such as drug compounds ( e.g. , compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations ( CFR ) ) , peptides , proteins , carbohydrates , monosaccharides , oligosaccharides , polysaccharides , nucleoproteins , mucoproteins , lipoproteins , synthetic polypeptides or proteins , small molecules linked to proteins , glycoproteins , steroids , nucleic acids , DNAs , acids , DNAs , RNAs , nucleotides , nucleosides , oligonucleotides , antisense oligonucleotides , lipids , hormones , vitamins , and cells . In certain embodiments , the additional therapeutically active agent is a cancer agent ( e.g. , a biotherapeutic or chemo therapeutic cancer agent ) . In other embodiments , the additional therapeutically active agent is an anti - inflammatory agent . - 115 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000157 ] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent . The amount of additional therapeutic agent in the presently disclosed compositions will range from about 50 % to 100 % of the amount normally present in a composition comprising that agent as the only therapeutically active agent .

Methods of Use [ 000158 ] The bifunctional compounds described herein are useful for degrading BRAF in biological samples , or in patients via a ubiquitin proteolytic pathway . Thus , an embodiment of this disclosure provides a method of treating a BRAF - mediated disease or disorder . As used herein , the term " BRAF - mediated disease or disorder " means any disease , disorder , or other deleterious condition in which BRAF is known to play a role . In some instances , an BRAF- mediated disease or disorder is a proliferative disorder or an autoimmune disorder . Examples of proliferative disorders include cancer . [ 000159 ] In one aspect , provided herein are methods of treating or preventing cancer in a subject in need thereof . In certain embodiments , the methods comprise the step of orally administering to the subject an amount of a bifunctional compounds ( s ) described herein capable of inducing proteolytic degradation of BRAF . In certain embodiments , the amount is effective to treat or prevent the cancer . [ 000160 ] In certain embodiments , the cancer is any cancer described below . In particular embodiments , the cancer comprises a solid tumor . In certain embodiments , the cancer is a B cell malignancy . In certain embodiments , the cancer is selected from the group consisting of chronic lymphocytic leukemia ( CLL ) , small lymphocytic lymphoma ( SLL ) , transformed CLL or Richter's transformation , small cell lymphoma , follicular lymphoma ( FL ) , diffuse large B- cell lymphoma ( DLBCL ) , non - Hodgkin lymphoma , mantle cell lymphoma ( MCL ) , marginal zone lymphoma ( MZL ) , Waldenstrom macroglobulinemia ( WM ) , and central nervous system ( CNS ) lymphoma . In certain embodiments , the cancer is chronic lymphocytic leukemia . In certain embodiments , the cancer is small cell lymphoma . In certain embodiments , the cancer is follicular lymphoma . In certain embodiments , the cancer is diffuse large B - cell lymphoma . In certain embodiments , the cancer is non - Hodgkin lymphoma . In certain embodiments , the cancer is mantle cell lymphoma . In certain embodiments , the cancer is marginal zone lymphoma . In certain embodiments , the cancer is Waldenstrom macroglobulinemia . In certain - 116 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT embodiments , the cancer is small lymphocytic lymphoma ( SLL ) . In certain embodiments , the cancer is CNS lymphoma . In certain embodiments , the cancer is transformed CLL or Richter's transformation . In certain embodiments , the cancer is chronic lymphocytic leukemia ( CLL ) . [ 000161 ] In another aspect , provided herein are methods of degrading BRAF in a subject in need thereof . The methods comprise the step of orally administering to the subject an amount of a bifunctional compound ( s ) described herein and capable of inducing proteolytic degradation of BRAF . In certain embodiments , the amount is effective to degrade BRAF in the subject . The BRAF can be expressed in any cells or tissues of the subject . [ 000162 ] In another aspect , provided herein are methods of preventing B cell activation in a subject in need thereof . The methods comprise the step of orally administering to the subject an amount of a bifunctional compound ( s ) described herein and capable of inducing proteolytic degradation of BRAF . In certain embodiments , the amount is effective to prevent B cell activation . In certain embodiments , the B cell expresses CD69 . In certain embodiments , the B cell expresses CD86 . In certain embodiments , the B cell expresses CD69 and CD86 . [ 000163 ] In the methods , the bifunctional compound ( s ) described herein comprise a moiety capable of specifically binding BRAF and further comprise a moiety capable of recruiting a ubiquitin ligase to degrade the BRAF . Particular compounds with each capability are described herein . The compounds can be administered in any form , including pharmaceutically acceptable salts and pharmaceutical compositions . [ 000164 ] The bifunctional compound ( s ) described herein can be administered in any dose deemed suitable by the practitioner of skill . In certain embodiments , the dose is 0.1-10mg / kg . In certain embodiments , the dose is 0.1-900 mg / kg . In certain embodiments , the dose is 0.1-800 mg / kg . In certain embodiments , the dose is 0.1-700 mg / kg . In certain embodiments , the dose is 0.1-600 mg / kg . In certain embodiments , the dose is 0.1-500 mg / kg . In certain embodiments , the dose is 0.1-400 mg / kg . In certain embodiments , the dose is 0.1-300 mg / kg . In certain embodiments , the dose is 0.1-200 mg / kg . In certain embodiments , the dose is 0.1- 100 mg / kg . In certain embodiments , the dose is selected from the group consisting of 1mg / kg , 200 mg / kg , 300 mg / kg , 450 mg / kg , 600 mg / kg , 800 mg / kg , and 1000 mg / kg . In certain embodiments , the dose is about 25 mg / kg . In certain embodiments , the dose is about 50 mg / kg . In certain embodiments , the dose is about 75 mg / kg . In certain embodiments , the dose is about 100 mg / kg . In certain embodiments , the dose is about 150 mg / kg . In certain embodiments , the dose is about 200 mg / kg . In certain embodiments , the dose is about 250 mg / kg . In certain - 117- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT embodiments , the dose is about 300 mg / kg . In certain embodiments , the dose is about 4mg / kg . In certain embodiments , the dose is about 450 mg / kg . In certain embodiments , the dose is about 500 mg / kg . In certain embodiments , the dose is about 600 mg / kg . In certain embodiments , the dose is about 700 mg / kg . In certain embodiments , the dose is about 7mg / kg . In certain embodiments , the dose is about 800 mg / kg . In certain embodiments , the dose is about 900 mg / kg . In certain embodiments , the dose is about 1000 mg / kg . [ 000165 ] The dose can be administered on a schedule deemed suitable by the person of skill in the art . In certain embodiments , the dose is administered once per day . In certain embodiments , the dose is administered twice per day . In certain embodiments , the dose is administered three times per day . In certain embodiments , the dose is administered four times per day . In certain embodiments , the dose is administered in divided doses . In certain embodiments , the dose is administered in two divided doses per day . In certain embodiments , the dose is administered in three divided doses per day . In certain embodiments , the dose is administered in four divided doses per day . [ 000166 ] Dosing can continue for any length of time deemed suitable by the person of skill in the art . In certain embodiments , the dose is administered daily for fourteen days . In certain embodiments , the dose is administered daily for thirteen days . In certain embodiments , the dose is administered daily for twelve days . In certain embodiments , the dose is administered daily for eleven days . In certain embodiments , the dose is administered daily for ten days . In certain embodiments , the dose is administered daily for nine days . In certain embodiments , the dose is administered daily for eight days . In certain embodiments , the dose is administered daily for seven days . In certain embodiments , the dose is administered daily for six days . In certain embodiments , the dose is administered daily for five days . In certain embodiments , the dose is administered daily for four days . In certain embodiments , the dose is administered daily for three days . In certain embodiments , the dose is administered daily for two days . In certain embodiments , the dose is administered for one day . [ 000167 ] In the dosing schedule , the doses can be administered on consecutive days or cyclicly , according to the judgment of the practitioner of skill . In certain embodiments , the doses are administered on consecutive days . In certain embodiments , the doses are administered with an interval between doses . In certain embodiments , the interval is one day . In certain embodiments , the interval is two days . In certain embodiments , the interval is three - 118 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT days . In certain embodiments , the interval is four days . In certain embodiments , the interval is five days . In certain embodiments , the interval is six days . [ 000168 ] In certain embodiments , the dose is administered weekly . In certain embodiments , the dose is administered twice per week . In certain embodiments , the dose is administered three times per week . [ 000169 ] In certain embodiments , the dose ( s ) are administered for a period of time with a first interval between dose ( s ) , and then the dose ( s ) are re - administered for a period of time following the first interval between dose ( s ) , wherein this dosing regimen can be repeated ( i.e. , cyclicly or cyclically , for example , after a second , third , etc. interval between subsequent administrations of dose ( s ) ) according to the judgment of the practitioner of skill . For example , in one embodiment , a first dose is administered for one week , followed by a first interval of one week without the first dose administration ; then , a second dose is re - administered for another week , followed by a second interval of one week without the first or second dose administration , and so on cyclically . Other perturbations for first , second , third , etc. dose ( s ) followed by perturbations for first , second , third , etc. interval ( s ) , and combinations thereof , are contemplated herein as would be appreciated by the practitioner of skill and the need of the subject , cell , tissue , and / or patient . For example , in one embodiment , a first dose is administered daily for one week , followed by a first interval of three weeks without the first daily dose administration ; then , a second dose is re - administered biweekly for another week , followed by a second interval of four weeks without the first daily or second biweekly dose administration , and so on cyclically . [ 000170 ] The compound can be administered by any route of administration deemed suitable by the practioner of skill . In certain embodiments , the dose is administered orally . Formulations and techniques for administration are described elsewhere herein . [ 000171 ] In certain embodiments , term " cancer " includes , but is not limited to , the following cancers : epidermoid Oral : buccal cavity , lip , tongue , mouth , pharynx , squamous cell carcinoma of the head and neck ( HNSCC ) ; Cardiac : sarcoma ( angiosarcoma , fibrosarcoma , rhabdomyosarcoma , liposarcoma ) , myxoma , rhabdomyoma , fibroma , lipoma , and teratoma ; Lung : bronchogenic carcinoma ( squamous cell or epidermoid , undifferentiated small cell , undifferentiated large cell , adenocarcinoma ) , alveolar ( bronchiolar ) carcinoma , bronchial adenoma , sarcoma , lymphoma , chondromatous hamartoma , mesothelioma , non - small cell lung cancer ( NSCLC ) ; Gastrointestinal : gastric cancer , esophagus ( squamous cell carcinoma , - 119 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT larynx , adenocarcinoma , leiomyosarcoma , lymphoma ) , stomach ( carcinoma , lymphoma , leiomyosarcoma ) , pancreas ( ductal adenocarcinoma , insulinoma , glucagonoma , gastrinoma , carcinoid tumors , vipoma ) , small bowel or small intestines ( adenocarcinoma , lymphoma , carcinoid tumors , Karposi's sarcoma , leiomyoma , hemangioma , lipoma , neurofibroma , fibroma ) , large bowel or large intestines ( adenocarcinoma , tubular adenoma , villous adenoma , hamartoma , leiomyoma ) , colon , colon - rectum , colorectal , microsatellite stable colorectal cancer ( MSS CRC ) , rectum ; Genitourinary tract : kidney ( adenocarcinoma , Wilm's tumor ( nephroblastoma ) , lymphoma , leukemia ) , bladder and urethra ( squamous cell carcinoma , transitional cell carcinoma , adenocarcinoma ) , prostate ( adenocarcinoma , sarcoma ) , testis ( seminoma , teratoma , embryonal carcinoma , teratocarcinoma , choriocarcinoma , sarcoma , interstitial cell carcinoma , fibroma , fibroadenoma , adenomatoid tumors , lipoma ) , metastatic castrate - resistant prostate cancer ( mCRPC ) , muscle - invasive urothelial cancer ; Liver : hepatoma ( hepatocellular carcinoma ) , cholangiocarcinoma , hepatoblastoma , angiosarcoma , hepatocellular adenoma , hemangioma , biliary passages ; Bone : osteogenic sarcoma ( osteosarcoma ) , fibrosarcoma , malignant fibrous histiocytoma , chondrosarcoma , Ewing's sarcoma , malignant lymphoma ( reticulum cell sarcoma ) , multiple myeloma ( MM ) , malignant giant cell tumor chordoma , osteochronfroma ( osteocartilaginous exostoses ) , benign chondroma , chondroblastoma , chondromyxofibroma , osteoid osteoma and giant cell tumors ; Nervous system : skull ( osteoma , hemangioma , granuloma , xanthoma , osteitis deformans ) , meninges ( meningioma , meningiosarcoma , gliomatosis ) , brain ( astrocytoma , medulloblastoma , glioma , ependymoma , germinoma ( pinealoma ) , glioblastoma multiform , oligodendroglioma , schwannoma , retinoblastoma , congenital tumors ) , spinal cord neurofibroma , meningioma , glioma , sarcoma ) ; Gynecological : uterus ( endometrial carcinoma ) , cervix ( cervical cancer , cervical carcinoma , pre - tumor cervical dysplasia ) , ovaries ( ovarian carcinoma ( serous cystadenocarcinoma , mucinous cystadenocarcinoma , unclassified carcinoma ) , granulosa - thecal cell tumors , Sertoli - Leydig cell tumors , dysgerminoma , malignant teratoma ) , vulva ( squamous cell carcinoma , intraepithelial carcinoma , adenocarcinoma , fibrosarcoma , melanoma ) , vagina ( clear cell carcinoma , squamous cell carcinoma , botryoid sarcoma ( embryonal rhabdomyosarcoma ) , fallopian tubes ( carcinoma ) , breast , triple - negative breast cancer ( TNBC ) , platinum - resistant epithelial ovarian cancer ( EOC ) ; Hematologic : blood ( myeloid leukemia ( acute and chronic ) , acute lymphoblastic leukemia , chronic lymphocytic leukemia , myeloproliferative diseases , multiple myeloma , myelodysplastic syndrome ) , Hodgkin's disease , non - Hodgkin's lymphoma ( malignant - 120 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT lymphoma ) hairy cell ; lymphoid disorders ( e.g. , mantle cell lymphoma , s'mörtsnedlaW macroglobulinemia , Marginal zone lymphoma , and Follicular lymphoma ) ; Skin : malilymphgnant melanoma , basal cell carcinoma , squamous cell carcinoma , Karposi's sarcoma , keratoacanthoma , moles or dysplastic nevi , lipoma , angioma , dermatofibroma , keloids , psoriasis ; Thyroid gland : papillary thyroid carcinoma , follicular thyroid carcinoma ; medullary thyroid carcinoma , undifferentiated thyroid cancer , multiple endocrine neoplasia type 2A , multiple endocrine neoplasia type 2B , familial medullary thyroid cancer , pheochromocytoma , paraganglioma ; Adrenal glands : neuroblastoma ; and metatstaic melanoma . [ 000172 ] In certain embodiments , the term " autoimmune disease " includes , but is not limited to , the following autoimmune diseases : uticaria , graft - versus - host disease ( GVHD ) , acute graft - versus - host disease , pemphigus vulgaris , achalasia , Addison's disease , Adult Still's disease , agammaglobulinemia , alopecia areata , amyloidosis , ankylosing spondylitis , anti- GBM / anti - TBM nephritis , antiphospholipid syndrome , autoimmune angioedema , autoimmune dysautonomia , autoimmune encephalomyelitis , autoimmune hepatitis , autoimmune inner ear disease ( AIED ) , autoimmune myocarditis , autoimmune oophoritis , autoimmune orchitis , autoimmune pancreatitis , autoimmune retinopathy , axonal and neuronal neuropathy ( AMAN ) , ólaB disease , Behcet's disease , benign mucosal pemphigoid , bullous pemphigoid , Castleman disease ( CD ) , Celiac disease , Chagas disease , chronic inflammatory demyelinating polyneuropathy ( CIDP ) , chronic recurrent multifocal osteomyelitis ( CRMO ) , Churg - Strauss Syndrome ( CSS ) or Eosinophilic Granulomatosis ( EGPA ) , cicatricial pemphigoid , Cogan's syndrome , cold agglutinin disease , congenital heart block , coxsackie myocarditis , CREST syndrome , Crohn's disease , dermatitis herpetiformis , dermatomyositis , Devic's disease ( neuromyelitis optica ) , discoid lupus , Dressler's syndrome , endometriosis , eosinophilic esophagitis ( EoE ) , eosinophilic fasciitis , erythema nodosum , essential mixed cryoglobulinemia , Evans syndrome , fibromyalgia , fibrosing alveolitis , giant cell arteritis ( temporal arteritis ) , giant cell myocarditis , glomerulonephritis , Goodpasture's syndrome , granulomatosis with polyangiitis , Graves ' disease , Guillain - Barre syndrome , Hashimoto's thyroiditis , hemolytic anemia , Henoch - Schonlein purpura ( HSP ) , herpes gestationis or pemphigoid gestationis ( PG ) , hidradenitis suppurativa ( HS ) ( Acne Inversa ) , hypogammal globulinemia , IgA nephropathy , IgG4 - related sclerosing disease , immune thrombocytopenic purpura ( ITP ) , inclusion body myositis ( IBM ) , interstitial cystitis ( IC ) , juvenile arthritis , juvenile diabetes ( Type 1 diabetes ) , juvenile myositis ( JM ) , Kawasaki -121- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT disease , Lambert - Eaton syndrome , leukocytoclastic vasculitis , lichen planus , lichen sclerosus , ligneous conjunctivitis , linear IgA disease ( LAD ) , lupus , lyme disease ( chronic ) , Meniere's disease , microscopic polyangiitis ( MPA ) , mixed connective tissue disease ( MCTD ) , Mooren's ulcer , Mucha - Habermann disease , Multifocal Motor Neuropathy ( MMN ) or MMNCB , multiple sclerosis , myasthenia gravis , myositis , narcolepsy , neonatal lupus , neuromyelitis optica , neutropenia , ocular cicatricial pemphigoid , optic neuritis , palindromic rheumatism ( PR ) , PANDAS , paraneoplastic cerebellar degeneration ( PCD ) , paroxysmal nocturnal hemoglobinuria ( PNH ) , Parry Romberg syndrome , pars planitis ( peripheral uveitis ) , Parsonnage - Turner syndrome , pemphigus , peripheral neuropathy , perivenous encephalomyelitis , pernicious anemia ( PA ) , POEMS syndrome , polyarteritis nodosa , polyglandular syndromes type I , II , or III , polymyalgia rheumatica , polymyositis , postmyocardial infarction syndrome , postpericardiotomy syndrome , primary biliary cirrhosis , primary sclerosing cholangitis , progesterone dermatitis , psoriasis , psoriatic arthritis , pure red cell aplasia ( PRCA ) , pyoderma gangrenosum , Raynaud's phenomenon , reactive arthritis , reflex sympathetic dystrophy , relapsing polychondritis , restless legs syndrome ( RLS ) , retroperitoneal fibrosis , rheumatic fever , rheumatoid arthritis , sarcoidosis , Schmidt syndrome , scleritis , scleroderma , s'nergöjS syndrome , sperm and testicular autoimmunity , stiff person syndrome ( SPS ) , subacute bacterial endocarditis ( SBE ) , Susac's syndrome , sympathetic ophthalmia ( SO ) , Takayasu's arteritis , temporal arteritis ( giant cell arteritis ) , thrombocytopenic purpura ( TTP ) , Tolosa - Hunt syndrome ( THS ) , transverse myelitis , Type 1 diabetes , ulcerative colitis ( UC ) , undifferentiated connective tissue disease ( UCTD ) , uveitis , vasculitis , vitiligo , Vogt - Koyanagi - Harada Disease , and Wegener's granulomatosis ( or Granulomatosis with Polyangiitis ( GPA ) ) . [ 000173 ] In certain embodiments , the term " inflammatory disease " includes , but is not limited to , the following inflammatory diseases : encephalitis , myelitis , meningitis , arachnoiditis , neuritis , dacryoadenitis , scleritis , episcleritis , keratitis , retinitis , chorioretinitis , blepharitis , conjunctivitis , uveitis , otitisexterna , otitismedia , labyrinthitis , mastoiditis , endocarditis , myocarditis , pericarditis , vasculitis , arteritis , phlebitis , capillaritis , sinusitis , rhinitis , pharyngitis , laryngitis , tracheitis , bronchitis , bronchiolitis , pneumonitis , pleuritis , mediastinitis , stomatitis , gingivitis , gingivostomatitis , glossitis , tonsillitis , sialadenitis / parotitis , cheilitis , pulpitis , gnathitis , esophagitis , gastritis , gastroenteritis , enteritis , colitis , enterocolitis , duodenitis , ileitis , caecitis , appendicitis , proctitis , hepatitis , ascendingcholangitis , cholecystitis , pancreatitis , peritonitis , dermatitis , folliculitis , cellulitis , -122- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT hidradenitis , arthritis , dermatomyositis , myositis , synovitis / tenosynovitis , bursitis , enthesitis , fasciitis , capsulitis , osteochondritis / osteitis / osteomyelitis , epicondylitis , tendinitis , panniculitis , spondylitis , periostitis , chondritis , nephritis , glomerulonephritis , pyelonephritis , ureteritis , cystitis , urethritis , oophoritis , salpingitis , endometritis , parametritis , cervicitis , vaginitis , vulvitis , mastitis , orchitis , epididymitis , prostatitis , seminalvesiculitis , balanitis , posthitis , balanoposthitis , chorioamnionitis , funisitis , omphalitis , insulitis , hypophysitis , thyroiditis , parathyroiditis , adrenalitis , lymphangitis , and lymphadenitis .

Articles of Manufacture and Kits [ 000174 ] Also provided are articles of manufacture comprising any of the compounds or pharmaceutical compositions described herein . The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions . Examples of a suitable container include , but are not limited to , a bottle , a vial , a syringe , an intravenous bag , or a tube . [ 000175 ] Also provided are kits comprising any of the compounds or pharmaceutical compositions described herein . The kits can contain the compounds or pharmaceutiucal compositions in suitable containers or packaging materials , including , but not limited to , a bottle , a vial , a syringe , an intravenous bag , or a tube . The kits can comprise the compounds or pharmaceutical compositions for administration to a subject , cell , tissue , and / or individual in single - dose form or in multiple - dose form . The kits can further comprise instructions or a label for administering the compounds or pharmaceutiucal compositions to a subject , cell , tissue , and / or individual according to any of the methods disclosed herein . The kits can further comprise equipment for administering the compounds or pharmaceutiucal compositions to a subject , cell , tissue , and / or individual , including , but not limited to , needles , syringes , tubing , or intravenous bags . The kits can further comprise instructions for producing any of the compounds or pharmaceutiucal compositions disclosed herein . [ 000176 ] Also provided are articles of manufacture comprising any of the compounds or pharmaceutical compositions described herein . The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions . The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions . Examples of a suitable container include , but are not limited to , a bottle , a vial , a syringe , an intravenous bag , or a tube . -123- 1100573566 5 AMERICAS [ 000177 ] Attorney Docket No .: 121843.002NU - 3200 PCT This disclosure will be more fully understood by reference to the following Examples . They should not , however , be construed as limiting the scope of this disclosure . It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims . [ 000178 ] EXAMPLES Additional embodiments are disclosed in further detail in the following examples , which are not in any way intended to limit the scope of the claims .

Analytical Methods and Instrumentation [ 000179 ] Proton nuclear magnetic resonance ( NMR ) spectra were obtained on Bruker Ascend ™ 500 MHz spectrometer . NMR spectra are reported as follows : chemical shift & ( ppm ) , multiplicity , coupling constant J ( Hz ) , and ( relative ) integration . The abbreviations s = singlet , d = doublet , t = triplet , q = quartet , m = multiplet , and br = broad are used throughout . Mass spectral data were measured using the following systems : Waters Acquity i - class ultra- performance liquid chromatography ( UPLC ) system with Acquity Photo Diode Array Detector , Acquity Evaporative Light Scattering Detector ( ELSD ) , and Waters ZQ Mass Spectrometer . Data was acquired using Waters MassLynx 4.1 software and purity was characterized by UV wavelength 220 nm , evaporative light scattering detection ( ELSD ) , and electrospray positive ion ( ESI ) ( column : Acquity UPLC BEH C18 1.7 μ 2.1 x 50 mm ) . Solvents used : acetonitrile / water , containing 0.1 % formic acid ; flow rate 0.7 mL / min . Preparatory HPLC purifications were conducted with a flow rate of 15 mL / min and detection by UV wavelength at 214 nm and 254 nm ( Column : Jupiter © 10 Mμ Proteo 90 Å , 250 x 21.mm A , solvent : acetonitrile / water , containing a modifier such as 0.1 % trifluoroacetic acid ) .

Abbreviations used in the examples include : [ 000180 ] Abbreviation Name acetonitrile CH3CN or ACN aq . aqueous atm BINAP Boc atmospheres ( 1,1 ' - binaphthalene - 2,2 ' - diyl ) bis ( diphenylphosphine ) t - butoxycarbonyl - 124- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Abbreviation Name CCCDCCO carbon tetrachloride deuterated chloroform carbon monoxide gas COcarbon dioxide CS2CO3 cesium carbonate CuBr copper ( I ) bromide Cu ( OAc ) 2 copper ( II ) acetate DCM dichloromethane DEAD diethyl azodicarboxylate DIPEA or DIEA DMF DMSO equiv ESI Et3N diisopropylethylamine N , N - dimethylformamide dimethylsulfoxide equivalent electrospray ionization triethylamine EtOAc ethyl acetate EtOH ethanol FA FC h O₂H HATU formic acid flash chromatography hours water 1- [ bis ( dimethylamino ) methylene ] -1H - 1,2,3 - triazolo [ 4,5 - b ] pyridinium 3- oxide hexafluorophosphate hydrogen chloride HCHOAC acetic acid K2COpotassium carbonate KI potassium iodide KOH potassium hydroxide KOtBu potassium tert - butoxide LiAlHlithium aluminum hydride LiOH lithium hydroxide MeOH methanol min minutes Nnitrogen Na2CO3 sodium carbonate Na2SO4 sodium sulfate NaH sodium hydride NaHCO3 sodium bicarbonate NaOH sodium hydroxide NBS NH4CNMR Pd2 ( dba ) Pd ( dppf ) Cl N - bromosuccinimide ammonium chloride nuclear magnetic resonance tris ( dibenzylideneacetone ) dipalladium ( 0 ) [ 1,1 ' - bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( II ) Pd / C palladium on carbon Pd ( OAc ) 2 palladium ( II ) acetate - 125 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Abbreviation Name PyBOP Prep - TLC RuPhos - Pd- Gsat . STAB t - BuOH THF T3P benzotriazol - 1 - yloxytripyrrolidinophosphonium hexafluorophosphate preparatory thin layer chromatography chloro ( 2 - dicyclohexylphosphino - 2 ' , 6 ' - diisopropoxy - 1,1 ' - biphenyl ) [ 2- ( 2'- amino - 1,1 ' - biphenyl ) ] palladium ( II ) saturated sodium triacetoxyborohydride tert - butanol tetrahydrofuran propylphosphonic anhydride - 126 - 1100573566 5 AMERICAS Table 1. Compounds Compound Number CHEMICAL STRUCTURE AND NAME 0 = 5 = NH F N -N N HN Attorney Docket No .: 121843.002NU - 3200 PCT N N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN- O = S = 0 NH F N -N -N 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN- & 0 = 5 = NH .F N N -N FN -N rac - N- { 3- [ 1- ( 6- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN- 0 = 8 = 0 NH F -N N -N N- { 3- [ 1- ( 6- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin- - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 128 - 1100573566 5 AMERICAS 0 = 5 = 0 NH F N N ( & -NH Attorney Docket No .: 121843.002NU - 3200 PCT N rac - N- { 3- [ 1- ( 4 - { [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin - 4- yl ] oxy } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide O = 5 = ` NH .F a ﺕ N ( & -NH rac - N- { 3- [ 1- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4- carbonyl } piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 129 - 1100573566 5 AMERICAS N N N- NH ( & -N N -NH Attorney Docket No .: 121843.002 rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide NH F 0 = 5 = N N a N < & 1 : -N -NH rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) -4- methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS 0 == NH F N N- a -N a ( -NH Attorney Docket No .: 121843.002 rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide N N - N O = S = NH FL N -N -NH N NU - 3200 PCT N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 131 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 0 = 5 = 0 NH F Wataoot N N -NH N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazine - 1- carbonylphenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenylpropane - 1 - sulfonamide 0 = 5 = 0 NH F N N -N -NH N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazine - 1- carbonylphenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 132 - 1100573566 5 AMERICAS 0 = S = ZI LL .N .

N -N N- Attorney Docket No .: 121843.002NU - 3200 PCT 1 & < • תוי -NH rac - N- { 3- [ 1- ( 4- { 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperazine - 1- carbonylphenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide 0 = 8 = NH F N -N N ( & -NH rac - N- [ 3- ( 1- { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbonyl ) piperazine - 1- carbonyl ] phenyl - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide - 133 - 1100573566 5 AMERICAS N - N O = S = NH F -NH : Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 134 - 1100573566 5 AMERICAS N - N O = S = NH F N -N וי -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 135 - 1100573566 5 AMERICAS N N - N O = S = NH F -N -NH N- TUL & Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) -4 - methylpiperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 136 - 1100573566 5 AMERICAS N - N O = S = NH F N -N N- ﺕ & דוי -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2 - fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 137 - 1100573566 5 AMERICAS N N - N O = S = NH F -N 381 די -NH Attorney Docket No .: 121843.002NU - 3200 PCT F rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin- - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 138 - 1100573566 5 AMERICAS N O = S = .NH N - N F N- -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- 81 די rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 139 - 1100573566 5 AMERICAS N - N 0 = S = NH F N- -N Attorney Docket No .: 121843.002NU - 3200 PCT II & -NH rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 140 - 1100573566 5 AMERICAS N - N O = S = NH F Attorney Docket No .: 121843.002NU - 3200 PCT -N & -NH rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2 - fluorophenyl } piperidin - 4 - yl ) methyl ] piperidin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 141 - 1100573566 5 AMERICAS N - N O = S = NH LL F 1 & דויי -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 1- ( -- F 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4 - yl ) methyl ] piperidin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 142 - 1100573566 5 AMERICAS N N - N O = S = NH F Attorney Docket No .: 121843.002NU - 3200 PCT -N N- 81 די -NH : rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidin - 4- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 143 - 1100573566 5 AMERICAS N - N O = S = NH F Attorney Docket No .: 121843.002NU - 3200 PCT -NH Book וי rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 144 - 1100573566 5 AMERICAS -N · ד F Attorney Docket No .: 121843.002NU - 3200 PCT HN Book & rac - N- [ 3- ( 1- { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenylpiperidine - 4 - carbonyl ) piperazin - 1- yl ] phenyl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide HN EN N- -N NH F N.

N : HN- N N- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5- yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione S N HN- N F -N -NH & HN O = S = N- rac- ( 3R ) -3- [ 2- ( 2- { 4- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] piperazin - 1 - yl } -2 - oxoethyl ) -1,2,3,4- tetrahydroisoquinolin - 6 - yl ] piperidine - 2,6 - dione HN N -N N -NH F -S N : HN- N- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione O = S = -NH F S N = HN N N- -N HN & rac- ( 3R ) -3- { 6- [ 6 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl } amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 2- yl ] pyridin - 3 - yl } piperidine - 2,6 - dione - 147 - 1100573566 5 AMERICAS F HN - S ○ = S = S- EN -NH N 1 & -NH Attorney Docket No .: 121843.002NU - 3200 PCT F rac - N- [ 3- ( 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } -4 - fluoropiperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 148 - 1100573566 5 AMERICAS S- F HN - S N O === = N -NH N 81 ) דוי -NH Attorney Docket No .: 121843.002NU - 3200 PCT N rac - N- [ 3- ( 5- { 2 - [ ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) -4 - methylpiperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide .S . F N N -N . N F HN N -N .

O = S = N- / & N rac- ( 3S ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) -4 - fluoropiperidin - 1 - yl ] phenyl } piperidine- 2,6 - dione - 149 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N F HN S.

O = S = N- N N -N 1 & rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) -4 - methylpiperidin - 1 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione HN - S F = 5 = N S N -N -NH -NH ..... ( & 1 : rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 150 - 1100573566 5 AMERICAS HN N- F- N S N = N N Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( 3S ) -3- [ 4- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) phenyl ] piperidine- 2,6 - dione S F HN - S ○ = S = N -NH -N ar ןוי -NH rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide - 151 - 1100573566 5 AMERICAS N. F HN - S = 5 = N -NH -N Attorney Docket No .: 121843.002NU - 3200 PCT N- 3002rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide HN & EN -N -N S N -NH -F EN -N .

NH rac- ( 3R ) -3- { 6- [ 4- ( 2- { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) -2 - oxoethyl ) piperidin - 1 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione - 152 - 1100573566 5 AMERICAS N- O = S = HN F N N- N : N N IN & Attorney Docket No .: 121843.002NU - 3200 PCT S rac- ( 3S ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) pyridin - 3 - yl ] piperidine - 2,6- dione N NH F S N : HN- N N -N HN N -N ( 3R ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5- yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl } methyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione - 153 - 1100573566 5 AMERICAS F HN N- N = N N N N N IN & Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( 3S ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } -4 - methylpiperidin - 1 - yl ) pyridin - 3- yl ] piperidine - 2,6 - dione F .S . N N -N H -N HN O = S = N- N / & N rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl } methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione - 154 - 1100573566 5 AMERICAS O = $ = HN 1HN -NH F HN a Attorney Docket No .: 121843.002NU - 3200 PCT S N rac - N- { 3- [ 5- ( 2 - { [ 4- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } phenyl ) piperidin - 4- yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide N. O == HN - S N -NH -F N -N Our & -NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 155 - 1100573566 5 AMERICAS O = $ = doroo HN F F HN- -N N N ﺐﺗ HN -NH & Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 4- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } phenyl ) piperidin - 4- yl ] acetylpiperazin - 1 - yl ) -3 - fluorophenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide S- HN - S F O = S = O N -NH N- -N -NH N N - דוי rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 156 - 1100573566 5 AMERICAS HN & -N S N N -N -N N- -NH -N NH O = S = Attorney Docket No .: 121843.002 rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) acetyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide .N . & & NH N S.

N -N -N N -NH F rac - N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( R ) -1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) pyrrolidine - 3- carbonyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS O = $ = HN F F HN- -N N N a N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - fluoro - 4- { 4 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yloxy ) cyclohexanecarbonyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide HN- & 1 ) !!! O = S = NH F F -N N- -NH N rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,2,3,4 - tetrahydroisoquinolin - 2- yl } acetyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide - 158 - 1100573566 5 AMERICAS O = S = HN F S N- HN F HO dorop N -N N- a F HN- -NH & Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 4- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } -2 - fluorophenyl ) -4- hydroxypiperidin - 4 - yl ] acetyl } piperazin - 1 - yl ) -3 - fluorophenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide H .

F HN N 1 S N | N N rac- ( 3S ) -3- [ 6- ( 3- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } azetidin - 1 - yl ) pyridin - 3- yl ] piperidine - 2,6 - dione - 159 - 1100573566 5 AMERICAS S- F HN - S = 5 = N = N -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT -N N- N & ) דוי -NH rac - N- [ 3- ( 5- { 2 - [ ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidin- - yl ) phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide = F HN - S S- EN -NH -NH 8005 N 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 5- [ 2 - ( { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin- - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide F HN N- N N N N N & rac- ( 3R ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) pyridin - 3- yl ] piperidine - 2,6 - dione HN - S ○ = S = N -NH -F N- -N N N- 1 & -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide NU - 3200 PCT S- HN - S F ○ = S = N.

N -NH N- -N a -NH : N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 162 - 1100573566 5 AMERICAS S.

N N 0 = 5 = HN - S -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- -N -NH N a N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 163 - 1100573566 5 AMERICAS N F HN - S O = S = N -NH N -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 5-2 - [ ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 2 - yl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide F HN - S N -NH N -N ar -NH N- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 N- [ 3- ( 5- { 2 - [ ( 5- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 2 - yl ) amino ] pyrimidin - 4 - yl } -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide NU - 3200 PCT N HN - S D = S = O -NH N & . דוי -NH rac - N- [ 3- ( 5- { 2 - [ ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin- - yl ) pyridin - 2 - yl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 165 - 1100573566 5 AMERICAS F HN - S = S = N -NH -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide F = S = HN - S N S- N -NH -N N- and -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide F HN - S S N -NH -F N- -N & דוי. . -NH rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide - 167 - 1100573566 5 AMERICAS 0 = 8 = 0 NH F .N N. .N . S -N N Attorney Docket No .: 121843.002NU - 3200 PCT HN NH -N - ( 4 - { [ 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin- - yl ) amino ] -1H - pyrazol - 1 - yl ) methyl ) piperidin - 1 - yl ] methyl } piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide HN- -N NH N N N F NH NH O = S = 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 - { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] -1H - pyrazol - 1 - yl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide NU - 3200 PCT S HN - S F = 9 ) = N N -NH -N N- 81 ) ןווי -NH rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) -4 - methylpiperidin- - yl ) methyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide - 169 - 1100573566 5 AMERICAS 0 = 5 = N F. HN IN Attorney Docket No .: 121843.002NU - 3200 PCT -NH N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide O = S = F HN N.

.N .

N -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethylpiperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide S O = S = O HN - S -NH -N N & -NH rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 1,2 - dihydroisoquinolin - 6- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide O = S = HN F HN- N- N -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexyl ] methyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- O = S = HN fluorophenyl ) propane - 1 - sulfonamide N ( & -N N -NH LL F N S HN- N N rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } -4 - methylpiperidin- - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide F- HN .N .

' N ' N -NH N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 172 - 1100573566 5 AMERICAS N F- HN N.

N- -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide N F HN O = S = HN- a -NH N ( & rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3- { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 1,2 - dihydroisoquinolin - 6- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 173 - 1100573566 5 AMERICAS N S. N O = S = O HN - S NH -N .

.N . -NH N Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethylpiperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide S. N O = S = O F HN - S N NH -N .

N -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide O = $ = HN .

F N HN -N N -N -N HND & -NH rac - 5- { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide - 175 - 1100573566 5 AMERICAS N S - NH F N. HN N -N Attorney Docket No .: 121843.002NU - 3200 PCT N & -NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 1,2 - dihydroisoquinolin - 6- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide O = S = HN F N N N .N . N N -NH - 176 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide HN ZI 0 = 5 = N N- -N HN & -NH rac - 5- ( 4 - { [ 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl ) methyl ) piperidin - 1 - yl ] methyl } piperidin - 1 - yl ) -N - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide - 177 - 1100573566 5 AMERICAS TO = S = NH N. N HN . a -NH ( & Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 1,2 - dihydroisoquinolin - 6- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } methyl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 178 - 1100573566 5 AMERICAS O = S = HN .

F N HN N N -N N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexyl ] methyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide S.

HN - S F N -NH -N -N N & -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 1,2 - dihydroisoquinolin - 6- yl } piperidin - 4 - yl ) methyl ] -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide O = s = HN N HN ـﻡﺓ a HN HN -N OH ( 2S , 4R ) -1 - [ ( 2S ) -2- [ 5- ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] phenylpiperidin - 1 - yl ) -5 - oxopentanamido ] -3,3 - dimethylbutanoyl ] -4 - hydroxy - N- [ ( 1S ) -1- [ 4- ( 4-1nethyl - 1,3 - thiazol - 5 - yl ) phenyl ] ethyl ] pyrrolidine - 2 - carboxamide - 180 - 1100573566 5 AMERICAS S HN - S F O == O N -NH -F Attorney Docket No .: 121843.002NU - 3200 PCT N- -N Ch N -NH N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 181 - 1100573566 5 AMERICAS F HN - S O == O Attorney Docket No .: 121843.002NU - 3200 PCT N -NH -F N -N -NH or N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 182 - 1100573566 5 AMERICAS S O == HN- F N -NH N ךווי -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl ) phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 183 - 1100573566 5 AMERICAS HN - S F O = & p = S N -NH N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl ) phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide 0 = 5 = HN F S N.

IZ N. N- roop -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenylpyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide N F = 5 = HN N. IN N. N- -NH ° N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } pyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide O = S = HN F N HN- N N N- N- ﺐﺗ HN & 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperazin - 1- yl ) acetyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide NU - 3200 PCT N F- S HN N- -NH N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidine - 3- carbonyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide F O = S = O HN - S S EN -NH -N Boog -NH HN < & 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - 5- [ 4- ( 4- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] phenoxy } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide O = S = HN F N HN- HN- & -N -NH rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] aminophenyl ) piperidin - 1- yl ] acetyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide 0 = $ = HN F HN N N a N -NH N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } oxy ) cyclohexanecarbonyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide -187- 1100573566 5 AMERICAS O = u0000 = HN .

F N S N- a N- HN- N -NH Attorney Docket No .: 121843.002 N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide O = S = HN N F HN- N N N -N & -NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - { [ 1- ( 1- { 3 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidin - 4 - yl ] oxyphenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS O = S = HN F 1N N HN- N ( & -NH -N Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - { [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperidin - 4 - yl ] oxyphenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide HN & 1 ) N- -N ﺕ O = S = NH -F -NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - { [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,2,3,4 - tetrahydroisoquinolin - 2- yl } acetyl ) piperidin - 4 - yl ] oxyphenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 189 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N.

F O = S = HN ' 1S N. N Grobon -NH N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3- { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidine - 3- carbonyl ] piperidin - 4 - yl ) phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide S- F HN - S ○ = S = N -NH -N a N- -N -NH & HN rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } phenyl ) piperidin - 1- yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 190 - 1100573566 5 AMERICAS HN- יוו 1 & -N N HN N Attorney Docket No .: 121843.002NU - 3200 PCT 0 = S - NH F rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3- [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,2,3,4 - tetrahydroisoquinolin - 2- yl } acetyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide N N O = S = O HN - S NH -N .

.N . -NH N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } pyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide - 191 - 1100573566 5 AMERICAS S .N .

N -N HN - S -NH Attorney Docket No .: 121843.002NU - 3200 PCT -NH N N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidine - 3- carbonyl ] piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide N HN- -N & 1 ) NH N F N = S N HN N - N 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - 5- [ 4- ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] -N - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide 0 = 5 = F HN N. N. -N -NH .N & HN rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] aminophenyl ) piperidin - 1- yl ] acetyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide F HN ' 1S N. N -NH N N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yloxy ) cyclohexanecarbonyl ] piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 193 - 1100573566 5 AMERICAS 0 = 5 = F HN N. N N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxycyclohexanecarbonyl ] piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide O = S = F- HN 1N N N N .N .

-NH N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } pyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide - 194 - 1100573566 5 AMERICAS O = S = HN F S ' N N .N . N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } pyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide a N- 1O = S = -N HN HN F N N NH & 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperazin - 1- yl ) acetyl ] piperidin - 4 - yl } methyl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide S.

F HN - S N O = S = O N NH N - N -NH : N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidine - 3- carbonyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide - 196- 1100573566 5 AMERICAS 0 = 55 = HN N N. IN N. N Attorney Docket No .: 121843.002NU - 3200 PCT -N C -N HN & N -NH rac - 5- { 4- [ 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl ) methyl ) piperidine - 1 - carbonyl ] piperidin - 1 - yl } -N - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide NH & -N -NH O = S = -N 1HN HN F N N - 197 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] aminophenyl ) piperidin - 1- yl ] acetyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide O = S = HN HN FL N N N -S -N N- -NH N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yloxy ) cyclohexanecarbonyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide N- O = S = HN . -N HN F N N -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl } methyl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN- יוו 1 & N- -N N NH N ' N S.

HN - S rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1 - { [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,2,3,4 - tetrahydroisoquinolin - 2- ylacetyl ) piperidin - 4 - yl ] methyl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide S N HN- F 1N -N N HN O = S = & HN- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperazin - 1- yl ) acetyl ] -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide NU - 3200 PCT N ` N ' S. ' N ' -NH F 1 HN O = S = N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidine - 3- carbonyl ] -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide -N ave -N HN & -NH S EN F -NH HN O = S = 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 rac - 5- ( 4- { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] -1,2,3,4 - tetrahydroisoquinoline - 2 - carbonyl } piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide NU - 3200 PCT S N N F HN- HN O = S = -NH & HN- rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } phenyl ) piperidin - 1- yl ] acetyl - 1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide S N ' N ' ZI F HN N abs .N . abs .N . & rac- ( 3S ) -3- ( 2 - { [ ( 1r , 4r ) -4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - tetrahydroisoquinolin - 7 - yl ) piperidine - 2,6 - dione 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } cyclohexyl ] methyl } -1,2,3,4- - 201 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N N N S. N abs abs / N ZI F- HN N H .N . & rac- ( 3S ) -3- ( 2 - { [ ( 1r , 4r ) -4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } cyclohexyl ] methyl } -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) piperidine - 2,6 - dione ' N ' N ° ZI .N . ' N ' .N . & ' N ' ZI F HN rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione - 202 - 1100573566 5 AMERICAS -N a N -N N- י -NH Attorney Docket No .: 121843.002NU - 3200 PCT S N F -NH HN - = 8 = N ( 3S ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6- dione - 203 - 1100573566 5 AMERICAS 1S -N NH F HN S = C N a -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N ( 3R ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] phenylpiperidine - 2,6- dione S- EN HN - S -NH -N N -NH N ( & 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 7 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 1,2 - dihydroisoquinolin - 6- yl } piperidin - 4 - yl ) methyl ] -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide O = S = HN F HN 1N a -NH N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 7 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenoxy } cyclohexyl ] methyl } - - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide HN O = $ = O & HN -N -NH F N- HN- 1N N rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 7- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] aminophenyl ) piperidin - 1- yl ] acetyl } -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 205 - 1100573566 5 AMERICAS N HN- N HN F N N Attorney Docket No .: 121843.002NU - 3200 PCT & NH ﻢﻬﻬﻫ rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 7- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } - - fluorophenyl ) propane - 1 - sulfonamide S O = > = HN - S N -NH book N N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 7 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -7- azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide - 206 - 1100573566 5 AMERICAS .N . F HN - S = 5 = N -NH -N N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1s , 4s ) -4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 207- 1100573566 5 AMERICAS .N . O == O HN - S EN -NH -N -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 208 - 1100573566 5 AMERICAS N.

HN - S N -NH -N -N -N Attorney Docket No .: 121843.002NU - 3200 PCT ( & -NH rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 ' - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] - [ 1,4 ' - bipiperidin ] -4 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide N.

F HN N -S = IN abs abs / -N . & 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4- [ 4- ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide NU - 3200 PCT HN -8 = F.

N.

.N IZ abs abs / -N . & N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1s , 4s ) -4- [ 4- ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide O = $ = HN FL S HN N -N ןווי -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4 - ( { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) methyl ) cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide HN F- 1HN N & -N -NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2 - { [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidin - 4 - yl ] methyl } -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide O = S = HN F HN 1N N ( & -NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -4- fluoropiperidine - 4 - carbonyl } -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide -211- 1100573566 5 AMERICAS O = S = HN F HN 1 N -N ar N- ( & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2 - ( { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide HN -NH N -N 0 = S = F HN - ( 4 - { [ ( 3R ) -3 - { [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] methyl } pyrrolidin - 1 - yl ] methyl } piperidin - 1 - yl ) -N - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide - 212 - 1100573566 5 AMERICAS N HN - S Attorney Docket No .: 121843.002NU - 3200 PCT N -NH -N -N N -NH N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl ) -2 - methylpropyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide O = S = HN F S N- HN N -N C -NH N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin- - yl ) methyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide - 213 - 1100573566 5 AMERICAS HN - S F ○ = S = ○ N S N -NH -NH Attorney Docket No .: 121843.002NU - 3200 PCT HN - { 4 - [ ( 4- { 1 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] -2 - methylpropan - 2 - yl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide 0 = S = HN F 1N S HN- N N -N HN N -NH -N - { 4 - [ ( 4 - { [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] methyl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2- carboxamide -214- 1100573566 5 AMERICAS 0 = S = HN F 1HN Attorney Docket No .: 121843.002NU - 3200 PCT N- N ' NI ... & NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 2- [ 4- ( 3- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 4 - yl ) propyl ) piperazin - 1 - yl ] acetyl } -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide O = S = HN F -N N 1HN N N N ` ' N " 1NH off rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 215 - 1100573566 5 AMERICAS HN & 1 ) N . 0 = 8 = 0 NH F -N IN N. .N .

N.

Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - oxo - 2,3 - dihydro - 1H - isoindol - 5- yl } hexanoyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide NH -F -N N N. S HN & 1N .N . rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - oxo - 2,3 - dihydro - 1H - isoindol - 5- yl } hexanoyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide - 216 - 1100573566 5 AMERICAS 0 = 5 = N F HN N. N -N . ' N ' Ni ( & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ] - 1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide HN F 1HN- N N N & NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide -217- 1100573566 5 AMERICAS 1HN N O = 5 = ' N ' N -N . N NI . & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide S. N ' N ' ' N ' ZI 1F HN O == ` N ' .N . NII . & -NH rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide -218- 1100573566 5 AMERICAS N HN - S F N -N -NH Attorney Docket No .: 121843.002NU - 3200 PCT -NH Book rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide O = S = HN F HN- 1N- N & .NH rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -2 - azaspiro [ 3.3 ] heptan - 6 - yl } amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide -219- 1100573566 5 AMERICAS O = S = HN F 1HN a N N & Attorney Docket No .: 121843.002NU - 3200 PCT NH rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl ] - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] piperidin - 4 - yl ) phenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide O = S = HN 1F HN N a N N HN & rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } azetidine - 3- carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide - 220 - 1100573566 5 AMERICAS HN F HN N N 1N -N N / & Attorney Docket No .: 121843.002NU - 3200 PCT N H rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2- ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - 1,3- benzodiazol - 4 - yl } piperidine - 4 - carbonyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide 0 = S = HN F HN 1N N -N N -N / & 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H- 1,3 - benzodiazol - 4 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4- yl } -2 - fluorophenyl ) propane - 1 - sulfonamide IN O = S = OF N N N- HN- -N . -N N HN- N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3S ) -1- { 1 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] -3 - methyl - 2 - oxo - 2,3- dihydro - 1H - 1,3 - benzodiazol - 5 - yl } pyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide O = $ = HN 1F S N HN- N -N & -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1- sulfonamide O = $ = HN F 1N N HN a ﻢﺤﻣﺩ N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) pyrrolidine - 3- carbonyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide O = S = HN F 1N HN N NH N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenylpyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 223 - 1100573566 5 AMERICAS HN F 1HN- N a N N NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenylpyrrolidin - 3- yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide O = S = HN 1F HN N- -N HN- 1 rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 224 - 1100573566 5 AMERICAS O = S = HN F 1 S N HN- N N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1 - { [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl ) oxy ) cyclohexyl ] methyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide HN - S F = 5 = N S. N -NH -N -N -N -NH HN & rac - 5- { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridine - 2 - carboxamide -225- 1100573566 5 AMERICAS S- N N ○ = S = ○ HN - S -NH Attorney Docket No .: 121843.002NU - 3200 PCT HN & -NH rac - 4- [ 4 - ( { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin- - yl ) amino ] -2 - azaspiro [ 3.3 ] heptan - 2 - yl ) methyl ) piperidin - 1 - yl ] -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] benzamide S F HN - S ○ = S = N N -NH -N HN & -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 rac - 4- { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] benzamide NU - 3200 PCT 0 = 5 = N F HN .N . IN N -NH N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 2 - [ ( 38 ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethyl - 2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide -227- 1100573566 5 AMERICAS 0 = 5 = HN F N N.

N IZ N.

N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3- yl ] ethylpiperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide O = S = HN F N HN N -N N- HN & rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperazin - 1- yl ) acetyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 228 - 1100573566 5 AMERICAS HN F 1N N HN N -N ﺐﺗ N ( & N -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide N off NII . & -NH F HN .

N ' N ' ZI O = 5 = rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2 - ( { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H- isoindol - 5 - yl ) oxy ) acetyl ] piperidin - 4 - yl ) phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 229 - 1100573566 5 AMERICAS HN F 1N S N N- < & -NH -N HN- a N Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 3 - yl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl ) phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide N N S. a N- F NH 0 = 5 = -N N & -NH : rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbonyl ) -4 - methylpiperidine- - carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide - 230 - 1100573566 5 AMERICAS N ZI H NH F a a 0 = 55 = ( & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbonyl ) -4 - methylpiperidine- - carbonyl ] piperidin - 4 - yl ) -5- { 2 - [ ( propan - 2 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide HO NH F a N- 0 = 55 = -N N -NH N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide -231- 1100573566 5 AMERICAS N N S.

N a N- .NH F a ( & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) -4- methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane- - sulfonamide -N & -NH 1NH F S rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) -4- methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide -232- 1100573566 5 AMERICAS HN ³N -S .N . 1F -NH N : NH & Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( 3S ) -3- { 6- [ 4- ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -5- { 2 - [ ( propan - 2- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1 - carbonyl ) piperidin - 1- yl ] pyridin - 3 - yl } piperidine - 2,6 - dione -N HN- -N & HN S N F = S = ZI rac - N- ( 3- { 2- [ 1- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } phenyl ) piperidin - 4- yl ] acetylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ] -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ) propane - 1 - sulfonamide - 233 - 1100573566 5 AMERICAS 0 = S = 0 ` NH F -N 1N₂H S HN- & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 4 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide N₂H N N O = S = NH F N S N -N ar -NH N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -234- 1100573566 5 AMERICAS O = S = NH H2N N N F N S Attorney Docket No .: 121843.002NU - 3200 PCT N- -N N- 1 & ןוי -NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide N. NH HN- -N N- & -N FN F H 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- [ 4- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperazin - 1 - yl ] phenyl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide 0 = 5 = NH F N- goooloop N₂H N N < & -NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) acetyl ] piperazin - 1 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide N NH S ' N N O == O HN- N- Book & -N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] phenyl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 236 - 1100573566 5 AMERICAS N₂H N N S N O = S = NH F N Attorney Docket No .: 121843.002NU - 3200 PCT -NH oor N ןוי N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -237- 1100573566 5 AMERICAS N₂H N N S O = S = NH F Attorney Docket No .: 121843.002NU - 3200 PCT N -NH N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide N₂H N S -N NH LL F O = & = ( & -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } -4- methylpiperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide HN & 1 -N -N N NHN S N ZI rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) acetyl ] -4 - methylpiperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide - 239 - 1100573566 5 AMERICAS O = S = HN NHF N N NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - methyl - 2 - oxo - 2,3- dihydro - 1H - 1,3 - benzodiazol - 4 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN- Good & HN = 5 = F N -N NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide HN ' N. NH -N boo HN & -N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide HN & -N -N -N HN F N. N. IZ 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide HN- & book N -N O = 5 = HN ' F N -N rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide HN F = 5 = HN- Look -N -N S N N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide -242- 1100573566 5 AMERICAS S N. NH N · ד ZI = 5 = Attorney Docket No .: 121843.002NU - 3200 PCT HN & -N -N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN & 1 ) -N -N N- N. F. N NHHN O = S = rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1 - ( { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) acetyl ] piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide - 243 - 1100573566 5 AMERICAS N NH S N 0 = S = Attorney Docket No .: 121843.002NU - 3200 PCT HN- & 1 ) ﺩ rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) acetyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide 0 = 8 = NH F N -N -NH N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidine - 4- carbonyl } piperidin - 4 - yl ) -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide -244- 1100573566 5 AMERICAS HN -N F O = > = HN Attorney Docket No .: 121843.002NU - 3200 PCT N. NH & -N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) ethyl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide HN & -N -N N O == O HN N -N N. N. IN rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- { 2 - [ ( propan - 2 - yl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide - 245 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 0 = 8 = 0 NH .F Jooolopp N₂H .N . N & -NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) acetyl ] piperidin - 4 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide O = S = .NH N₂H N ' N F N S -NH N N- & ויי rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 246 - 1100573566 5 AMERICAS N₂H N ³N N - S - NH F N N NH & Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( 3S ) -3- { 6- [ 4- ( 4- { 4- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione HN- & -N N O = S = HN F.

N -N S N rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide -247- 1100573566 5 AMERICAS 0 = 5 = NH F N 2 N N- -N N & N- -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4- carbonyl } piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide F = & = HN N. IN HN- -N & 1 -N C N rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 248 - 1100573566 5 AMERICAS O = 5 = 0 ` NH .F -N 2N₂H S ( -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - { [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] methyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide 0 = 8 = 0 NH F HN- F .N & 2N- NHO -NH N S N₂H rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] amino } -2- fluorophenyl ) -4 - hydroxypiperidin - 4 - yl ] acetyl } azetidin - 3 - yl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide - 249 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 0 = 5 = NH F -N N ( & Soooloop N₂H N -NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1- [ 2- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) acetyl ] azetidin - 3 - yl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ﻢﻤﻤﻧﺓ HN & -N HN N NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -250 - 1100573566 5 AMERICAS 0 = 8 = NH .F N N a Attorney Docket No .: 121843.002NU - 3200 PCT -N & oop N -NH rac - N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4- carbonyl } piperidin - 4 - yl ) -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide 0 = 5 = NH F N 218 N₂H N. S ﺱاء -N & oop -NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } -4 - methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide -251- 1100573566 5 AMERICAS HN N NH F N N- & NH Attorney Docket No .: 121843.002 rac - N- [ 3- ( 2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } -2,7- diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] piperidin - 4 - yl } -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide -N O == HN F.

HN- N book & 1 ) N. N rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4- carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS 0 = 8 = 0 NH N S -N N < & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4- carbonyl } piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -N -NHEN S ' N ' N. F HN - S- = S = H N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1 - [ ( 1r , 4r ) -4 - ( { 6 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] -1,2,3,4- tetrahydroisoqumolin - 2 - yl } methyl ) cyclohexanecarbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide -253 - 1100573566 5 AMERICAS 0 = 5 = NH F N N₂H .N . S N- וי -NH Attorney Docket No .: 121843.002 N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1 - ( { 1 - [ ( 1r , 4r ) -4- { 3 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl } methyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide O = S = NH 2224 N₂H N N IZ N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1 - ( { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl } methyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS 2O = 5 = NH F -N S a N -N HN Attorney Docket No .: 121843.002NU - 3200 PCT N₂H . N N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1 - [ ( 1 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexyl ] methyl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide 2& ' N ' F HN - S = S = N -NH-N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - { [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,2,3,4- tetrahydroisoquinolin - 2 - yl } acetyl ) piperidin - 4 - yl ] methyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide - 255 - 1100573566 5 AMERICAS 0 = 8 = 227 N₂H N NH .N . N -N ( & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidine - 4 - carbonyl } -4 - methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide 0 = 5 = NH F -N 2N₂H N S -N oop . rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 256 - 1100573566 5 AMERICAS N₂H NH F 0 = 5 = -N N- & & .NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- { 2- [ 4- ( 3- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 4 - yl } propyl ) piperazin - 1 - yl ] acetyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide & NH N N₂H N ' N ' ! ' S -N N NH F 0 = 5 = rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide -257- 1100573566 5 AMERICAS N₂H N S NH F O = S = " ` N " N N & .NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2- N₂H N fluorophenylpropane - 1 - sulfonamide N -N & 1 .NH N- Baracte 0 = 5 = NH F rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -4 - methylpiperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide -258 - 1100573566 5 AMERICAS N₂H N N- N Begrad NH F ' N ' & NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide HN N יי < 1 & HN F NHN N S ' rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - oxo - 2,3 - dihydro - 1H- isoindol - 5 - ylhexanoyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide - 259 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT HN F- NHN N N HN- & 1 ) . N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - oxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } hexanoyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide N₂H N · S . -N ☑ N O == NH F & NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- fluorophenylpropane - 1 - sulfonamide 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -2 - azaspiro [ 3.5 ] nonan - 7 - yl } -1,3 - thiazol - 4 - yl ] -2- - 260 - 1100573566 5 AMERICAS N₂H N NH 0 = 55 = ' N !!! & NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl } -1,3 - thiazol - 4 - yl ] - N₂H N 2 - fluorophenyl } propane - 1 - sulfonamide S Broad O = S = NH F & NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -4 - methylpiperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide -261- 1100573566 5 AMERICAS N₂H N NH F O == O S N ﺕ & 1 .NH Attorney Docket No .: 121843.002 rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] piperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide " N " !! & 1 NH H2N ar -N S N F NH O = S = rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] piperidin - 4 - yl } propan - 2 - yl ) -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS N₂H S NH o = s = o N -N N NI & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] -2 - azaspiro [ 3.5 ] nonan - 7 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide N N₂H -N NH -N . .N . Nu . & -NH rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] piperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide - 263 - 1100573566 5 AMERICAS -N₂H N N - -S - NH O = S = F N -N . N. NI . & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- { 1- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] piperidin - 4 - yl } propan - 2 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide N N₂H -N -F N ' N. N & -NH NH O = S = rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperidine - 4 - carbonyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide - 264 - 1100573566 5 AMERICAS S N N₂H -F 2 NH = $ = N .N . N & -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl } piperidine - 4 - carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide .N . NH ﻡﻮﻧﺓ & S N F = 5 = rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 265 - 1100573566 5 AMERICAS H2N N NH F 0 = 5 = N & NH Attorney Docket No .: 121843.002 rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -2 - azaspiro [ 3.5 ] nonan - 7 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide N₂H NH & NH S ☑ N N- rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl } -1,3 - thiazol - 4 - yl ] - - fluorophenyl } propane - 1 - sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS N₂H N -S .

NH F N ﺵاﺩ & NH Attorney Docket No .: 121843.002 rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -4 - methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide N₂H S. N & 1 NH Sparoads NH F N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3- dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS N₂H N NH F N☑ .

O = 5 = -N N N / & Attorney Docket No .: 121843.002NU - 3200 PCT N H rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - methyl - 2 - oxo - 2,3- dihydro - 1H - 1,3 - benzodiazol - 4 - yl } piperidine - 4 - carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol - 4 - yl ] - - fluorophenyl } propane - 1 - sulfonamide N₂H . .N .

ZI = S = · ד N = S -N a N- -NH HN & rac - 5- ( 4- { 9- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] - - azaspiro [ 5.5 ] undecane - 3 - carbonyl } piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2- carboxamide -268- 1100573566 5 AMERICAS 253 N₂H O = S = NH F -N -☑ -N .

Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } pyrrolidin - 3- yl ] acetyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -N HN F N HN ﺄﻣﻮﻧﺓ & -N N. -NHN rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide - 269 - 1100573566 5 AMERICAS HN- Attorney Docket No .: 121843.002NU - 3200 PCT N₂H 0 = 5 = NH F -N N- a -NH 4 - ( { 4- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2- yl ] piperidin - 1 - yl } methyl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] benzamide HN & O == N₂H .N .

NH F N S -N rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 270 - 1100573566 5 AMERICAS 0 = 5 = NH F N 2N₂H .N . S N -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - { [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } oxy ) cyclohexyl ] methyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- N sulfonamide -N₂H N = S 2F -NH NII . & -NH .N . rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo - 2,3 - dihydro - 1H- isoindol - 5 - yl } piperidin - 4 - yl ) methyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide -271- 1100573566 5 AMERICAS -S - NH F O = S = O N₂H N ' N ' -NH Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } pyrrolidin - 3 - yl ] ethyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide N₂H D = 8 = 0 NH F -N -N HN- & rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -272 - 1100573566 5 AMERICAS 0 = 5 = NH F -N 261 N₂H N S a -N ( & N- -NH Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide ' N ' N OH N · N . NI . & -NH N rac - 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -5- ( 3 - { [ 3- ( 4- { 4 - [ ( 1Z ) -1- ( hydroxyimino ) -2,3 - dihydro - 1H - inden - 5 - yl ] - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) phenyl ) azetidin - 1 - yl ] methyl } azetidin - 1 - yl ) -2,3 - dihydro - 1H - isoindole- 1,3 - dione - 273 - 1100573566 5 AMERICAS 2CI S = F יוד : HN abs N NH F -N N -N Attorney Docket No .: 121843.002NU - 3200 PCT N ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,4 - dioxotetrahydropyrimidin - 1 ( 2H ) -yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) -3 - fluoropyrrolidine- - sulfonamide NISIO = S - NH F CI ' N ' N ' N ' N. N.

NH abs ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) -3 - fluoropyrrolidine- - sulfonamide -274- 1100573566 5 AMERICAS = S ) = O -NH F 2CI EN ' N ' .N . N NH & Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1- sulfonamide ' N ' O = S = O N - -S - NH CI F. N. F N N NH & rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine- - sulfonamide - 275 - 1100573566 5 AMERICAS O == O -NH F F N N .N . ' N ' .N .

NH & Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide O = S = OF CI- -F -N N abs N. N N ( IZ N- ( 5 - chloro - 3- ( 1- ( 4 - ( ( R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1- sulfonamide -276- 1100573566 5 AMERICAS O = S = 2F -NH F -N .

Attorney Docket No .: 121843.002NU - 3200 PCT abs N H ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) - - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) cyclopentanesulfonamide O = S = -NH F ' N ' .N . 2F N F & ' N ' rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) - - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) cyclopentanesulfonamide O = S = C S - NH F N .N .

F N N. .N .

CI N ³N 1 & N 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) cyclopentanesulfonamide ' N ' S - NH F O = $ = O 2CI N F F ' N ' ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) cyclopentanesulfonamide CI -N . O == O NH F F. .N . IZ -N N F .N .

( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4 - yl ) methyl ) -1,4- diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1- sulfonamide -278- 1100573566 5 AMERICAS -N . O = S = NH F 2F F.

Attorney Docket No .: 121843.002NU - 3200 PCT N N- F ' N ' N .N .

( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4 - yl ) methyl ) -1,4 - diazepan - 1- yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide CI- 2 NH -F .N . N ' N ' IZ N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide -279 - 1100573566 5 AMERICAS CI- 2 N O = 8 = NH -F Attorney Docket No .: 121843.002NU - 3200 PCT ' N ' N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide O = 8 = NH CI- -F 2 N -N . ' N ' N N.

IZ N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide - 280 - 1100573566 5 AMERICAS 2CI- O = 8 = NH -F N Attorney Docket No .: 121843.002NU - 3200 PCT ' N ' N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide O = 8 = NH CI- -F 2 N -N . N ' N ' IZ .N .

' N ' N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide -281- 1100573566 5 AMERICAS O = S = Cl NH N -F N. IZ Attorney Docket No .: 121843.002NU - 3200 PCT ' N ' N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide CI NH F N N a -N HN- N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide -282- 1100573566 5 AMERICAS CI N NH .F -N Attorney Docket No .: 121843.002NU - 3200 PCT HN- N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide N Cl ﺕ NH F N N- -N N- -N N- HN- N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1- yl ] phenyl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide - 283 - 1100573566 5 AMERICAS 0 = S = ﻒﻳ = CI N NH -N N -N Attorney Docket No .: 121843.002NU - 3200 PCT / & HN rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } -4 - fluoropiperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide -284- 1100573566 5 AMERICAS CI 0 = 8 = N.

NH F -N ãN N -N HN- Attorney Docket No .: 121843.002NU - 3200 PCT N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide - 285 - 1100573566 5 AMERICAS CI 0 = 8 = NH -N a N -N Attorney Docket No .: 121843.002NU - 3200 PCT HN- N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide Cl N NH == F N N N ãN N N HN- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1- yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide HN☑ -NH F .N . ' N ' N. ' N ' FN CI & rac - N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide ( R ) N -S - NH O = SS = F F N N.

ZI ' N ' N- ( 3- ( 1- ( 4 - ( ( R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine- - sulfonamide - 287 - 1100573566 5 AMERICAS CI N : .N . N.

N HN - S - N Attorney Docket No .: 121843.002NU - 3200 PCT .N . N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide S - NH F N N. N N 291 CI ' N ' ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine- - sulfonamide -288- 1100573566 5 AMERICAS N N CI- NH · F a N -N N- N- Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin- - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide F ' N ' 0 = 5 = N - S - NH F EN .N . N ZI N ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine- - sulfonamide - 289 - 1100573566 5 AMERICAS F 0 = S = N - S - NH F CI N N N. N ' N ' ZI Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide CI- N N NH F O = S = -N N N -N N HN ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin- - yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide -290- 1100573566 5 AMERICAS F CI -NH N F N.

Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide ' N ' F ﮎے O = S = O N - S - NH F CI N ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide - 291- 1100573566 5 AMERICAS F O = S = O N- -S - NH F CI ' N ' N ' N ' ‚ N.

' N ' Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 7- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } -7 - azaspiro [ 3.5 ] nonan - 2- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide O = S = O N - S - NH F .N . ' N ' .N . 2F ' N ' N N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide N .N . N ' -N N F- -F 3 NH O == -N N 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] phenyl } - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ] pyrrolidine - 1 - sulfonamide O = S = O S - NH F F N N .N . ' N ' N. N ' N ' N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide F N - S - NH ' N ' N F F CN ' N ' ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide - 293 - 1100573566 5 AMERICAS N F- NH N N N -N N N H Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- [ 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1- yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide F ' N ' N - S - NH F F N .N . N. N.

' N ' ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin- - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } -3 - fluoropyrrolidine - 1- sulfonamide - 294 - 1100573566 5 AMERICAS F -S - NH F F N ' N ' N.

' N ' H Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide CI -N NH -F N H N. N N. ( 3R ) -3- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) piperidine - 2,6 - dione -295- 1100573566 5 AMERICAS CI -N NH -F N IN Attorney Docket No .: 121843.002NU - 3200 PCT N N N 1- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( inethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) phenyl ) -1,3 - diazinane - 2,4 - dione H CI · N . = 8 = NH F N N & N. -N a rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( inethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 1 - yl ] phenylpiperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione -296- 1100573566 5 AMERICAS 3CI -N NH · F H N Attorney Docket No .: 121843.002NU - 3200 PCT N. N ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione -N CI- 3-F N N N ( 3R ) -3- ( 4- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) piperidine - 2,6 - dione - 297 - 1100573566 5 AMERICAS N ` NH -F 3CI N Attorney Docket No .: 121843.002 N. N N -N 1- ( 4- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) -1,3 - diazinane - 2,4 - dione H CI -N . = 5 = NH F ' N ' N ³N N.

-N - & rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione NU - 3200 PCT 1100573566 5 AMERICAS -N O = $ = CI- NH -F N N IZ H Attorney Docket No .: 121843.002NU - 3200 PCT N : 1- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) -1,3 - diazinane - 2,4 - dione -N NH -F 3CI -N N : H N ( 3R ) -3- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione - 299 - 1100573566 5 AMERICAS F O = S = O N - S - NH CI F N ' N ' ' N ' N Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1- sulfonamide N - S - NH F O = S = O CI N ' N ' ZI N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide - 300 - 1100573566 5 AMERICAS F O = S = O N - S - NH F CI N ' N ' N.

ZI Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1- sulfonamide N F N - S - NH O = SS = CI F N N N ' N ' ZI ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3- fluoropyrrolidine - 1 - sulfonamide - 301 - 1100573566 5 AMERICAS S - NH F CI N ' N ' ' N ' ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide F S - NH O = S = CI F N N N N ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3- fluoropyrrolidine - 1 - sulfonamide -302- 1100573566 5 AMERICAS F ○ = S = N - S - NH F CI N ' N ' N. N.

Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3- fluoropyrrolidine - 1 - sulfonamide F ○ = S = N - S - NH NH CI F N N N N. N ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3- fluoropyrrolidine - 1 - sulfonamide - 303 - 1100573566 5 AMERICAS -S - NH O = S = CI F ' N ' N ' N ' ' N ' H Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide C O = S = O N - S - NH F CI ' N ' N N N. ' N ' N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide - 304 - 1100573566 5 AMERICAS -S - NH O = S = CI F N N ' N ' ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide -S - NH O = S = CI F N N ' N ' .N N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide -305- 1100573566 5 AMERICAS N CI- O = S = NH -F Attorney Docket No .: 121843.002NU - 3200 PCT ' N ' .N . ' N ' ( RS ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) butane - 2 - sulfonamide 1100 & O = 8 = CI- NH -F ' N ' N.

' N ' rac- ( 2R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] butane - 2- sulfonamide - 306 - 1100573566 5 AMERICAS 3CI- 1 & O = S = NH -F IZ Attorney Docket No .: 121843.002NU - 3200 PCT rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) butane - 2 - sulfonamide CI- O = S = NH -F N -N . N ( ( R ) N N ( 2RS ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } butane - 2- sulfonamide -307- 1100573566 5 AMERICAS F- O = S = O -NH F CI ' N ' ' N ' N.

( R ) ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1- sulfonamide ' N F- -NH F CI N & rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1- sulfonamide - 308 - 1100573566 5 AMERICAS F- S - NH F N ' CI ' N ' N.

( R ) N Attorney Docket No .: 121843.002NU - 3200 PCT N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide FR N - S - NH ○ = S = F F N N N. N .N . N ( R ) N ZI CI ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide - 309 - 1100573566 5 AMERICAS FR 0 = S = F. N - S - NH N CI ' N ' N Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide FR O = S = -NH F CI N N N .N . ( R ) ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide - 310 - 1100573566 5 AMERICAS F- N - S - NH F O = S = O CI N ' N ' N 1 & ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoroazetidine - 1 - sulfonamide N LL F O = S = N - S - NH F ' N ' N ( R ) ZI N CI N N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide - 311- 1100573566 5 AMERICAS CI- N N N- F N -N Attorney Docket No .: 121843.002NU - 3200 PCT F NH O == O = N HN N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] - - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide N .N .

N - S - NH O = S = F ' N ' N ( R ) H N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide -312 - 1100573566 5 AMERICAS N - S - NH = S = F F N N .N . & ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide N O = SS = O -S - NH F N F N N ( R ) ' N N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide - 313 - 1100573566 5 AMERICAS -S - NH = S = F N .N . N : F N & ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide ' N ' F .N .

N - S S - NH F = S = CI N ( R ) N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide - 314 - 1100573566 5 AMERICAS N & N NH F F N ' N ' 3EN CI Attorney Docket No .: 121843.002NU - 3200 PCT N- rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -1,4- diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide -NH F F N N ﺕ ( R ) N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -1,4 - diazepan- - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide - 315 - 1100573566 5 AMERICAS N - S - NH F O == O CI N N .N .

F & N ' Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2 - fluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide N - S - NH O = S = F N F & ' N ' ZI H CI N N rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide - 316 - 1100573566 5 AMERICAS a O = SS = O N - S - NH F F N N ( R ) N Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide N 0 = S = -S - NH F 3F N & N rac - N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide -317- 1100573566 5 AMERICAS a 3 O = S = N - S - NH CI F N N N N ( R ) N Attorney Docket No .: 121843.002NU - 3200 PCT N- { 5 - chloro - 3- [ 1- ( 6- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide N O = S = N - S - NH F CI N N & rac - N- { 5 - chloro - 3- [ 1- ( 6- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide - 318 - 1100573566 5 AMERICAS -S - NH = S = F CI N N FL ' N ' .N .

( R ) Attorney Docket No .: 121843.002NU - 3200 PCT N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide N O = S = O N - S - NH F CI N N LL F N. & rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } pyrrolidine - 1 - sulfonamide -319- 1100573566 5 AMERICAS N N N CI- NH F -N Attorney Docket No .: 121843.002NU - 3200 PCT H N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl } methyl ) piperazin- - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide N N N N F 3NH F O = 5 = F -N N H N- [ 5- ( difluoromethyl ) -3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine- - sulfonamide - 320 - 1100573566 5 AMERICAS -S - NH = S = F 3F F N ' N ' .N . N & ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine- - sulfonamide CI N N : .N . N NH 0 = s = N -N N- N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1- yl ] pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide - 321 - 1100573566 5 AMERICAS O = S = O N - S - NH F N : CI N N N 1 & Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine- - sulfonamide N N- = S = N -S - NH F ' N ' CI N N N { ( R ) ZI N N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide -322- 1100573566 5 AMERICAS N Cl NH F N N -N F -N N H Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] - - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide N 0 = S = N - S - NH F N N F F .N .

{ ( R ) ' N ' N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine- - sulfonamide -323- 1100573566 5 AMERICAS a N - S - NH = S = F CI N F ' N ' 1 & ' N ' H Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine- - sulfonamide LL F N N- -S - NH = S = CI F N ( R ) ZI N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide - 324- 1100573566 5 AMERICAS CI- N N N -N N- F F NH -N Attorney Docket No .: 121843.002NU - 3200 PCT · TILL ( R ) N HN- ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin- - yl ] -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1- sulfonamide N FR N - S - NH O = S = CI F N N F N ' N ' ZI ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide -325- 1100573566 5 AMERICAS FR -S - NH F = SS = CI N ' N ' F LL N N. ( R ) Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } -3- fluoropyrrolidine - 1 - sulfonamide N CI- NH O = 5 = F -N a -N F N HN- N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl } methyl ) piperazin- - yl ] phenyl } -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide -326- 1100573566 5 AMERICAS Cl N N N F -N F NH O = S = N N- N Attorney Docket No .: 121843.002NU - 3200 PCT F N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl } methyl ) piperazin- - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide N CI- NH O = S = .N . N -N F F N N N- N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl } methyl ) piperazin- - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide - 327 - 1100573566 5 AMERICAS Cl N N NH LL F F N- -N N- HN- Attorney Docket No .: 121843.002NU - 3200 PCT ( R ) F ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3- fluoropyrrolidine - 1 - sulfonamide N S - NH O = S = O CI F N N N ( R ) N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylcyclopentanesulfonamide -328- 1100573566 5 AMERICAS -S - NH O = S = O F N CI N ' N ' .N . N N & Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylcyclopentanesulfonamide N S - NH O = S = F CI N ( R ) ' N ' N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1- yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } cyclopentanesulfonamide -329- 1100573566 5 AMERICAS -N = 5 = ` NH -F N N ( R ) Attorney Docket No .: 121843.002NU - 3200 PCT N. N N ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione H -N NH -F N N N & rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione - 330 - 1100573566 5 AMERICAS -N = 5 = F NH -F N N ( R ) Attorney Docket No .: 121843.002 N. ( 3R ) -3- ( 4- ( 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } phenyl ) piperidine - 2,6 - dione 0 = 8 = NH F " ( R ) N ( R ) N N- [ 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide NU - 3200 PCT 1100573566 5 AMERICAS -N NH -F - IZ ( R ) Attorney Docket No .: 121843.002NU - 3200 PCT N. F N ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ] -3 - fluorophenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione H N N = 8 = NH F N ( s ) N.

N F N ( 3S ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ] -2 - fluorophenyl } piperazin - 1 - yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione - 332 - 1100573566 5 AMERICAS 0 = 8 = NH F IZ & Attorney Docket No .: 121843.002NU - 3200 PCT N N rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 4- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperazin - 1 - yl ) methyl ) piperidin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( R ) N ( R ) 0 = S = F N - S - NH F N N CI N N- ( 5 - chloro - 3- ( 1- ( 4 - ( ( 3R , 5R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) - 3,5 - dimethylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide - 333 - 1100573566 5 AMERICAS CI- N NH .N . N ﺵﺩ -N N Attorney Docket No .: 121843.002NU - 3200 PCT N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide ' N ' O = S = CI -NH F N ' N .N .

N ' N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] -3 - fluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide - 334 - 1100573566 5 AMERICAS S - NH F ○ = S = 3CI N ' N ' F N N. .F N Attorney Docket No .: 121843.002 rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2,3 - difluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide O == O N - S - NH F N ' N 3CI N N F N ' N ' NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2,5 - difluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide CI- N.

HN - S - N O = S = N F IN FL 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3,5 - difluorophenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide N ﺶﮑﻫ N .N . N N CI- NH F -N N N N N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidin - 4 - yl ) methyl ) piperazin- - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] cyclopentanesulfonamide - 336 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000181 ] Synthesis of N- { 2- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2 - methylpropyl } oxane - 4 - carboxamide וו O = S HN .

HN- Boc HN- -OH NH NHCI , HATU , DIEA DMF Step - HCl / dioxane -N₂H Cl Step - NH CI TEA , DCM Step - HN FL N N S NH NH Lawesson's reagent -NHTHF NH Step - 2 OH HATU , DIEA , DMF HN- Step - CI CI -NHPd ( OAc ) 2 , BINAP , CS2CO3 , dioxane Step - HN -NHNBS , DMA Step - NH HOAc , Pd ( PPh3 ) 2Cl2 , Bu3SnH , DCM Step - HCI in dioxane N NH Boo Step - HN [ 000182 ] Step - 1 : dimethylethyl ) carbamate ( 2 ) Synthesis of tert - butyl N- ( 2 - carbamoyl - 2,2- To a mixture of 3 - [ ( tert - butoxycarbonyl ) amino ] -2,2 - dimethylpropanoic acid ( 5 g , 23.01 mmol , equiv ) and NH4Cl ( 6.15g , 115.06 mmol , 5 equiv ) in DMF ( 50 mL ) was added HATU ( 13.g , 34.52 mmol , 1.5 equiv ) and DIEA ( 8.92 g , 69.03 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl N- ( 2 - carbamoyl - 2,2 - dimethylethyl ) carbamate ( 3.5 g , crude ) as a yellow oil .

₂HN 1100573566 5 AMERICAS [ 000183 ] Step - 2 : Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 2 - carbamothioyl - 2,2- Synthesis of tert - butyl dimethylethyl ) carbamate ( 3 ) To a mixture of tert - butyl N- ( 2 - carbamoyl - 2,2 - dimethylethyl ) carbamate ( 3.5 g , 16.183 mmol , equiv ) in THF ( 40 mL ) was added Lawesson's Reagent ( 3.27 g , 8.091 mmol , 0.5 equiv ) at room temperature . The resulting mixture was stirred overnight at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography , eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl N- ( 2 - carbamothioyl - 2,2 - dimethylethyl ) carbamate ( 1.6 g , 38.30 % ) as a white solid . LCMS : C10H20N2O2S requires : 232.1 , found : m / z = 233.1 [ M + H ] * . [ 000184 ] Step - 3 : Synthesis of tert - butyl N- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2- fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -2- methylpropyl carbamate ( 4 ) To a mixture of tert - butyl N- ( 2 - carbamothioyl - 2,2 - dimethylethyl ) carbamate ( 370 mg , 1.mmol , 1 equiv ) and NBS ( 283 mg , 1.59 mmol , 1 equiv ) in DMA ( 5 mL ) was added prop - 2 - en- - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2 - fluorophenyl } carbamate ( 556 mg , 1.59 mmol , equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography , eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl N- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -2 - methylpropyl } carbamate ( 200 mg , 20.11 % ) as a white solid . LCMS : C26H29C1FN5O4S requires : 561.2 , found : m / z = 562.1 [ M + H ] * . [ 000185 ] Step - 4 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 1 - amino - 2 - methylpropan - 2- yl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 5 ) A solution of tert - butyl N- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -2 - methylpropyl } carbamate ( 190 mg , 0.3mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 5 mL , 4 M ) was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure to afford prop - 2 - en - 1 - yl N- { 3- [ 2- ( 1 - amino - 2 - methylpropan - 2 - yl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } carbamate ( 110 mg , crude ) as a yellow oil . LCMS : C21H21CIFN5O2S requires : 461.1 , found : m / z = 462.0 [ M + H ] * . -338- 1100573566 5 AMERICAS [ 000186 ] Attorney Docket No .: 121843.002NU - 3200 PCT Step - 5 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- [ 2- methyl - 1- ( oxan - 4 - ylformamido ) propan - 2 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } carbamate ( 6 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 1 - amino - 2 - methylpropan - 2 - yl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 200 mg , 0.43 mmol , equiv ) and oxane - 4 - carboxylic acid ( 84 mg , 0.64 mmol , 1.5 equiv ) in DMF ( 2 mL ) was added HATU ( 246 mg , 0.64 mmol , 1.5 equiv ) and DIEA ( 279 mg , 2.16 mmol , 5 equiv ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography , eluted with PE : EtOAc ( 5 : 1 ) to afford prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- [ 2 - methyl - 1- ( oxan - 4- ylformamido ) propan - 2 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 150 mg , 53.11 % ) as a yellow oil . LCMS : C27H29CIFN5O4S requires : 573.2 , found : m / z = 574.1 [ M + H ] * . [ 000187 ] Step - 6 : Synthesis of N- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] -2 - methylpropyl } oxane - 4 - carboxamide ( 7 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- [ 2 - methyl - 1- ( oxan - 4- ylformamido ) propan - 2 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 140 mg , 0.244 mmol , equiv ) and Pd ( PPh3 ) 2Cl2 ( 3.42 mg , 0.005 mmol , 0.02 equiv ) in DCM ( 2 mL ) was added HOAc ( 35.15 mg , 0.586 mmol , 2.4 equiv ) and n - HnSзuB ( 106.47 mg , 0.366 mmol , 1.5 equiv ) at 0 ° C . The resulting mixture was stirred for 0.5 h at 0 ° C . The reaction was quenched by the addition of saturated NaHCO3 aqueous at 0 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford N- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] -2- methylpropyl } oxane - 4 - carboxamide ( 120 mg , crude ) as a yellow oil . LCMS : C23H25CIFN5O2S requires : 489.1 , found : m / z = 490.1 [ M + H ] * . [ 000188 ] Step - 7 : Synthesis of N- ( 2- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) -2 - methylpropyl ) tetrahydro - 2H - pyran - 4- carboxamide ( 8 ) To a mixture of N- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2- yl ] -2 - methylpropyl } oxane - 4 - carboxamide ( 80 mg , 0.163 mmol , 1 equiv ) in DCM ( 2 mL ) was -339- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT added TEA ( 49.56 mg , 0.489 mmol , 3 equiv ) and propane - 1 - sulfonyl chloride ( 34.92 mg , 0.2mmol , 1.5 equiv ) at room temperature . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- ( 2- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) -2- methylpropyl ) tetrahydro - 2H - pyran - 4 - carboxamide ( 100 mg , crude ) as a brown oil . LCMS : C26H31C1FN5O4S2 requires : 595.1 , found : m / z = 596.1 [ M + H ] * . [ 000189 ] Step - 8 : Synthesis of tert - butyl N- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -2- [ 2 - methyl - 1- ( oxan - 4 - ylformamido ) propan - 2 - yl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) carbamate ( 9 ) To a mixture of N- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2 - methylpropyl } oxane - 4 - carboxamide ( 70 mg , 0.1mmol , 1 equiv ) and tert - butyl carbamate ( 20.63 mg , 0.176 mmol , 1.5 equiv ) in dioxane ( 2 mL ) was added Pd ( OAc ) 2 ( 2.64 mg , 0.012 mmol , 0.1 equiv ) , Cs2CO3 ( 61.21 mg , 0.187 mmol , 1.equiv ) , and BINAP ( 21.94 mg , 0.035 mmol , 0.3 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 3 h at 90 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by Prep - TLC CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl N- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -2- [ 2 - methyl - 1- ( oxan - 4 - ylformamido ) propan - 2 - yl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) carbamate ( 45 mg , 50.96 % ) as a white solid . LCMS : C31H41FN6O6Srequires : 676.3 , found : m / z = 677.2 [ M + H ] * . [ 000190 ] Step - 9 : Synthesis of N- { 2- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2 - methylpropyl } oxane - 4 - carboxamide A solution of tert - butyl N- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -2- [ 2 - methyl - 1- ( oxan - 4 - ylformamido ) propan - 2 - yl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) carbamate ( 35 mg , 0.0mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 5 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was purified by reverse phase flash chromatography with O₂H : MeCN ( 3 : 1 ) to afford N- { 2- [ 5- ( 2- aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2- methylpropyl } oxane - 4 - carboxamide ( 28.8 mg , 92.71 % ) as an off - white solid . LCMS : C26H33FN6O4S2 requires : 576.2 , found : m / z = 577.2 [ M + H ] * . – H¹ NMR ( 400 MHz , CD3OD ) 8 8.10 – 8.08 ( m , 1H ) , 7.71 – 7.67 ( m , 1H ) , 7.53 – 7.51 ( m , 1H ) , 7.40 -7.36 ( m , 1H ) , 6.67 – 6.64 ( m , 1H ) , 3.92 – 3.88 ( m , 2H ) , 3.56 – 3.54 ( m , 2H ) , 3.42 -3. - 340 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( m , 2H ) , 3.183.14 ( m , 2H ) , 2.57 – 2.42 ( m , 1H ) , 1.90 – 1.84 ( m , 2H ) , 1.74 – 1.62 ( m , 4H ) , 1.52 ( s , 6H ) , 1.06 – 1.04 ( m , 3H ) . [ 000191 ] Synthesis of N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- ( piperidin - 4 - yl ) propan- - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide pyridine , DCM Step - ( 1 ) HN -S = F HN- N N N₂H NHNBS , DMA Step - ( 2 ) F HN -NH Step - NH CI ( 3 ) HN - S = O HOAc , Pd ( PPh3 ) 2Cl2 , HnSзuB , DCM , rt , 0.5 h Step - HCl / dioxane , DCM ( 4 ) NH HCI HN -8 = Step - HN- HN . N₂H ( 5 ) ( 6 ) [ 000192 ] Step - 1 : Synthesis of tert - butyl 4- ( 2- ( 4- ( 3 - ( ( ( allyloxy ) carbonyl ) amino ) -2- fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) thiazol - 2 - yl ) propan - 2 - yl ) piperidine - 1- carboxylate ( 3 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenylcarbamate ( 2.4 g , 6.98 mmol , 1 equiv ) in DMA ( 20.0 mL ) was added NBS ( 1.g , 6.98 mmol , 1 equiv ) for 15 min at room temperature followed by the addition of tert - butyl 4- ( 1 - carbamothioyl - 1 - methylethyl ) piperidine - 1 - carboxylate ( 2.0 g , 6.98 mmol , 1 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried - 341 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- tert - butyl yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 1.g , 41.84 % ) as a white solid . LCMS : C30H35C1FN5O4S requires : 615.2 , found : m / z = 616.[ M + H ] + . [ 000193 ] Step - 2 : Synthesis of tert - butyl 4- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 1.0 g , 1.623 mmol , 1 equiv ) and HOAc ( 243.66 mg , 4.058 mmol , 2.5 equiv ) in DCM ( 4 mL ) was added Pd ( PPh3 ) 2Cl2 ( 22.78 mg , 0.032 mmol , 0.02 equiv ) and n - HnSзuB ( 755.83 mg , 2.5mmol , 1.6 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 0.5 h at room temperature under the nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl 4- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2- yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 700 mg , crude ) as a brown oil . The crude product was used in the next step directly without further purification . LCMS : C26H31C1FN5O2S requires : 531.2 , found : m / z = 532.2 [ M + H ] * . [ 000194 ] Step - 3 : Synthesis of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] propan - 2 - yl } piperidine - 1- carboxylate ( 5 ) g , To a mixture of tert - butyl 4- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 1.6 g , 3.007 mmol , 1 equiv ) and pyridine ( 0.24 g , 3.007 mmol , 1.0 equiv ) in DCM ( 15 mL ) was added propane - 1 - sulfonyl chloride ( 0.3.007 mmol , 1.0 equiv ) dropwise at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under vacuum . The crude product was dissolved in THF ( 5 mL ) , ACN ( 5 mL ) , and H2O ( 5 mL ) . Na2CO3 ( 3.7 g , 35.190 mmol , equiv ) was added at room temperature . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under vacuum . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was -342- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol- - yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 1.0 g , 52.11 % ) as a yellow solid . LCMS : C29H37C1FN5O4S2 requires : 637.2 , found : m / z = 638.2 [ M + H ] * . [ 000195 ] Step - 4 : Synthesis of tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) propan - 2 - yl ] piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] propan - 2 - yl } piperidine - 1 - carboxylate ( 1.0 g , 1.5mmol , 1 equiv ) and BocNH2 ( 917.79 mg , 7.835 mmol , 5.0 equiv ) in 1,4 - dioxane ( 10 mL ) was added BrettPhos Pd G3 ( 142.0 mg , 0.157 mmol , 0.1 equiv ) and CS2CO3 ( 1.02g , 3.134 mmol , 2.0 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred at 80 ° C overnight under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4- yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) propan - 2 - yl ] piperidine - 1- carboxylate ( 800 mg , 82.51 % ) as a yellow solid . LCMS : C34H47FN6O6S2 requires : 718.3 , found : m / z = 719.1 [ M + H ] * . [ 000196 ] Step - 5 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4- yl ) propan - 2 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenylpropane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) propan - 2 - yl ] piperidine - 1- carboxylate ( 800 mg , 1.113 mmol , 1 equiv ) in DCM ( 8 mL ) was added HCl ( gas ) in 1,4- dioxane ( 2 mL , 4 M ) . The resulting mixture was stirred at room temperature for 2 h . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in Water ( 0.1 % formic acid ( FA ) ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4 - yl ) propan - 2 - yl ] -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride ( 553 mg , 89.52 % ) as a yellow solid . LCMS : C24H31FN6O2S2 requires : 518.2 , found : m / z = 519.2 [ M + H ] * . 1H NMR ( 400 MHz , CD3OD ) § 8.10 ( d , J = 6.8 Hz , 1H ) , 7.69 ( d , J = 1.6 Hz , 1H ) , 7.52 – 7.( m , 1H ) , 7.40 – 7.36 ( m , 1H ) , 6.66 – 6.64 ( m , 1H ) , 3.51 – 3.40 ( m , 2H ) , 3.23 – 3.13 ( m , 2H ) , -343- 1100573566 5 AMERICAS - – - Attorney Docket No .: 121843.002NU - 3200 PCT - 3.05 2.85 ( m , 2H ) , 2.24 – 2.16 ( m , 1H ) , 2.01 – 1.82 ( m , 4H ) , 1.71 – 1.65 ( m , 2H ) , 1.55 ( s , 6H ) , 1.10 – 1.07 ( m , 3H ) . [ 000197 ] - Synthesis of N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride salt ( 1 ) NHNBS , DMA Step - || O = S HN F N HCI N HN ( 10 ) HN CI N₂H . TEA , DCM Step - H Myox ( 2 ) NH HOAc , Pd ( PPh3 ) 2Cl2 , . BuzSnH , DCM Step - ( 3 ) N N₂H HN . HN Step - 4 Step - HN- HCI HN . ( 4 ) ( 5 ) [ 000198 ] Step - 1 : Synthesis of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2 - fluorophenyl } carbamate ( 1.1 g , 3.145 mmol , 1.00 equiv ) and NBS ( 559.8 mg , 3.145 mmol , 1.0 equiv ) in DMA ( 13 mL ) was added tert - butyl 4 - carbamothioylpiperidine - 1 - carboxylate ( 922.2 mg , 3.774 mmol , 1.20 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted -344- 1100573566 5 AMERICAS NH2 Attorney Docket No .: 121843.002NU - 3200 PCT with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop- - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 580 mg , 32.12 % ) as a yellow solid . LCMS : C27H29C1FN5O4S requires : 573.2 , found : m / z = 574.[ M + H ] + . [ 000199 ] 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- Step - 2 : Synthesis of tert - butyl chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 600 mg , 1.0mmol , 1 equiv ) and HOAc ( 156.9 mg , 2.612 mmol , 2.5 equiv ) in DCM ( 8 mL ) was added Pd ( PPh3 ) 2Cl2 ( 14.7 mg , 0.021 mmol , 0.02 equiv ) and n - HnSзuB ( 486.7 mg , 1.672 mmol , 1.equiv ) in portions at 0 ° C . The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum to afford tert- butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine- - carboxylate ( 510 mg , crude ) as a red oil . The resulting mixture was used in the next step directly without further purification . LCMS : C23H25C1FN5O2S requires : 489.1 , found : m / z = 490.1 [ M + H ] * . [ 000200 ] Step - 3 : Synthesis of tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 2 g , 4.082 mmol , 1 equiv ) and TEA ( 1.24 g , 12.2mmol , 3 equiv ) in DCM ( 20 mL ) was added propane - 1 - sulfonyl chloride ( 873.08 mg , 6.1mmol , 1.5 equiv ) dropwise at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under vacuum . To the crude product in H2O ( 7 mL ) , MeCN ( 7 mL ) , and THF ( 7 mL ) was added Na2CO3 ( 1.06 g , 10.065 mmol , 2.equiv ) at room temperature . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 1.58 g , 64.93 % ) as a yellow solid . LCMS : C26H31C1FN5O4S2 requires : 595.1 , found : m / z = 596.1 [ M + H ] * . - 345- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 [ 000201 ] Step - 4 : Synthesis of tert - butyl butoxycarbonyl ) amino ) pyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 5 ) To a mixture of NU - 3200 PCT 4- ( 5- ( 2 - ( ( tert- tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 1 g , 1.677 mmol , 1 equiv ) and tert - butyl carbamate ( 982.6 mg , 8.385 mmol , 5 equiv ) in 1,4 - dioxane ( 10 mL ) was added BrettPhos Pd G3 ( 152 mg , 0.168 mmol , 0.1 equiv ) and Cs2CO3 ( 1.1 g , 3.354 mmol , 2 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 80 ° C under a nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 5- ( 2 - ( ( tert- butoxycarbonyl ) amino ) pyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2- yl ) piperidine - 1 - carboxylate ( 850 mg , 74.87 % ) as a yellow solid . LCMS : C31H41FN6O6Srequires : 676.3 , found : m / z = 677.3 [ M + H ] * . [ 000202 ] Step - 5 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- ( 5- ( 2 - ( ( tert - butoxycarbonyl ) amino ) pyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 1.5 g , 2.217 mmol , 1 equiv ) in DCM ( 3 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 12 mL , 4 M ) at room temperature . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % formic acid ( FA ) ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 649.6 mg , 57.13 % ) as a yellow solid . LCMS : C21H25FN6O2S2 requires : 476.3 , found : m / z = 477.3 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.09 ( d , J = 6.0 Hz , 1H ) , 7.68 – 7.66 ( m , 1H ) , 7.49 – 7.28 ( m , 2H ) , 6.65 – 6.63 ( m , 1H ) , 3.60 – 3.48 ( m , 3H ) , 3.28 – 3.16 ( m , 2H ) , 3.17 – 3.05 ( m , 2H ) , 2.49 – 2.39 ( m , 2H ) , 2.- 2.09 ( m , 2H ) , 1.94 – 1.78 ( m , 2H ) , 1.14 – 0.98 ( m , 3H ) . [ 000203 ] Synthesis of - – N- { 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride salt - 346 - 1100573566 5 AMERICAS Boc 6 = HN- HCI S N Pd / C , NH OAc , MeOH Step - Boc IZ Attorney Docket No .: 121843.002NU - 3200 PCT -S = O HCl / dioxane Step - HCI HN [ 000204 ] Step - 1 : Synthesis of tert - butyl 4-4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 2 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 700 mg , 1.174 mmol , 1 equiv ) and NH4OAc ( 905.14 mg , 11.740 mmol , 10 equiv ) in MeOH ( 10 mL ) was added Pd / C ( 7mg ) at room temperature . The resulting mixture was stirred for 30 min at 40 ° C . The resulting mixture was filtered . The filtrate was concentrated under reduced pressure . The residue was purified by C18 silica gel column chromatography eluted with CH3CN : H2O ( 1 : 1 ) to afford tert- butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 2- yl } piperidine - 1 - carboxylate ( 450 mg , 68.23 % ) as a yellow solid . LCMS : C26H32FN5O4Srequires : 561.2 , found : m / z = 562.2 [ M + H ] * . [ 000205 ] Step - 2 : Synthesis of N- ( 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyrimidin - 4 - yl ) - 1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 450 mg , 0.801 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 5 mL , 4 N ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . This resulted in N- ( 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride salt ( 300.1 mg , crude ) as a yellow solid . LCMS : C21H24FN5O2S2 requires : 461.1 , found : m / z = 462.1 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 9.30 – 9.28 ( m , 1H ) , 8.76 - 8.74 ( m , 1H ) , 7.71 – 7.67 ( m , 1H ) , 7.50 - 7.38 ( m , 3H ) , 3.60 – 3.55 ( m , 3H ) , 3.27 – 3.22 ( m , 2H ) , 3.16 – 3.12 ( m , 2H ) , 2.48 – 2.43 ( m , 2H ) , 2.20 – 2.14 ( m , 2H ) , 1.89 – 1.83 ( m , 2H ) , 1.06 – 1.03 ( m , 3H ) . - - · – - 347 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000206 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperidin - 4 - yl ) phenyl ] - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide Boc HO NHCI , HATU , DIEA , DMF Step - HOAc , Pd ( PPh3 ) 2Cl2 , Bu3SnH , DCM N₂H IZ = 5 = HN- Lawesson's reagent N S NH N₂H THF NBS , DMA Step - 2 Step - Boo Bod N₂H F Step - Boc Boc HN HCl / dioxane Step - i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H Step - 0 = 5 = HN- Boc NH N₂H Boc Brettphos Pd G3 , ³OCsC , 1,4 - dioxane Step - [ 000207 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 4- ( 4 - carbamoylphenyl ) piperidine - 1- To a mixture of 4- [ 1- ( tert - butoxycarbonyl ) piperidin - 4 - yl ] benzoic acid ( 5 g , 16.37 mmol , equiv ) and NH4Cl ( 4.37 g , 81.86 mmol , 5 equiv ) in DMF ( 50 mL ) was added HATU ( 9.33 g , 24.55 mmol , 1.5 equiv ) and DIEA ( 6.34 g , 49.11 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was - 348 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The product was washed with EtOAc . The precipitated solids were collected by filtration to afford tert - butyl 4- ( 4 - carbamoylphenyl ) piperidine - 1 - carboxylate ( 4.8 g , 96.31 % ) as a white solid . LCMS : C17H24N2O3 requires : 304.2 , found : m / z = 305.2 [ M + H ] * . [ 000208 ] carboxylate ( 3 ) Step - 2 : Synthesis of tert - butyl 4- ( 4 - carbamothioylphenyl ) piperidine - 1- To a mixture of tert - butyl 4- ( 4 - carbamoylphenyl ) piperidine - 1 - carboxylate ( 3 g , 9.85 mmol , equiv ) in THF ( 30 mL ) was added Lawesson's Reagent ( 1.99 g , 4.92 mmol , 0.5 equiv ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with aqueous NaHCO3 and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - carbamothioylphenyl ) piperidine - 1 - carboxylate ( 2.2 g , 69.66 % ) as a white solid . LCMS : C17H24N2O2S requires : 320.1 , found : m / z = 321.[ M + H ] + . [ 000209 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1- carboxylate ( 5 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenyl } carbamate ( 1.8 g , 5.14 mmol , 1 equiv ) in DMA ( 20 mL ) was added tert - butyl 4- ( 4 - carbamothioylphenyl ) piperidine - 1 - carboxylate ( 1.98 g , 6.17 mmol , 1.2 equiv ) and NBS ( 1.83 g , 10.29 mmol , 2 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin- - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2- yl ] phenylpiperidine - 1 - carboxylate ( 1.8 g , 48.95 % ) as a yellow solid . LCMS : C33H33C1FN5O4S requires : 649.2 , found : m / z = 650.2 [ M + H ] * . [ 000210 ] Step - 4 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 6 ) -349- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.8 g , 2.mmol , 1 equiv ) and HOAc ( 415 mg , 6.93 mmol , 2.5 equiv ) in DCM ( 20 mL ) was added n- HnSзuB ( 1.29 g , 4.43 mmol , 1.6 equiv ) and Pd ( PPh3 ) 2Cl2 ( 39 mg , 0.05 mmol , 0.02 equiv ) at ° C under a nitrogen atmosphere . The resulting mixture was stirred for 30 min at room temperature . The reaction was quenched with saturated aqueous NaHCO3 at 0 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.5 g , crude ) as a brown solid . LCMS : C29H29C1FN5O2S requires : 565.2 , found : m / z = 566.2 [ M + H ] * . [ 000211 ] Step - 5 : Synthesis of tert - butyl 4- ( 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) phenyl ) piperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.5 g , 2.65 mmol , 1 equiv ) in DCM ( 15 mL ) was added propane - 1 - sulfonyl chloride ( 755 mg , 5.30 mmol , 2 equiv ) and TEA ( 804 mg , 7.95 mmol , equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 5 mL ) , O₂H ( 5 mL ) , and MeCN ( 5 mL ) . Na2CO3 ( 1.13 g , 10.68 mmol , 5 equiv ) was added at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was concentrated under vacuum . The residue was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 4- ( 5- ( 2- chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2- yl ) phenyl ) piperidine - 1 - carboxylate ( 1.1 g , 73.77 % ) as a yellow solid . LCMS : C32H35CIFN5O4S2 requires : 671.2 , found : m / z = 672.2 [ M + H ] * . [ 000212 ] Step - 6 : Synthesis of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 8 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 600 mg , 0.89 mmol , equiv ) and tert - butyl carbamate ( 522.80 mg , 4.465 mmol , 5 equiv ) in dioxane ( 6 mL ) was - 350 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT added BrettPhos Pd G3 ( 81 mg , 0.089 mmol , 0.1 equiv ) and Cs2CO3 ( 581 mg , 1.78 mmol , equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for h at 80 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 400 mg , 53.57 % ) as a yellow solid . LCMS : C37H45FN6O6S2 requires : 752.2 , found : m / z = 753.3 [ M + H ] * . [ 000213 ] Step - 7 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperidin - 4- yl ) phenyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide A mixture of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 400 mg , 0.53 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 5 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was purified by Prep - HPLC with the following conditions : Column : XBridge Prep OBD CColumn , 30 * 150 mm , 5 mμ ; Mobile Phase A : water ( 10 mmol / L NH4HCO3 ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 30 % B to 38 % B in 8 min ; Wave Length : 220/254 nm ; ₁₁R ( min ) : 6.75 to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperidin - 4 - yl ) phenyl ] -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 223.7 mg , 70.01 % ) as a yellow solid . LCMS : C27H29FN6O2S2 requires : 552.2 , found : m / z = 553.2 [ M + H ] * . ' H NMR ( 400 MHz , DMSO - εd ) 8 8.15 – 8.06 ( m , 1H ) , 7.98 – 7.93 ( m , 2H ) , 7.56 – 7.52 ( m , 1H ) , 7.40 – 7.37 ( m , 2H ) , 7.24 – 7.16 ( m , 2H ) , 6.79 ( s , 2H ) , 6.18 – 6.16 ( m , 1H ) , 3.21 – 3.12 ( m , 2H ) , 2.97 – 2.( m , 2H ) , 2.77 – 2.69 ( m , 3H ) , 1.80 – 1.71 ( m , 2H ) , 1.69 – 1.57 ( m , 4H ) , 0.94 – 0.90 ( m , 3H ) . [ 000214 ] - Synthesis of = - - 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- ( 4- { 3,8 - diazabicyclo [ 3.2.1 ] octan - 8 - yl } -3- fluorophenyl ) pyrimidin - 2 - amine ; trifluoroacetic acid salt ﻝا -N . HN F N .N . .N . F N N .NH 1100573566 5 AMERICAS N₂O ( 1 ) HN Boc DMSO , DIEA Step - N₂O .

HN TFA , DCM Step - ( 2 ) Boc H2 , Pd / C , EtOH Attorney Docket No .: 121843.002NU - 3200 PCT N₂H .

Step - ( 3 ) HN OH NH Boc HN F .CI ( 4 ) Brettphos Pd G3 , ³OC₂sC , 1,4 - dioxane Step - [ 000215 ] ( 5 ) Boc Step - 1 : Synthesis of tert - butyl diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 2 ) 8- ( 2 - fluoro - 4 - nitrophenyl ) -3,8- To a mixture of 1,2 - difluoro - 4 - nitrobenzene ( 1.0 g , 6.286 mmol , 1 equiv ) and DIEA ( 2.44 g , 18.858 mmol , 3.0 equiv ) in in DMSO ( 10 mL ) was added tert - butyl 3,8- diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 1.33 g , 6.286 mmol , 1.0 equiv ) in portions at room temperature . The resulting mixture was stirred for 3 h at 100 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 8- ( 2 - fluoro - 4 - nitrophenyl ) -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 1.2 g , 54.33 % ) as a yellow solid . LCMS : C17H22FN3O4 requires : 351.2 , found : m / z = 352.[ M + H ] * . [ 000216 ] Step - 2 : Synthesis of diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 3 ) tert - butyl 8- ( 4 - amino - 2 - fluorophenyl ) -3,8- To a mixture of tert - butyl 8- ( 2 - fluoro - 4 - nitrophenyl ) -3,8 - diazabicyclo [ 3.2.1 ] octane - 3- carboxylate ( 600 mg , 1.708 mmol , 1 equiv ) in EtOH ( 10 mL ) was added Pd / C ( 299.84 mg , 2.818 mmol , 1.65 equiv ) in portions at room temperature . The resulting mixture was stirred for h at room temperature under a hydrogen atmosphere . The resulting mixture was filtered . The filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 8- ( 4 - amino - 2- -352- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT fluorophenyl ) -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 400 mg , 72.89 % ) as a yellow solid . LCMS : C17H24FN3O2 requires : 321.2 , found : m / z = 322.2 [ M + H ] * . [ 000217 ] Step - 3 : Synthesis of tert - butyl 8- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl } amino ) -2 - fluorophenyl ] -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 5 ) To a mixture of tert - butyl 8- ( 4 - amino - 2 - fluorophenyl ) -3,8 - diazabicyclo [ 3.2.1 ] octane - 3- carboxylate ( 380 mg , 1.182 mmol , 1 equiv ) and ( { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 629.49 mg , 1.300 mmol , 1.equiv ) in 1,4 - dioxane ( 4 mL ) was added BrettPhos Pd G3 ( 107.18 mg , 0.118 mmol , 0.1 equiv ) and Cs2CO3 ( 770.46 mg , 2.364 mmol , 2.0 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred overnight at 80 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 5 : 1 ) to afford tert- butyl 8- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] -3,8 - diazabicyclo [ 3.2.1 ] octane - 3- carboxylate ( 385 mg , 42.35 % ) as a yellow solid . LCMS : C37H46F2N8O4S2 requires : 768.3 , found : m / z = 769.3 [ M + H ] * . [ 000218 ] Step - 4 : Synthesis of 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- ( 4- { 3,8 - diazabicyclo [ 3.2.1 ] octan - 8 - yl } -3- fluorophenyl ) pyrimidin - 2 - amine ; trifluoroacetic acid To a mixture of tert - butyl 8- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] -3,8- diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 380 mg , 0.494 mmol , 1 equiv ) in DCM ( 3 mL ) was added TFA ( 3 mL ) dropwise at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure to afford 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5- yl ] -N- ( 4- ( 3,8 - diazabicyclo [ 3.2.1 ] octan - 8 - yl } -3 - fluorophenyl ) pyrimidin - 2 - amine ; trifluoroacetic acid salt ( 350 mg , crude ) as a red solid . LCMS : C32H38F2N8O2S2 requires : 668.3 , found : m / z = 669.3 [ M + H ] * . ' H NMR ( 300 MHz , CD3OD ) 8 8.24 ( d , J = 4.8 Hz , 1H ) , 7.72 – 7.62 ( m , 2H ) , 7.32 ( d , J = 8.4 Hz , 2H ) , 7.20 ( d , J = 8.7 Hz , 1H ) , 6.95 – 7.82 ( m , 1H ) , 6.60 – 6.50 ( m , 1H ) , 4.28 ( s , 2H ) , 3.49 – 3.38 ( m , 2H ) , 3.28 – 3.17 ( m , 4H ) , 2.82 – 2.76 ( m , 3H ) , 2.-2.21 ( m , 2H ) , 2.09 – 1.98 ( m , 2H ) , 1.58 – 1.52 ( m , 9H ) , 1.18 - 1.02 ( m , 3H ) . _ - -353- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000219 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4 - methylpiperidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HOAc , Pd ( PPh3 ) 2Cl2 , Bu3SnH , DCM ₂HN Lawesson's reagent N₂H . F Step - Boc HN . F THF O = S HN F N N -S NH HN- Step - HCI in dioxane -Boc Step - NH i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H O = S HN .

HN Step - NH O = S HN .

Boc NBS , DMA Step - Boc HN .

-NHPd2 ( dba ) 3 , XPhos , CsCO3 , dioxane Step - Boc [ 000220 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 4 - carbamothioyl - 4 - methylpiperidine - 1- To a mixture of tert - butyl 4 - carbamoyl - 4 - methylpiperidine - 1 - carboxylate ( 4 g , 16.5 mmol , equiv ) in THF ( 40 mL ) was added Lawesson's Reagent ( 3.34 g , 8.25 mmol , 0.5 equiv ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over -354- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4 - carbamothioyl - 4 - methylpiperidine - 1 - carboxylate ( 2.1 g , 44.31 % ) as a yellow oil . LCMS : C12H22N2O2S requires : 258.1 , found : m / z = 259.0 [ M + H ] * . [ 000221 ] = Step - 2 : Synthesis of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -4 - methylpiperidine - 1- carboxylate ( 4 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenylcarbamate ( 3 g , 8.57 mmol , 1 equiv ) in DMA ( 30 mL ) was added NBS ( 1.53 g , 8.57 mmol , 1 equiv ) and tert - butyl 4 - carbamothioyl - 4 - methylpiperidine - 1 - carboxylate ( 2.66 g , 10.29 mmol , 1.2 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop- - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -4 - methylpiperidine - 1 - carboxylate ( 2.1 g , 36.63 % ) as a yellow solid . LCMS : C28H31C1FN5O4S requires : 587.2 , found : m / z = 588.[ M + H ] + . [ 000222 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) thiazol - 2 - yl ) -4 - methylpiperidine - 1 - carboxylate ( 5 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] aminophenyl ) -1,3 - thiazol - 2 - yl ] -4 - methylpiperidine - 1 - carboxylate ( 2.1 g , 3.57 mmol , 1 equiv ) and Pd ( PPh3 ) 2Cl2 ( 50.13 mg , 0.07 mmol , 0.02 equiv ) in DCM ( 30 mL ) was added HOAc ( 514.6 mg , 8.57 mmol , 2.4 equiv ) and n - HnSзuB ( 1.56 g , 5.35 mmol , 1.equiv ) at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred for 0.5 h at 0 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) thiazol - 2 - yl ) -4- methylpiperidine - 1 - carboxylate ( 1.6 g , 92.82 % ) as a yellow oil . LCMS : C24H27C1FN5O2S requires : 503.2 , found : m / z = 504.1 [ M + H ] + . [ 000223 ] Step - 4 : Synthesis of tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) -4 - methylpiperidine - 1 - carboxylate ( 6 ) -355- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] -4 - methylpiperidine - 1 - carboxylate ( 1.6 g , 3.17 mmol , 1 equiv ) in DCM ( 20 mL ) was added TEA ( 963.7 mg , 9.52 mmol , 3 equiv ) and propane - 1 - sulfonyl chloride ( 679.0 mg , 4.76 mmol , 1.5 equiv ) at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under reduced pressure . To the crude product in THF ( 10 mL ) , MeCN ( 10 mL ) , and O₂H ( 10 mL ) was added Na2CO3 ( 2 g , 19.25 mmol , 10 equiv ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -4 - methylpiperidine - 1 - carboxylate ( 1.1 g , 92.38 % ) as a yellow solid . LCMS : C27H33C1FN5O4S2 requires : 609.2 , found : m / z = 610.1 [ M + H ] * . [ 000224 ] Step - 5 : Synthesis of tert - butyl 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) -4 - methylpiperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -4 - methylpiperidine - 1 - carboxylate ( 1 g , 1.63 mmol , equiv ) and Pd2 ( dba ) 3 ( 150 mg , 0.16 mmol , 0.1 equiv ) in dioxane ( 10 mL ) was added XPhos ( 156.2 mg , 0.32 mmol , 0.2 equiv ) , Cs2CO3 ( 1.1 g , 3.27 mmol , 2 equiv ) and tert - butyl carbamate ( 287.9 mg , 2.45 mmol , 1.5 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred overnight at 80 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 9 : 1 ) to afford tert - butyl 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) -4 - methylpiperidine - 1- carboxylate ( 1 g , 77.72 % ) as a brown solid . LCMS : C32H43FN6O6S2 requires : 690.3 , found : m / z = 691.2 [ M + H ] * . [ 000225 ] Step - 6 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide A mixture of tert - butyl 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) -4 - methylpiperidine - 1 - carboxylate ( 1 g , 1.44 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was -356- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT purified by reverse phase flash chromatography with H2O : MeCN ( 1 : 3 ) to afford N- { 3- [ 5- ( 2- aminopyrimidin - 4 - yl ) -2- ( 4 - methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide ( 614.8 mg , 84.49 % ) as a yellow solid . LCMS : C22H27FN6O2S2 requires : 490.2 , found : m / z = 491.1 [ M + H ] * . 1H NMR ( 400 MHz , CD3OD ) 8 8.11 ( d , J = 6.4 Hz , 1H ) , 7.71 – 7.67 ( m , 1H ) , 7.53 – 7.50 ( m , 1H ) , 7.40 – 7.36 ( m , 1H ) , 6.67 – 6.64 ( m , 1H ) , 3.42 – 3.35 ( m , 3H ) , 3.32 – 3.30 ( m , 1H ) , 3.- – 3.14 ( m , 2H ) , 2.56 – 2.50 ( m , 2H ) , 2.15 – 2.08 ( m , 2H ) , 1.90 – 1.84 ( m , 2H ) , 1.62 ( s , 3H ) , 1.08 – 1.04 ( m , 3H ) . [ 000226 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2 - azaspiro [ 3.5 ] nonan - 7- yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid salt Boc - N Boc - N HN F HN S N F N N₂H HATU , DIEA , NH4CI , DMF Boc - N OH Step - BocNH HN BrettphosPdG3 , ³OC₂sC , dioxane Step - N Boc - N HOAc , Pd ( PPh3 ) 2ClHnSзuB , DCM Step - HN HN Boc NH Boc - N Lawesson's reagent THF Step - N₂H TFA , DCM HN Step - OH Boc - N NHNBS , DMA Step - i ) TEA , DCM ii ) Na2CO3 , THF : O₂H : ACN Step - HN F N₂H Boc - N OH HN O = S [ 000227 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 7 - carbamoyl - 2 - azaspiro [ 3.5 ] nonane - 2- -357- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of 2- ( tert - butoxycarbonyl ) -2 - azaspiro [ 3.5 ] nonane - 7 - carboxylic acid ( 4 g , 14.mmol , 1 equiv ) and HATU ( 8.47 g , 22.28 mmol , 1.5 equiv ) in DMF ( 40 mL ) was added NH4Cl ( 3.97 g , 74.26 mmol , 5 equiv ) and the mixture was stirred for 15 min . Then , DIEA ( 5.76 g , 44.55 mmol , 3 equiv ) was added . The resulting mixture was stirred at room temperature for one hour . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford tert - butyl 7 - carbamoyl - 2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 3.5 g , 87.82 % ) as a white solid . LCMS : C14H24N2O3 requires : 268.2 , found : m / z = 269.3 [ M + H ] * . [ 000228 ] Step - 2 : Synthesis of tert - butyl 7 - carbamothioyl - 2 - azaspiro [ 3.5 ] nonane - 2- carboxylate ( 3 ) To a mixture of tert - butyl 7 - carbamoyl - 2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 3.5 g , 13.mmol , 1 equiv ) in THF ( 40 mL ) was added Lawesson's Reagent ( 2.64 g , 6.53 mmol , 0.5 equiv ) . The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 7 - carbamothioyl- - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 2.5 g , 51.89 % ) as a white solid . LCMS : C14H24N2O2S requires : 284.2 , found : m / z = 285.2 [ M + H ] * . [ 000229 ] Step - 3 : Synthesis of tert - butyl 7- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2- carboxylate ( 4 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenylcarbamate ( 3.07 g , 8.78 mmol , 1 equiv ) in DMA ( 20 mL ) was added NBS ( 1.g , 8.78 mmol , 1 equiv ) and the mixture was stirred for 15 min . Then , tert - butyl 7- carbamothioyl - 2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 2.5 g , 8.79 mmol , 1 equiv ) was added . The resulting mixture was stirred at 60 ° C for 2 h . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford tert - butyl 7- [ 5- ( 2 - chloropyrimidin- - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -2- azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 1.4 g , 19.48 % ) as a yellow solid . LCMS : C30H33CIFN5O4S requires : 613.2 , found : m / z = 614.2 [ M + H ] * . [ 000230 ] Step - 4 : Synthesis of tert - butyl 7- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 5 ) To a mixture of tert - butyl 7- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 1.4 g , -358- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 2.28 mmol , 1 equiv ) in DCM ( 10 mL ) was added HOAc ( 329 mg , 5.47 mmol , 2.4 equiv ) and Pd ( PPh3 ) 2Cl2 ( 32 mg , 0.046 mmol , 0.02 equiv ) . Then , n - HnSзuB ( 995 mg , 3.42 mmol , 1.equiv ) was added at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred at room temperature for one hour . The reaction was quenched with saturated aqueous NaHCOat 0 ° C . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 7- [ 4- ( 3- amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane- - carboxylate ( 750 mg , 58.96 % ) as a yellow solid . LCMS : C26H29C1FN5O2S requires : 529.2 , found : m / z = 530.4 [ M + H ] * . [ 000231 ] Step - 5 : Synthesis of tert - butyl 7- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 6 ) To a mixture of tert - butyl 7- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 750 mg , 1.42 mmol , 1 equiv ) and TEA ( 430 mg , 4.25 mmol , 3 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 6mg , 4.25 mmol , 3 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under vacuum . To the above mixture was added THF ( 10 mL ) , ACN ( 10 mL ) , and Na2CO3 ( 2249 mg , 21.22 mmol , 15 equiv ) in O₂H ( mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 7- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 7mg , 79.15 % ) as a yellow solid . LCMS : C29H35CIFN5O4S2 requires : 635.2 , found : m / z = 636.[ M + H ] + . [ 000232 ] Step - 6 : Synthesis of tert - butyl 7- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 7 ) To a mixture of tert - butyl 7- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 750 mg , 1.mmol , 1 equiv ) and tert - butyl carbamate ( 691 mg , 5.9 mmol , 5 equiv ) in 1,4 - dioxane ( 10 mL ) was added Cs2CO3 ( 768 mg , 2.36 mmol , 2 equiv ) and BrettPhos Pd G3 ( 107 mg , 0.12 mmol , 0.1 equiv ) . The resulting mixture was stirred at 80 ° C for one hour under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel -359- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 7- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 800 mg , 85.19 % ) as a yellow solid . LCMS : C34H45FN6O6S2 requires : 716.3 , found : m / z = 717.2 [ M + H ] * . [ 000233 ] Step - 7 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2- azaspiro [ 3.5 ] nonan - 7 - yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid To a mixture of tert - butyl 7- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) -2 - azaspiro [ 3.5 ] nonane - 2 - carboxylate ( 500 mg , 0.7 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2 - azaspiro [ 3.5 ] nonan - 7 - yl ) -1,3 - thiazol - 4 - yl ] - - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid salt ( 211 mg , 47.54 % ) as a yellow solid . LCMS : C24H29FN6O2S2 requires : 516.2 , found : m / z = 517.2 [ M + H ] * . – ' H NMR ( 400 MHz , DMSO - do ) 8 8.05 ( d , J = 5.2 Hz , 1H ) , 7.51 - 7.42 ( m , 1H ) , 7.13 – 7.- ( m , 1H ) , 6.92 – 6.84 ( m , 1H ) , 6.71 ( s , 2H ) , 6.14 ( d , J = 5.2 Hz , 1H ) , 3.53 ( s , 2H ) , 3.45 ( s , 2H ) , 2.97 ( s , 1H ) , 2.91 – 2.82 ( m , 2H ) , 2.08 - 1.97 ( m , 4H ) , 1.74 - 1.61 ( m , 2H ) , 1.60 – 1.41 ( m , 4H ) , 0.97 – 0.83 ( m , 3H ) . [ 000234 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - azaspiro [ 5.5 ] undecan- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide HN F HN ∞ N. N N₂H - 360 - 1100573566 5 AMERICAS Boc - N Boc - N HATU , DIEA , NHCI , DMF Boc - N OH Step - HN CI N BocNHBrettphosPdG3 , CS2CO3 , dioxane Step - Boc - N Attorney Docket No .: 121843.002NU - 3200 PCT S Lawesson's reagent Boc - N ☑ NHTHF Step - NH HOAc , Pd ( PPh3 ) 2Cl2 , Boc - N BuzSnH , DCM Step - HN NHF i ) TEA , DCM Boc - N ii ) Na2CO3 , THF : O₂H : ACN CI Step - TFA , DCM HN Step - HN Boc HN N₂H NBS , DMA Step - HN ' F [ 000235 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 9 - carbamoyl - 3 - azaspiro [ 5.5 ] undecane - 3- To a mixture of 3- ( tert - butoxycarbonyl ) -3 - azaspiro [ 5.5 ] undecane - 9 - carboxylic acid ( 3 g , 10.mmol , 1 equiv ) and HATU ( 5.75 g , 15.13 mmol , 1.5 equiv ) in DMF ( 30 mL ) was added NH4Cl ( 2.7 g , 50.44 mmol , 5 equiv ) and the mixture was stirred for 15 min . Then , DIEA ( 3.91 g , 30.mmol , 3 equiv ) was added . The resulting mixture was stirred at room temperature for one hour . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford tert - butyl 9 - carbamoyl - 3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 2.1 g , 70.23 % ) as a yellow solid . LCMS : C16H28N2O3 requires : 296.2 , found : m / z = 297.2 [ M + H ] * . [ 000236 ] carboxylate ( 3 ) Step - 2 : Synthesis of tert - butyl 9 - carbamothioyl - 3 - azaspiro [ 5.5 ] undecane - 3- To a mixture of tert - butyl 9 - carbamoyl - 3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 2.2 g , 7.mmol , 1 equiv ) in THF ( 30 mL ) was added Lawesson's Reagent ( 1.5 g , 3.71 mmol , 0.5 equiv ) . The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl 9 - carbamothioyl - 3- azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.43 g , 55.49 % ) as an off - white solid . LCMS : C16H28N2O2S requires : 312.2 , found : m / z = 313.3 [ M + H ] * . - 361 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000237 ] Step - 3 : Synthesis of tert - butyl 9- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -3- azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 4 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenylcarbamate ( 1.3 g , 3.72 mmol , 1 equiv ) in DMA ( 10 mL ) was added NBS ( 6mg , 3.72 mmol , 1 equiv ) and the mixture was stirred for 15 min . Then , tert - butyl 9- carbamothioyl - 3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.51 g , 4.83 mmol , 1.3 equiv ) was added . The resulting mixture was stirred at 60 ° C for 2 h . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford tert - butyl 9- [ 5- ( 2- chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3- thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.14 g , 38.68 % ) as a yellow solid . LCMS : C32H37CIFN5O4S requires : 641.2 , found : m / z = 642.4 [ M + H ] * . [ 000238 ] Step - 4 : Synthesis of tert - butyl 9- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 5 ) To a mixture of tert - butyl 9- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.g , 2.02 mmol , 1 equiv ) in DCM ( 10 mL ) was added HOAc ( 0.29 g , 4.83 mmol , 2.4 equiv ) and Pd ( PPh3 ) 2Cl2 ( 28 mg , 0.04 mmol , 0.02 equiv ) . Then , n - HnSзuB ( 884 mg , 3.04 mmol , 1.5 equiv ) was added at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred at room temperature for one hour . The reaction was quenched with saturated aqueous NaHCO3 at 0 ° C . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 9- [ 4- ( 3 - amino - 2- fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3- carboxylate ( 1.02 g , 90 % ) as a yellow solid . LCMS : C28H33C1FN5O2S requires : 557.2 , found : m / z 558.2 [ M + H ] * . == [ 000239 ] Step - 5 : Synthesis of tert - butyl 9- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3- carboxylate ( 6 ) To a mixture of tert - butyl 9- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1 g , 1.79 mmol , 1 equiv ) and TEA ( 0.g , 5.38 mmol , 3 equiv ) in DCM ( 15 mL ) was added propane - 1 - sulfonyl chloride ( 0.38 g , 2.mmol , 1.5 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . -362- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT The resulting mixture was concentrated under vacuum . To the above mixture was added THF ( 10 mL ) , ACN ( 10 mL ) , and Na2CO3 ( 2.85 g , 26.85 mmol , 15 equiv ) in H2O ( 10 mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 9- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.12 g , 89.40 % ) as a yellow solid . LCMS : C31H39C1FN5O4S2 requires : 663.2 , found : m / z = 664.[ M + H ] + . [ 000240 ] Step - 6 : Synthesis of tert - butyl 9- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 7 ) To a mixture of tert - butyl 9- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.1 g , 1.mmol , 1 equiv ) and tert - butyl carbamate ( 0.97 g , 8.28 mmol , 5 equiv ) in 1,4 - dioxane ( 10 mL ) was added Cs2CO3 ( 1.08 g , 3.32 mmol , 2 equiv ) and BrettPhos Pd G3 ( 150 mg , 0.17 mmol , 0.1 equiv ) . The resulting mixture was stirred at 80 ° C for one hour under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1:10 ) to afford tert - butyl 9- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.2 g , 84.63 % ) as a yellow solid . LCMS : C36H49FN6O6S2 requires : 744.3 , found : m / z = 745.3 [ M + H ] * . [ 000241 ] Step - 7 : Synthesis = of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3- azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenylpropane - 1 - sulfonamide To a mixture of tert - butyl 9- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.2 g , 1.61 mmol , 1 equiv ) in DCM ( 12 mL ) was added TFA ( 4 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : H2O ( 0.1 % NH4HCO3 ) ( 1 : 1 ) to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - azaspiro [ 5.5 ] undecan - 9- yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 520.8 mg , 57.69 % ) as a light yellow solid . LCMS : C26H33FN6O2S2 requires : 544.2 , found : m / z = 545.3 [ M + H ] * . - 363 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT H¹ NMR ( 400 MHz , CD3OD ) 8 8.04 ( d , J = 5.2 Hz , 1H ) , 7.70 – 7.60 ( m , 1H ) , 7.34 – 7.21 ( m , - 2H ) , 6.28 ( d , J = 5.2 Hz , 1H ) , 3.19 – 2.91 ( m , 7H ) , 2.09 – 2.00 ( m , 2H ) , 1.98 – 1.67 ( m , 8H ) , - 1.57 – 1.50 ( m , 2H ) , 1.46 – 1.34 ( m , 2H ) , 1.05 – 0.97 ( m , 3H ) . [ 000242 ] Synthesis of N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride salt ( 1 ) NH HN F- HCI N N HN . ₂HN ( 10 ) NBS , DMA Step - HN N₂H . ( 2 ) HOAc , Pd ( PPh3 ) 2Cl2 , BuzSnH , DCM Step - HN ( 3 ) N₂H F HN . F .CI TEA , DCM Step - NHStep - 4 Step - HN ( 4 ) ( 5 ) HCI HN [ 000243 ] Step - 1 : Synthesis of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2 - fluorophenyl } carbamate ( 1.1 g , 3.145 mmol , 1.00 equiv ) and NBS ( 559.8 mg , 3.145 mmol , 1.0 equiv ) in DMA ( 13 mL ) was added tert - butyl 4 - carbamothioylpiperidine - 1 - carboxylate ( 922.2 mg , 3.774 mmol , 1.20 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted -364- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop- - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 580 mg , 32.12 % ) as a yellow solid . LCMS : C27H29C1FN5O4S requires : 573.2 , found : m / z = 574.[ M + H ] + . [ 000244 ] Step - 2 : Synthesis of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 600 mg , 1.0mmol , 1 equiv ) and HOAc ( 156.9 mg , 2.612 mmol , 2.5 equiv ) in DCM ( 8 mL ) was added Pd ( PPh3 ) 2Cl2 ( 14.7 mg , 0.021 mmol , 0.02 equiv ) and n - HnSзuB ( 486.7 mg , 1.672 mmol , 1.equiv ) in portions at 0 ° C . The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum to afford tert- butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine- - carboxylate ( 510 mg , crude ) as a red oil . The resulting mixture was used in the next step directly without further purification . LCMS : C23H25C1FN5O2S requires : 489.1 , found : m / z = 490.1 [ M + H ] + . [ 000245 ] Step - 3 : Synthesis of tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 2 g , 4.082 mmol , 1 equiv ) and TEA ( 1.24 g , 12.2mmol , 3 equiv ) in DCM ( 20 mL ) was added propane - 1 - sulfonyl chloride ( 873.08 mg , 6.1mmol , 1.5 equiv ) dropwise at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under vacuum . To the crude product in H2O ( 7 mL ) , MeCN ( 7 mL ) , and THF ( 7 mL ) was added Na2CO3 ( 1.06 g , 10.065 mmol , 3.equiv ) at room temperature . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 1.58 g , 69.85 % ) as a yellow solid . LCMS : C26H31C1FN5O4S2 requires : 595.1 , found : m / z = 596.1 [ M + H ] * . -365- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 [ 000246 ] Step - 4 : Synthesis of tert - butyl butoxycarbonyl ) amino ) pyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 5 ) To a mixture NU - 3200 PCT 4- ( 5- ( 2 - ( ( tert- of tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 1.0 g , 1.677 mmol , 1 equiv ) and BocNH2 ( 982.57 mg , 8.385 mmol , 5 equiv ) in 1,4 - dioxane ( 12 mL ) was added BrettPhos Pd G3 ( 152.1 mg , 0.168 mmol , 0.1 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 80 ° C under nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 5- ( 2 - ( ( tert - butoxycarbonyl ) amino ) pyrimidin - 4- yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 850 mg , 87.86 % ) as a white solid . LCMS : C31H41FN6O6S2 requires : 676.3 , found : m / z = 677.3 [ M + H ] * . [ 000247 ] Step - 5 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- ( 5- ( 2 - ( ( tert - butoxycarbonyl ) amino ) pyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 1.5 g , 2.263 mmol , 1 equiv ) in DCM ( 3 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 12 mL , 4 M ) at room temperature . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % FA ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride salt ( 649.6 mg , 54.60 % ) as a yellow solid . LCMS : C21H25FN6O2Srequires : 476.3 , found : m / z = 477.3 [ M + H ] * . - ' H NMR ( 400 MHz , CD3OD ) 8 8.09 ( d , J = 6.0 Hz , 1H ) , 7.68 – 7.66 ( m , 1H ) , 7.49 – 7.28 ( m , 2H ) , 6.65 – 6.63 ( m , 1H ) , 3.60 – 3.48 ( m , 3H ) , 3.28 – 3.16 ( m , 2H ) , 3.17 – 3.05 ( m , 2H ) , 2.- = - – 2.39 ( m , 2H ) , 2.21 – 2.09 ( m , 2H ) , 1.94 – 1.78 ( m , 2H ) , 1.14 – 0.98 ( m , 3H ) . [ 000248 ] Synthesis of N- ( 3- { 1- [ 4- ( azetidin - 3 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl - 2 - fluorophenyl ) propane - 1 - sulfonamide ; trifluoroacetic acid salt - 366- 1100573566 5 AMERICAS Br = NH O = S N₂H Attorney Docket No .: 121843.002 NH NH F Boc Pd ( AMPHOS ) 2Cl2 , CsF , dioxane , O₂H Step - TFA , DCM Step - Boc NH .F COH NH Boc NH OH NU - 3200 PCT i ) TEA , DCM ii ) Na2CO3 , THF : O₂H : ACN Step - [ 000249 ] Step - 1 : Synthesis of tert - butyl of tert - butyl 3- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } azetidine - 1 - carboxylate ( 2 ) To a mixture of tert - butyl 3- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } azetidine - 1- carboxylate ( 100 mg , 0.22 mmol , 1 equiv ) and 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) aniline ( 78 mg , 0.33 mmol , 1.5 equiv ) in dioxane ( 3 mL ) was added CsF ( mg , 0.44 mmol , 2 equiv ) in O₂H ( 0.3 mL ) and Pd ( AMPHOS ) 2Cl2 ( 31 mg , 0.044 mmol , 0.equiv ) . The resulting mixture was stirred at 95 ° C for 2 h under nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1:10 ) to afford tert - butyl 3- { 4- [ 4- ( 3 - amino - 2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } azetidine - 1 - carboxylate ( 100 mg , 89.09 % ) as a yellow solid . LCMS : C28H28FN5O2 requires : 485.2 , found : m / z = 486.3 [ M + H ] * . [ 000250 ] Step - 2 : Synthesis of tert - butyl 3- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) azetidine - 1 - carboxylate ( 3 ) -367- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 3- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl } azetidine - 1 - carboxylate ( 60 mg , 0.12 mmol , 1 equiv ) and TEA ( 38 mg , 0.37 mmol , equiv ) in DCM ( 3 mL ) was added propane - 1 - sulfonyl chloride ( 53 mg , 0.37 mmol , 3 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under vacuum . To the above mixture was added THF ( 1.5 mL ) , ACN ( 1.5 mL ) , and Na2CO3 ( 196 mg , 1.86 mmol , 15 equiv ) in O₂H ( 1.5 mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 3- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1- yl } phenyl ) azetidine - 1 - carboxylate ( 50 mg , 64.97 % ) as a yellow solid . LCMS : C31H34FN5O4S requires : 591.2 , found : m / z = 592.3 [ M + H ] * . [ 000251 ] Step - 3 : Synthesis of N- ( 3- { 1- [ 4- ( azetidin - 3 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ; trifluoroacetic acid To a mixture of tert - butyl 3- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl } phenyl ) azetidine - 1 - carboxylate ( 45 mg , 0.076 mmol , 1 equiv ) in DCM ( 4 mL ) was added TFA ( 1 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- ( 3- { 1- [ 4- ( azetidin - 3 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ; trifluoroacetic acid salt ( 18 mg , 37.24 % ) as a white solid . LCMS : C26H26FN5O2S requires : 491.2 , found : m / z = 492.[ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.66 – 8.41 ( m , 3H ) , 7.95 ( d , J = 8.4 Hz , 2H ) , 7.72 – 7.46 ( m , 5H ) , 7.37 – 7.17 ( m , 2H ) , 4.27 – 4.16 ( m , 1H ) , 4.16 – 4.08 ( m , 2H ) , 4.07 – 3.94 ( m , 2H ) , 3.14 – 2.92 ( m , 2H ) , 1.94 – 1.64 ( m , 2H ) , 1.12 – 0.80 ( m , 3H ) . [ 000252 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidine - 4- carbonyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt - 368 - 1100573566 5 AMERICAS HN- F Boc Boc - N OH HATU , DIEA , DMF Step - N₂H BrettPhos Pd G3 , 3OC₂sC , dioxane Step - O = S = S.

-N Boc N Boc HCI N NH Boc HN ' Attorney Docket No .: 121843.002NU - 3200 PCT O = S . · S = HOAc , Pd ( PPh3 ) ₂lC , HnSзuB DCM Step - HCI in dioxane HCI N₂H F -N Boc Step - NH i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H Step - [ 000253 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonylpiperidine - 1 - carboxylate ( 3 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 2 g , 4.22 mmol , 1 equiv ) and 1- ( tert- butoxycarbonyl ) piperidine - 4 - carboxylic acid ( 1.45 g , 6.33 mmol , 1.5 equiv ) in DMF ( 20 mL ) was added HATU ( 2.41 g , 6.33 mmol , 1.5 equiv ) and DIEA ( 2.73 g , 21.10 mmol , 5 equiv ) at room temperature . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- -369- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carboxylate ( 1.4 g , 43.58 % ) as a brown oil . LCMS : C33H38C1FN6O5S requires : 684.2 , found : m / z = 685.3 [ M + H ] * . [ 000254 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] aminophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1- carboxylate ( 1.1 g , 1.60 mmol , 1 equiv ) and HOAc ( 241 mg , 4.01 mmol , 2.5 equiv ) in DCM ( 10 mL ) was added Pd ( PPh3 ) 2Cl2 ( 22 mg , 0.032 mmol , 0.02 equiv ) and n - HnSзuB ( 747 mg , 2.56 mmol , 1.6 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 30 min at room temperature . The reaction was quenched by the addition of saturated aqueous NaHCO3 at 0 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3- amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carboxylate ( 700 mg , 63.83 % ) as a yellow oil . LCMS : C29H34C1FN6O3S requires : 600.2 , found : m / z = 601.3 [ M + H ] * . [ 000255 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carbonyl ) piperidine - 1- carboxylate ( 5 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1 - carboxylate ( 700 mg , 1.16 mmol , 1 equiv ) in DCM ( 7 mL ) was added TEA ( 353 mg , 3.49 mmol , 3 equiv ) and propane - 1 - sulfonyl chloride ( 199 mg , 1.39 mmol , 1.2 equiv ) at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 3 mL ) , O₂H ( 3 mL ) , and MeCN ( 3 mL ) . Na2CO3 ( 456 mg , 4.mmol , 5 equiv ) was added at room temperature . The resulting mixture was stirred overnight at ° C . The resulting mixture was concentrated under vacuum . The residue was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl 4- ( 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2- - 370 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) piperidine - 1 - carbonyl ) piperidine - 1 - carboxylate_ ( 800 mg , crude ) as a brown solid . LCMS : C32H40C1FN6O5S2 requires : 706.2 , found : m / z = 707.2 [ M + H ] * . [ 000256 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) piperidine - 1 - carbonyl ] piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1 - carboxylate ( 1 g , 1.41 mmol , 1 equiv ) and tert - butyl carbamate ( 828 mg , 7.07 mmol , 5 equiv ) in dioxane ( mL ) was added BrettPhos Pd G3 ( 128 mg , 0.14 mmol , 0.1 equiv ) and Cs2CO3 ( 921 mg , 2.mmol , 2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) piperidine - 1 - carbonyl ] piperidine - 1 - carboxylate ( 700 mg , 56.55 % ) as a yellow solid . LCMS : C37H50FN7O7S2 requires : 787.3 , found : m / z = 788.3 [ M + H ] * . [ 000257 ] Step - 5 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidine - 4- carbonyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) piperidine - 1 - carbonyl ] piperidine - 1- carboxylate ( 700 mg , 0.761 mmol , 1 equiv ) in HC1 in 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidine - 4 - carbonyl ) piperidin - 4 - yl ] -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 544.7 mg , crude ) as a yellow solid . LCMS : C27H34FN7O3S2 requires : 587.2 , found : m / z = 588.2 [ M + H ] * . = 1H NMR ( 400 MHz , CD3OD ) 8 8.09 - 8.06 ( m , 1H ) , 7.72 – 7.68 ( m , 1H ) , 7.46 – 7.40 ( m , 1H ) , 7.38 – 7.36 ( m , 1H ) , 6.62 – 6.61 ( m , 1H ) , 4.65 – 4.62 ( m , 1H ) , 4.30 – 4.20 ( m , 1H ) , 3.77 – 3.( m , 1H ) , 3.69 3.61 ( m , 2H ) , 3.69 – 3.50 ( m , 1H ) , 3.47 - 3.38 ( m , 3H ) , 3.32 - 3.12 ( m , 5H ) , 2.92 – 2.90 ( m , 1H ) , 2.28 – 2.23 ( m , 3H ) , 1.91 – 1.84 ( m , 3H ) , 1.82 – 1.70 ( m , 1H ) , 1.07 - 1.( m , 3H ) . - 371 - 1100573566 5 AMERICAS [ 000258 ] Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidin - 4- ylmethyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenylpropane - 1 - sulfonamide hydrochloride salt HCl / dioxane DCM HN Step - Boc Boc HOAc , Pd ( PPh3 ) 2Cl2 , Bu3SnH , DCM Step - N - S = HN Boc HCI N F N - S = O S = O S.

N NH NaBH ( OAc ) 3 , DCM Step - HCI HCl / dioxane Step - NH F N₂H Boc S = CI i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H Step - N₂H Brettphos Pd G3 , ³OC₂sC , 1,4 - dioxane Step - HN F [ 000259 ] Step - 1 : Synthesis of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 2 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 1 g , 1.74 mmol , equiv ) and HOAc ( 261 mg , 4.35 mmol , 2.5 equiv ) in DCM ( 10 mL ) was added Pd ( PPh3 ) 2Cl -372- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 24 mg , 0.035 mmol , 0.02 equiv ) and n - HnSзuB ( 811 mg , 2.78 mmol , 1.6 equiv ) at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred for 30 min at room temperature . The reaction was quenched by saturated aqueous NaHCO3 at 0 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2- yl ] piperidine - 1 - carboxylate ( 1.5 g , crude ) as a brown solid . LCMS : C23H25CIFN5O2S requires : 489.1 , found : m / z = 490.1 [ M + H ] * . [ 000260 ] Step - 2 : Synthesis of tert - butyl 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 1.5 g , 3.06 mmol , 1 equiv ) in DCM ( 15 mL ) was added TEA ( 929 mg , 9.18 mmol , 3 equiv ) and propane - 1 - sulfonyl chloride ( 436 mg , 3.06 mmol , equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 5 mL ) , O₂H ( 5 mL ) , and MeCN ( 5 mL ) . Na2CO3 ( 1.13 g , 10.68 mmol , 5 equiv ) was added at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was concentrated under vacuum . The residue was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 5- ( 2 - chloropyrimidin- - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 2 g , 93.03 % ) as a brown solid . LCMS : C26H31C1FN5O4S2 requires : 595.2 , found : m / z [ M + H ] + . = 596. [ 000261 ] Step - 3 : Synthesis of N - 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 4 ) A mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 1.7 g , 2.85 mmol , 1 equiv ) in HC1 in 1,4 - dioxane ( 20 mL , 4 M ) was stirred for 2 h at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 1.4 g , crude ) as a yellow oil . LCMS : C21H23CIFN5O2S2 requires : 495.1 , found : m / z = 496.2 [ M + H ] * . -373- 1100573566 5 AMERICAS [ 000262 ] Attorney Docket No .: 121843.002NU - 3200 PCT Step - 4 : Synthesis of tert - butyl 4 - ( { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1- ylmethyl ) piperidine - 1 - carboxylate ( 5 ) To a mixture of N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 1.4 g , 2.82 mmol , 1 equiv ) in DCM ( 10 mL ) was added tert - butyl 4 - formylpiperidine - 1 - carboxylate ( 902 mg , 4.23 mmol , 1.5 equiv ) and NaOAc ( 2mg , 2.82 mmol , 1 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for one hour at room temperature . To the above mixture was added NaBH ( OAc ) 3 ( 1.2 g , 5.64 mmol , 2 equiv ) at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The reaction was quenched by the addition of water at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4 - ( { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) methyl ) piperidine - 1- carboxylate ( 1.2 g , 55.19 % ) as a yellow solid . LCMS : C32H42C1FN6O4S2 requires : 692.2 , found : m / z = 693.3 [ M + H ] * . [ 000263 ] Step - 5 : Synthesis of tert - butyl - { [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) piperidin - 1 - yl ] methyl } piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4 - ( { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) methyl ) piperidine - 1 - carboxylate ( 1.2 g , 1.73 mmol , 1 equiv ) and tert - butyl carbamate ( 1.01 g , 8.65 mmol , 5 equiv ) in 1,4 - dioxane ( mL ) was added BrettPhos Pd G3 ( 156 mg , 0.17 mmol , 0.10 equiv ) and Cs2CO3 ( 1.13 g , 3.mmol , 2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The crude product was purified by reverse phase flash chromatography with H2O : MeCN ( 1 : 7 ) to afford tert - butyl 4 - { [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) piperidin - 1 - yl ] methyl } piperidine - 1 - carboxylate ( 700 mg , 49.64 % ) as a yellow solid . LCMS : C37H52FN7O6S2 requires : 773.3 , found : m / z = 774.3 [ M + H ] * . -374- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000264 ] Step - 6 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidin - 4- ylmethyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4 - { [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) piperidin - 1 - yl ] methyl } piperidine - 1- carboxylate ( 700 mg , 1.034 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidin - 4 - ylmethyl ) piperidin - 4 - yl ] -1,3- pressure thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 596.3 mg , crude ) as a yellow solid . LCMS : C27H36FN7O2S2 requires : 573.2 , found : m / z = 574.3 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.15 – 8.12 ( m , 1H ) , 7.74 – 7.70 ( m , 1H ) , 7.48 – 7.40 ( m , 1H ) , — 7.38 7.33 ( m , 1H ) , 6.64 – 6.62 ( m , 1H ) , 3.90 – 3.83 ( m , 2H ) , 3.77 – 3.68 ( m , 1H ) , 3.65 – 3.= ( m , 1H ) , 3.48 – 3.40 ( m , 2H ) , 3.30 – 3.19 ( m , 3H ) , 3.17 – 3.09 ( m , 4H ) , 2.61 – 2.42 ( m , 5H ) , 2.20 – 2.10 ( m , 2H ) , 1.89 – 1.83 ( m , 2H ) , 1.75 – 1.61 ( m , 2H ) , 1.07 – 1.03 ( m , 3H ) . [ 000265 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( piperidin - 4 - yl ) pyrazol - 4- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt HN -8 = F HCI S N HN . N N -375- 1100573566 5 AMERICAS i ) propane - 1 - sulfonyl chloride , TEA , DCM ( 1 ) ii ) Na2CO3 , THF : MeCN : O₂H Step - ( 4 ) SHN F NH NBS , DMA Step - N₂H ( 5 ) Pd2 ( dba ) 3 , Davephos , t - BuONa , dioxane [ 000266 ] Step - 1 : Synthesis Step - ( 2 ) HN Attorney Docket No .: 121843.002NU - 3200 PCT HOAc , Pd ( PPh3 ) 2Cl2 , BuzSnH , DCM Step - HN = F HCI - dioxane , DCM ( 3 ) N₂H ( 6 ) HN Step - HN of prop - 2 - en - 1 - yl HN N- { 3- [ 2 - tert - butyl - 5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 2 ) To a mixture of 2,2 - dimethylpropanethioamide ( 0.97 g , 8.234 mmol , 1.2 equiv ) in DMA ( mL ) was added NBS ( 1.22 g , 6.862 mmol , 1.0 equiv ) at 0 ° C . The resulting mixture was stirred for 15 min at room temperature . To the above mixture was added prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2- chloropyrimidin - 4 - yl ) acetyl ] -2 - fluorophenyl } carbamate ( 2.4 g , 6.862 mmol , 1.0 equiv ) at room temperature . The resulting mixture was stirred for additional 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford prop - 2 - en - 1 - yl N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 2.6 g , 84.78 % ) as a yellow solid . LCMS : C21H20C1FN4O2S requires : 446.1 , found : m / z = 447.1 [ M + H ] * . = [ 000267 ] Step - 2 : Synthesis of 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol- - yl ] -2 - fluoroaniline ( 3 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } carbamate ( 2.5 g , 5.594 mmol , 1 equiv ) and HOAc ( 0.84 g , 13.985 mmol , 2.5 equiv ) in DCM ( 30 mL ) was added n - HnSзuB ( 2.61 g , 8.950 mmol , 1.6 equiv ) and -376- 1100573566 5 AMERICAS HCI Attorney Docket No .: 121843.002NU - 3200 PCT Pd ( PPh3 ) 2Cl2 ( 78.52 mg , 0.112 mmol , 0.02 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure to afford 3- [ 2 - tert- butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 2.4 g , crude ) as a yellow oil . The crude product was used in the next step directly without further purification . LCMS : C17H16CIFN4S requires : 362.1 , found : m / z = 363.1 [ M + H ] * . [ 000268 ] Step - 3 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 4 ) To a mixture of 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 2.4 g , 5.117 mmol , 1 equiv ) and TEA ( 1.55 g , 15.351 mmol , 3.0 equiv ) in DCM ( 30 mL ) was added propane - 1 - sulfonyl chloride ( 1.46 g , 10.234 mmol , 2.0 equiv ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 10 mL ) , CH3CN ( 10 mL ) , and O₂H ( 10 mL ) . Na2CO3 ( 5.42 g , 51.170 mmol , 10.0 equiv ) was added at room temperature . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford N- { 3- [ 2 - tert - butyl - 5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 2.0 g , 83.33 % ) as a yellow solid . LCMS : C20H22C1FN4O2S2 requires : 468.1 , found : m / z = 469.[ M + H ] + . 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- [ 000269 ] Step - 4 : Synthesis of tert - butyl ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyrazol - 1- ylpiperidine - 1 - carboxylate ( 6 ) To a mixture of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 500 mg , 1.099 mmol , 1 equiv ) and tert - butyl 4- ( 4- aminopyrazol - 1 - yl ) piperidine - 1 - carboxylate ( 351.26 mg , 1.319 mmol , 1.2 equiv ) in dioxane ( mL ) was added DavePhos ( 129.75 mg , 0.330 mmol , 0.3 equiv ) , Pd2 ( dba ) 3 ( 150.96 mg , 0.1mmol , 0.15 equiv ) and t - BuONa ( 158.43 mg , 1.648 mmol , 1.5 equiv ) at room temperature under a nitrogen atmosphere . The final reaction mixture was irradiated with microwave radiation for 2 h at 120 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 4 - [ ( 4- { 2 - tert - butyl- - 377- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] pyrazol - 1 - yl } piperidine - 1 - carboxylate ( 600 mg , 78.12 % ) as a white solid . LCMS : C33H43FN8O4S2 requires : 698.3 , found : m / z = 699.3 [ M + H ] * . [ 000270 ] Step - 5 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( piperidin - 4 - yl ) pyrazol - 4- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- [ 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyrazol - 1 - yl } piperidine - 1- carboxylate ( 550 mg , 0.787 mmol , 1 equiv ) in DCM ( 3 mL ) was added HCl ( gas ) in 1,4- dioxane ( 3 mL , 4 N ) at room temperature . The resulting mixture was stirred overnight at room temperature . The resulting mixture was concentrated under vacuum . The residue was purified by reverse phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in Water ( 10 mmol / L NH4HCO3 ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( piperidin - 4 - yl ) pyrazol - 4- - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 409.3 mg , 81.88 % ) as a yellow solid . LCMS : C28H35FN8O2S2 requires : 598.2 , found : m / z = 599.3 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.38 – 7.74 ( m , 2H ) , 7.– 7.63 ( m , 2H ) , 7.52 ( s , 1H ) , 7.38 – 7.32 ( m , 1H ) , 6.77 ( s , 1H ) , 4.57 ( s , 1H ) , 3.64 – 3.54 ( m , 2H ) , 3.32 - 3.22 ( m , 2H ) , 3.10 ( s , 2H ) , 2.42 – 2.26 ( m , 4H ) , 1.92 – 1.78 ( m , 2H ) , 1.56 ( s , 9H ) , 1.04 -0.96 ( m , 3H ) . [ 000271 ] Synthesis of N- ( 3- { 2 - tert - butyl - 5- [ 2- ( 1,2,3,4 - tetrahydroisoquinolin - 6- ylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride salt O = HN F N S = HCI N N HN . NH -378- 1100573566 5 AMERICAS N₂H .

F HN HN Attorney Docket No .: 121843.002NU - 3200 PCT HN F HCI CI HCl / dioxane Pd2 ( dba ) 3 , Davephos , t - BuONa , dioxane HN HN . Step - 1 Step - .NH [ 0000272 ] Step - 1 : Synthesis of tert - butyl 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -3,4 - dihydro - 1H- isoquinoline - 2 - carboxylate ( 3 ) To a mixture of tert - butyl 6 - amino - 3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 444 mg , 1.mmol , 1.2 equiv ) and N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 700 mg , 1.49 mmol , 1 equiv ) in dioxane ( 5 mL ) was added Pd2 ( dba ) 3 ( 205 mg , 0.22 mmol , 0.15 equiv ) , DavePhos ( 176 mg , 0.44 mmol , 0.3 equiv ) , and t - BuONa ( 215 mg , 2.24 mmol , 1.5 equiv ) at room temperature under a nitrogen atmosphere . The final reaction mixture was irradiated with microwave radiation for 2 h at 120 ° C under the nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -3,4- dihydro - 1H - isoquinoline - 2 - carboxylate ( 700 mg , 61.99 % ) as a yellow solid . LCMS : C34H41FN6O4S2 requires : 680.3 , found : m / z = 681.3 [ M + H ] * . [ 000273 ] – Step - 2 : Synthesis of N- ( 3- { 2 - tert - butyl - 5- [ 2- ( 1,2,3,4 - tetrahydroisoquinolin- - ylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 700 mg , 1.028 mmol , 1 equiv ) in HC1 / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with MeCN : O₂H ( 7 : 1 ) to afford N- ( 3- { 2 - tert- butyl - 5- [ 2- ( 1,2,3,4 - tetrahydroisoquinolin - 6 - ylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- - 379- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT fluorophenyl ) propane - 1 - sulfonamide hydrochloride salt ( 401.2 mg , 66.86 % ) as a yellow solid . LCMS : C29H33FN6O2S2 requires : 580.2 , found : m / z = 581.2 [ M + H ] + . 1H NMR ( 400 MHz , CD3OD ) § 8.25 – 8.20 ( m , 1H ) , 7.66 – 7.61 ( m , 1H ) , 7.52 – 7.41 ( m , 2H ) , - = 7.39 - 7.34 ( m , 2H ) , 7.25 – 7.23 ( m , 1H ) , 6.78 – 6.76 ( m , 1H ) , 4.40 ( s , 2H ) , 3.58 – 3.55 ( m , 2H ) , 3.32 – 3.20 ( m , 2H ) , 3.11 – 3.07 ( m , 2H ) , 1.86 – 1.80 ( m , 3H ) , 1.54 ( s , 9H ) , 1.50 – 1.( m , 1H ) , 1.04 – 1.01 ( m , 3H ) . - [ 000274 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( piperidin - 4- propane - 1- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } sulfonamide hydrochloride salt ( 1 ) F O = S HN F- HCI N NH ' S ' HN- HN N₂H . HN F ( 2 ) HCI - dioxane / DCM ₂dP ( dba ) 3 , Davephos , t - BuONa , dioxane Step - ( 3 ) HN Step - HN F HN- HCI -NH [ 000275 ] Step - 1 : Synthesis of tert - butyl 4- { 3 - [ ( 4-2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenyl } piperidine - 1 - carboxylate ( 3 ) To a mixture of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 500 mg , 1.066 mmol , 1 equiv ) and tert - butyl 4- ( 3- aminophenyl ) piperidine - 1 - carboxylate ( 353.59 mg , 1.279 mmol , 1.2 equiv ) in dioxane ( 5 mL ) was added DavePhos ( 125.87 mg , 0.320 mmol , 0.3 equiv ) , Pd2 ( dba ) 3 ( 146.44 mg , 0.160 mmol , 0.15 equiv ) and t - BuONa ( 153.69 mg , 1.599 mmol , 1.5 equiv ) at room temperature under a nitrogen atmosphere . The final reaction mixture was irradiated with microwave radiation for h at 120 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was - 380 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenylpiperidine - 1 - carboxylate ( 650 mg , 86.00 % ) as a yellow solid . LCMS : C36H45FN6O4S2 requires : 708.3 , found : m / z = 709.3 [ M + H ] * . [ 000276 ] Step - 2 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( piperidin - 4- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride To a mixture of tert - butyl 4- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenylpiperidine - 1 - carboxylate ( 550 mg , 0.776 mmol , 1 equiv ) in DCM ( 3 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 3 mL , N ) at room temperature . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH3CN : O₂H ( 70:30 ) to afford N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 447 mg , 89.29 % ) as a yellow solid . LCMS : C31H37FN6O2S2 requires : 608.2 , found : m / z = 609.3 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8.20 ( d , J = 6.4 Hz , 1H ) , 7.78 – 7.68 ( m , 1H ) , 7.52 – 7.28 ( m , 5H ) , 7.18 ( d , J = 7.2 Hz , 1H ) , 6.70 ( d , J = 6.0 Hz , 1H ) , 3.58 – 3.48 ( m , 2H ) , 3.26 – 3.18 ( m , 2H ) , 3.15 – 3.05 ( m , 2H ) , 2.99 – 2.92 ( m , 1H ) , 2.25 – 2.12 ( m , 2H ) , 2.07 – 1.92 ( m , 2H ) , 1.89 – 1.78 ( m , 2H ) , 1.54 ( s , 9H ) , 1.- 1.05 ( m , 3H ) . = – - [ 000277 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( piperidin - 4- yloxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride salt N.

HN = HCI N. N HN .

NH 1100573566 5 AMERICAS F HN $ = HN Attorney Docket No .: 121843.002NU - 3200 PCT N₂H CI Boc HN . Pd2 ( dba ) 3 , Davephos , t - BuONa , dioxane Step - 1 Step - Boc HN N HCI HCI / dioxane HN NH [ 000278 ] 4- ( 3- ( 4- ( 2 - tert - butyl - 4- [ 2 - fluoro - 3- Step - 1 : Synthesis of tert - butyl ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenoxy } piperidine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 4- ( 3 - aminophenoxy ) piperidine - 1 - carboxylate ( 374 mg , 1.27 mmol , 1.2 equiv ) and N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 500 mg , 1.06 mmol , 1 equiv ) in dioxane ( 5 mL ) was added Pd2 ( dba ) 3 ( 146 mg , 0.16 mmol , 0.15 equiv ) , DavePhos ( 125 mg , 0.32 mmol , 0.3 equiv ) and t - BuONa ( 153 mg , 1.59 mmol , 1.5 equiv ) at room temperature under a nitrogen atmosphere . The final reaction mixture was irradiated with microwave radiation for 2 h at 120 ° C under nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenoxy } piperidine - 1 - carboxylate ( 500 mg , 58.23 % ) as a yellow solid . LCMS : C36H45FN6O5S2 requires : 724.2 , found : m / z = 725.3 [ M + H ] * . [ 000279 ] Step - 2 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( piperidin - 4- yloxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride A mixture of tert - butyl 4- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenoxy } piperidine - 1 - carboxylate ( 500 mg , 0. mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( piperidin - 4 - yloxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 414.0 mg , crude ) as an orange solid . LCMS : C31H37FN6O3S2 requires : 624.2 , found : m / z = 625.2 [ M + H ] + . -382- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1H NMR ( 400 MHz , CD3OD ) 8 8.15 – 8.12 ( m , 1H ) , 7.66 – 7.62 ( m , 1H ) , 7.46 – 7.41 ( m , 1H ) , 7.40 -7.34 ( m , 3H ) , 7.07 - 7.05 ( m , 2H ) , 6.73 – 6.70 ( m , 1H ) , 4.86 - 4.77 ( m , 1H ) , 3.47 - 3.- ( m , 2H ) , 3.36 – 3.26 ( m , 2H ) , 3.09 – 3.05 ( m , 2H ) , 2.23 – 2.20 ( m , 2H ) , 2.10 – 2.04 ( m , 2H ) , –79.1 1.86 ( m , 2H ) , 1.53 ( s , 9H ) , 1.04 – 1.00 ( m , 3H ) . [ 000280 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( pyrrolidin - 3- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride salt F- HN N - Boc HN- N₂O -Br Pd ( dppf ) ₂lC , 3OC₂K , dioxane , O₂H Step - O = S HN F- N N HN HCI N₂O H2 , Pd / C EtOH , DMF N₂H HCl / dioxane Step - Step - HN F HCI HN- NH NH F HN of ₂dP ( dba ) 3 , Davephos , t - BuONa , dioxane Step - [ 000281 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 3- ( 4 - nitrophenyl ) -2,5 - dihydropyrrole - 1- To a mixture of tert - butyl 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -2,5 - dihydropyrrole- - carboxylate ( 1 g , 3.388 mmol , 1 equiv ) and Pd ( dppf ) Cl2 ( 148.73 mg , 0.203 mmol , 0.06 equiv ) in dioxane ( 9 mL ) and O₂H ( 3 mL ) was added Cs2CO3 ( 2.21 g , 6.776 mmol , 2 equiv ) and 3- bromo - 1 - nitrobenzene ( 684.33 mg , 3.388 mmol , 1 equiv ) at room temperature under a nitrogen -383- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT atmosphere . The resulting mixture was stirred overnight at 90 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 3- ( 3 - nitrophenyl ) -2,5 - dihydropyrrole - 1 - carboxylate ( 700 mg , 67.62 % ) as a yellow solid . [ 000282 ] Step - 2 : Synthesis of tert - butyl 3- ( 3 - aminophenyl ) pyrrolidine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 3- ( 3 - nitrophenyl ) -2,5 - dihydropyrrole - 1 - carboxylate ( 1.4 g , 4.mmol , 1 equiv ) in DMF ( 5 mL ) and EtOH ( 5 mL ) was added Pd / C ( 1.4 g ) at room temperature . The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere . The resulting mixture was filtered . The filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 3- ( 3 - aminophenyl ) pyrrolidine - 1 - carboxylate ( 900 mg , 64.02 % ) as a yellow solid . LCMS : C15H22N2O2 requires : 262.2 , found : m / z = 263.1 [ M + H ] * . [ 000283 ] 3- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- Step - 3 : Synthesis of tert - butyl ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenyl } pyrrolidine - 1 - carboxylate ( 5 ) To a mixture of tert - butyl 3- ( 3 - aminophenyl ) pyrrolidine - 1 - carboxylate ( 268 mg , 1.02 mmol , 1.2 equiv ) and N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 400 mg , 0.85 mmol , 1 equiv ) in dioxane ( 5 mL ) was added Pd2 ( dba ) 3 ( 117 mg , 0.12 mmol , 0.15 equiv ) , DavePhos ( 100 mg , 0.25 mmol , 0.3 equiv ) and t - BuONa ( 122 mg , 1.28 mmol , 1.5 equiv ) at room temperature under a nitrogen atmosphere . The final reaction mixture was irradiated with microwave radiation for 2 h at 120 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 3- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenylpyrrolidine - 1- carboxylate ( 220 mg , 33.41 % ) as a yellow solid . LCMS : C35H43FN6O4S2 requires : 694.3 , found : m / z = 695.2 [ M + H ] * . -384- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000284 ] Step - 4 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( pyrrolidin - 3- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride A mixture of tert - butyl 3- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } pyrrolidine - 1 - carboxylate ( 400 mg , 0.5mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 5 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( pyrrolidin - 3 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide hydrochloride ( 313.1 mg , crude ) as a yellow solid . LCMS : C30H35FN6O2S2 requires : 594.2 , found : m / z = 595.2 [ M + H ] * . ' H NMR ( 300 MHz , CD3OD ) 8 8.26 ( d , J = 5.1 Hz , 1H ) , 7.65 – 7.62 ( m , 2H ) , 7.56 – 7.53 ( m , 1H ) , 7.44 – 7.41 ( m , 1H ) , 7.38 – 7.26 ( m , 2H ) , 7.00 – 6.97 ( m , 1H ) , 6.52 – 6.50 ( m , 1H ) , 3.- 3.71 ( m , 1H ) , 3.59 - 3.55 ( m , 2H ) , 3.48 -3.40 ( m , 1H ) , 3.28 - 3.21 ( m , 1H ) , 3.06 - 3.01 ( m , 2H ) , 2.60 - 2.50 ( m , 1H ) , 2.25 – 2.06 ( m , 1H ) , 1.85 – 1.70 ( m , 2H ) , 1.54 ( s , 9H ) , 1.02 – 0.( m , 3H ) . [ 000285 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( piperidin - 4 - ylmethyl ) pyrazol - 4- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt 2-5 = F- HCI N N HN- NH -385- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT HN HO H2 , Pd / C NH N₂O DIAD , PPh3 , THF MeOH N₂O N₂H Pd2 ( dba ) 3 , Davephos , t - BuONa , dioxane Step - 1 Step - 2 Step - F- HN HN- HCl / dioxane HN F HCI HN- Step - 4 NH [ 000286 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 4 - [ ( 4 - nitropyrazol - 1 - yl ) methyl ] piperidine - 1- To a mixture of 4 - nitropyrazole ( 2 g , 17.68 mmol , 1 equiv ) and tert - butyl 4- ( hydroxymethyl ) piperidine - 1 - carboxylate ( 3.81 g , 17.68 mmol , 1 equiv ) in THF ( 20 mL ) was added DIAD ( 3.58 g , 17.68 mmol , 1 equiv ) and PPh3 ( 4.64 g , 17.68 mmol , 1 equiv ) at room temperature . The resulting mixture was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4 - [ ( 4 - nitropyrazol - 1- yl ) methyl ] piperidine - 1 - carboxylate ( 2 g , 32.79 % ) as a yellow solid . LCMS : C14H22N4Orequires : 310.2 , found : m / z = 311.2 [ M + H ] * . [ 000287 ] Step - 2 : Synthesis of tert - butyl 4 - [ ( 4 - aminopyrazol - 1 - yl ) methyl ] piperidine- - carboxylate ( 3 ) To a mixture of tert - butyl 4 - [ ( 4 - nitropyrazol - 1 - yl ) methyl ] piperidine - 1 - carboxylate ( 2 g , 6.mmol , 1 equiv ) in MeOH ( 10 mL ) was added Pd / C ( 1.0 g ) at room temperature . The resulting mixture was stirred for 1 h at room temperature under a hydrogen atmosphere . The resulting mixture was filtered . The filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert- butyl 4 - [ ( 4 - aminopyrazol - 1 - yl ) methyl ] piperidine - 1 - carboxylate ( 1 g , 49.81 % ) as a pink solid . LCMS : C14H24N4O2 requires : 280.2 , found : m / z = 281.1 [ M + H ] * . - 386 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- [ 000288 ] Step - 3 : Synthesis of tert - butyl ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyrazol - 1- ylmethyl ) piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4 - [ ( 4 - aminopyrazol - 1 - yl ) methyl ] piperidine - 1 - carboxylate ( 358 mg , 1.27 mmol , 1.2 equiv ) and N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 500 mg , 1.06 mmol , 1 equiv ) in dioxane ( 5 mL ) was added Pd2 ( dba ) 3 ( 146 mg , 0.16 mmol , 0.15 equiv ) , DavePhos ( 125 mg , 0.32 mmol , 0.3 equiv ) , and t - BuONa ( 153 mg , 1.59 mmol , 1.5 equiv ) at room temperature under nitrogen atmosphere . The final reaction mixture was irradiated with microwave radiation for 2 h at 120 ° C under nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 6 : 1 ) to afford tert - butyl 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyrazol - 1- yl } methyl ) piperidine - 1 - carboxylate ( 500 mg , 59.21 % ) as a yellow oil . LCMS : C34H45FN8O4Srequires : 712.3 , found : m / z = 713.3 [ M + H ] * . [ 000289 ] Step - 4 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( piperidin - 4- ylmethyl ) pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide hydrochloride A mixture of tert - butyl 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyrazol - 1 - yl ) methyl ) piperidine- - carboxylate ( 500 mg , 0.70 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was purified by reverse phase flash chromatography with MeCN : O₂H ( 9 : 1 ) to afford N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( piperidin - 4 - ylmethyl ) pyrazol - 4 - yl ] amino } pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 369.1 mg , 85.19 % ) as an orange solid . LCMS : C29H37FN8O2S2 requires : 612.3 , found : m / z = 613.[ M + H ] + . ' H NMR ( 400 MHz , CD3OD ) 8 8.48 – 8.17 ( m , 1H ) , 7.75 – 7.64 ( m , 3H ) , 7.60 – 7.( m , 1H ) , 7.42 – 7.38 ( m , 1H ) , 6.84 – 6.57 ( m , 1H ) , 4.26 – 4.14 ( m , 2H ) , 3.46 – 3.33 ( m , 2H ) , 3.192.98 ( m , 4H ) , 2.41 - 2.20 ( m , 1H ) , 1.93 – 1.79 ( m , 4H ) , 1.65 – 1.56 ( m , 11H ) , 1.09 – 1.05 ( m , 3H ) . = - [ 000290 ] Synthesis of - _ N- ( 2 - fluoro - 3- { 1- [ 4- ( piperidin - 4 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt - 387- 1100573566 5 AMERICAS Br O = S .

-Boc Pd ( dppf ) Cl2 , KOAc , dioxane 2niP₂B Step - i ) TEA , DCM ii ) Na2CO3 , THF : H2O : ACN Step - NH 0 = 8 = NH Pd ( aMphos ) ₂lC , CSF , dioxane , O₂H Step - NH .F -F HCI -Boc Boc NH Attorney Docket No .: 121843.002NU - 3200 PCT NH Br- NH Cu ( OAc ) 2 , pyridine , molecular sieves 4A Step - HCl / dioxane Step - -Boc Br- 0 = $ = NH HCI NH Boc [ 000291 ] Step - 1 : Synthesis of tert - butyl dioxaborolan - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 2 ) 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- To a mixture of tert - butyl 4- ( 4 - bromophenyl ) piperidine - 1 - carboxylate ( 6 g , 17.634 mmol , equiv ) and bis ( pinacolato ) diboron ( 13.4 g , 52.902 mmol , 3 equiv ) in dioxane ( 60 mL ) was added Pd ( dppf ) Cl2 CH2Cl2 ( 1.4 g , 1.763 mmol , 0.1 equiv ) and KOAc ( 5.2 g , 52.902 mmol , equiv ) in portions at room temperature under a nitrogen atmosphere . The resulting mixture was stirred at 85 ° C overnight under the nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 82:18 ) to afford tert - butyl 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- - 388 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT dioxaborolan - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 4.8 g , 70.28 % ) as a yellow oil . LCMS : C22H34BNO4 requires : 387.3 , found : m / z = 388.2 [ M + H ] * . [ 000292 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] piperidine - 1 - carboxylate ( 2.5 g , 6.454 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol- - yl ) pyridine ( 2.2 g , 9.681 mmol , 1.5 equiv ) in pyridine ( 20 mL ) was added molecular sieves 4A ( 2.2 g ) and Cu ( OAc ) 2 ( 820.3 mg , 12.908 mmol , 2 equiv ) in portions at room temperature under an oxygen atmosphere . The resulting mixture was stirred at 100 ° C under the oxygen atmosphere overnight . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 70:30 ) to afford tert- butyl 4- [ 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperidine - 1 - carboxylate ( 2 g , 64.10 % ) as a light yellow solid . LCMS : C24H27BrN4O2 requires : 482.1 , found : m / z = 483.[ M + H ] + . [ 000293 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperidine - 1- carboxylate ( 1.5 g , 3.103 mmol , 1 equiv ) and 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) aniline ( 1.5 g , 6.206 mmol , 2 equiv ) in dioxane ( 15 mL ) and O₂H ( 1.5 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 0.44 g , 0.621 mmol , 0.2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred at 95 ° C under the nitrogen atmosphere for 2 h . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 45:55 ) to afford tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.g , 62.75 % ) as a yellow solid . LCMS : C30H32FN5O2 requires : 513.3 , found : m / z = 514.3 [ M + H ] * . [ 000294 ] Step - 4 : Synthesis of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl } piperidine - 1 - carboxylate ( 1.5 g , 2.920 mmol , 1 equiv ) and TEA ( 0.89 g , 8.7mmol , 3 equiv ) in DCM ( 15 mL ) was added propane - 1 - sulfonyl chloride ( 0.62 g , 4.380 mmol , 1.5 equiv ) dropwise at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The reaction was quenched with water at 0 ° C . The resulting mixture was concentrated - 389- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT under vacuum . To the above mixture was added THF ( 10 mL ) , ACN ( 10 mL ) , and Na2CO( 619.8 mg , 5.847 mmol , 2 equiv ) in O₂H ( 10 mL ) at room temperature . The resulting mixture was stirred overnight at 60 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue product was purified by reverse phase flash chromatography with MeCN : H2O ( 60:40 ) to afford tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperidine - 1- carboxylate ( 1.0 g , 55.25 % ) as a yellow solid . LCMS : C33H38FN5O4S requires : 619.3 , found : m / z = 620.3 [ M + H ] * . [ 000295 ] Step - 5 : Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperidin - 4 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ) phenyl ) piperidine - 1 - carboxylate ( 1 g , 1.614 mmol , 1 equiv ) and HCl ( gas ) in 1,4 - dioxane ( 20 mL , 4 N ) was stirred at room temperature overnight . The resulting mixture was concentrated under vacuum . This resulted in N- ( 2 - fluoro - 3- { 1- [ 4- ( piperidin - 4 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride ( 576.8 mg , crude ) as a yellow solid . LCMS : C28H30FN5O2S requires : 519.2 , found : m / z = 520.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.81 – 8.74 ( m , 2H ) , 8.68 ( s , 1H ) , 8.26 – 8.21 ( m , 2H ) , 8.03 - 7.96 ( m , 2H ) , 7.65 – 7.49 ( m , 3H ) , 7.45 – 7.32 ( m , 2H ) , 3.61 – 3.52 ( m , 2H ) , 3.26 – 3.12 ( m , 4H ) , 3.113.01 ( m , 1H ) , 2.18 – 2.12 ( m , 2H ) , 2.09 – 1.95 ( m , 2H ) , 1.93 – 1.84 ( m , 2H ) , 1.- 1.03 ( m , 3H ) . - - [ 000296 ] Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide O = S = NH -F N N ' NH 1100573566 5 AMERICAS Boc i ) TEA , DCM , rt , 1 h ii ) Na2CO3 , THF : O₂H : ACN Step - Br NH N N- Cu ( OAc ) 2 , pyridine , molecular sieves 4A Step - Br Boc Attorney Docket No .: 121843.002NU - 3200 PCT NHF ₂HN -Boc N Pd ( aMphos ) Cl2 , CSF , dioxane , O₂H Step - CNH Boc F HCl / dioxane Step - 0 = 8 = NH -F ' N ' NH [ 000297 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 2 ) To a mixture of tert - butyl . 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] piperazine - 1 - carboxylate ( 1 g , 2.57 mmol , 1 equiv ) in pyridine ( 10 mL ) was added 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 865 mg , 3.86 mmol , 1.5 equiv ) , Cu ( OAc ) 2 ( 1.87 g , mmol , 2 equiv ) , and molecular sieves ( 4A ) ( 865 mg ) at room temperature under an oxygen atmosphere . The resulting mixture was stirred overnight at 100 ° C under the oxygen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert- butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 500 mg , 32.07 % ) as a brown oil . MS ( ESI ) calc'd for ( C23H26BrN5O2 ) [ M + H ] * , 484.1 ; found , 484.[ 000298 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1- carboxylate ( 2 g , 4.12 mmol , 1 equiv ) in dioxane ( 20 mL ) and H2O ( 4 mL ) was added 2 - fluoro- 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) aniline ( 1.96 g , 8.25 mmol , 2 equiv ) , PdAMPHOS ( 584 mg , 0.86 mmol , 0.2 equiv ) , and CsF ( 1.25 g , 8.25 mmol , 2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred 2 h at 95 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 6 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3 - amino- - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 1.8 g , 76.25 % ) as a yellow solid . MS ( ESI ) calc'd for ( C29H31FN6O2 ) [ M + H ] * , 515.3 ; found , 515.1 . -391- 1100573566 5 AMERICAS [ 000299 ] Step - 3 : Synthesis of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 1.8 g , 3.49 mmol , 1 equiv ) and TEA ( 1.06 g , 10.49 mmol , equiv ) in DCM ( 20 mL ) was added propane - 1 - sulfonyl chloride ( 748 mg , 5.24 mmol , 1.equiv ) at 0 ° C . The resulting mixture was stirred one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 10 mL ) , MeCN ( 10 mL ) , and O₂H ( 10 mL ) . Then Na2CO3 ( 2 g , 19.25 mmol , 10 equiv ) was added at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 1 g , 58.55 % ) as a yellow solid . MS ( ESI ) calc'd for ( C32H37FN6O4S ) [ M + H ] * , 621.3 ; found , 621.2 . [ 000300 ] Step - 4 : Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide A mixture of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 1 g , 1.61 mmol , 1 equiv ) in HCl in 1,4- dioxane ( 20 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with H2O ( 0.5 % NH4HCO3 ) : MeCN ( 7 : 1 ) to afford N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide - - ( 514.mg , 60.69 % ) as a white solid . MS ( ESI ) calc'd for ( C27H29FN6O2S ) [ M + H ] * , 521.2 ; found , 521.2 . ' H NMR ( 400 MHz , DMSO - do ) 8 8.66 ( s , 1H ) , 8.54 - 8.52 ( m , 2H ) , 7.79 – 7.77 ( m , 2H ) , 7.47 - 7.42 ( m , 3H ) , 7.30 – 7.23 ( m , 2H ) , 7.09 – 7.07 ( m , 2H ) , 6.20 ( s , 1H ) , 3.15 – 3.( m , 4H ) , 3.01 - 2.97 ( m , 2H ) , 2.89 – 2.81 ( m , 4H ) , 1.72 – 1.63 ( m , 2H ) , 0.95 - 0.89 ( m , 3H ) . [ 000301 ] Synthesis of N- ( 3- ( 2- ( 1- ( 2- ( 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin- – – 4 - yl ) -5- ( 2 - aminopyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide -392- 1100573566 5 AMERICAS HN- ﻢﺤﻣﺩ ( 1 ) Boc i ) TEA , DCM , rt , 1 h ii ) Na2CO3 , THF : MeCN : O₂H Step - ﻢﻠﻫ Cl TEA , DCM , rt Step - HN HCI -N N- Boc N S.

Boc NHBoc -NH ( 3 ) Step - Attorney Docket No .: 121843.002NU - 3200 PCT F O = S = NH HN ( 4 ) Boc NH HOAc , Pd ( PPh3 ) 2Cl2 , BuzSnH , DCM , rt , 0.5 h Step - tert - butyl carbamate Brettphos Pd G3 , CsCO3 , F O = S = HCI / dloxane , rt 1,4 - dioxane , 80 ° C NH FO = S = NH F O = $ = NH Step - 5 Step - ( 7 ) HCI ( 6 ) ₂HN -Boc ( 5 ) CI [ 000302 ] Step - 1 : Synthesis of prop - 2 - en - 1 - yl N- ( 3- { 2- [ 1- ( 2 - chloroacetyl ) piperidin - 4- yl ] -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) carbamate ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 1000 mg , 2.110 mmol , 1 equiv ) and TEA ( 640.53 mg , 6.330 mmol , 3.0 equiv ) in DCM ( 5 mL ) was added chloroacetyl chloride ( 238.3 mg , 2.1mmol , 1.0 equiv ) at 0 ° C . The resulting mixture was stirred for 2 h at room temperature . The reaction was quenched with water / ice at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 8 : 1 ) to afford prop- - en - 1 - yl N- ( 3- ( 2- [ 1- ( 2 - chloroacetyl ) piperidin - 4 - yl ] -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol- -393- 1100573566 5 AMERICAS NH2 Attorney Docket No .: 121843.002NU - 3200 PCT 4 - yl ) -2 - fluorophenyl ) carbamate ( 800 mg , 68.88 % ) as a yellow solid . LCMS : C24H22C12FN5O3S requires : 549.1 , found : m / z = 550.1 [ M + H ] * . [ 000303 ] Step - 2 : Synthesis of tert - butyl 7- ( 2- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2- fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl } - - oxoethyl ) -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 4 ) To a mixture of prop - 2 - en - 1 - yl N- ( 3- ( 2- [ 1- ( 2 - chloroacetyl ) piperidin - 4 - yl ] -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) carbamate ( 1.5 g , 2.725 mmol , equiv ) and tert - butyl 2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 0.31 g , 1.363 mmol , 0.5 equiv ) in DMSO ( 10 mL ) was added DIEA ( 1.06 g , 8.175 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred at 80 ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by Prep - TLC ( CH2Cl2 : EtOAc 2 : 1 ) to afford tert - butyl 7- ( 2- { 4- [ 5- ( 2 - chloropyrimidin- - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidin- - yl ) -2 - oxoethyl ) -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 700 mg , 34.70 % ) as a yellow solid . LCMS : C36H43C1FN7O5S requires : 739.3 , found : m / z = 740.3 [ M + H ] * . [ 000304 ] Step - 3 : Synthesis of tert - butyl 7- ( 2- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl } -2 - oxoethyl ) -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 5 ) To a mixture of tert - butyl 7- ( 2- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] aminophenyl ) -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) -2 - oxoethyl ) -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 1.2 g , 1.621 mmol , 1 equiv ) and Pd ( PPh3 ) 2Cl2 ( 0.02 g , 0.032 mmol , 0.02 equiv ) in DCM ( 15 mL ) was added HOAc ( 0.24 g , 4.053 mmol , 2.5 equiv ) at room temperature under a nitrogen atmosphere . To the above mixture was added n - Bu3SnH ( 0.75 g , 2.594 mmol , 1.6 equiv ) at 0 ° C . The resulting mixture was stirred for an additional min at room temperature . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 92 : 8 ) to afford tert - butyl 7- ( 2- { 4- [ 4- ( 3 - amino - 2- fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) -2 - oxoethyl ) -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 570 mg , 53.59 % ) as a yellow solid . LCMS : C32H39CIFN7O3S requires : 655.3 , found : m / z = 656.3 [ M + H ] * . -394- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000305 ] Step - 4 : Synthesis of tert - butyl 7- ( 2- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl } -2 - oxoethyl ) - 2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 6 ) To a mixture of tert - butyl 7- ( 2- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 2 - yl ] piperidin - 1 - yl } -2 - oxoethyl ) -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 1.1 g , 1.676 mmol , 1 equiv ) and TEA ( 508.88 mg , 5.028 mmol , 3 equiv ) in DCM ( 11 mL ) was added propane - 1 - sulfonyl chloride ( 358.55 mg , 2.514 mmol , 1.5 equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . To the above mixture was added THF ( 10 mL ) , ACN ( 10 mL ) , and Na2CO( 0.36 g , 3.352 mmol , 2 equiv ) in H2O ( 10 mL ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) afford tert - butyl 7- ( 2- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- to sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) -2 - oxoethyl ) -2,7 - diazaspiro [ 3.5 ] nonane- - carboxylate ( 980 mg , 76.69 % ) as a yellow solid . LCMS : C35H45C1FN7O5S2 requires : 761.3 , found : m / z = 762.3 [ M + H ] * . [ 000306 ] Step - 5 : Synthesis of tert - butyl 7- { 2- [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) piperidin - 1 - yl ] -2 - oxoethyl } -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 7 ) To a mixture of tert - butyl 7- ( 2- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) -2 - oxoethyl ) -2,7 - diazaspiro [ 3.5 ] nonane- - carboxylate ( 900 mg , 1.181 mmol , 1 equiv ) and tert - butyl carbamate ( 691.49 mg , 5.9mmol , 5 equiv ) in 1,4 - dioxane ( 10 mL ) was added BrettPhos Pd G3 ( 100.87 mg , 0.111 mmol , 0.094 equiv ) and Cs2CO3 ( 769.29 mg , 2.362 mmol , 2 equiv ) at room temperature under nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 7- { 2- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) piperidin - 1 - yl ] -2 - oxoethyl } -2,7 - diazaspiro [ 3.5 ] nonane- - carboxylate ( 500 mg , 50.24 % ) as a light yellow solid . LCMS : C40H55FN8O7S2 requires : 842.4 , found : m / z = 843.4 [ M + H ] * . - 395 - 1100573566 5 AMERICAS [ 000307 ] Step - 6 : Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( 2- { 2,7- diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide hydrochloride To tert - butyl 7- { 2- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) piperidin - 1 - yl ] -2 - oxoethyl } -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 500 mg , 0.593 mmol , 1 equiv ) was added HCl ( gas ) in 1,4 - dioxane ( 10 mL , 4 N ) at room temperature . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under vacuum . This resulted in N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( 2- { 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ) piperidin - 4- yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 501.4 mg , crude ) as a yellow solid . LCMS : C30H39FN8O3S2 requires : 642.3 , found : m / z = 643.2 [ M + H ] * . H¹ NMR ( 400 MHz , CD3OD ) § 8.10 ( d , J = 6.8 Hz , 1H ) , 7.70 – 7.67 ( m , 1H ) , 7.51 – 7.44 ( m , 1H ) , 7.43 — 7.33 ( m , 1H ) , 6.66 – 6.60 ( m , 1H ) , 4.63 – 4.57 ( m , 1H ) , 4.50 – 4.27 ( m , 2H ) , 4.( s , 2H ) , 3.96 ( s , 2H ) , 3.90 – 3.86 ( m , 1H ) , 3.65 – 3.58 ( m , 2H ) , 3.55 – 3.44 ( m , 1H ) , 3.42 – 3.35 ( m , 1H ) , 3.31 – 3.20 ( m , 2H ) , 3.19 – 3.13 ( m , 2H ) , 3.05 – 3.00 ( m , 1H ) , 2.44 – 2.35 ( m , 2H ) , 2.33 2.23 ( m , 2H ) , 2.25 - 2.10 ( m , 2H ) , 2.06 - 1.94 ( m , 1H ) , 1.90 – 1.82 ( m , 3H ) , 1.– 1.04 ( m , 3H ) . - – - - [ 000308 ] Synthesis of N- { 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride salt Boc HCI HN F N - S = Pd / C , NHOAc , MeOH Step - S Boc N HCl / dioxane Step - HN HCI [ 000309 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 2 ) - 396 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 700 mg , 1.174 mmol , 1 equiv ) and NH4OAc ( 905.14 mg , 11.740 mmol , 10 equiv ) in MeOH ( 10 mL ) was added Pd / C ( 7mg ) at room temperature . The resulting mixture was stirred for 30 min at 40 ° C . The resulting mixture was filtered . The filtrate was concentrated under reduced pressure . The residue was purified by reverse phase chromatography eluted with CH3CN : H2O ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 2- yl } piperidine - 1 - carboxylate ( 450 mg , 68.23 % ) as a yellow solid . LCMS : C26H32FN5O4Srequires : 561.2 , found : m / z = 562.2 [ M + H ] * . [ 000310 ] Step - 2 : Synthesis of N- { 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyrimidin - 4 - yl ) - 1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 450 mg , 0.801 mmol , 1 equiv ) in HCl ( gas ) in 1,4- dioxane ( 5 mL , 4 N ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . This resulted in N- ( 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride salt ( 300.mg , crude ) as a yellow solid . LCMS : C21H24FN5O2S2 requires : 461.1 , found : m / z = 462.[ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 9.30 – 9.28 ( m , 1H ) , 8.76 – 8.74 ( m , 1H ) , 7.71 – 7.( m , 1H ) , 7.50 – 7.38 ( m , 3H ) , 3.60 – 3.55 ( m , 3H ) , 3.27 – 3.22 ( m , 2H ) , 3.16 – 3.12 ( m , 2H ) , 2.48 – 2.43 ( m , 2H ) , 2.20 – 2.14 ( m , 2H ) , 1.89 – 1.83 ( m , 2H ) , 1.06 – 1.03 ( m , 3H ) . [ 000311 ] Synthesis of N- ( 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol- - yl ] phenyl } propane - 1 - sulfonamide - - HN- F EN N - S = O S = O S. -397- 1100573566 5 AMERICAS Boc- Boc NHF Br NO3 S NO₂rBuC , EtOAc DMF Step - 1 Step - Fe , NH4Cl MeOH Boc Step - Br HCl / dioxane Step - HN- Boc NHi ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H , Br Step - Attorney Docket No .: 121843.002NU - 3200 PCT NO2 NBS , DMF Step - Boc OH Boc HO- HN - S = Pd ( dppf ) ₂lC , ³OC₂K , dioxane : O₂H Step - Br NO [ 000312 ] Step - 1 : Synthesis of 2 - bromo - 1- ( 2 - fluoro - 3 - nitrophenyl ) ethanone ( 2 ) To a mixture of 1- ( 2 - fluoro - 3 - nitrophenyl ) ethanone ( 2 g , 10.92 mmol , 1 equiv ) in EtOAc ( mL ) was added copper ( II ) bromide ( 4.88 g , 21.84 mmol , 2 equiv ) at room temperature . The resulting mixture was stirred overnight at 75 ° C . The precipitated solids were filtered out . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 6 : 1 ) to afford 2 - bromo - 1- ( 2 - fluoro - 3- nitrophenyl ) ethanone ( 2 g , 61.50 % ) as a yellow oil . LCMS : C8H5BrFNO3 requires : 260.9 , found : m / z = 262.0 [ M + H ] * . [ 000313 ] Step - 2 : Synthesis of tert - butyl 4- [ 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2- yl ] piperidine - 1 - carboxylate ( 4 ) To a mixture of 2 - bromo - 1- ( 2 - fluoro - 3 - nitrophenyl ) ethanone ( 2 g , 7.63 mmol , 1 equiv ) in DMF ( 20 mL ) was added tert - butyl 4 - carbamothioylpiperidine - 1 - carboxylate ( 2.05 g , 8.39 mmol , 1.1 equiv ) at room temperature . The resulting mixture was stirred for 5 h at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- [ 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2- yl ] piperidine - 1 - carboxylate ( 2 g , 57.88 % ) as a yellow oil . LCMS : C19H22FN3O4S requires : 407.1 , found : m / z = 408.1 [ M + H ] * . -398- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000314 ] Step - 3 : Synthesis of tert - butyl 4- [ 5 - bromo - 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3- thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 5 ) To a mixture of tert - butyl 4- [ 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carboxylate ( 2 g , 4.90 mmol , 1 equiv ) in DMF ( 20 mL ) was added NBS ( 960 mg , 5.39 mmol , 1.1 equiv ) at room temperature . The resulting mixture was stirred overnight at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4- [ 5 - bromo - 4- ( 2 - fluoro - 3- nitrophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 1.2 g , 45.24 % ) as a yellow oil . LCMS : C19H21 BrFN3O4S requires : 485.0 , found : m / z = 486.1 [ M + H ] * . [ 000315 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5 - bromo - 1,3- thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- [ 5 - bromo - 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2 - yl ] piperidine- - carboxylate ( 1 g , 2.05 mmol , 1 equiv ) in saturated aqueous NH4Cl ( 10 mL ) and MeOH ( mL ) was added Fe ( 114 mg , 2.05 mmol , 5 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 70 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5 - bromo - 1,3 - thiazol - 2 - yl ] piperidine- - carboxylate ( 500 mg , 46.89 % ) as a yellow oil . LCMS : C19H23BrFN3O2S requires : 455.0 , found : m / z = 456.1 [ M + H ] * . [ 000316 ] of tert - butyl 4- ( 5 - bromo - 4- ( 2 - fluoro - 3- Step - 5 : Synthesis ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5 - bromo - 1,3 - thiazol - 2- yl ] piperidine - 1 - carboxylate ( 1.2 g , 2.62 mmol , 1 equiv ) in DCM ( 12 mL ) was added TEA ( 7mg , 7.88 mmol , 3 equiv ) and propane - 1 - sulfonyl chloride ( 749 mg , 5.25 mmol , 2 equiv ) at ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was disolved in THF ( 5 mL ) , O₂H ( 5 mL ) , and MeCN ( 5 mL ) . Na2CO3 ( 1.13 g , 10.68 mmol , 5 equiv ) was added at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was concentrated under vacuum . The residue was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate - 399 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 5 - bromo - 4- ( 2 - fluoro- 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carboxylate_ ( 1 g , 56.88 % ) as a brown solid . LCMS : C22H29BrFN3O4S2 requires : 561.1 , found : m / z = 562.1 [ M + H ] * . [ 000317 ] Step - 6 : Synthesis of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 9 ) To a mixture of tert - butyl 4- { 5 - bromo - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl } piperidine - 1 - carboxylate ( 1 g , 1.77 mmol , 1 equiv ) and pyridin - 4 - yl boronic acid ( 218 mg , 1.77 mmol , 1 equiv ) in dioxane ( 10 mL ) and H2O ( 1 mL ) was added Pd ( dppf ) Cl( 130 mg , 0.17 mmol , 0.1 equiv ) and K2CO3 ( 491 mg , 3.55 mmol , 2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 500 mg , 40.13 % ) as a yellow solid . LCMS : C27H33FN4O4S2 requires : 560.2 , found : m / z 561.2 [ M + H ] + . [ 000318 ] = Step - 7 : Synthesis of N- { 2 - fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3- thiazol - 4 - yl ] phenylpropane - 1 - sulfonamide A mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyridin - 4 - yl ) - 1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 600 mg , 1.07 mmol , 1 equiv ) in HC1 / 1,4 - dioxane ( mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product ( 500 mg ) was purified by Prep - HPLC with the following conditions Column : XBridge Prep OBD C18 Column , 30 * 150 mm , mμ5 ; Mobile Phase A : water ( 10 mmol / L NH4HCO3 ) ; Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 20 % B to 30 % B in 10 min ; Wave Length : 254 nm ; Rt1 ( min ) : 8.6 to afford N- { 2- fluoro - 3- [ 2- ( piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 324.8 mg , 65.77 % ) as a white solid . LCMS : C22H25FN4O2S2 requires : 460.1 , found : m / z 461.1 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.45 – 8.44 ( m , 2H ) , 7.61 – 7.57 ( m , 1H ) , 7.– 7.23 ( m , 4H ) , 3.29 – 3.19 ( m , 3H ) , 2.95 – 2.91 ( m , 2H ) , 2.86 – 2.79 ( m , 2H ) , 2.21 – 2.18 ( m , 2H ) , 1.86 – 1.62 ( m , 4H ) , 0.98 – 0.94 ( m , 3H ) . [ 000319 ] = Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperidin - 4 - yl ) phenyl ] - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 400 - 1100573566 5 AMERICAS Boc HO IN = S = HN- NHCI , HATU DIEA , DMF N₂H HOAc , Pd ( PPh3 ) 2Cl2 , HnSзuB , DCM Step - 0 = 5 = ćoB Step - Boc HN N₂H .

Boc Attorney Docket No .: 121843.002NU - 3200 PCT N N S NH Lawesson's reagent THF Step - Boc HCl / dioxane Step - i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H Step - 0 = 6 = HN- N₂H S Boc NH NBS , DMA Step - Boc N₂H < Brettphos Pd G3 , ³OCsC , 1,4 - dioxane Step - [ 000320 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl of tert - butyl 4- ( 4 - carbamoylphenyl ) piperidine - 1- To a mixture of 4- [ 1- ( tert - butoxycarbonyl ) piperidin - 4 - yl ] benzoic acid ( 5 g , 16.37 mmol , equiv ) and NH4Cl ( 4.37 g , 81.86 mmol , 5 equiv ) in DMF ( 50 mL ) was added HATU ( 9.33 g , 24.55 mmol , 1.5 equiv ) and DIEA ( 6.34 g , 49.11 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The product was washed with EtOAc . The precipitated solids were collected by filtration to afford - 401 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT tert - butyl 4- ( 4 - carbamoylphenyl ) piperidine - 1 - carboxylate ( 4.8 g , 96.31 % ) as a white solid . LCMS : C17H24N2O3 requires : 304.2 , found : m / z = 305.2 [ M + H ] + . [ 000321 ] carboxylate ( 3 ) Step - 2 : Synthesis of tert - butyl 4- ( 4 - carbamothioylphenyl ) piperidine - 1- To a mixture of tert - butyl 4- ( 4 - carbamoylphenyl ) piperidine - 1 - carboxylate ( 3 g , 9.85 mmol , equiv ) in THF ( 30 mL ) were added Lawesson's Reagent ( 1.99 g , 4.92 mmol , 0.5 equiv ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with aqueous NaHCO3 and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - carbamothioylphenyl ) piperidine - 1 - carboxylate ( 2.2 g , 69.66 % ) as a white solid . LCMS : C17H24N2O2S requires : 320.1 , found : m / z = 321.[ M + H ] + . [ 000322 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1- carboxylate ( 5 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenyl } carbamate ( 1.8 g , 5.14 mmol , 1 equiv ) in DMA ( 20 mL ) was added tert - butyl 4- ( 4 - carbamothioylphenyl ) piperidine - 1 - carboxylate ( 1.98 g , 6.17 mmol , 1.2 equiv ) and NBS ( 1.83 g , 10.29 mmol , 2 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin- - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2- yl ] phenyl } piperidine - 1 - carboxylate ( 1.8 g , 48.95 % ) as a yellow solid . LCMS : C33H33C1FN5O4S requires : 649.2 , found : m / z = 650.2 [ M + H ] * . [ 000323 ] Step - 4 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] aminophenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.8 g , 2.mmol , 1 equiv ) and HOAc ( 415 mg , 6.93 mmol , 2.5 equiv ) in DCM ( 20 mL ) was added n- -402- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Bu3SnH ( 1.29 g , 4.43 mmol , 1.6 equiv ) and Pd ( PPh3 ) 2Cl2 ( 39 mg , 0.05 mmol , 0.02 equiv ) at ° C under a nitrogen atmosphere . The resulting mixture was stirred for 30 min at room temperature . The reaction was quenched with saturated aqueous NaHCO3 at 0 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.5 g , crude ) as a brown solid . LCMS : C29H29CIFN5O2S requires : 565.2 , found : m / z = 566.2 [ M + H ] * . [ 000324 ] Step - 5 : Synthesis of tert - butyl 4- ( 4- ( 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) phenyl ) piperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 1.5 g , 2.65 mmol , 1 equiv ) in DCM ( 15 mL ) was added propane - 1 - sulfonyl chloride ( 755 mg , 5.30 mmol , 2 equiv ) and TEA ( 804 mg , 7.95 mmol , equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 5 mL ) , O₂H ( 5 mL ) , and MeCN ( 5 mL ) . Na2CO3 ( 1.13 g , 10.68 mmol , 5 equiv ) was added at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was concentrated under vacuum . The residue was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 4- ( 5- ( 2- chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2- yl ) phenyl ) piperidine - 1 - carboxylate ( 1.1 g , 73.77 % ) as a yellow solid . solid . LCMS : C32H35CIFN5O4S2 requires : 671.2 , found : m / z = 672.2 [ M + H ] * . [ 000325 ] Step - 6 : Synthesis of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 8 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] phenyl } piperidine - 1 - carboxylate ( 600 mg , 0.89 mmol , equiv ) and tert - butyl carbamate ( 522.80 mg , 4.465 mmol , 5 equiv ) in dioxane ( 6 mL ) was added BrettPhos Pd G3 ( 81 mg , 0.089 mmol , 0.1 equiv ) and Cs2CO3 ( 581 mg , 1.78 mmol , equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for h at 80 ° C . The resulting mixture was concentrated under reduced pressure . The residue was - 403 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT purified by silica gel column chromatography , eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 4- ( 5-2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 400 mg , 53.57 % ) as a yellow solid . LCMS : C37H45FN6O6S2 requires : 752.2 , found : m / z = 753.3 [ M + H ] * . [ 000326 ] Step - 7 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperidin - 4- yl ) phenyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide A mixture of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) phenyl ] piperidine - 1 - carboxylate ( 400 mg , 0.53 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 5 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was purified by Prep - HPLC with the following conditions Column : XBridge Prep OBD CColumn , 30 * 150 mm , 5 mµ ; Mobile Phase A : water ( 10 mmol / L NH4HCO3 ) ; Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 30 % B to 38 % B in 8 min ; Wave Length : 220/254 nm ; ₁₁R ( min ) : 6.75 to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperidin - 4 - yl ) phenyl ] -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 223.7 mg , 70.01 % ) as a yellow solid . LCMS : C27H29FN6O2S2 requires : 552.2 , found : m / z = 553.2 [ M + H ] * . = – ' H NMR ( 400 MHz , DMSO - do ) 8 8.15 – 8.06 ( m , 1H ) , 7.98 – 7.93 ( m , 2H ) , 7.56 – 7.52 ( m , H ) , 7.40 – 7.37 ( m , 2H ) , 7.24 – 7.16 ( m , 2H ) , 6.79 ( s , 2H ) , 6.18 – 6.16 ( m , 1H ) , 3.21 – 3.( m , 2H ) , 2.97 – 2.93 ( m , 2H ) , 2.77 – 2.69 ( m , 3H ) , 1.80 – 1.71 ( m , 2H ) , 1.69 – 1.57 ( m , 4H ) , 0.94 0.90 ( m , 3H ) . - [ 000327 ] Synthesis of N- ( 2 - fluoro - 3- { 5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt HN CH3NH2 HCI , IN -N .

HCI N N N HN DIEA , DMSO , 80 ° C Step - HN HCI / dioxane , DCM HCI Step - N- HN- _ NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000328 ] tert - butyl 4-4- [ 2 - fluoro - 3- ( propane - 1- Step - 1 : Synthesis of sulfonamido ) phenyl ] -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl } piperidine - 1- carboxylate ( 2 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 300 mg , 0.503 mmol , 1 equiv ) and CH3NH2 HCl ( 101.9 mg , 1.509 mmol , 3 equiv ) in DMSO ( 3 mL ) was added DIEA ( 195.mg , 1.509 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred at 80 ° C overnight . The residue was purified by reverse phase column chromatography eluted with CH3CN : O₂H ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 280 mg , 94.19 % ) as a light yellow solid . LCMS : C27H35FN6O4S2 requires : 590.2 , found : m / z = 591.3 . [ M + H ] * . [ 000329 ] Step - 2 : Synthesis of N- ( 2 - fluoro - 3- { 5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 280 mg , 0.4mmol , 1 equiv ) in DCM ( 3 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 3 mL , 4 N ) at room temperature . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . This resulted in N- ( 2 - fluoro - 3- { 5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) phenyl ) propane - 1- sulfonamide hydrochloride salt ( 174.0 mg , crude ) as a yellow solid . LCMS : C22H27FN6O2Srequires : 490.2 , found : m / z = 491.2 . [ M + H ] * . - 1H NMR ( 400 MHz , CD3OD ) 8 8.14 ( s , 1H ) , 7.72 – 7.62 ( m , 1H ) , 7.49 – 7.43 ( m , 1H ) , 7.42 – 7.35 ( m , 1H ) , 6.72 ( s , 1H ) , 3.72 – 3.49 ( m , 3H ) , 3.31 – 3.20 ( m , 2H ) , 3.20 – 3.12 ( m , 2H ) , 2.( s , 3H ) , 2.51 – 2.36 ( m , 2H ) , 2.26 – 2.05 ( m , 2H ) , 1.98 – 1.76 ( m , 2H ) , 1.16 – 1.00 ( m , 3H ) . [ 000330 ] Synthesis of - N- { 2 - fluoro - 3- [ 5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2- yl ] amino } pyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1- sulfonamide hydrochloride salt -405- 1100573566 5 AMERICAS HN 0 = 5 = HN- N₂H TROH N Attorney Docket No .: 121843.002NU - 3200 PCT Nabs .OH HCI 0 = 5 = HCl / dioxane D = 5 = EtOH Step - abs OH abs H -OH HCI Step - HN Boc CI [ 000331 ] Step - 1 : Synthesis of tert - butyl 4-4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 2 - ylpiperidine - 1 - carboxylate ( 2 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 300 mg , 0.503 mmol , 1 equiv ) in EtOH ( 2 mL ) was added ( R ) - ( - ) - 2 - amino - 1 - propanol ( 113 mg , 1.509 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred overnight at 70 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with H2O : MeCN ( 3 : 1 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol- - ylpiperidine - 1 - carboxylate ( 210 mg , 62.45 % ) as a yellow solid . LCMS : C29H39FN6O5Srequires : 634.2 , found : m / z = 635.3 [ M + H ] + . [ 000332 ] Step - 2 : Synthesis of N- { 2 - fluoro - 3- [ 5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2- yl ] amino } pyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1- sulfonamide hydrochloride A mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( 2 - { [ ( 2R ) -1- hydroxypropan - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 210 ) mg , 0.331 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 2- fluoro - 3- [ 5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2 - yl ] amino } pyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3- thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride salt ( 150.4 mg , crude ) as a yellow solid . LCMS : C24H31FN6O3S2 requires : 534.2 , found : m / z = 535.2 [ M + H ] * . - 406 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT – - H¹ NMR ( 400 MHz , CD3OD ) 8 8.14 ( s , 1H ) , 7.80 – 7.69 ( m , 1H ) , 7.47 – 7.40 ( m , 1H ) , 7.38 – 7.30 ( m , 1H ) , 6.71 ( s , 1H ) , 4.05 ( s , 1H ) , 3.83 – 3.45 ( m , 5H ) , 3.33 – 3.24 ( m , 2H ) , 3.22 – 3.– - ( m , 2H ) , 2.46 – 2.43 ( m , 2H ) , 2.21 – 2.14 ( m , 2H ) , 1.90 – 1.84 ( m , 2H ) , 1.28 – 1.21 ( m , 3H ) , 1.08 1.04 ( m , 3H ) . [ 000333 ] Synthesis of N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 4- ( piperidin - 4- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenylpropane - 1 - sulfonamide hydrochloride salt F N. N HCI HN HN NH NH NBS , DMA HOAc , Pd ( PPh3 ) 2Cl2 , HnSзuB , DCM Step - HN N - Boc N₂H F N HN HN . Brettphos Pd G3 , CsCO3 , 1,4 - dioxane O = S = Step - Step - N₂H Cl . i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H Step - HCl / dioxane HCI DCM HN HN O = s = Step - Boc [ 000334 ] Ci Step - 1 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- methyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenylcarbamate ( 1 ) N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- To a mixture of prop - 2 - en - 1 - yl fluorophenylcarbamate ( 2 g , 5.718 mmol , 1 equiv ) in DMA ( 10 mL ) was added NBS ( 1.02 g , 5.731 mmol , 1 equiv ) and the mixture was stirred for 15 min . Then , thioacetamide ( 516 mg , 6.862 mmol , 1.2 equiv ) was added . The resulting mixture was stirred at 60 ° C for 2 h . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3- - 407- 1100573566 5 AMERICAS NH Attorney Docket No .: 121843.002NU - 3200 PCT thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 1 g , 35.42 % ) as a yellow solid . LCMS : C18H14CIFN4O2S requires : 404.1 , found : m / z = 405.1 [ M + H ] * . [ 000335 ] Step - 2 : Synthesis of 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4- yl ] -2 - fluoroaniline ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] - - fluorophenylcarbamate ( 1 g , 2.47 mmol , 1 equiv ) in DCM ( 10 mL ) was added HOAc ( 3mg , 5.928 mmol , 2.4 equiv ) and Pd ( PPh3 ) 2Cl2 ( 34.68 mg , 0.049 mmol , 0.02 equiv ) . Then , n- HnSзuB ( 1.08 g , 3.705 mmol , 1.5 equiv ) was added at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred at room temperature for one hour . The reaction was quenched with saturated aqueous NaHCO3 at 0 ° C . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 7mg , 79.51 % ) as a yellow solid . LCMS : C14H10C1FN4S requires : 320.0 , found : m / z = 321.[ M + H ] + . [ 000336 ] Step - 3 : Synthesis of N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol- - yl ] -2 - fluorophenylpropane - 1 - sulfonamide To a mixture of 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 1mg , 0.468 mmol , 1 equiv ) and TEA ( 142 mg , 1.404 mmol , 3 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 200 mg , 1.404 mmol , 3 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under vacuum . To the above mixture was added THF ( 5 mL ) , ACN ( 5 mL ) , and Na2CO3 ( 7mg , 7.02 mmol , 15 equiv ) in H2O ( 5 mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- { 3- [ 5- ( 2 - chloropyrimidin- - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 113.4 mg , 56.63 % ) as a light yellow solid . LCMS : C17H16ClFN4O2S2 requires : 426.0 , found : m / z = 427.0 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( d , J = 5.2 Hz , 1H ) , 7.76 – 7.63 ( m , 1H ) , 7.50 – 7.30 ( m , 2H ) , 7.15 – 7.02 ( m , 1H ) , 3.19 – 3.07 ( m , 2H ) , 2.81 ( s , 3H ) , 1.93 – 1.74 ( m , 2H ) , 1.13 – 0.( m , 3H ) . [ 000337 ] Step - 4 : Synthesis of tert - butyl 4- { 4 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -2 - methyl - 1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenyl } piperidine - 1 - carboxylate ( 4 ) - 408 - 1100573566 5 AMERICAS To a mixture of Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 500 mg , 1.171 mmol , 1 equiv ) and tert - butyl 4- ( 4- aminophenyl ) piperidine - 1 - carboxylate ( 647 mg , 2.342 mmol , 2 equiv ) in 1,4 - dioxane ( 10 mL ) was added Cs2CO3 ( 763 mg , 2.342 mmol , 2 equiv ) and BrettPhos Pd G3 ( 106 mg , 0.117 mmol , 0.1 equiv ) . The resulting mixture was stirred at 80 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4 - [ ( 4- { 4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -2 - methyl - 1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenylpiperidine - 1 - carboxylate ( 500 mg , 57.62 % ) as a yellow solid . LCMS : C33H39FN6O4S2 requires : 666.3 , found : m / z = 667.3 [ M + H ] * . [ 000338 ] Step - 5 : Synthesis of N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 4- ( piperidin - 4- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenylpropane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- { 4 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -2 - methyl- 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidine - 1 - carboxylate ( 1.0 g , 1.5 mmol , equiv ) in DCM ( 10 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 5 mL , 4 N ) at 0 ° C . The resulting mixture was stirred overnight at room temperature . The resulting mixture was concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 4- ( piperidin - 4- afford yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide = hydrochloride salt ( 561.3 mg , 61.12 % ) as a yellow solid . LCMS : C28H31FN6O2S2 requires : 566.2 , found : m / z = 567.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3COOD ) 8 8.24 ( d , J = 5.6 Hz , 1H ) , 7.82 – 7.70 ( m , 1H ) , 7.68 – 7.59 ( m , 2H ) , 7.56 – 7.46 ( m , 1H ) , 7.44 – 7.34 ( m , 1H ) , 7.– 7.20 ( m , 2H ) , 6.62 ( d , J = 5.6 Hz , 1H ) , 3.77 – 3.63 ( m , 2H ) , 3.34 – 3.16 ( m , 2H ) , 3.14 – 3.- - ( m , 2H ) , 2.87 ( s , 4H ) , 2.11 ( s , 4H ) , 1.87 – 1.72 ( m , 2H ) , 1.07 – 0.94 ( m , 3H ) . [ 000339 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4 - yl ) ethyl ] - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt - 409- 1100573566 5 AMERICAS Boc -OH NH4CI , HATU , DIEA DMF , rt , 2 h Step - Boo CI Boc [ 000340 ] HOAc , Pd ( PPh3 ) 2Cl2 , HnSзuB , DCM , rt , 0.5 h Step - 1 : Step - Boc O = S- HN .

F N HN HCI Attorney Docket No .: 121843.002NU - 3200 PCT N · S NH -NHLawesson's reagent THF , rt , o / n Step - Boc N₂H . F CI -NH i ) TEA , DCM , rt , 1h ii ) Na2CO3 , THF : MeCN : O₂H , ° C , o / n Step - Boc HCI HCl / dioxane , DCM , rt , o / n Step - HN Boc Synthesis of tert - butyl NBS , DMA , 60 ° C , 2 h NH Step - Cl N₂H . ° Brettphos Pd G3 , CsCO3 , 1,4 - dioxane , 80 ° C , 2 h Step - 4- ( 2 - carbamoylethyl ) piperidine - 1- carboxylate ( 2 ) To a mixture of 3- [ 1- ( tert - butoxycarbonyl ) piperidin - 4 - yl ] propanoic acid ( 5.0 g , 19.430 mmol , equiv ) , HATU ( 11.08 g , 29.145 mmol , 1.5 equiv ) , and NH4Cl ( 5.19 g , 97.150 mmol , 5.equiv ) in DMF ( 50 mL ) was added DIEA ( 7.53 g , 58.290 mmol , 3.0 equiv ) dropwise at room temperature . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl 4- ( 2 - carbamoylethyl ) piperidine - 1 - carboxylate ( 3.2 g , 64.25 % ) as a white solid . LCMS : C13H24N2O3 requires : 256.2 , found : m / z = 257.2 [ M + H ] * . [ 000341 ] carboxylate ( 3 ) Step - 2 : Synthesis of tert - butyl 4- ( 2 - carbamothioylethyl ) piperidine - 1- - 410 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- ( 2 - carbamoylethyl ) piperidine - 1 - carboxylate ( 3.0 g , 11.703 mmol , equiv ) in THF ( 30 mL ) was added Lawesson's Reagent ( 2.36 g , 5.851 mmol , 0.5 equiv ) . The resulting mixture was stirred for at 50 ° C overnight . The reaction was quenched by the addition of saturated aqueous sodium hyposulfite at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 1 : 1 ) to afford tert- butyl 4- ( 2 - carbamothioylethyl ) piperidine - 1 - carboxylate ( 1.5 g , 47.05 % ) as a white solid . LCMS : C13H24N2O2S requires : 272.2 , found : m / z = 273.2 [ M + H ] * . [ 000342 ] = Step - 3 : Synthesis of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1- carboxylate ( 5 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenyl } carbamate ( 1.92 g , 5.506 mmol , 1.00 equiv ) in DMA ( 15 mL ) was added NBS ( 980.06 mg , 5.506 mmol , 1.0 equiv ) for 15 min at room temperature followed by the addition of tert - butyl 4- ( 2 - carbamothioylethyl ) piperidine - 1 - carboxylate ( 1.5g , 5.506 mmol , 1.00 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 6 : 1 ) to afford tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 1.2 g , 36.19 % ) as a white solid . LCMS : C29H33C1FN5O4S requires : 601.2 , found : m / z = 602.[ M + H ] + . [ 000343 ] Step - 4 : Synthesis of tert - butyl 4- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 1.2 g , 1.9mmol , 1 equiv ) and HOAc ( 0.30 g , 4.982 mmol , 2.5 equiv ) in DCM ( 12 mL ) was added n- HnSзuB ( 0.93 g , 3.189 mmol , 1.6 equiv ) and Pd ( PPh3 ) 2C12 ( 27.98 mg , 0.040 mmol , 0.02 equiv ) at room temperature . The resulting mixture was stirred for 0.5 h at room temperature under a nitrogen atmosphere . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate - 411 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT was concentrated under reduced pressure to afford tert - butyl 4- { 2- [ 4- ( 3 - amino - 2- fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 800 mg , crude ) as a yellow oil . The crude product was used in the next step directly without further purification . LCMS : C25H29C1FN5O2S requires : 517.2 , found : m / z = 518.2 [ M + H ] * . [ 000344 ] Step - 5 : Synthesis of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- { 2- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 800 mg , 1.544 mmol , 1 equiv ) and TEA ( 468.mg , 4.632 mmol , 3.0 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 440.mg , 3.088 mmol , 2.0 equiv ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 3 mL ) , ACN ( 3 mL ) , and O₂H ( 3 mL ) . Na2CO3 ( 799.mg , 7.545 mmol , 6.89 equiv ) was added at room temperature . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 680 mg , 85.00 % ) as a yellow solid . LCMS : C28H35C1FN5O4S2 requires : 623.2 , found : m / z = 624.2 [ M + H ] * . [ 000345 ] Step - 6 : Synthesis of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1- carboxylate ( 8 ) To a mixture of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] ethyl } piperidine - 1 - carboxylate ( 660 mg , 1.057 mmol , equiv ) and tert - butyl carbamate ( 619.34 mg , 5.285 mmol , 5.0 equiv ) in 1,4 - dioxane ( 7 mL ) was added Cs2CO3 ( 689.02 mg , 2.114 mmol , 2.0 equiv ) and BrettPhos Pd G3 ( 95.85 mg , 0.1mmol , 0.1 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) ethyl ] piperidine - 1 - carboxylate ( 400 mg , 53.67 % ) as a white solid . LCMS : C33H45FN6O6S2 requires : 704.3 , found : m / z = 705.3 [ M + H ] * . -412- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000346 ] Step - 7 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4- yl ) ethyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) ethyl ] piperidine - 1 - carboxylate ( 380 mg , 0.539 mmol , 1 equiv ) in DCM ( 2 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 6 mL , M ) . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % NH4HCO3 ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4 - yl ) ethyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 205.9 mg , 67.55 % ) as a yellow solid . LCMS : C23H29FN6O2S2 requires : 504.2 , found : m / z = 505.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) § 8.00 ( s , 1H ) , 7.62 – 7.58 ( m , 1H ) , 7.39 – 7.19 ( m , 1H ) , 6.58 – 6.47 ( m , 1H ) , 3.82 – 3.42 ( m , 1H ) , 3.36 – 3.25 ( m , 2H ) , 3.14 – 2.98 ( m , 4H ) , 2.94 – 2.86 ( m , 2H ) , 2.03 – 1.90 ( m , 2H ) , 1.– 1.65 ( m , 5H ) , 1.48 – 1.31 ( m , 2H ) , 0.97 – 0.93 ( m , 3H ) . [ 000347 ] - Synthesis of N- ( 3- { 5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4- yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride salt Boc 0 = 5 = N₂H DIEA , DMSO Step - ZI HN . N. N. HCI F N : F -NH O = S- HCl / dioxane DCM Step - HCI HN- Boc - 413 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000348 ] Step - 1 : Synthesis of tert - butyl 4- { 5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 2 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 500 mg , 0.83 mmol , 1 equiv ) and DIEA ( 325 mg , 2.51 mmol , 3 equiv ) in DMSO ( 5 mL ) was added aminocyclopropane ( 1mg , 2.51 mmol , 3 equiv ) at room temperature . The resulting mixture was stirred overnight at ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography ( 1 : 1 ) to afford tert - butyl 4- { 5- [ 2- with O₂H : MeCN ( cyclopropylamino ) pyrimidin - 4 - yl ] -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl } piperidine - 1 - carboxylate ( 400 mg , 75.78 % ) as a yellow solid . LCMS : C29H37FN6O4S2 requires : 616.2 , found : m / z = 617.3 [ M + H ] * . [ 000349 ] Step - 2 : Synthesis of N- ( 3- { 5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- { 5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] -4- [ 2 - fluoro - 3- ( propane- - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 400 mg , 0.649 mmol , equiv ) in DCM ( 10 mL ) was added HC1 in 1,4 - dioxane ( 1 mL , 4 M ) at room temperature . The resulting mixture was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- ( 3- { 5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] - 2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide hydrochloride salt ( 213.6 mg , crude ) as a yellow solid . LCMS : C24H29FN6O2S2 requires : 516.2 , found : m / z 517.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.13 ( d , J = 6.8 Hz , 1H ) , 7.67 – 7.65 ( m , 1H ) , 7.457.43 ( m , 1H ) , 7.38 – 7.36 ( m , 1H ) , 6.66 ( d , J = 6.8 Hz , 1H ) , 3.56 – 3.52 ( m , 3H ) , 3.24 -– 3.12 ( m , 4H ) , 2.71 – 2.69 ( m , 1H ) , 2.42 – 2.38 ( m , 2H ) , 2.14 – 2.09 ( m , 2H ) , 1.88 – 1.82 ( m , 2H ) , 1.06 – 1.00 ( m , 5H ) , 0.83 – 0.75 ( m , 2H ) . [ 000350 ] Synthesis of – - - - = N- ( 2 - fluoro - 3- { 5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt - 414 - 1100573566 5 AMERICAS > O = S = O = 5 = ZH CI N₂H DIEA , DMSO , 80 ° C , o / n Step - HN Attorney Docket No .: 121843.002NU - 3200 PCT N N HCI S N 0 = 5 = Boc -NH HCl / dioxane IN b = Step - HCI HN- [ 000351 ] Step - 1 : Synthesis of tert - butyl 4-4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl } piperidine- - carboxylate ( 2 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 500 mg , 0.839 mmol , 1 equiv ) and isopropylamine ( 148.74 mg , 2.517 mmol , 3.0 equiv ) in DMSO ( 5 mL ) was added DIEA ( 325.22 mg , 2.517 mmol , 3.0 equiv ) at room temperature . The resulting mixture was stirred at ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2- yl } piperidine - 1 - carboxylate ( 490 mg , 94.41 % ) as a yellow solid . LCMS : C29H39FN6O4Srequires : 618.3 , found : m / z = 619.1 [ M + H ] * . [ 000352 ] Step - 2 : Synthesis of N- ( 2 - fluoro - 3- { 5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] - 2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- [ 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl } piperidine - 1 - carboxylate ( 490 mg , 0.7mmol , 1 equiv ) in HCl ( gas ) / 1,4 - dioxane ( 5 mL , 4 M ) was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was - 415 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT purified by C18 reverse phase flash chromatography with ACN : H2O ( 0.5 % HCl ) ( 1 : 1 ) to afford N- ( 2 - fluoro - 3-5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4- yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt ( 185.9 mg , 45.26 % ) as a yellow solid . LCMS : C24H31FN6O2S2 requires : 518.2 , found : m / z = 519.2 [ M + H ] * . - ' H NMR ( 300 MHz , CD3OD ) 8 8.12 ( d , J = 6.6 Hz , 1H ) , 7.70 – 768 ( m , 1H ) , 7.52 - 7.35 ( m , 2H ) , 6.69 ( s , 1H ) , 4.01 ( s , 1H ) , 3.64 – 3.52 ( m , 3H ) , 3.30 – 3.25 ( m , 2H ) , 3.20 – 3.08 ( m , 2H ) , 2.47 – 2.43 ( m , 2H ) , 2.28 – 2.08 ( m , 2H ) , 1.96 – 1.79 ( m , 2H ) , 1.37 – 1.23 ( m , 6H ) , 1.10 – 1.( m , 3H ) . – - [ 000353 ] Synthesis of yl ] phenylpropane - 1 - sulfonamide ZH = 8 = N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- N NH NH Br NH Br -SEM ( 3 ) SEM - CI , NaH , THF EN ( 1 ) ( 2 ) Step - Pd ( dppf ) Cl2 , CS2CO3 , dioxane : O₂H , 90 ° C , 2h Step - CI i ) TEA , DCM , rt , 1 h NH NH TFA : DCM ( 1 : 1 ) -F ii ) Na2CO3 , THF : O₂H : ACN , ( 5 ) ° C , o / n Step - 3 SEM Step - [ 000354 ] Step - 1 : Synthesis of NH .NH ( 4 ) SEM 4- ( 4 - bromo - 1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 3 - yl ) pyridin ( 2 ) To a mixture of 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 5 g , 22.315 mmol , 1 equiv ) in THF ( mL ) was added NaH ( 1.07 g , 44.630 mmol , 2 equiv , 60 % in mineral oil ) at 0 ° C . After the mixture was stirred for 30 min , SEM - Cl ( 5.58 g , 33.473 mmol , 1.5 equiv ) was added at 0 ° C . The resulting mixture was stirred at room temperature for 2 h . The reaction was quenched with water . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column - 416 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford 4- ( 4 - bromo - 1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 3 - yl ) pyridine ( 6.8 g , 86.00 % ) as a yellow oil . MS ( ESI ) calc'd for ( C14H20BrN3OSi ) [ M + H ] † , 354.1 ; found , 354.0 . [ 000355 ] Step - 2 : Synthesis of ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 4 - yl ] aniline ( 4 ) - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1 - { [ 2- To a mixture of 4- ( 4 - bromo - 1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 3 - yl ) pyridine ( 5.0 g , 14.111 mmol , 1 equiv ) and 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) aniline ( 4.01 g , 16.933 mmol , 1.2 equiv ) in dioxane ( 50 mL ) and H2O ( 10 mL ) was added CS2CO3 ( 9.g , 28.222 mmol , 2 equiv ) and Pd ( dppf ) Cl2 CH2Cl2 ( 2.3 g , 2.822 mmol , 0.2 equiv ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford 2 - fluoro - 3- [ 3- ( pyridin - 4- yl ) -1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 4 - yl ] aniline ( 4.2 g , 77.40 % ) as a yellow solid . MS ( ESI ) calc'd for ( C20H25FN4OSi ) [ M + H ] * , 385.2 ; found , 385.2 . [ 000356 ] Step - 3 : Synthesis of N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 5 ) To a mixture of 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 4- yl ] aniline ( 4.2 g , 10.922 mmol , 1 equiv ) and TEA ( 3.3 g , 32.766 mmol , 3 equiv ) in DCM ( mL ) was added propane - 1 - sulfonyl chloride ( 3.1 g , 21.844 mmol , 2 equiv ) at room temperature . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 12 mL ) , ACN ( 12 mL ) , and O₂H ( 12 mL ) . Then Na2CO3 ( 3.7 g , 35.190 mmol , 6 equiv ) was added at room temperature . The resulting mixture was stirred at 50 ° C overnight . The bulk of the organic solvents were removed under reduced pressure . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol - 4 - yl ] phenyl } propane - 1- sulfonamide ( 2.5 g , 86.88 % ) as a yellow solid . MS ( ESI ) calc'd for ( C23H31FN4O3SSi ) [ M + H ] * , 491.2 ; found , 491.2 . [ 000357 ] Step - 4 : Synthesis of yl ] phenylpropane - 1 - sulfonamide N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- -417- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol- - yl ] phenylpropane - 1 - sulfonamide ( 2.5 g , 5.095 mmol , 1 equiv ) in DCM ( 15 mL ) was added TFA ( 15 mL ) . The resulting mixture was stirred at room temperature for 2 h . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 1.55 g , 84.41 % ) as a yellow solid . MS ( ESI ) calc'd for ( C17H17FN4O2S ) [ M + H ] † , 361.1 ; found , 361.0 . [ 000358 ] Synthesis of N- ( 2 - fluoro - 3- { 2- [ 4- ( piperazin - 1 - yl ) phenyl ] -5- ( pyridin - 4 - yl ) - 1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt Br N₂H Boc -N N - Boc NODMF , rt , o / n Step - Boc Br NH NH S. NH F HCI NH N -N S ã NONBS , DMF , rt , o / n f i ) TEA , DCM , rt , 1h ii ) Na2CO3 , THF : MeCN : O₂H , ° C , o / n Step - Boc Step - Br NH F HCI / dioxane , DCM , N N - Boc rt , o / n Step - Boc HN- NOFe , NH4Cl MeOH , 70 ° C , 2 h Step - Br HO OH ' B ' Pd ( dppf ) Cl2 , K2CO3 , dioxane : O₂H , HCI NH 80 ° C , 2 h Step - [ 000359 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol- - yl ] phenylpiperazine - 1 - carboxylate ( 4 ) To a mixture of 2 - bromo - 1- ( 2 - fluoro - 3 - nitrophenyl ) ethanone ( 2 g , 7.633 mmol , 1 equiv ) in DMF ( 20 mL ) was added tert - butyl 4- ( 4 - carbamothioylphenyl ) piperazine - 1 - carboxylate ( 2.g , 8.396 mmol , 1.1 equiv ) at room temperature . The resulting mixture was stirred at room - 418 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT temperature overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 2 - fluoro - 3- nitrophenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 3.2 g , 86.52 % ) as a yellow solid . LCMS : C24H25FN4O4S requires : 484.2 , found : m / z = 485.2 [ M + H ] * . [ 000360 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 5 - bromo - 4- ( 2 - fluoro - 3 - nitrophenyl ) - 1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 5 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2- yl ] phenylpiperazine - 1 - carboxylate ( 3 g , 6.191 mmol , 1 equiv ) in DMF ( 30 mL ) was added NBS ( 1.21 g , 6.810 mmol , 1.1 equiv ) at room temperature . The resulting mixture was stirred at room temperature overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by C18 reverse phase flash chromatography with ACN : O₂H ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 5- bromo - 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 900 mg , 25.8 % ) as a yellow solid . LCMS : C24H24BrFN4O4S requires : 562.1 , found : m / z [ M + H ] + . == 563. [ 000361 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5 - bromo- 1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 6 ) To a mixture of tert - butyl 4- { 4- [ 5 - bromo - 4- ( 2 - fluoro - 3 - nitrophenyl ) -1,3 - thiazol - 2- yl ] phenylpiperazine - 1 - carboxylate ( 900 mg , 1.588 mmol , 1 equiv ) in saturated aqueous NH4Cl ( 2 mL ) and MeOH ( 8 mL ) was added Fe ( 55.75 mg , 0.995 mmol , 0.6 equiv ) in portions at room temperature . The resulting mixture was stirred for 2 h at 70 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by C18 reverse phase flash chromatography with ACN : O₂H ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) - - bromo - 1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 800 mg , 94.44 % ) as a yellow solid . LCMS : C24H26BrFN4O2S requires : 532.1 , found : m / z = 533.1 [ M + H ] * . Step - 4 : Synthesis of tert - butyl 4- ( 4- { 5 - bromo - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl } phenyl ) piperazine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5 - bromo - 1,3 - thiazol - 2- yl ] phenylpiperazine - 1 - carboxylate ( 800 mg , 1.500 mmol , 1 equiv ) and TEA ( 455.26 mg , 4.500 mmol , 3.0 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 320.77 mg , - 419 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 2.250 mmol , 1.5 equiv ) in portions at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 3 mL ) , ACN ( 3 mL ) , and H2O ( 3 mL ) . Na2CO3 ( 953.67 mg , 9.000 mmol , 6 equiv ) was added at room temperature . The resulting mixture was stirred at ° C overnight . The resulting mixture was concentrated under reduced pressure . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 5 : 1 ) to afford tert - butyl 4- ( 4- { 5 - bromo - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl } phenyl ) piperazine - 1 - carboxylate ( 900 mg , 93.83 % ) as a yellow solid . LCMS : C27H32BrFN4O4S2 requires : 638.1 , found : m / z = 639.1 [ M + H ] * . [ 000362 ] Step - 5 : Synthesis of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 2 - yl } phenyl ) piperazine - 1 - carboxylate ( 8 ) To a mixture of tert - butyl 4- ( 4- { 5 - bromo - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) phenyl ) piperazine - 1 - carboxylate ( 900 mg , 1.407 mmol , 1 equiv ) and pyridin - 4- ylboronic acid ( 259.45 mg , 2.111 mmol , 1.5 equiv ) in dioxane ( 10 mL ) and H2O ( 1 mL ) was added Pd ( dppf ) Cl2 CH2Cl2 ( 229.26 mg , 0.281 mmol , 0.2 equiv ) in portions at room temperature . The resulting mixture was stirred for 2 h at 90 ° C under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : EtOAc ( 5 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 2- yl } phenyl ) piperazine - 1 - carboxylate ( 200 mg , 22.28 % ) as a yellow solid . LCMS : C32H36FN5O4S2 requires : 637.2 , found : m / z = 638.2 [ M + H ] * . [ 000363 ] Step - 6 : Synthesis of N- ( 2 - fluoro - 3- { 2- [ 4- ( piperazin - 1 - yl ) phenyl ] -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -5- ( pyridin - 4- yl ) -1,3 - thiazol - 2 - yl } phenyl ) piperazine - 1 - carboxylate ( 200 mg , 0.313 mmol , 1 equiv ) in DCM ( 2 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 2 mL , 4M ) . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.5 % HCl ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- ( 2 - fluoro - 3- { 2- [ 4- ( piperazin - 1- - 420 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) phenyl ] -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt ( 136.9 mg , 80.90 % ) as a yellow solid . LCMS : C27H28FN5O2S2 requires : 537.2 , found : m / z = 538.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.97 ( d , J = 6.2 Hz , 2H ) , 8.56 ( d , J = 6.2 Hz , 2H ) , 8.31 - 8.( m , 2H ) , 8.13 – 8.08 ( m , 1H ) , 7.96 ( d , J = 2.6 Hz , 1H ) , 7.65 – 7.52 ( m , 2H ) , 7.28 -7.25 ( m , 1H ) , - 3.32 – 3.26 ( m , 8H ) , 3.21 – 3.13 ( m , 2H ) , 1.97 – 1.86 ( m , 2H ) , 1.09 – 1.05 ( m , 3H ) . [ 000364 ] Synthesis - of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazin - 1- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride salt F HN · N . -CI = N HN F HCI S -N . -N .

N₂H Boc Brettphos Pd G3 , ³OC₂sC , HCI in dioxane Step - 1,4 - dioxane Step - HN N NH HN HCI -S = Boc [ 000365 ] Step - 1 : Synthesis of tert - butyl -NH 4-4 - [ ( 4-2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenyl } piperazine - 1 - carboxylate ( 2 ) - 421 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 800 mg , 1.70 mmol , 1 equiv ) in dioxane ( 10 mL ) was added tert - butyl 4- ( 4 - aminophenyl ) piperazine - 1 - carboxylate ( 1.18 g , 4.265 mmol , 2.5 equiv ) , Brett PhosPdG3 ( 154 mg , 0.17 mmol , 0.1 equiv ) , and Cs2CO3 ( 1.11 g , 3.41 mmol , 2 equiv ) at room temperature . The resulting mixture was stirred 2 h at 80 ° C under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with H2O : MeCN ( 1 : 8 ) to afford tert - butyl 4- { 4 - [ ( 4- { 2- tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] phenylpiperazine - 1 - carboxylate ( 500 mg , 39.23 % ) as a yellow solid . LCMS : C35H44FN7O4S2 requires : 709.3 , found : m / z = 710.2 [ M + H ] + . [ 000366 ] Step - 2 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazin - 1- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide hydrochloride A mixture of tert - butyl 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenylpiperazine - 1 - carboxylate ( 500 mg , 0.70 mmol , equiv ) in HC1 / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 3- [ 2 - tert - butyl - 5- ( 2- { [ 4- ( piperazin - 1 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide hydrochloride salt ( 371.7 mg , crude ) as a brown solid . LCMS : C30H36FN7O2Srequires : 609.2 , found : m / z = 610.2 [ M + H ] * . = ' H NMR ( 400 MHz , CD3OD ) 8 8.11 ( s , 1H ) , 7.62 – 7.45 ( m , 2H ) , 7.36 - 7.32 ( m , 3H ) , 7.14 – 7.12 ( m , 2H ) , 6.78 ( s , 1H ) , 3.59 – 3.41 ( m , 8H ) , 3.09 – 3.06 ( m , 2H ) , 1.84 – 1.79 ( m , 2H ) , 1.( s , 9H ) , 1.07 -1.03 ( m , 3H ) . [ 000367 ] Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazine - 1 - carbonyl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt O = S- CNH F N -NH HCI 1100573566 5 AMERICAS HO to NH EDCI , HOBt , TEA , DCM : DMF ( 10 : 1 ) Step - Attorney Docket No .: 121843.002NU - 3200 PCT O = S . NH .F NH .

Cu ( OAc ) 2 , pyr , 110 ° C , molecular sieves 4A , O2 , o / n Step - NH Look [ 000368 ] Step - 1 : Synthesis of HCI / dioxane , DCM rt , o / n Step - Boc tert - butyl dioxaborolan - 2 - yl ) benzoyl ] piperazine - 1 - carboxylate ( 3 ) CNH .F HCI goog -NH 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- To a mixture of 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) benzoic acid ( 3.2 g , 12.8mmol , 1.2 equiv ) in DCM ( 20 mL ) and DMF ( 2 mL ) was added HOBT ( 1.74 g , 12.886 mmol , 1.2 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 2.0 g , 10.738 mmol , 1.00 equiv ) at room temperature . To the above mixture was added EDCI ( 2.47 g , 12.886 mmol , 1.2 equiv ) at room temperature . The resulting mixture was stirred for 2 h at room temperature . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) benzoyl ] piperazine - 1 - carboxylate ( 2.2 g , 49.21 % ) as a white solid . LCMS : C22H33BN2Orequires : 416.2 , found : m / z = 417.2 [ M + H ] * . [ 000369 ] Step - 2 : Synthesis of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } benzoyl ) piperazine - 1 - carboxylate ( 5 ) To a stirred mixture of tert - butyl 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) benzoyl ] piperazine - 1 - carboxylate ( 1.50 g , 3.603 mmol , 1.5 equiv ) and N- ( 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 0.58 g , 1.609 mmol , 0.equiv ) in pyridine ( 15 mL ) was added Cu ( OAc ) 2 ( 0.87 g , 4.804 mmol , 2.0 equiv ) and molecular sieves 4A ( 0.58 g ) at room temperature . The resulting mixture was stirred at 110 ° C overnight -423- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT under an oxygen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) benzoyl ) piperazine - 1- carboxylate ( 400 mg , 25.67 % ) as a yellow solid . LCMS : C33H37FN6O5S requires : 648.3 , found : m / z = 649.3 [ M + H ] * . [ 000370 ] Step - 3 : Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazine - 1 - carbonyl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride To a mixture of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ) benzoyl ) piperazine - 1 - carboxylate ( 400 mg , 0.617 mmol , 1 equiv ) in DCM ( mL ) was added HC1 in 1,4 - dioxane ( 5 mL , 4 M ) . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.5 % HCl ) , 10 % to 50 % gradient in min ; detector , UV 254 nm to afford N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazine - 1 - carbonyl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide hydrochloride salt ( 216.3 mg , 57.98 % ) as a white solid . LCMS : C28H29FN6O3S requires : 548.2 , found : m / z = 549.3 [ M + H ] * . ' H NMR ( 400 MHz , DMSO - do ) 8 9.74 ( s , 1H ) , 9.48 – 9.44 ( m , 2H ) , 9.07 – 9.02 ( m , 1H ) , 8.- 8.80 ( m , 1H ) , 8.15 – 8.09 ( m , 2H ) , 7.93 – 7.89 ( m , 2H ) , 7.75 – 7.68 ( m , 2H ) , 7.57 – 7.48 ( m , - 1H ) , 7.46 – 7.38 ( m , 1H ) , 7.38 – 7.30 ( m , 1H ) , 3.78 – 3.41 ( m , 4H ) , 3.21 – 3.16 ( m , 4H ) , 3.- 3.03 ( m , 2H ) , 1.78 – 1.63 ( m , 2H ) , 0.98 – 0.89 ( m , 3H ) . [ 000371 ] - - - Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperidin - 4 - yloxy ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt O = S CNH HCI F N -NH -424- 1100573566 5 AMERICAS -NH OH Br NaH , NMP ° C to 120 ° C , o / n NH Step - O = 5- NH Attorney Docket No .: 121843.002NU - 3200 PCT Pd ( dppf ) ₂lC Br KOAc , dioxane HCl / dioxane 90 ° C , 2 h Step - HCI NH Cu ( OAc ) 2 , pyridine , molecular sieves 4A , O110 ° C , o / n Step - rt , o / n -NH Boc Step - [ 000372 ] Step - 1 : Synthesis of tert - butyl 4- ( 4 - bromophenoxy ) piperidine - 1- carboxylate ( 2 ) To a mixture of NaH ( 238.47 mg , 9.93 mmol , 1 equiv ) in NMP ( 20 mL ) was added tert - butyl - hydroxypiperidine - 1 - carboxylate ( 2 g , 9.93 mmol , 1 equiv ) at 0 ° C . The resulting mixture was stirred one hour at 0 ° C under a nitrogen atmosphere . To the above mixture was added 4- bromofluorobenzene ( 1.74 g , 9.93 mmol , 1 equiv ) at 0 ° C . The resulting mixture was stirred overnight at 120 ° C under the nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - bromophenoxy ) piperidine - 1 - carboxylate ( 1.3 g , 33.05 % ) as a white solid . LCMS : C16H22BrNO3 requires : 355.1 , found : m / z = 356.1 [ M + H ] * . [ 000373 ] Step - 2 : Synthesis of tert - butyl dioxaborolan - 2 - yl ) phenoxy ] piperidine - 1 - carboxylate ( 3 ) 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- To a mixture of tert - butyl 4- ( 4 - bromophenoxy ) piperidine - 1 - carboxylate ( 1.3 g , 3.64 mmol , equiv ) in dioxane ( 10 mL ) was added 4,4,5,5 - tetramethyl - 2- ( tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( 1.85 g , 7.29 mmol , 2 equiv ) , KOAc ( 1.07 g , 10.94 mmol , 3 equiv ) , and Pd ( dppf ) Cl2 ( 1.34 g , 1.85 mmol , 0.5 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred 2 h at 90 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl 4- [ 4- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenoxy ] piperidine - 1 - carboxylate ( 1 g , 61.15 % ) as a yellow solid . -425- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C22H34BNO5 requires : 403.3 , found : m / z = 404.2 [ M + H ] * . [ 000374 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenoxy ) piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenoxy ] piperidine - 1 - carboxylate ( 1 g , 2.47 mmol , 1 equiv ) in pyridine ( 10 mL ) was added N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 893 mg , 2.47 mmol , 1 equiv ) , Cu ( OAc ) 2 ( 900 mg , 4.95 mmol , 2 equiv ) , and molecular sieves 4A ( 8mg ) at room temperature . The resulting mixture was stirred at 110 ° C overnight under an oxygen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with the following conditions H2O : MeCN ( 1 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenoxy ) piperidine - 1 - carboxylate ( 400 mg , 24.11 % ) as a white solid . LCMS : C33H38FN5O5S requires : 635.3 , found : m / z = 636.2 [ M + H ] * . [ 000375 ] Step - 4 : Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( piperidin - 4 - yloxy ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ) phenoxy ) piperidine - 1 - carboxylate ( 500 mg , 0.78 mmol , 1 equiv ) in HCl / 1,4- dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- ( 2 - fluoro - 3- { 1- [ 4- ( piperidin - 4 - yloxy ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide hydrochloride salt ( 341.3 mg , crude ) as a yellow solid . LCMS : C28H30FN5O3S requires : 535.2 , found : m / z = 536.2 [ M + H ] * . 1H NMR ( 400 MHz , CD3OD ) 8 8.75 – 8.73 ( m , 2H ) , 8.58 ( s , 1H ) , 8.21 – 8.20 ( m , 2H ) , 7.93 – 7.91 ( m , 2H ) , 7.58 – 7.56 ( m , 1H ) , 7.38 – 7.30 ( m , 2H ) , 7.23 – 7.20 ( m , 2H ) , 3.47 – 3.40 ( m , 2H ) , 3.23 - 3.26 ( m , 2H ) , 3.14 – 3.11 ( m , 2H ) , 2.26 – 2.20 ( m , 2H ) , 2.10 – 2.05 ( m , 2H ) , 1.( s , 1H ) , 1.87 1.81 ( m , 2H ) , 1.05 - 1.01 ( m , 3H ) . [ 000376 ] - - Synthesis of N- { 2 - fluoro - 3- [ 1- ( piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] phenylpropane - 1 - sulfonamide hydrochloride salt -426- 1100573566 5 AMERICAS 0 = 5- NH S- NH F Attorney Docket No .: 121843.002NU - 3200 PCT N- N a NH HCI Br N - Boc S NH .F F NH Cs2CO3 , DMF , 100 ° C HCI dioxane , DCM Step - Step - O = S- NH F HCI N NH N N - Boc [ 000377 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } piperidine - 1 - carboxylate ( 3 ) To a stirred mixture of N- ( 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1- sulfonamide ( 400 mg , 1.110 mmol , 1 equiv ) and tert - butyl 4 - bromopiperidine - 1 - carboxylate ( 322.50 mg , 1.221 mmol , 1.1 equiv ) in DMF ( 4 mL ) was added Cs2CO3 ( 723.22 mg , 2.2mmol , 2.0 equiv ) at room temperature . The resulting mixture was stirred at 100 ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } piperidine - 1 - carboxylate ( 220 mg , 36.46 % ) as a yellow solid . LCMS : C27H34FN5O4S requires : 543.2 , found : m / z = 544.2 [ M + H ] * . [ 000378 ] Step - 2 : Synthesis of N- { 2 - fluoro - 3- [ 1- ( piperidin - 4 - yl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide hydrochloride -427 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl } piperidine - 1 - carboxylate ( 200 mg , 0.368 mmol , 1 equiv ) in DCM ( 2 mL ) was added HCl ( gas ) in 1,4 - dioxane ( 2 mL , 4 M ) . The resulting mixture was stirred at room temperature overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in Water ( 0.5 % HCl ) , 10 % to 50 % gradient in min ; detector , UV 254 nm to afford N- { 2 - fluoro - 3- [ 1- ( piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) pyrazol- - yl ] phenylpropane - 1 - sulfonamide hydrochloride salt ( 140 mg , 79.28 % ) as a yellow solid . LCMS : C22H26FN5O2S requires : 443.2 , found : m / z = 444.1 [ M + H ] * .

- ' H NMR ( 400 MHz , CD3OD ) 8 8.78 – 8.67 ( m , 2H ) , 8.19 - 8.11 ( m , 3H ) , 7.63 – 7.52 ( m , 1H ) , 7.397.29 ( m , 2H ) , 4.85 – 4.79 ( m , 1H ) , 3.73 – 3.62 ( m , 2H ) , 3.39 – 3.36 ( m , 1H ) , 3.35 - 3.( m , 1H ) , 3.21 3.11 ( m , 2H ) , 2.55 – 2.22 ( m , 4H ) , 1.91 – 1.79 ( m , 2H ) , 1.10 – 0.95 ( m , 3H ) . [ 000379 ] Synthesis of N- { 2 - fluoro - 3- [ 3- ( morpholin - 4 - yl ) -1- ( piperidin - 4 - yl ) pyrazol- - yl ] phenylpropane - 1 - sulfonamide ; trifluoroacetic acid salt HN N₂O ( 1 ) Br Br Boc a N - Boc Cs2CO3 , DMF , 120 ° C , o / n Boc Step - NH F OH F F F NH Fe , NHCI , MeOH , 70 ° C , 2 h Boc Br - = Br DIEA , DMF , 120 ° C , o / n Br Br Step - N₂H N₂O ( 3 ) ( 2 ) CI .

₂HN i ) TEA , DCM , rt , 1 h ii ) Na2CO3 , THF : MeCN : O₂H , ° C , o / n Step - NH F Step - Boc Br ( 4 ) F NH( 5 ) Pd ( dppf ) ₂lC , 3OC₂K , dioxane : O₂H , ° C , 2 h Step - NH OH F TFA , DCM , rt , 1 h N - Boc NH ( 6 ) [ 000380 ] ( 7 ) Step - Step - 1 : Synthesis of tert - butyl 4- ( 4 - bromo - 3 - nitropyrazol - 1 - yl ) piperidine- - carboxylate ( 2 ) - 428 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of 4 - bromo - 3 - nitro - 1H - pyrazole ( 2 g , 10.418 mmol , 1 equiv ) in DMF ( 20 mL ) was added tert - butyl 4 - bromopiperidine - 1 - carboxylate ( 3.03 g , 11.460 mmol , 1.1 equiv ) and CS2CO3 ( 3.39 g , 10.418 mmol , 1 equiv ) at room temperature . The resulting mixture was stirred at 120 ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 20:80 ) to afford tert - butyl 4- ( 4 - bromo - 3 - nitropyrazol- - yl ) piperidine - 1 - carboxylate ( 3 g , 76.74 % ) as a yellow solid . LCMS : C13H19BrN4O4 requires : 374.1 , found : m / z = 375.1 [ M + H ] * . [ 000381 ] Step - 2 : Synthesis of tert - butyl 4- ( 3 - amino - 4 - bromopyrazol - 1 - yl ) piperidine- - carboxylate ( 3 ) To a mixture of tert - butyl 4- ( 4 - bromo - 3 - nitropyrazol - 1 - yl ) piperidine - 1 - carboxylate ( 3 g , 7.9mmol , 1 equiv ) and Fe ( 22.32 mg , 0.400 mmol , 5 equiv ) in MeOH ( 30 mL ) was added saturated aqueous NH4Cl ( 4 mL ) at room temperature . The resulting mixture was stirred for 2 h at 70 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 3- amino - 4 - bromopyrazol - 1 - yl ) piperidine - 1 - carboxylate ( 2.6 g , 94.19 % ) as a yellow solid . LCMS : C13H21BrN4O2 requires : 344.1 , found : m / z = 345.1 [ M + H ] * . [ 000382 ] Step - 3 : Synthesis of tert - butyl 4- [ 4 - bromo - 3- ( morpholin - 4 - yl ) pyrazol - 1- yllpiperidine - 1 - carboxylate ( 4 ) ( 2.5 g , To a mixture of tert - butyl 4- ( 3 - amino - 4 - bromopyrazol - 1 - yl ) piperidine - 1 - carboxylate 7.241 mmol , 1 equiv ) and DIEA ( 2.81 g , 21.723 mmol , 3 equiv ) in DMF ( 25 mL ) was added - bromo - 2- ( 2 - bromoethoxy ) ethane ( 2.02 g , 8.689 mmol , 1.2 equiv ) at room temperature . The resulting mixture was stirred overnight at 120 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 75:25 ) to afford tert- butyl 4- [ 4 - bromo - 3- ( morpholin - 4 - yl ) pyrazol - 1 - yl ] piperidine - 1 - carboxylate ( 1.4 g , 46.55 % ) as a yellow oil . LCMS : C17H16ClFN4O2S2 requires : 414.1 , found : m / z = 414.2 [ M + H ] * . [ 000383 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( morpholin - 4 - yl ) pyrazol - 1 - yl ] piperidine - 1 - carboxylate ( 6 ) -429- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- [ 4 - bromo - 3- ( morpholin - 4 - yl ) pyrazol - 1 - yl ] piperidine - 1- carboxylate ( 1.4 g , 3.371 mmol , 1 equiv ) and 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) aniline ( 1.04 g , 4.382 mmol , 1.3 equiv ) in dioxane ( 15 mL ) and O₂H ( 1.mL ) was added Pd ( dppf ) Cl2 CH2Cl2 ( 274.59 mg , 0.337 mmol , 0.1 equiv ) and K2CO3 ( 931.mg , 6.742 mmol , 2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 90 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( morpholin - 4 - yl ) pyrazol - 1 - yl ] piperidine - 1 - carboxylate ( 1 g , 66.59 % ) as a dark yellow oil . LCMS : C23H32FN5O3 requires : 445.3 , found : m / z = 446.2 [ M + H ] * . [ 000384 ] Step - 5 : Synthesis of tert - butyl 4-4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( morpholin - 4 - yl ) pyrazol - 1 - yl } piperidine - 1 - carboxylate ( 7 ) To a mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -3- ( morpholin - 4 - yl ) pyrazol - 1- yl ] piperidine - 1 - carboxylate ( 1 g , 2.244 mmol , 1 equiv ) and TEA ( 1.14 g , 11.220 mmol , 5 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 384.07 mg , 2.693 mmol , 1.2 equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under vacuum . To the above mixture was added Na2CO3 ( 0.71 g , 6.732 mmol , 3 equiv ) in THF ( 10 mL ) , MeCN ( 10 mL ) , and H2O ( 10 mL ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) . The residue product was purified by reverse phase flash chromatography with MeCN : H2O ( 60:40 ) to afford tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( morpholin - 4 - yl ) pyrazol - 1- yl } piperidine - 1 - carboxylate ( 600 mg , 48.46 % ) as a yellow solid . LCMS : C26H38FN5O5S requires : 551.3 , found : m / z = 552.3 [ M + H ] * . ' H NMR ( 300 MHz , CD3OD ) 8 7.75 ( d , J = 2.Hz , 1H ) , 7.70 – 7.61 ( m , 1H ) , 7.40 – 7.34 ( m , 1H ) , 7.21 – 7.12 ( m , 1H ) , 4.33 – 4.16 ( m , 3H ) , 3.77 – 3.72 ( m , 4H ) , 3.19 – 3.09 ( m , 2H ) , 3.06 – 2.90 ( m , 6H ) , 2.15 – 2.03 ( m , 2H ) , 1.97 – 1.( m , 4H ) , 1.50 ( s , 9H ) , 1.08 – 1.03 ( m , 3H ) . - - [ 000385 ] Step - 6 : Synthesis of N- { 2 - fluoro - 3- [ 3- ( morpholin - 4 - yl ) -1- ( piperidin - 4- yl ) pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide , trifluoroacetic acid To a mixture of tert - butyl 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( morpholin - 4- yl ) pyrazol - 1 - yl } piperidine - 1 - carboxylate ( 600 mg , 1.088 mmol , 1 equiv ) in DCM ( 9 mL ) was - 430 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT added TFA ( 3 mL ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under vacuum . This resulted in N- { 2- fluoro - 3- [ 3- ( morpholin - 4 - yl ) -1- ( piperidin - 4 - yl ) pyrazol - 4 - yl ] phenylpropane - 1 - sulfonamide , trifluoroacetic acid salt ( 232.0 mg , crude ) as a yellow solid . LCMS : C21H30FN5O3S requires : 451.2 , found : m / z = 452.1 [ M + H ] * . H¹ NMR ( 300 MHz , CD3OD ) 8 7.77 ( d , J = 2.4 Hz , 1H ) , 7.69 – 7.63 ( m , 1H ) , 7.40 – 7.35 ( m , 1H ) , 7.19 – 7.14 ( m , 1H ) , 4.51 – 4.38 ( m , 1H ) , 3.77 – 3.72 ( m , 4H ) , 3.62 – 3.56 ( m , 2H ) , 3.– 3.10 ( m , 4H ) , 3.02 – 2.99 ( m , 4H ) , 2.32 – 2.27 ( m , 4H ) , 1.91 – 1.84 ( m , 2H ) , 1.08 – 1.03 ( m , 3H ) . [ 000386 ] Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperazin - 1 - yl ) phenyl ] - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride salt N₂H NH N -N NH N HCI NH NH -N N - Boc F NBS , DMA Step - i ) TEA , DCM ii ) Na2CO3 , THF : MeCN : O₂H Step - NH F HN- Boc NH HCl / dioxane -N N - Boc -N N - Boc -N N - Boc HOAc , Pd ( PPh3 ) 2Cl2 , Bu3SnH , DCM Step - N₂H Brettphos Pd G3 , ³OCsC , 1,4 - dioxane Step - NH F -N NH HCI Step - NH NH 1100573566 5 AMERICAS -N N - Boc Attorney Docket No .: 121843.002NU - 3200 PCT [ 000387 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro- - { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1- carboxylate ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenyl } carbamate ( 2 g , 5.71 mmol , 1 equiv ) in DMA ( 20 mL ) was added tert - butyl 4- ( 4 - carbamothioylphenyl ) piperazine - 1 - carboxylate ( 2.21 g , 6.86 mmol , 1.2 equiv ) and NBS ( 508 mg , 2.85 mmol , 0.5 equiv ) at 0 ° C . The resulting mixture was stirred 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography , eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2- en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] phenylpiperazine - 1 - carboxylate ( 1.5 g , 36.26 % ) as a yellow green solid . LCMS : C32H32CIFN6O4S requires : 650.2 , found : m / z = 651.[ M + H ] + . [ 000388 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 3 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 1.5 g , 2.mmol , 1 equiv ) , HOAc ( 332 mg , 5.53 mmol , 2.4 equiv ) , and Pd ( PPh3 ) 2Cl2 ( 32 mg , 0.046 mmol , 0.02 equiv ) in DCM ( 15 mL ) was added n - HnSзuB ( 1 g , 3.45 mmol , 1.5 equiv ) at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred for 30 min at room temperature . The reaction was quenched by the addition of saturated aqueous NaHCO3 ( 10 mL ) at 0 ° C . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin- - yl ) -1,3 - thiazol - 2 - yl ] phenylpiperazine - 1 - carboxylate ( 1.2 g , 83.59 % ) as a yellow solid . LCMS : C28H28C1FN6O2S requires : 566.2 , found : m / z = 567.2 [ M + H ] * . [ 000389 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 1.2 g , 2.11 mmol , 1 equiv ) and TEA ( 642 mg , -432- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 6.34 mmol , 3 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 452 mg , 3.mmol , 1.5 equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The crude product was dissolved in THF ( 10 mL ) , MeCN ( 10 mL ) , and O₂H ( 10 mL ) . Na2CO3 ( 2 g , 19.25 mmol , equiv ) was added at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was concentrated under vacuum . The residue was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2- yl ] phenylpiperazine - 1 - carboxylate ( 1 g , 69.46 % ) as a yellow - green solid . LCMS : C31H34C1FN6O4S2 requires : 672.2 , found : m / z = 673.2 [ M + H ] * . [ 000390 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 5-2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 5 ) To a mixture of tert - butyl 4- { 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] phenyl } piperazine - 1 - carboxylate ( 1 g , 1.48 mmol , equiv ) in dioxane ( 10 mL ) was added tert - butyl carbamate ( 870 mg , 7.42 mmol , 5 equiv ) , Cs2CO3 ( 967 mg , 2.97 mmol , 2 equiv ) , and BrettPhos Pd G3 ( 134 mg , 0.15 mmol , 0.1 equiv ) at room temperature . The resulting mixture was stirred 2 h at 80 ° C under nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography with H2O : MeCN ( 1 : 7 ) to afford tert - butyl 4- [ 4- ( 5- { 2- [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 500 mg , 42.42 % ) as a yellow solid . LCMS : C36H44FN7O6S2 requires : 753.3 , found : m / z = 754.2 [ M + H ] * . [ 000391 ] Step - 5 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperazin - 1- yl ) phenyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide hydrochloride A mixture of tert - butyl 4- [ 4- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 500 mg , 0.663 mmol , 1 equiv ) in HCl / 1,4 - dioxane ( 10 mL , 4 M ) was stirred overnight at room temperature . The resulting mixture was concentrated under reduced pressure to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( piperazin - 1 - yl ) phenyl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide hydrochloride salt ( 383.5 mg , crude ) as a red solid . - 433 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C26H28FN7O2S2 requires : 553.2 , found : m / z = 554.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.02 – 7.99 ( m , 3H ) , 7.73 – 7.69 ( m , 1H ) , 7.52 – 7.48 ( m , 1H ) , 7.41 – 7.37 ( m , 1H ) , - 7.16 – 7.14 ( m , 2H ) , 6.58 – 6.56 ( m , 1H ) , 3.67 – 3.57 ( m , 4H ) , 3.40 – 3.38 ( m , 4H ) , 3.17 – 3.( m , 2H ) , 1.89 1.83 ( m , 2H ) , 1.06 – 1.02 ( m , 3H ) . [ 000392 ] Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2- methyl - 1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt NH CI N HN H HCI S - N HN F F .F N F OH S -N .

N ' N ' NH N₂H . CI O = S = HN CI ' N ' N Boc DMAP , pyridine Step - F N N N N ' N ' Boc N. -CI N Brettphos Pd G3 , Cs2CO3 , dioxane S - N Step - HN F TFA , DCM N LL LL LL F OH Step - 3 -N . .N . N ' N ' NH [ 000393 ] Step - 1 : Synthesis of ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol- - yl ] -2 - fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 2 ) To a stirred mixture of 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluoroaniline ( 2.62 g , 8.162 mmol , 0.78 equiv ) and methylethylamine hydrochloride ( 1 g , - 434 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT .464 mmol , 1 equiv ) in pyridine ( 30 mL ) was added DMAP ( 256 mg , 2.093 mmol , 0.2 equiv ) . The resulting mixture was stirred at -30 ° C for 10 min under a nitrogen atmosphere . To the above mixture was added sulfonyl chloride ( 1.77 g , 13.08 mmol , 1.25 equiv ) at -30 ° C under the nitrogen atmosphere . The resulting mixture was stirred at -30 ° C for 20 min under the nitrogen atmosphere and then was stirred at room temperature for one hour under the nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 2 ) to afford ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2- methyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 1.1 g , 79.82 % ) as a brown solid . LCMS : C17H17C1FN5O2S2 requires : 441.1 , found : m / z = 442.2 [ M + H ] * . [ 000394 ] Step - 2 : Synthesis of tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin- - ylamino ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 3 ) To a stirred mixture of ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 1.1 g , 2.489 mmol , 1 equiv ) and tert - butyl 4- ( 6- aminopyridin - 3 - yl ) piperazine - 1 - carboxylate ( 901 mg , 3.236 mmol , 1.3 equiv ) in dioxane ( mL ) was added Brettphos Pd G3 ( 226 mg , 0.249 mmol , 0.1 equiv ) and Cs2CO3 ( 1.62 g , 4.9mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C for one hour under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5- yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 700 mg , 37.01 % ) as a yellow solid . LCMS : C31H38FN9O4S2 requires : 683.3 , found : m / z = 684.4 [ M + H ] * . [ 000395 ] Step - 3 : Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] pyrimidin - 2- amine ; trifluoroacetic acid To a stirred mixture of tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1- carboxylate ( 700 mg , 1.024 mmol , 1 equiv ) in DCM ( 12 mL ) was added TFA ( 4 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . The residue was purified by C18 reverse phase column chromatography with ACN : H2O ( 1 : 3 ) to afford 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- -435- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] pyrimidin - 2- amine ; trifluoroacetic acid salt ( 520.4 mg , 71.04 % ) as an orange solid . LCMS : C26H30FN9O2Srequires : 583.2 , found : m / z = 584.2 [ M + H ] * . H¹ NMR ( 400 MHz , CD3OD ) 8 8.58 – 8.52 ( m , 1H ) , 8.20 – 8.13 ( m , 1H ) , 7.82 – 7.77 ( m , 1H ) , 7.69 – 7.60 ( m , 1H ) , 7.57 – 7.50 ( m , 1H ) , 7.48 – 7.40 ( m , 1H ) , 7.40 – 7.32 ( m , 1H ) , 6.95 – 6.- ( m , 1H ) , 3.66 – 3.50 ( m , 4H ) , 3.50 – 3.29 ( m , 4H ) , 3.27 – 3.17 ( m , 2H ) , 2.86 – 2.79 ( m , 6H ) , 1.16 – 1.08 ( m , 3H ) . [ 000396 ] Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2- methyl - 1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperidin - 4 - yl ) pyridin - 2 - yl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt F -N HN N OH -N . -N . IN N. N N₂H . .N . HN Boc Brettphos Pd G3 , ³OC₂sC , 1,4 - dioxane Step - TFA , DCM Step - HN N LL F LL F OH -NH -N HN F .NH Boc [ 000397 ] Step - 1 : Synthesis of tert - butyl 4-16 - ( [ 4- [ 4- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin- - yl ) amino ) pyridin - 3 - yl ] piperidine - 1 - carboxylate ( 2 ) - 436 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluorophenyl sulfamoyl ) ( ethyl ) methylamine ( 300 mg , 0.679 mmol , 1 equiv ) and tert - butyl 4- ( 6 - aminopyridin - 3 - yl ) piperidine - 1 - carboxylate ( 282 mg , 1.018 mmol , 1.5 equiv ) in dioxane ( 10 mL ) was added Brettphos Pd G3 ( 62 mg , 0.068 mmol , 0.1 equiv ) and Cs2CO3 ( 442 mg , 1.358 mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5- yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperidine - 1 - carboxylate ( 350 mg , 67.95 % ) as a brown solid . LCMS : C32H39FN8O4S2 requires : 682.3 , found : m / z = 683.2 [ M + H ] * . [ 000398 ] Step - 2 : Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperidin - 4 - yl ) pyridin - 2 - yl ] pyrimidin - 2- amine ; trifluoroacetic acid To a mixture of tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperidine - 1 - carboxylate ( 3mg , 0.498 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C under an air atmosphere . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . This resulted in 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperidin - 4 - yl ) pyridin - 2 - yl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt ( 319.4 mg , 91.05 % ) = 583.2 [ M + H ] . H¹ as a brown solid . LCMS : C27H31FN8O2S2 requires : 582.2 , found : m / z NMR ( 400 MHz , DMSO - εd ) § 11.09 – 11.05 ( m , 1H ) , 9.69 – 9.65 ( m , 1H ) , 8.76 – 8.69 ( m , 1H ) , 8.55 – 8.46 ( m , 1H ) , 8.19 – 8.14 ( m , 1H ) , 7.97 – 7.90 ( m , 1H ) , 7.86 – 7.79 ( m , 1H ) , 7.= – 7.49 ( m , 1H ) , 7.48 – 7.39 ( m , 1H ) , 7.39 – 7.31 ( m , 1H ) , 6.72 – 6.66 ( m , 1H ) , 3.46 – 3.39 ( m , – 2H ) , 3.113.00 ( m , 4H ) , 3.00 – 2.90 ( m , 1H ) , 2.81 – 2.76 ( m , 3H ) , 2.69 – 2.64 ( m , 3H ) , 2.- 1.96 ( m , 2H ) , 1.87 – 1.72 ( m , 2H ) , 1.06 – 0.98 ( m , 3H ) . [ 000399 ] - Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2- methyl - 1,3 - thiazol - 5 - yl ] -N- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt - 437 - 1100573566 5 AMERICAS F O = S - N HN N Attorney Docket No .: 121843.002NU - 3200 PCT F F F OH F N NH O = S - N -N₂H HN HN N -Boc CI Brettphos Pd G3 , 3OC₂sC , dioxane Step - HN TFA , DCM Step - S ' S ' OH NH N- Boc [ 000400 ] Step - 1 : Synthesis of tert - butyl 4- [ 4 - ( { 4- [ 4- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin- - ylamino ) -2 - fluorophenyl ] piperazine - 1 - carboxylate ( 2 ) To a stirred mixture of ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 450 mg , 1.018 mmol , 1 equiv ) and tert - butyl 4- ( 4 - amino - 2 - fluorophenyl ) piperazine - 1 - carboxylate ( 451 mg , 1.527 mmol , 1.5 equiv ) in dioxane ( 10 mL ) was added Brettphos Pd G3 ( 92 mg , 0.102 mmol , 0.1 equiv ) and Cs2CO3 ( 6mg , 2.036 mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C for 2 h under a nitrogen atmosphere . The residue was purified by C18 reverse phase column chromatography with ACN : O₂H ( 7 : 3 ) to afford tert - butyl 4- [ 4 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] piperazine - 1- carboxylate ( 400 mg , 50.45 % ) as a yellow solid . LCMS : C32H38F2N8O4S2 requires : 700.2 , found : m / z = 701.2 [ M + H ] * . [ 000401 ] Step - 2 : Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] -N- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] pyrimidin - 2 - amine ; trifluoroacetic acid - 438 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a stirred mixture of tert - butyl 4- [ 4 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] piperazine - 1- carboxylate ( 400 mg , 0.571 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated in 4- [ 4- ( 3- under reduced pressure . This resulted { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] -N- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt ( 345.9 mg , crude ) as an orange solid . LCMS : C27H30F2N8O2S2 requires : 600.2 , found : m / z = 601.1 [ M + H ] * .

- - ' H NMR ( 400 MHz , CD3OD ) 8 8.29 – 8.23 ( m , 1H ) , 7.71 – 7.60 ( m , 2H ) , 7.37 – 7.27 ( m , 3H ) , 7.097.00 ( m , 1H ) , 6.52 – 6.46 ( m , 1H ) , 3.45 – 3.38 ( m , 4H ) , 3.33 – 3.14 ( m , 4H ) , 3.27 – 3.( m , 2H ) , 2.82 – 2.76 ( m , 6H ) , 1.13 – 1.05 ( m , 3H ) . [ 000402 ] - Synthesis of N- { 2 - fluoro - 3- [ 1- ( 4 - formylphenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] phenylpropane - 1 - sulfonamide F N- ' N ' NH NH TFA , DCM , rt , 1 h -F ' N ' SEM Step - [ 000403 ] Step - 1 : Synthesis NH N of O = S = C IN K2CO3 , DMSO . 110 ° C , o / n Step - 0 = 0 = N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] phenylpropane - 1 - sulfonamide ( 2 ) To a mixture of N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1 - { [ 2- ( trimethylsilyl ) ethoxy ] methyl } pyrazol- - yl ] phenylpropane - 1 - sulfonamide ( 2.0 g , 4.076 mmol , 1 equiv ) in DCM ( 15 mL ) was added TFA ( 5 mL ) . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel - 439 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT column chromatography eluted with CH2Cl2 : MeOH ( 8 : 1 ) to afford N- { 2 - fluoro - 3- [ 3- ( pyridin- - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 1.0 g , 68.07 % ) as a yellow solid . LCMS : C17H17FN4O2S requires : 360.1 , found : m / z = 361.1 [ M + H ] * . [ 000404 ] Step - 2 : Synthesis of N- { 2 - fluoro - 3- [ 1- ( 4 - formylphenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide To a mixture of N- ( 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1- sulfonamide ( 500 mg , 1.387 mmol , 1 equiv ) and 4 - fluorobenzaldehyde ( 516.55 mg , 4.1mmol , 3.0 equiv ) in DMSO ( 1 mL ) was added K2CO3 ( 958.67 mg , 6.935 mmol , 5.0 equiv ) in portions at room temperature . The resulting mixture was stirred at 110 ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 10 mmol / L NH4HCO3 ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- { 2 - fluoro - 3- [ 1- ( 4 - formylphenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ( 297.3 mg , 46.13 % ) as a light yellow solid . LCMS : C24H21FN4O3S requires : 464.1 , found : m / z = 465.[ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 10.06 ( s , 1H ) , 8.71 ( s , 1H ) , 8.55 ( d , J = 1.8 Hz , 2H ) , 8.23 8.19 ( s , 2H ) , 8.12 ( d , J = 8.6 Hz , 2H ) , 7.66 – 7.55 ( m , 3H ) , 7.28 – 7.13 ( m , 2H ) , 3.10 – 3.02 ( m , 2H ) , 1.87 – 1.73 ( m , 2H ) , 1.05 – 0.95 ( m , 3H ) . [ 000405 ] Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( 4 - formylpiperidin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide -N N. IZ O = S = - 440 - 1100573566 5 AMERICAS to NH -F ' N ' NH -N N Br molecular sieves ( 4A ) , Cu ( OAc ) 2 , pyr Step - Br N- PPTS THF Step - Attorney Docket No .: 121843.002NU - 3200 PCT HN L - proline , 3OC₂K , Cul , DMSO Step - [ 000406 ] Step - 1 : Synthesis of N- { 3- [ 1- ( 4 - bromophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 2 ) To a stirred mixture of N- ( 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1- sulfonamide ( 3 g , 8.324 mmol , 1 equiv ) and 2- ( 4 - bromophenyl ) -4,4,5,5 - tetramethyl - 1,3,2- dioxaborolane ( 3.53 g , 12.486 mmol , 1.5 equiv ) in pyridine ( 50 mL ) was added Cu ( OAc ) ( 3.02 g , 16.648 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 3 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford N- { 3- [ 1- ( 4 - bromophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 2.4 g , 39.16 % ) as a brown semi - solid . LCMS : C23H20BrFN4O2S requires : 514.1 , found : m / z = 515.0 [ M + H ] * . [ 000407 ] Step - 2 : Synthesis of N- [ 3- ( 1- { 4- [ 4- ( dimethoxymethyl ) piperidin - 1- yl ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 3 ) To a stirred mixture of N- { 3- [ 1- ( 4 - bromophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 2.4 g , 4.657 mmol , 1 equiv ) and 4- ( dimethoxymethyl ) piperidine ( 1.11 g , 6.986 mmol , 1.5 equiv ) in DMSO ( 20 mL ) was added L - proline ( 214 mg , 1.863 mmol , 0.4 equiv ) , K2CO3 ( 1.93 g , 13.971 mmol , 3 equiv ) , and CuI ( 177 mg , 0.931 mmol , 0.2 equiv ) . The resulting mixture was stirred at 100 ° C overnight under - 441 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford N- [ 3- ( 1- { 4- [ 4- ( dimethoxymethyl ) piperidin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 700 mg , 22.79 % ) as a brown solid . LCMS : C31H36FN5O4S requires : 593.3 , found : m / z = 594.2 [ M + H ] * . [ 000408 ] Step - 3 : Synthesis of N- ( 2 - fluoro - 3- { 1- [ 4- ( 4 - formylpiperidin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide To a stirred mixture of N- [ 3- ( 1- { 4- [ 4- ( dimethoxymethyl ) piperidin - 1 - yl ] phenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 500 mg , 0.842 mmol , 1 equiv ) in THF ( 5 mL ) was added PPTS ( 423 mg , 1.684 mmol , 2 equiv ) . The resulting mixture was stirred at 70 ° C overnight under a nitrogen atmosphere . The residue was purified by C18 reverse phase column chromatography with ACN : H2O ( 1 : 1 ) to afford N- ( 2 - fluoro - 3- { 1- [ 4- ( 4- formylpiperidin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide ( 348.7 mg , 74.09 % ) as a light yellow solid . LCMS : C29H30FN5O3S requires : 547.2 , found : m / z = – 548.2 [ M + H ] * . ' H NMR ( 400 MHz , DMSO - εd ) § 9.70 – 9.64 ( m , 2H ) , 8.72 – 8.68 ( m , 1H ) , 8.64 -8.56 ( m , 2H ) , 7.82 - 7.75 ( m , 2H ) , 7.56 – 7.43 ( m , 3H ) , 7.39 – 7.25 ( m , 2H ) , 7.16 – 7.- = - - ( m , 2H ) , 3.75 – 3.66 ( m , 2H ) , 3.07 – 2.99 ( m , 2H ) , 2.98 – 2.87 ( m , 2H ) , 2.56 – 2.51 ( m , 1H ) , 2.01 -1.92 ( m , 2H ) , 1.76 – 1.55 ( m , 4H ) , 0.96 – 0.88 ( m , 3H ) . [ 000409 ] Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 5 - yl ] -N - isopropylpyrimidin - 2 - amine ; trifluoroacetic acid salt HN S. N F LL F N NH -LL IN OH -442 - 1100573566 5 AMERICAS NH Boc F N₂H NBS , DMA , 60 ° C , 2 h Step - Boc HCI N NH DMAP , SO2Cl2 , -30 ° C ~ rt NH O = S = Step - TFA , DCM rt , 1h Step - Attorney Docket No .: 121843.002NU - 3200 PCT N CI IZ = S = CI HOAc , Pd ( PPh3 ) 2Cl2 , Bu3SnH , DCM , rt , 0.5 h Step - -N₂H DIEA , DMSO , 80 ° C , o / n Step - OH ‍NH NH [ 000410 ] Step - 1 : Synthesis of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- { [ ( prop - 2 - en - 1 - yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 3 ) A mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenyl } carbamate ( 4.29 g , 12.277 mmol , 1.0 equiv ) and NBS ( 1.75 g , 9.822 mmol , 0.equiv ) in DMA ( 15 mL ) was stirred for 15 min at room temperature . To the above mixture was added tert - butyl 4 - carbamothioylpiperidine - 1 - carboxylate ( 3.0 g , 12.277 mmol , 1 equiv ) in portions at room temperature . The resulting mixture was stirred for an additional 2 h at room temperature . The reaction was quenched with water / ice at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3 - { [ ( prop - 2 - en - 1- yloxy ) carbonyl ] amino } phenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 3.4 g 48.23 % ) as a yellow solid . LCMS : C27H29C1FN5O4S requires : 573.2 , found : m / z = 574.2 [ M + H ] * . - 443 - 1100573566 5 AMERICAS [ 000411 ] Step - 2 : Synthesis of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 4 ) To a mixture of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- { 3 - [ ( ethoxycarbonyl ) amino ] -2- fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 3.4 g , 6.049 mmol , 1 equiv ) and Pd ( PPh3 ) 2Cl2 ( 84.92 mg , 0.121 mmol , 0.02 equiv ) in DCM ( 35 mL ) was added HOAc ( 908.mg , 15.123 mmol , 2.5 equiv ) dropwise at room temperature under a nitrogen atmosphere . To the above mixture was added n - HnSзuB ( 2817.14 mg , 9.678 mmol , 1.6 equiv ) dropwise at ° C . The resulting mixture was stirred for one hour at room temperature . The reaction was quenched with saturated aqueous sodium hyposulfite at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 2- yl ] piperidine - 1 - carboxylate ( 2.5 g , 84.34 % ) as a yellow solid . LCMS : C23H25CIFN5O2S requires : 489.1 found : m / z = 490.1 [ M + H ] * . [ 000412 ] – Step - 3 : Synthesis of tert - butyl 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carboxylate ( 6 ) To a stirred mixture of tert - butyl 4- [ 4- ( 3 - amino - 2 - fluorophenyl ) -5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 1.0 g , 2.041 mmol , 1 equiv ) and N - ethyl - N- methylsulfamoyl chloride ( 1.93 g , 12.246 mmol , 6.0 equiv , in situ ) in DCM ( 10 mL ) was added TEA ( 1.03 g , 10.205 mmol , 5.0 equiv ) at room temperature . The resulting mixture was stirred for 3 h at 70 ° C . The reaction was quenched with water / ice at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 2 : 1 ) to afford 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 500 mg , 40.09 % ) as a yellow solid . LCMS : C26H32C1FN6O4S2 requires : 610.2 found : m / z = 611.2 [ M + H ] * . [ 000413 ] tert - butyl Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl ] piperidine - 1- carboxylate ( 7 ) - 444 - 1100573566 5 AMERICAS To a mixture of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 4- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 500 mg , 0.818 mmol , 1 equiv ) and isopropylamine ( 145.08 mg , 2.454 mmol , 3.0 equiv ) in DMSO ( 5 mL ) was added DIEA ( 317.22 mg , 2.454 mmol , 3.0 equiv ) dropwise at room temperature . The resulting mixture was stirred at 80 ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 2 : 1 ) to afford 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -5- [ 2- tert - butyl ( isopropylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 350 mg , 67.50 % ) as a yellow solid . LCMS : C29H40FN7O4S2 requires : 633.3 found : m / z = 634.3 [ M + H ] * [ 000414 ] Step - 5 : Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 5 - yl ] -N - isopropylpyrimidin - 2 - amine ; trifluoroacetic acid To a mixture of tert - butyl 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -5- [ 2- ( isopropylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 2 - yl ] piperidine - 1 - carboxylate ( 350 mg , 0.5mmol , 1 equiv ) in DCM ( 2 mL ) was added TFA ( 2 mL ) . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % TFA ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 5 - yl ] -N - isopropylpyrimidin - 2 - amine ; trifluoroacetic acid salt ( 339.6 mg , 94.94 % ) as a yellow solid . LCMS : C24H32FN7O2S2 requires : 533.2 found : m / z = 534.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.07 ( d , J = 6.2 Hz , 1H ) , 7.72 – 7.62 ( m , 1H ) , 7.38 – 7.27 ( m , 2H ) , 6.48 ( s , 1H ) , 4.05 – 3.95 ( m , 1H ) , 3.58 – 3.50 ( m , 3H ) , 3.26 – 3.15 ( m , 4H ) , 2.85 – 2.77 ( m , 3H ) , 2.41 – 2.31 ( m , 2H ) , 2.19 – 2.04 ( m , 2H ) , 1.– 1.18 ( m , 6H ) , 1.21 – 1.05 ( m , 3H ) . = [ 000415 ] - Synthesis of N- ( 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide ; trifluoroacetic acid salt - 445 - 1100573566 5 AMERICAS 8 = NH -F N O = S = NH F.

** -F HO BOC ' N ' -N . .N .

N Attorney Docket No .: 121843.002NU - 3200 PCT NH B- = 8 = NH -F Cu ( OAc ) 2 , pyr , molecular sieves 4A , O2 , 100 ° C , o / n NH N Step - N Boc TFA , DCM rt , 1 h Step - O = S = F -F NH HO- -F [ 000416 ] Step - 1 : Synthesis of tert - butyl N .NH 4- ( 5- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 2 - yl ) piperazine - 1 - carboxylate ( 3 ) To a mixture of N- ( 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] phenyl } propane - 1- sulfonamide ( 600 mg , 1.665 mmol , 1 equiv ) and tert - butyl 4- [ 5- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) pyridin - 2 - yl ] piperazine - 1 - carboxylate ( 972.14 mg , 2.498 mmol , 1.5 equiv ) in pyridine ( 4 mL ) was added Cu ( OAc ) 2 ( 604.76 mg , 3.330 mmol , 2.0 equiv ) and molecular sieves 4A ( 600 mg ) at room temperature . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was extracted with EtOAc . The combined - 446 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 5- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 2 - yl ) piperazine - 1- carboxylate ( 440 mg , 42.51 % ) as a white solid . LCMS : C31H36FN7O4S requires : 621.3 , found : m / z = 622.3 [ M + H ] * . [ 000417 ] Step - 2 : Synthesis of N- ( 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide ; trifluoroacetic acid To a mixture of tert - butyl 4- ( 5- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl } pyridin - 2 - yl ) piperazine - 1 - carboxylate ( 440 mg , 0.708 mmol , 1 equiv ) in DCM ( 3 mL ) was added TFA ( 3 mL ) . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by reverse - phase flash chromatography with the following conditions : column , Csilica gel ; mobile phase , MeCN in Water ( 0.1 % TFA ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford N- ( 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide ; trifluoroacetic acid salt ( 314.4 mg , 68.03 % ) as a yellow solid . LCMS : C26H28FN7O2S requires : 521.2 , found : m / z = 522.1 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.78 ( s , 1H ) , 8.76 – 8.69 ( m , 2H ) , 8.58 ( s , 1H ) , 8.24 – 8.18 ( m , 1H ) , 8.( d , J = 6.8 Hz , 2H ) , 7.62 – 7.56 ( m , 1H ) , 7.43 – 7.28 ( m , 2H ) , 7.12 ( d , J = 9.2 Hz , 1H ) , 4.08 – 3.80 ( m , 4H ) , 3.48 – 3.32 ( m , 4H ) , 3.21 – 3.06 ( m , 2H ) , 1.99 – 1.70 ( m , 2H ) , 1.10 – 0.92 ( m , 3H ) . - [ 000418 ] Synthesis of - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4- yl ) ethynyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid salt F. HN- HO S.

LL F N N O = S = IZ NH - 447 - 1100573566 5 AMERICAS ( 1 ) ( 5 ) i ) TEA , DCM , rt , 1 h ii ) Na2CO3 , THF : MeCN : O₂H Step - N₂H NHNBS , DMA , 60 ° C Step - Boc - N ( 7 ) Br ( 6 ) Step - Attorney Docket No .: 121843.002NU - 3200 PCT ₂rBuC , t - BuONO , ACN ( 2 ) Step - N₂H TFA , DCM Step - Boc HN- HO F ( 8 ) ( 10 ) ₂HN Br N₂H yox Brettphos Pd G3 , ³OCsC , 1,4 - dioxane , 80 ° C Step - N₂H . HOAc , Pd ( PPh3 ) 2Cl2 , F HnSзuB , DCM , rt Step - Br Boc ( 9 ) NH [ 000419 ] Step - 1 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 2 - amino - 5- ( 2 - chloropyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenylcarbamate ( 3 g , 8.578 mmol , 1 equiv ) in DMA ( 30 mL ) was added NBS ( 1.53 g , 8.578 mmol , 1 equiv ) at 0 ° C . The resulting mixture was stirred for 15 min at 0 ° C . To the above mixture was added thiourea ( 0.78 g , 10.294 mmol , 1.2 equiv ) at 0 ° C . The resulting mixture was stirred for an additional 2 h at 60 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : EtOAc ( 1 : 1 ) to afford prop - 2- en - 1 - yl N- { 3- [ 2 - amino - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } carbamate ( 3.1 g , 89.05 % ) as a yellow solid . LCMS : C17H13C1FN5O2S requires : 405.1 , found : m / z = 406.0 [ M + H ] * . [ 000420 ] Step - 2 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 3 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2 - amino - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } carbamate ( 3 g , 7.392 mmol , 1 equiv ) in MeCN ( 30 mL ) was added CuBr( 825.55 mg , 3.696 mmol , 0.5 equiv ) and t - BuONO ( 762.30 mg , 7.392 mmol , 1 equiv ) at 0 ° C . The resulting mixture was stirred for 3 h at 0 ° C . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford prop - 2 - en - 1 - yl N- { 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- - 448 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 1.5 g , 43.20 % ) as an off - white solid . LCMS : C17H11BrClFN4O2S requires : 468.0 , found : m / z = 469.0 [ M + H ] * . [ 000421 ] Step - 3 : Synthesis of 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluoroaniline ( 4 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] - - fluorophenylcarbamate ( 1.2 g , 2.555 mmol , 1 equiv ) and Pd ( PPh3 ) 2Cl2 ( 0.04 g , 0.051 mmol , 0.02 equiv ) in DCM ( 10 mL ) was added HOAc ( 0.40 g , 6.643 mmol , 2.6 equiv ) and n - Bu3SnH ( 1.19 g , 4.088 mmol , 1.6 equiv ) at 0 ° C under a nitrogen atmosphere . The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluoroaniline ( 603 mg , 61.20 % ) as a yellow solid . LCMS : C13H7BrClFN4S requires : 383.9 , found : m / z = 385.0 [ M + H ] + . [ 000422 ] Step - 4 : Synthesis of N- { 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 6 ) To a mixture of 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 6mg , 1.564 mmol , 1 equiv ) and TEA ( 791.14 mg , 7.820 mmol , 5 equiv ) in DCM ( 650 mL ) was added propane - 1 - sulfonyl chloride ( 267.57 mg , 1.877 mmol , 1.2 equiv ) at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under vacuum . To the above mixture was added Na2CO3 ( 497.18 mg , 4.692 mmol , 3 equiv ) in THF ( 10 mL ) , MeCN ( 10 mL ) , and O₂H ( 10 mL ) at room temperature . The resulting mixture was stirred overnight at 50 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to CH2Cl2 : MeOH ( 10 : 1 ) to afford N- { 3- [ 2 - bromo - 5- ( 2- chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 701 mg , 91.16 % ) as a yellow solid . LCMS : C16H13BrClFN4O2S2 requires : 489.9 , found : m / z = 491.[ M + H ] + . [ 000423 ] Step - 5 : Synthesis of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro- 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] ethynyl } piperidine - 1 - carboxylate ( 8 ) - 449 - 1100573566 5 AMERICAS To a mixture of Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - bromo - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 710 mg , 1.444 mmol , 1 equiv ) and tert - butyl 4- ethynylpiperidine - 1 - carboxylate ( 453.24 mg , 2.166 mmol , 1.5 equiv ) in THF ( 300 mL ) was added TEA ( 100 mL ) , Pd ( PPh3 ) 4 ( 250.25 mg , 0.217 mmol , 0.15 equiv ) , and CuI ( 82.49 mg , 0.433 mmol , 0.3 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred at room temperature overnight under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- { 2- [ 5- ( 2- chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2- yl ] ethynylpiperidine - 1 - carboxylate ( 587 mg , 65.56 % ) as a yellow solid . LCMS : C28H31C1FN5O4S2 requires : 619.2 , found : m / z = 620.1 [ M + H ] * [ 000424 ] Step - 6 : Synthesis of tert - butyl 4- [ 2- ( 5-2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ) ethynyl ] piperidine - 1 - carboxylate ( 9 ) To a mixture of tert - butyl 4- { 2- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] ethynyl } piperidine - 1 - carboxylate ( 587 mg , 0.947 mmol , equiv ) and tert - butyl carbamate ( 554.42 mg , 4.735 mmol , 5 equiv ) in dioxane ( 15 mL ) was added BrettPhos Pd G3 ( 85.80 mg , 0.095 mmol , 0.1 equiv ) and Cs2CO3 ( 616.79 mg , 1.8mmol , 2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) . The residue product was purified by reverse phase flash chromatography with MeCN : O₂H ( 65:35 ) to afford tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert- butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 2 - yl ) ethynyl ] piperidine - 1 - carboxylate ( 270 mg , 40.70 % ) as a yellow solid . LCMS : C33H41FN6O6S2 requires : 700.3 , found : m / z = 701.3 [ M + H ] * . [ 000425 ] Step - 7 : Synthesis of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4- yl ) ethynyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid ( 10 ) To a mixture of tert - butyl 4- [ 2- ( 5- { 2 - [ ( tert - butoxycarbonyl ) amino ] pyrimidin - 4 - yl } -4- [ 2- fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ) ethynyl ] piperidine - 1 - carboxylate ( 270 mg , 0.385 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was - 450 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT concentrated under vacuum . This resulted in N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( piperidin - 4 - yl ) ethynyl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid ( 297.6 mg , crude ) as a yellow solid . LCMS : C23H25FN6O2S2 requires : 500.2 , found : m / z = 501.0 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.11 ( d , J = 5.6 Hz , 1H ) , 7.7.68 ( m , 1H ) , 7.40 – 7.33 ( m , 2H ) , 6.40 – 6.38 ( m , 1H ) , 3.47 – 3.41 ( m , 2H ) , 3.24 – 3.17 ( m , = - - 3H ) , 3.14 3.10 ( m , 2H ) , 2.27 - 2.22 ( m , 2H ) , 2.10 – 1.96 ( m , 2H ) , 1.88 – 1.82 ( m , 2H ) , 1.- 1.02 ( m , 3H ) . [ 000426 ] Synthesis of N- [ 3- ( 1- { 3 - azaspiro [ 5.5 ] undecan - 9 - yl } -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; trifluoroacetic acid salt HN ∞NI -N Boc - N ( 1 ) -OH O₂sM , TEA , DCM Step - F HN HN F N OH LL ד ד F F N ﻢﻫ -OMS ( 2 ) Boc - N S = NH -F NH ( 3 ) K2CO3 , DMF Step - F. HN FL TFA , DCM Boc - N ☑ OH -N HN Step - -N N ( 4 ) N N [ 000427 ] Step - 1 : Synthesis of tert - butyl 9- ( methanesulfonyloxy ) -3- azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 2 ) - 451 - 1100573566 5 AMERICAS ד ד F F Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 9 - hydroxy - 3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.0 g , 3.7mmol , 1 equiv ) and TEA ( 563.47 mg , 5.568 mmol , 1.5 equiv ) in DCM ( 5 mL ) was added methanesulfonic anhydride ( 711.28 mg , 4.083 mmol , 1.1 equiv ) dropwise at 0 ° C . The resulting mixture was stirred for 3 h at room temperature . The reaction was quenched by the addition of H2O at 0 ° C . The resulting mixture was extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure to afford tert - butyl 9- ( methanesulfonyloxy ) -3- azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 1.15 g , crude ) as a white solid . [ 000428 ] Step - 2 : Synthesis of tert - butyl 9- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3 - azaspiro [ 5.5 ] undecane - 3- carboxylate ( 4 ) To a mixture of tert - butyl 9- ( methanesulfonyloxy ) -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 2603.06 mg , 7.494 mmol , 6.0 equiv ) and N- { 2 - fluoro - 3- [ 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] phenylpropane - 1 - sulfonamide ( 450 mg , 1.249 mmol , 1.00 equiv ) in DMF ( 5 mL ) was added K2CO3 ( 345.12 mg , 2.498 mmol , 2.0 equiv ) at room temperature . The resulting mixture was stirred at 80 ° C overnight . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 9- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3 - azaspiro [ 5.5 ] undecane - 3- carboxylate ( 221 mg , 28.93 % ) as a yellow solid . LCMS : C32H42FN5O4S requires : 611.3 , found : m / z = 612.0 [ M + H ] * . [ 000429 ] Step - 3 : Synthesis of N- [ 3- ( 1- { 3 - azaspiro [ 5.5 ] undecan - 9 - yl } -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; trifluoroacetic acid To a stirred mixture of tert - butyl 9- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3 - azaspiro [ 5.5 ] undecane - 3 - carboxylate ( 200 mg , 0.327 mmol , equiv ) in DCM ( 0.5 mL ) was added TFA ( 0.5 mL ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH3CN : O₂H ( 10 : 1 ) to afford N- [ 3- ( 1- { 3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -3- ( pyridin - 4 - yl ) pyrazol- - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ; trifluoroacetic acid salt ( 165.3 mg , 78.96 % ) as 512.2 [ M + H ] . H¹ an off - white solid . LCMS : C27H34FN5O2S requires : 511.2 , found : m / z = NMR ( 400 MHz , CD3OD ) § 8.68 – 8.60 ( m , 2H ) , 8.08 – 7.92 ( m , 3H ) , 7.62 – 7.58 ( m , 1H ) , -452- 1100573566 5 AMERICAS - – Attorney Docket No .: 121843.002NU - 3200 PCT 7.49 – 7.45 ( m , 1H ) , 7.41 – 7.35 ( m , 1H ) , 3.97 – 3.91 ( m , 1H ) , 3.25 -3.11 ( m , 4H ) , 3.08 -3.( m , 2H ) , 2.03 – 1.93 ( m , 1H ) , 1.88 – 1.72 ( m , 5H ) , 1.58 – 1.52 ( m , 4H ) , 1.43 – 1.30 ( m , 3H ) , 1.27 – 1.23 ( m , 1H ) , 1.08 – 1.02 ( m , 3H ) . [ 000430 ] Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] -N- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt HN F- F OH N- N NH -453 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT F CI N₂H .N . NHCI ' N ' N NBS , DMA N ( 1 ) Step - H2N ( 2 ) CI N N₂H .

CI t - BuONO , EtOAc HOAc , Pd ( PPh3 ) 2Cl2 , N HnSзuB , DCM Step - 2 Step - 3 ( 4 ) ﮎا O = S - N ( 3 ) O = S - N -N₂H HN HN N N - Boc F- N : CI ' TEA , DCM N- N - Step - ( 5 ) CI Brettphos Pd G3 , CsCO3 , 1,4 - dioxane Step - O = S - N HN TFA , DCM OH N- Step - ד ד F F NH ( 6 ) N N Boc [ 000431 ] Step - 1 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 2 - amino - 5- ( 2 - chloropyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 2 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2- ( 2 - chloropyrimidin - 4 - yl ) acetyl ] -2- fluorophenyl } carbamate ( 5.0 g , 14.296 mmol , 1 equiv ) and NBS ( 2.54 g , 14.296 mmol , 1.equiv ) in DMA ( 40 mL ) was stirred for 15 min at 0 ° C . To the above mixture was added thiourea ( 1.31 g , 17.155 mmol , 1.2 equiv ) in portions at 0 ° C . The resulting mixture was stirred for an additional 2 h at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford prop - 2 - en - 1 - yl - 454 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - amino - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 3.8 g , 65.50 % ) as a yellow solid . LCMS : C17H13 CIFN5O2S requires : 405.1 , found : m / z = 406.[ M + H ] + . [ 000432 ] Step - 2 : Synthesis of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } carbamate ( 3 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 2 - amino - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } carbamate ( 3.0 g , 7.392 mmol , 1 equiv ) in EtOAc ( 30.0 mL ) was added tert- butyl nitrite ( 1.14 g , 11.088 mmol , 1.5 equiv ) in portions at room temperature . The resulting mixture was stirred for 4 h at 50 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 3 : 1 ) to afford prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } carbamate ( 1.5 g , 51.92 % ) as a yellow solid . LCMS : C17H12ClFN4O2S requires : 390.0 , found : m / z = 391.0 [ M + H ] * . – [ 000433 ] Step - 3 : Synthesis of 3-5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluoroaniline ( 4 ) To a mixture of prop - 2 - en - 1 - yl N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylcarbamate ( 1.5 g , 3.838 mmol , 1 equiv ) and HOAc ( 0.58 g , 9.595 mmol , 2.equiv ) in DCM ( 15 mL ) was added n - HnSзuB ( 1.79 g , 6.141 mmol , 1.6 equiv ) dropwise at ° C under a nitrogen atmosphere . The resulting mixture was stirred for one hour at room temperature under the nitrogen atmosphere . The reaction was quenched by the addition of sat . sodium hyposulfite at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 800 mg , 78.14 % ) as a yellow oil . LCMS : C13H8C1FN4S requires : 306.0 , found : m / z = 307.1 [ M + H ] * . [ 000434 ] Step - 4 : Synthesis of ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 5 ) To a mixture of 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 800 mg , 2.6mmol , 1 equiv ) and TEA ( 1.32 g , 13.040 mmol , 5.0 equiv ) in DCM ( 8 mL ) was added N - ethyl- N - methylsulfamoyl chloride ( 2.46 g , 15.648 mmol , 6.0 equiv ) at room temperature . The resulting mixture was stirred for 3 h at 70 ° C . The resulting mixture was concentrated under - 455 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 290 mg , 25.99 % ) as a yellow solid . LCMS : C16H15C1FN5O2S2 requires : 427.0 , found : m / z = 428.0 [ M + H ] * . [ 000435 ] Step - 5 : Synthesis of tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 6 ) To a mixture of ( { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 290 mg , 0.678 mmol , 1 equiv ) and tert - butyl 4- ( 6- aminopyridin - 3 - yl ) piperazine - 1 - carboxylate ( 245.24 mg , 0.881 mmol , 1.3 equiv ) in 1,4- dioxane ( 3 mL ) was added Cs2CO3 ( 441.63 mg , 1.356 mmol , 2.0 equiv ) and BrettPhos Pd G( 61.44 mg , 0.068 mmol , 0.1 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 80 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography , eluted with CH2Cl2 : MeOH ( 8 : 1 ) to afford tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 200 mg , 44.06 % ) as a yellow solid . LCMS : C30H36FN9O4S2 requires : 669.2 , found : m / z = 670.2 [ M + H ] * . [ 000436 ] Step - 6 : Synthesis of 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] pyrimidin - 2 - amine ; trifluoroacetic acid To a mixture of tert - butyl 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl } amino ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 200 mg , 0.2mmol , 1 equiv ) in DCM ( 2 mL ) was added TFA ( 2 mL ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % TFA ) , % to 50 % gradient in 10 min ; detector , UV 254 nm to afford 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] pyrimidin - 2 - amine ; trifluoroacetic acid salt ( 160.8 mg , 78.77 % ) as a yellow solid . LCMS : C25H28FN9O2S2 requires : 569.2 , found : m / z = 570.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( s , 1H ) , 8.62 – 8.58 ( m , 1H ) , 8.17 – 8.13 ( m , 1H ) , 7.79 – 7.75 ( m , 1H ) , 7.68 – 7.64 ( m , 1H ) , 7.56 ( s , 1H ) , 7.49 – 7.47 ( m , 1H ) , 7.39 – 7.34 ( m 1H ) , 7.01 ( d , J = 5.6 Hz , 1H ) , - 456 - 1100573566 5 AMERICAS = Attorney Docket No .: 121843.002NU - 3200 PCT 3.58 3.54 ( m , 4H ) , 3.47 - 3.43 ( m , 4H ) , 3.33 – 3.27 ( m , 2H ) , 2.81 ( s , 3H ) , 1.15 – 1.12 ( m , 3H ) . - [ 000437 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 5- ( piperazin - 1 - yl ) pyridin - 2- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid salt 0 = 5 = HN -CI 0 = 5 = HN F. F N. OH LL F N. .N . N ' N ' NH N₂H Boc Brettphos Pd G3 , ³OC₂sC , dioxane TFA , DCM Step - Step - SHN HN = > = OH NH Boc 4-6 - [ ( 4-2 - tert - butyl - 4- [ 2 - fluoro - 3- [ 000438 ] Step - 1 : Synthesis of tert - butyl ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyridin - 3- yl } piperazine - 1 - carboxylate ( 2 ) To a stirred mixture of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 600 mg , 1.279 mmol , 1 equiv ) and tert - butyl 4- ( 6- aminopyridin - 3 - yl ) piperazine - 1 - carboxylate ( 534 mg , 1.918 mmol , 1.5 equiv ) in dioxane ( mL ) was added Brettphos Pd G3 ( 116 mg , 0.128 mmol , 0.1 equiv ) and Cs2CO3 ( 834 mg , 2.5mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C for 2 h under a nitrogen atmosphere . -457- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- { 6 - [ ( 4- { 2- tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2- yl ) amino ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 620 mg , 61.35 % ) as a yellow solid . LCMS : C34H43FN8O4S2 requires : 710.3 , found : m / z = 711.4 [ M + H ] * . [ 000439 ] Step - 2 : Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 5- ( piperazin - 1 - yl ) pyridin - 2- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ; trifluoroacetic acid To a stirred mixture of tert - butyl 4- { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyridin - 3 - yl } piperazine - 1- carboxylate ( 600 mg , 0.844 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . This resulted in N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 5- ( piperazin- - yl ) pyridin - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ; trifluoroacetic acid salt ( 549.7 mg , crude ) as a brown solid . LCMS : C29H35FN8O2S2 requires : 610.2 , found : m / z = 611.2 [ M + H ] * . ' H NMR ( 400 MHz , DMSO - do ) 10.76 – 10.72 ( m , 1H ) , 9.72 – 9.68 ( m , 1H ) , 8.91 – 8.87 ( m , 2H ) , 7.95 – 7.90 ( m , 1H ) , 7.- 7.69 ( m , 2H ) , 7.58 - 7.47 ( m , 2H ) , 7.42 - 7.34 ( m , 1H ) , 6.75 – 6.69 ( m , 1H ) , 3.47 - 3.40 ( m , 4H ) , 3.40 -3.31 ( m , 4H ) , 3.03 – 2.95 ( m , 2H ) , 1.74 – 1.60 ( m , 2H ) , 1.50 – 1.46 ( m , 9H ) , 0.– 0.87 ( m , 3H ) . - [ 000440 ] - Synthesis of N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 5- ( piperazin - 1 - yl ) pyridin - 2- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ; trifluoroacetic acid salt HN F -N .

N IZ ד ד F F N -NH OH 1100573566 5 AMERICAS NHC i ) TEA , DCM HN -8 = N₂H -CI ii ) Na2CO3 , THF : MeCN : O₂H .CI Step - TFA , DCM Step - Attorney Docket No .: 121843.002NU - 3200 PCT Boc Brettphos Pd G3 , Cs2CO3 , dioxane Step - HN - S = -NH OH HN [ 000441 ] Step - 1 : Synthesis of N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 2 ) To a stirred mixture of 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluoroaniline ( 600 mg , 1.870 mmol , 1 equiv ) and TEA ( 568 mg , 5.61 mmol , 3 equiv ) in DCM ( 10 mL ) was added propane - 1 - sulfonyl chloride ( 800 mg , 5.61 mmol , 3 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . To the above mixture was added THF ( 5 mL ) , MeCN ( mL ) , and Na2CO3 ( 2.97 g , 28.05 mmol , 15 equiv ) in O₂H ( 5 mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 3 ) to afford N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 550 mg , 61.99 % ) as a brown solid . LCMS : C17H16C1FN4O2S2 requires : 426.0 , found : m / z = 427.0 [ M + H ] * . [ 000442 ] Step - 2 : Synthesis of tert - butyl 4- { 6 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -2 - methyl - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyridin - 3- ylpiperazine - 1 - carboxylate ( 3 ) To a stirred mixture of N- { 3- [ 5- ( 2 - chloropyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 550 mg , 1.288 mmol , 1 equiv ) and tert - butyl 4- ( 6- aminopyridin - 3 - yl ) piperazine - 1 - carboxylate ( 538 mg , 1.932 mmol , 1.5 equiv ) in dioxane ( mL ) was added Brettphos Pd G3 ( 117 mg , 0.129 mmol , 0.1 equiv ) and Cs2CO3 ( 839.52 mg , 2.576 mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C for one hour under a nitrogen - 459 - 1100573566 5 AMERICAS Boc Attorney Docket No .: 121843.002NU - 3200 PCT atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- { 6 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -2 - methyl - 1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 600 mg , 66.15 % ) as a brown solid . LCMS : C31H37FN8O4S2 requires : 668.2 , found : m / z = 669.2 [ M + H ] * . [ 000443 ] Step - 3 : Synthesis of in N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenylpropane - 1 - sulfonamide ; trifluoroacetic acid To a stirred mixture of tert - butyl 4- { 6 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -2- methyl - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 3mg , 0.449 mmol , 1 equiv ) in DCM ( 8 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . This resulted in N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide ; trifluoroacetic acid salt ( 225.1 mg , crude ) as a brown solid . LCMS : C26H29FN8O2S2 requires : 568.2 , found : m / z = 569.3 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.60 – 8.54 ( m , 1H ) , 8.– 8.16 ( m , 1H ) , 7.81 – 7.76 ( m , 1H ) , 7.68 – 7.59 ( m , 1H ) , 7.56 – 7.47 ( m , 2H ) , 7.43 – 7.35 ( m , 1H ) , 7.00 – 6.94 ( m , 1H ) , 3.56 – 3.51 ( m , 4H ) , 3.50 – 3.42 ( m , 4H ) , 3.13 – 3.05 ( m , 2H ) , 2.– 2.79 ( m , 3H ) , 1.92 – 1.76 ( m , 2H ) , 1.07 – 0.96 ( m , 3H ) . [ 000444 ] Synthesis of - – 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- ( 5- { 3,8 - diazabicyclo [ 3.2.1 ] octan - 8 - yl } pyridin - 2- yl ) pyrimidin - 2 - amine ; trifluoroacetic acid salt ﻝا · N .

F HN = IN N. .N . N F OH N NH - 460 - 1100573566 5 AMERICAS ﻝا N Attorney Docket No .: 121843.002NU - 3200 PCT NH2 CI F N - S = O HN ( 2 ) F DMAP , pyr N. -CI · N . Step - CI ( 1 ) N ( 3 ) HN N .N .N . ( 5 ) .N . Boc TFA , DCM N Step - N₂H .N .

' N ' N_ Boc ( 4 ) Brettphos Pd G3 , 3OC₂sC , 1,4 - dioxane Step - HN $ = FO IZ F F N ' N ' OH [ 000445 ] Step - 1 : Synthesis of ( { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 3 ) To a mixture of 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluoroaniline ( 3.0 g , 8.268 mmol , 1 equiv ) and DMAP ( 1.21 g , 9.922 mmol , 1.2 equiv ) in pyridine ( 1.5 mL ) was added N - ethyl - N - methylsulfamoyl chloride ( 2.61 g , 16.536 mmol , 2.0 equiv ) dropwise at room temperature . The resulting mixture was stirred overnight at 40 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : EtOAc ( 5 : 1 ) afford ( { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } sulfamoyl ) ( ethyl ) methylamine ( 1.82 g , 45.48 % ) as a yellow solid . LCMS : C20H23CIFN5O2S2 requires : 483.1 , found : m / z = 484.1 [ M + H ] * . to [ 000446 ] Step - 2 : Synthesis of tert - butyl 8- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl } amino ) pyridin - 3 - yl ] -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 5 ) To a mixture of ( { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl sulfamoyl ) ( ethyl ) methylamine ( 700 mg , 1.446 mmol , 1 equiv ) and tert - butyl 8- - 461 - 1100573566 5 AMERICAS NH Attorney Docket No .: 121843.002NU - 3200 PCT ( 6 - aminopyridin - 3 - yl ) -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 572.30 mg , 1.880 mmol , 1.3 equiv ) in 1,4 - dioxane ( 6 mL ) was added BrettPhos Pd G3 ( 131.10 mg , 0.145 mmol , 0.equiv ) and Cs2CO3 ( 942.43 mg , 2.892 mmol , 2.0 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 80 ° C under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 5 : 1 ) to afford tert - butyl 8- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 400 mg , 36.78 % ) as a yellow solid . LCMS : C36H46FN9O4S2 requires : 751.3 , found : m / z = 752.3 [ M + H ] * . [ 000447 ] Step - 3 : Synthesis of 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- ( 5- { 3,8 - diazabicyclo [ 3.2.1 ] octan - 8 - yl } pyridin - 2- yl ) pyrimidin - 2 - amine ; trifluoroacetic acid To a stirred mixture of tert - butyl 8- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] -3,8 - diazabicyclo [ 3.2.1 ] octane - 3 - carboxylate ( 390 mg , 0.519 mmol , equiv ) in DCM ( 2 mL ) was added TFA ( 2 mL ) dropwise at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % TFA ) , 10 % to 50 % gradient in 10 min ; detector , UV 254 nm to afford 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] -N- ( 5- { 3,8- diazabicyclo [ 3.2.1 ] octan - 8 - yl ) pyridin - 2 - yl ) pyrimidin - 2 - amine ; trifluoroacetic acid salt ( 352.mg , 86.25 % ) as a yellow solid . LCMS : C31H38FN9O2S2 requires : 651.3 , found : m / z = 652.[ M + H ] * . ' H NMR ( 300 MHz , CD3OD ) § 8.57 – 8.55 ( m , 1H ) , 8.07 ( d , J = 9.6 Hz , 1H ) , 7.( s , 1H ) , 7.62 ( d , J = 8.1 Hz , 1H ) , 7.52 – 7.48 ( m , 2H ) , 7.42 – 7.31 ( m , 1H ) , 6.96 ( d , J = 4.8 Hz , 1H ) , 4.57 – 4.43 ( m , 2H ) , 3.52 – 3.38 ( m , 2H ) , 3.31 -3.18 ( m , 4H ) , 2.85 – 2.79 ( m , 3H ) , 2.41 – - - 2.23 ( m , 2H ) , 2.21 – 2.11 ( m , 2H ) , 1.62 – 1.48 ( m , 9H ) , 1.20 – 1.08 ( m , 3H ) . [ 000448 ] Synthesis of 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 3- ( pyrimidin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine ; trifluoroacetic acid salt -462 - 1100573566 5 AMERICAS NH Br HCI O = S = IN ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT N F OH N - N F F Cl Pd ( dppf ) ₂lC , Na2CO3 , 1,4 - dioxane Step - N.

N -NH Br NBS ( 1.2 equiv ) , DMF , rt , 1 h HN - N HN- N - N B HO OH N - N PdAMPHOS , CSF , dioxane , O₂H Step - Boc Step - = S = ✓ Boc N N - Boc Cul , K2CO3 , L - proline , DMSO Step - TFA , DCM OH N - N Step - -NH [ 000449 ] Step - 1 : Synthesis of 4- ( 2H - pyrazol - 3 - yl ) pyrimidine ( 3 ) To a mixture of 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -2H - pyrazole ( 3.05 g , 15.7mmol , 1.2 equiv ) and 4 - chloropyrimidine ( 1.5 g , 13.097 mmol , 1.00 equiv ) in 1,4 - dioxane ( mL ) and O₂H ( 2 mL ) was added Na2CO3 ( 2.78 g , 26.194 mmol , 2.0 equiv ) and Pd ( dppf ) ₂lC ( 958.32 mg , 1.310 mmol , 0.1 equiv ) at room temperature . The resulting mixture was stirred overnight at 100 ° C under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 5 : 1 ) to afford 4- ( 2H - pyrazol - 3 - yl ) pyrimidine ( 790 mg , 41.27 % ) as a yellow solid . LCMS : C7H6N4 requires : 146.1 , found : m / z = 147.1 [ M + H ] * . [ 000450 ] Step - 2 : Synthesis of 4- ( 4 - bromo - 2H - pyrazol - 3 - yl ) pyrimidine ( 4 ) To a mixture of 4- ( 2H - pyrazol - 3 - yl ) pyrimidine ( 790 mg , 5.405 mmol , 1 equiv ) in DMF ( 8 mL ) was added NBS ( 1.06 g , 5.946 mmol , 1.1 equiv ) in portions at 0 ° C . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After - 463 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 5 : 1 ) to afford 4- ( 4 - bromo - 2H- pyrazol - 3 - yl ) pyrimidine ( 710 mg , 58.37 % ) as a yellow solid . LCMS : C7H5BrN4 requires : 224.0 , found : m / z = 225.0 [ M + H ] + . [ 000451 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyrimidin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 6 ) To a stirred mixture of 4- ( 4 - bromo - 2H - pyrazol - 3 - yl ) pyrimidine ( 710 mg , 3.155 mmol , 1 equiv ) and tert - butyl 4- ( 4 - iodophenyl ) piperazine - 1 - carboxylate ( 1.83 g , 4.732 mmol , 1.5 equiv ) in DMSO ( 8 mL ) was added L - proline ( 145.29 mg , 1.262 mmol , 0.4 equiv ) , K2CO3 ( 1.31 g , 9.mmol , 3.0 equiv ) , and CuI ( 120.17 mg , 0.631 mmol , 0.2 equiv ) at room temperature . The resulting mixture was stirred for 2 h at 100 ° C under a nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 5 : 1 ) to afford tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyrimidin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 310 mg , 20.24 % ) as a yellow solid . LCMS : C22H25BrN6O2 requires : 484.1 , found : m / z = 485.1 [ M + H ] * . [ 000452 ] Step - 4 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -3- ( pyrimidin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyrimidin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine- - carboxylate ( 310 mg , 0.639 mmol , 1 equiv ) and 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenylboronic acid ( 176.33 mg , 0.639 mmol , 1.0 equiv ) in 1,4 - dioxane ( 3.0 mL ) and O₂H ( 0.3 mL ) was added CsF ( 194.03 mg , 1.278 mmol , 2.0 equiv ) and PdCl2 ( AMPHOS ) ( 90.45 mg , 0.128 mmol , 0.2 equiv ) at room temperature under a nitrogen atmosphere . The resulting mixture was stirred for 2 h at 90 ° C under the nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : CH3OH ( 5 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyrimidin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 150 mg , 36.88 % ) as a pink solid . LCMS : C31H37FN8O4S requires : 636.3 , found : m / z = 637.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 9.06 ( s , 1H ) , 8.( d , J = 5.2 Hz , 1H ) , 7.93 ( s , 1H ) , 7.52 – 7.44 ( m , 1H ) , 7.28 – 7.22 ( m , 1H ) , 7.20 ( d , J = 8.8 Hz , 2H ) , 7.18 – 7.10 ( m , 2H ) , 7.00 ( d , J = 8.9 Hz , 2H ) , 3.59 – 3.54 ( m , 4H ) , 3.35 – 3.26 ( m , 4H ) , 3.21 – 3.12 ( m , 2H ) , 2.74 ( s , 3H ) , 1.50 ( s , 9H ) , 1.07 – 1.01 ( m , 3H ) . - - 464 - 1100573566 5 AMERICAS [ 000453 ] Step - 5 : Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyrimidin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine ; trifluoroacetic acid To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyrimidin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 150 mg , 0.236 mmol , 1 equiv ) in DCM ( 3 mL ) was added TFA ( 3 mL ) at room temperature . The resulting mixture was stirred for one hour at room temperature . The resulting mixture was concentrated under reduced pressure . The residue was purified by reversed - phase flash chromatography with the following conditions : column , C18 silica gel ; mobile phase , MeCN in water ( 0.1 % TFA ) , 10 % to 60 % gradient in 10 min ; detector , UV 254 nm to afford 4- { 4- [ 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyrimidin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine ; trifluoroacetic acid salt ( 130.8 mg , 85.34 % ) as a yellow solid . LCMS : C26H29FN8O2S requires : 536.2 , found : m / z = 537.4 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 9.02 8.97 ( m , 1H ) , 8.81 – 8.75 ( m , 1H ) , 8.43 ( s , 1H ) , 8.01 – 7.95 ( m , 1H ) , 7.92 – 7.84 ( m , 2H ) , 7.60 – 7.51 ( m , 1H ) , 7.31 – 7.23 ( m , 1H ) , 7.26 – 7.15 ( m , 3H ) , 3.56 – 3.49 ( m , 4H ) , 3.– 3.40 ( m , 4H ) , 3.26 – 3.16 ( m , 2H ) , 2.81 ( s , 3H ) , 1.15 – 1.07 ( m , 3H ) . [ 000454 ] = Synthesis of 4- { 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 4- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperidine ; trifluoroacetic acid salt N .N . O == O OH F N -NH -465- 1100573566 5 AMERICAS Br -NH PdAMPHOS , CSF , HO OH dioxane , O₂H Step - [ 000455 ] -N N - Boc Attorney Docket No .: 121843.002NU - 3200 PCT NBS , DMF L - proline , 3OC₂K , Cul , DMSO N -NH ot Pd ( dppf ) ₂lC , Cs2CO3 , DME : O₂H Step - Step - 1 : Step - Synthesis of Boc TFA , DCM Step - Boc Br Step - Boc = 0 = -NH OH 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenylpyrazole ( 2 ) To a mixture of 3 - bromo - 1H - pyrazole ( 1.6 g , 10.886 mmol , 1.2 equiv ) and 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenylboronic acid ( 2.5 g , 9.055 mmol , 1 equiv ) in 1,4 - dioxane ( 30 mL ) was added CSF ( 2.75 g , 18.104 mmol , 2 equiv ) in H2O ( 6 mL ) and PdAMPHOS ( 1.28 g , 1.811 mmol , 0.2 equiv ) . The resulting mixture was stirred at 90 ° C for h under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1/2 ) to afford - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenylpyrazole ( 1.9 g , 63.30 % ) as a yellow solid . LCMS : C12H15FN4O2S requires : 298.1 , found : m / z = 299.1 [ M + H ] * . [ 000456 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 3 ) To a mixture of 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenylpyrazole ( 800 mg , 2.6mmol , 1 equiv ) and tert - butyl 4- ( 4 - iodophenyl ) piperazine - 1 - carboxylate ( 1.56 g , 4.018 mmol , 1.50 equiv ) in DMSO ( 20 mL ) was added L - proline ( 123 mg , 1.073 mmol , 0.4 equiv ) , K2CO( 1.11 g , 8.046 mmol , 3 equiv ) , and CuI ( 102 mg , 0.536 mmol , 0.2 equiv ) . The resulting mixture was stirred at 100 ° C for three days under a nitrogen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) pyrazol - 1- - 466 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ] phenylpiperazine - 1 - carboxylate ( 630 mg , 37.85 % ) as a yellow solid . LCMS : = C27H35FN604S requires : 558.2 , found : m / z = 559.4 [ M + H ] * . [ 000457 ] Step - 3 : Synthesis of tert - butyl 4-4- [ 4 - bromo - 3- ( 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) pyrazol - 1 - yl ] phenyl } piperazine - 1- carboxylate ( 4 ) To a mixture of tert - butyl 4- { 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 620 mg , 1.11 mmol , 1 equiv ) in DMF ( 5 mL ) was added NBS ( 277 mg , 1.554 mmol , 1.4 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with saturated aqueous Na2S2O3 and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . This resulted in tert - butyl 4- { 4- [ 4 - bromo - 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 700 mg , 98.93 % ) as a yellow solid . LCMS : S4O6NFгB43H72C requires : 636.2 , found : m / z = 637.4 [ M + H ] * . [ 000458 ] Step - 4 : Synthesis of tert - butyl 4- { 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -4- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 700 mg , 1.098 mmol , 1 equiv ) and 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) pyridine ( 450 mg , 2.196 mmol , 2 equiv ) in DME ( 11 mL ) was added Cs2CO3 ( 715 mg , 2.196 mmol , 2 equiv ) in H2O ( 1.3 mL ) and Pd ( dppf ) 2lC2HC₂lC ( 89 mg , 0.11 mmol , 0.1 equiv ) . The final reaction mixture was irradiated with microwave radiation at 100 ° C for 30 min under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 3- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -4- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 420 mg , 57.16 % ) as a yellow solid . LCMS : C32H38FN7O4S requires : 635.3 , found : m / z = 636.4 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8.68 – 8.62 ( m , 2H ) , 8.35 – 8.30 ( m , 1H ) , 7.91 – 7.80 ( m , 5H ) , 7.57 – 7.49 ( m , 1H ) , 7.34 ( d , J = 8.7 Hz , 1H ) , 7.26 – 7.17 ( m , 1H ) , 6.96 – 6.90 ( m , 1H ) , 3.42 – 3.35 ( m , 4H ) , 3.29 – 3.19 ( m , - – = 2H ) , 2.89 – 2.82 ( m , 7H ) , 1.47 ( s , 9H ) , 1.14 – 1.06 ( m , 3H ) . [ 000459 ] Step - 5 : Synthesis of 4- { 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -4- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperidine ; trifluoroacetic acid - 467 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of tert - butyl 4- { 4- [ 3- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -4- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 420 mg , 0.661 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was concentrated under vacuum . This resulted in 4- { 4- [ 3- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -4- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperidine ; trifluoroacetic acid salt ( 411.2 mg , crude ) as a yellow solid . LCMS : C27H30FN7O2S requires : 535.2 , found : m / z = 536.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) § 8.96 – 8.87 ( m , 2H ) , 8.54 – 8.44 ( m , 2H ) , 8.39 ( d , J = 2.8 Hz , 1H ) , 8.10 – 8.01 ( m , 2H ) , 7.89 – 7.79 ( m , 1H ) , 7.58 – 7.46 ( m , 2H ) , 7.25 – 7.12 ( m , 1H ) , 7.01 – 6.89 ( m , 1H ) , 3.36 – 3.28 ( m , 6H ) , 3.20 3.11 ( m , 4H ) , 2.82 ( s , 3H ) , 1.12 – 1.04 ( m , 3H ) . - – General Procedure for Buchwald Coupling Followed by Deprotection [ 000460 ] [ 000461 ] Synthesis of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazin - 1- ylmethyl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide 0 = 9 = F HN CI N₂H 0 = 5 = F HN Boc -N .

N IZ N HN O == NH ﮏﻫ -N .

-Boc HN N NH [ 000462 ] Step - 1 : tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) benzyl ) piperazine - 1- carboxylate To a solution of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- tert - butyl 4- ( 4- fluorophenylpropane - 1 - sulfonamide ( 703 mg , 1.5 mmol ) and aminobenzyl ) piperazine - 1 - carboxylate ( 304 mg , 1.05 equiv ) in dioxane ( 10.00 mL ) was added sodium tert - butoxide ( 216 mg , 1.5 eq ) , Pd2 ( dba ) 3 or tris ( dibenzylideneacetone ) dipalladium ( 0 ) - 468 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 205 mg , 0.15 equiv ) , and 2 ' - ( dicyclohexylphosphanyl ) -N , N - dimethyl- [ 1,1 ' - biphenyl ] -2- amine ( DavePhos 177 mg , 0.3 mmol ) . Then the mixture was purged with nitrogen gas for min , followed by irradiation in a microwave reactor at 120 ° C for 2 h . The reaction mixture was filtered through a Celite plug and washed with ethyl acetate . Solvent was then removed by rotary evaporation . Silica gel column chromatography purification eluting with 0-70 % EtOAc : DCM provided tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) benzyl ) piperazine - 1- carboxylate .

N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazin - 1- ylmethyl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- [ 000463 ] Step - 2 : sulfonamide Tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) benzyl ) piperazine - 1 - carboxylate was dissolved in DCM : TFA ( 4 : ratio , 0.1 M ) at room temperature , followed by stirring for 3 h . The reaction mixture was concentrated , then triturated with ether , and used as - is ( 667 mg , 63 % over two steps ) . LCMS : C31H38FN7O2S2 requires 623.3 , found : m / z = 624.5 [ M + H ] * . = [ 000464 ] The following compounds were made using the above General Procedure for Buchwald Coupling Followed by Deprotection . [ 000465 ] tert - butyl 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] benzoate 0 = S = ( ZI HN N N S F N : LCMS : C31H36FN5O4S2 requires 625.2 , found : m / z = 626.5 [ M + H ] * . - 469- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000466 ] 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol- - yl ] pyrimidin - 2 - yl ) amino ] benzoic acid OH NH N N S ' N ZI LCMS : C27H28FN5O4S2 requires 569.2 , found : m / z = 570.5 [ M + H ] + . [ 000467 ] tert - butyl 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -2 - fluorophenyl } piperazine - 1- carboxylate S N NH F EN F O = S = LCMS : C35H43F2N7O4S2 requires 727.3 , found : m / z = 728.5 [ M + H ] * . [ 000468 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] amino } pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 470 - 1100573566 5 AMERICAS O = S = C ZI F HN Attorney Docket No .: 121843.002NU - 3200 PCT · N . H N N S F N : LCMS : C35H43F2N7O4S2 requires 627.2 , found : m / z = 628.5 [ M + H ] + . [ 000469 ] tert - butyl 4- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2 - fluorophenyl ] piperazine - 1- carboxylate N F NH S N F O = S : N.

LCMS : C35H44F2N8O4S2 requires 742.3 , found : m / z = 743.7 [ M + H ] * . [ 000470 ] 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] -N- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] pyrimidin - 2 - amine - 471 - 1100573566 5 AMERICAS IN N F NH N S N Attorney Docket No .: 121843.002NU - 3200 PCT O = S = ZI LCMS : C30H36F2N8O2S2 requires 642.2 , found : m / z = 643.6 [ M + H ] * . [ 000471 ] tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 3 - ( ( N - ethyl - N - methylsulfamoyl ) amino ) -2- fluorophenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -2 - chlorophenyl ) piperazine - 1 - carboxylate N N CI NH N S ' N F LCMS : C35H44C1FN8O4S2 requires 758.3 , found : m / z = 759.5 [ M + H ] * . [ 000472 ] 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] -N- [ 3 - chloro - 4- ( piperazin - 1 - yl ) phenyl ] pyrimidin - 2 - amine . -472- 1100573566 5 AMERICAS IN N CI NH N S N Attorney Docket No .: 121843.002NU - 3200 PCT O = S = ZI LCMS : C30H36CIFN8O2S2 requires 658.2 , found : m / z = 659.5 [ M + H ] * . [ 000473 ] General Procedure for SnAr Coupling Followed by Deprotection ( Version [ 000474 ] Synthesis of N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( piperidin - 4- ylmethyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- 1 ) sulfonamide F = 5 = HN HN ZI O == C HN N.

F N O == N₂H HN .N_ Boc N. -CI EN [ 000475 ] Step - 1 : tert - butyl -Boc HN = 6 = NH 4 - ( ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) methyl ) piperidine - 1- carboxylate - 473 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a solution of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 850 mg , 1.81 mmol ) and triethylamine ( 0.75 mL , equiv ) in dioxane ( 10 mL ) and isopropanol ( 2.5 mL ) was added tert - butyl 4- ( aminomethyl ) piperidine - 1 - carboxylate ( 505 mg , 1.3 equiv ) , and the solution was heated at ° C for 30 h . The reaction mixture was diluted with EtOAc ( 40 mL ) , and the resulting organic solution was washed with aqueous ammonium chloride , then brine , and dried with mag sulfate . Filtration and concentration of the organic solution provided the boc - protected intermediate tert - butyl 4 - ( ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) methyl ) piperidine - 1 - carboxylate . [ 000476 ] Step - 2 : N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( piperidin - 4 - ylmethyl ) amino ] pyrimidin - 4- yl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide The crude tert - butyl 4 - ( ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) methyl ) piperidine - 1 - carboxylate was dissolved in DCM ( 10 mL ) and TFA ( 3 mL ) . This reaction was stirred for 6 h , and was then concentrated onto silica . Silica gel column chromatography purification eluting with methanol : DCM ( 0-20 % ) provided N- [ 3- ( 2- tert - butyl - 5- { 2 - [ ( piperidin - 4 - ylmethyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 0.86g , 87 % over two steps ) . LCMS : C26H35FN6O2Srequires 546.2 , found : m / z = 547.5 [ M + H ] + . [ 000477 ] The following compounds were made using the above General Procedure for SnAr Coupling Followed by Deprotection ( Version 1 ) . [ 000478 ] N- ( 3- { 2 - tert - butyl - 5- [ 2- ( pyrrolidin - 3 - ylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4- yl } -2 - fluorophenyl ) propane - 1 - sulfonamide 0 = 5 = 0 ZI NH HN N N.

S F N : LCMS : C24H31FN6O2S2 requires 518.2 , found : m / z = 519.5 [ M + H ] * . [ 000479 ] [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 5- yl } pyrimidin - 2 - yl ) amino ] acetic acid -474- 1100573566 5 AMERICAS 0 = OH NU - 3200 PCT Attorney Docket No .: 121843.002 HN N. N F N - S LCMS : C22H26FN5O4S2 requires 507.1 , found : m / z = 506.5 [ M - H ] * . [ 000480 ] N- ( 3- { 2 - tert - butyl - 5- [ 2- ( piperidin - 4 - ylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4- yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ZI O = S = IN HN N.

S F N : = LCMS : C25H33FN6O2S2 requires 532.2 , found : m / z = 533.5 [ M + H ] * . [ 000481 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2 - methyl - 2- ( piperidin - 4 - yl ) propyl ] amino } pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide 0 = S = N HN N S F N : LCMS : C29H41FN6O2S2 requires 588.3 , found : m / z = 589.7 [ M - H ] * . [ 000482 ] N- { 3- [ 5- ( 2 - { [ 1,4 - bipiperidin ] -4 - ylamino } pyrimidin - 4 - yl ) -2 - tert - butyl - 1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -475- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT H IN -N .

D = S = ( HN ZI N N S F N - LCMS : C30H42FN7O2S2 requires 615.3 , found : m / z = 616.6 [ M + H ] * . [ 000483 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazin - 1 - yl ) cyclohexyl ] amino } pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide IN -N .

O = S = HN N ZI S F N : LCMS : C30H42FN7O2S2 requires 615.3 , found : m / z = 616.6 [ M + H ] * . [ 000484 ] N- { 3- [ 5- ( 2- { 7 - azaspiro [ 3.5 ] nonan - 2 - ylamino } pyrimidin - 4 - yl ) -2 - tert - butyl- 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide - 476 - 1100573566 5 AMERICAS ZI = S = Attorney Docket No .: 121843.002NU - 3200 PCT HN . N N.

S F N LCMS : C28H37FN6O2S2 requires 572.2 , found : m / z = 573.5 [ M + H ] * . [ 000485 ] General Procedure for Nucleophilic Substitution Followed by Oxidation 0 = 5 = HN -CI N₂H OH HN OH -NH O = S = HN N. NH [ 000486 ] Step - 1 : N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { [ ( 1r , 4r ) -4- ( hydroxymethyl ) cyclohexyl ] methyl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide To a solution of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 950 mg , 2.03 mmol ) and triethylamine ( 0.83 mL , equiv ) in dioxane ( 15 mL ) and isopropanol ( 5 ( 5 mL ) was added [ ( 1r , 4r ) -4- ( aminomethyl ) cyclohexyl ] methanol ( 571 mg , 1.1 equiv ) and the solution was heated at 60 ° C for 18 h . The reaction mixture was diluted with EtOAc ( 40 mL ) and the combined organic solution was washed with aqueous ammonium chloride , brine , dried over magnesium sulfate , filtered , and concentrated to provide N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { [ ( 1r , 4r ) -4- ( hydroxymethyl ) cyclohexyl ] methyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide ( 0.8 g ) . LCMS : C28H37FN6O2S2 requires 575.2 , found : m / z = 576.7 [ M + H ] * . [ 000487 ] Step - 2 : N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { [ ( 1r , 4r ) -4- formylcyclohexyl ] methyl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide -477- 1100573566 5 AMERICAS Crude Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { [ ( 1r , 4r ) -4- ( hydroxymethyl ) cyclohexyl ] methyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2- fluorophenyl ) propane - 1 - sulfonamide from the previous reaction was dissolved in DCM at rt and then DMP ( 0.66g , 1.1 equiv ) was added in one portion . The reaction stirred for 2 h and then concentrated onto silica and purified by silica gel column chromatography ( 0-100 % ethyl to provide acetate in DCM ) N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { [ ( 1r , 4r ) -4- formylcyclohexyl ] methyl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide ( 0.8g , 70 % over two steps ) . LCMS : C28H37FN6O2S2 requires 573.2 , found : m / z = 574.7 [ M + H ] * . [ 000488 ] The following compounds were made using the above General Procedure for Nucleophilic Substitution Followed by Oxidation . [ 000489 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4- ( hydroxymethyl ) cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide 0 = S = ZH HO HN N N.

S F N : LCMS : C27H36FN5O3S2 requires 561.2 , found : m / z = 562.6 [ M + H ] * . [ 000490 ] N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( ( 1r , 4r ) -4 - formylcyclohexyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide - 478 - 1100573566 5 AMERICAS 0 = Attorney Docket No .: 121843.002NU - 3200 PCT HN N.

S F N LCMS : C27H34FN5O3S2 requires 559.2 , found : m / z = 560.5 [ M + H ] * . [ 000491 ] General Procedure for Amide Coupling Followed by Deprotection of N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazine - 1- carbonyl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- [ 000492 ] Synthesis sulfonamide O == SHN COOH HN N O == C ZI HN N.

F N 0 = 9 = HN Boc O == HN NH [ 000493 ] Step - 1 : tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) benzoyl ) piperazine - 1- carboxylate - 479 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2- yl ) amino ) benzoic acid ( 0.5g , 0.887 mmol ) , and HATU ( 0.33g , 1 equiv ) were dissolved in DMF ( 0.2 M ) and DIEA ( 0.1 mL ) followed by the addition of tert - butyl piperazine - 1 - carboxylate ( 0.16 g , 1 equiv ) . The reaction was stirred for 2 h , followed by partition between water and ethyl acetate . The organic layer was separated , washed with brine , dried over magnesium sulfate , filtered , and concentrated . Crude tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) benzoyl ) piperazine - 1- carboxylate was used in the next step without purification . [ 000494 ] Step - 2 : N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperazine - 1- carbonyl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide Crude tert - butyl 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5- yl ) pyrimidin - 2 - yl ) amino ) benzoyl ) piperazine - 1 - carboxylate was dissolved in DCM ( 10 mL ) and TFA ( 2 mL ) was added . The reaction was then stirred for 3 h and then concentrated onto silica gel . Silica gel column chromatography ( 0-20 % methanol in DCM ) provided N- { 3- [ 2- tert - butyl - 5- ( 2 - { [ 4- ( piperazine - 1 - carbonyl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 0.2g , 36 % ) . LCMS : C31H36FN7O3S2 requires 637.2 , found : m / z = 638.5 [ M + H ] + . [ 000495 ] General Procedure for Buchwald Coupling Followed by BOC Deprotection [ 000496 ] Synthesis of N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide F 0 . HN N.

NH - 480 - 1100573566 5 AMERICAS N Attorney Docket No .: 121843.002 HN F. HN -N . -CI EN -N .

N IN NU - 3200 PCT F HN- S = -N . [ 000497 ] Step - 1 : tert - butyl -N .

N IN -NH 4- ( 4 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) phenyl ) piperidine - 1- carboxylate To a solution of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 600.00 mg , 1.2793 mmol ) and tert - butyl 4- ( 4- aminophenyl ) piperidine - 1 - carboxylate ( 530.38 mg , 1.9190 mmol ) in dioxane ( 15.00 mL ) was added sodium tert - butoxide ( 184.43 mg , 1.9190 mmol ) , Pd2 ( dba ) 3 ( 117.15 mg , 0.1279 mmol ) , and Dave - Phos 2 ' - ( dicyclohexylphosphanyl ) -N , N - dimethyl- [ 1,1 ' - biphenyl ] -2 - amine ( 503.mg , 1.2793 mmol ) . The mixture was purged with nitrogen gas for five minutes . The reaction mixture was then heated by microwave at 120 ° C for two hours . Solvent was evaporated under reduced pressure . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with 0-70 % EtOAc in hexanes , followed by a second purification using a Redi - Sep prepacked silica gel column purification eluting with a gradient of 0-40 % EtOAc in DCM to afford tert - butyl 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3- thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidine - 1 - carboxylate ( 0.605 g , 66.71 % ) . LCMS : C36H45FN6O4S2 , requires : 708.29 , found : m / z = 709.51 [ M + H ] * . ' H NMR ( 500 MHz , - 481 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT DMSO - do ) 8 9.65 ( s , 1H ) , 8.33 ( d , J = 5.2 Hz , 1H ) , 7.56 ( dd , J = 16.5 , 8.0 Hz , 3H ) , 7.37 ( t , J = 7.9 Hz , 1H ) , 7.13 ( d , J = 8.4 Hz , 2H ) , 3.07 – 2.95 ( m , 2H ) , 2.81 ( s , 2H ) , 1.75 ( d , J = 12.8 Hz , 2H ) , 1.66 ( p , J = 7.5 Hz , 2H ) , 1.47 ( s , 9H ) , 1.43 ( s , 9H ) , 0.90 ( t , J = 7.4 Hz , 3H ) . [ 000498 ] Step - 2 : N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( piperidin - 4- yl ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide To a solution of tert - butyl 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidine - 1 - carboxylate ( 0.55g , 0.903mmol ) in DCM ( 5 mL ) was added 4 N HCl in dioxane solution ( 5 mL ) . The solution was stirred for two hours . Solvent was removed under reduced pressure and the product was lyophilized to dryness to afford N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperidin - 4- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 0.55 g , 94.6 % ) as an HCl salt . LCMS : C31H37FN6O2S2 , requires : 608.24 , found : m / z = 609.[ M + H ] + . [ 000499 ] The following compounds were made using the above General Procedure for Buchwald Coupling Followed by BOC Deprotection . [ 000500 ] 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol- - yl } pyrimidin - 2 - yl ) amino ] benzoic acid [ M + H ] * 626.5 , then 570.5 . [ 000501 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] amino } pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide [ M + H ] * 728.5 , then 628.5 . [ 000502 ] 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] -N- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] pyrimidin - 2 - amine [ M + H ] 743.7 , then 643.6 . [ 000503 ] 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] -N- [ 3 - chloro - 4- ( piperazin - 1 - yl ) phenyl ] pyrimidin - 2 - amine [ M + H ] * 759.5 , then 659.5 ( Boc deprotection ) . [ 000504 ] The following scheme uses the above General Procedure for Buchwald Coupling Followed by BOC Deprotection . - 482 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT HN HN HN -N NH [ 000505 ] Tert - butyl 4- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) phenyl ] piperidine - 1 - carboxylate N- NH S N F ○ == LCMS : C36H46FN7O4S2 , requires : 723.3 , found : m / z = 724.5 [ M + H ] * . [ 000506 ] 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3- thiazol - 5 - yl ] -N- [ 4- ( piperidin - 4 - yl ) phenyl ] pyrimidin - 2 - amine - 483 - 1100573566 5 AMERICAS NH .N .

S ' N F ZI Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C31H38FN7O2S2 , requires : 623.3 , found : m / z = 624.4 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 9.70 ( s , 2H ) , 8.82 ( s , 1H ) , 7.64 ( d , J = 8.3 Hz , 2H ) , 7.56 ( t , J = 7.7 Hz , 1H ) , 7.( t , J = 6.7 Hz , 1H ) , 7.35 ( t , J = 7.9 Hz , 1H ) , 7.13 ( d , J = 8.3 Hz , 2H ) , 3.75 – 3.65 ( m , 6H ) , 3.( dd , J = 15.3 , 4.9 Hz , 1H ) , 3.37 ( d , J = 12.4 Hz , 2H ) , 3.08 ( d , J = 7.2 Hz , 1H ) , 3.05 ( d , J = 7.Hz , 1H ) , 2.99 ( d , J = 12.1 Hz , 2H ) , 2.84 – 2.74 ( m , 1H ) , 2.67 ( s , 2H ) , 1.93 ( d , J = 13.7 Hz , 2H ) , 1.81 ( q , J = 13.1 Hz , 2H ) , 1.47 ( s , 9H ) , 1.00 ( t , J = 7.1 Hz , 3H ) . [ 000507 ] The following scheme uses the above General Procedure for Buchwald Coupling Followed by BOC Deprotection .

HN F HN NH HN [ 000508 ] Tert - butyl 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carboxylate - 484 - 1100573566 5 AMERICAS N N NH S N F Attorney Docket No .: 121843.002NU - 3200 PCT ZI LCMS : C34H44FN9O4S2 requires : 725.29 , found : m / z = 726.52 [ M + H ] * . [ 000509 ] 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine N.

N N NH .N . N S ' N O = ZI - LCMS : C29H36FN9O2S2 requires : 625.24 , found : m / z = 626.44 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.92 ( s , 1H ) , 9.68 ( s , 1H ) , 9.17 ( s , 2H ) , 8.50 ( d , J = 5.4 Hz , 1H ) , 8.06 ( s , 1H ) , 7.92 ( s , 1H ) , 7.88 – 7.84 ( m , 1H ) , 7.74 ( d , J = 9.3 Hz , 1H ) , 7.54 ( t , J = 7.9 Hz , 1H ) , 7.45 ( t , J = 6.8 Hz , 1H ) , 7.36 ( t , J = 7.9 Hz , 1H ) , 6.68 ( d , J = 5.3 Hz , 1H ) , 5.16 ( d , J = 7.4 Hz , 1H ) , 3.– 3.65 ( m , 1H ) , 3.54 – 3.44 ( m , 1H ) , 3.40 ( t , J = 5.2 Hz , 4H ) , 3.07 ( q , J = 7.1 Hz , 2H ) , 2.68 ( s , 3H ) , 1.48 ( s , 9H ) , 1.01 ( t , J = 7.1 Hz , 3H ) . - - 485 - 1100573566 5 AMERICAS [ 000510 ] Attorney Docket No .: 121843.002NU - 3200 PCT The following scheme uses the above General Procedure for Buchwald Coupling Followed by BOC Deprotection .

N F -S = HN- N -CI N HN = 0 . -8 = N N.

N IZ N. N.

F HN · S = -N .

N.

N N N NH [ 000511 ] Tert - butyl 4- { 6 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -2 - methyl- 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] pyridin - 3 - yl } piperazine - 1 - carboxylate S N N NH N F ZI = 5 = - 486 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT = LCMS : C31H37FN8O4S2 requires : 668.23 , found : m / z = 669.51 [ M + H ] * . ' H NMR ( 500 MHz , CDC13 ) 8 8.31 ( d , J = 5.2 Hz , 1H ) , 8.29 ( s , 1H ) , 8.08 ( d , J = 9.0 Hz , 1H ) , 8.03 ( d , J = 2.9 Hz , 1H ) , 7.75 – 7.67 ( m , 1H ) , 7.41 ( td , J = 7.2 , 6.5 , 1.7 Hz , 1H ) , 7.35 – 7.29 ( m , 2H ) , 6.83 ( d , J = 17.4 Hz , 1H ) , 6.50 ( d , J = 5.2 Hz , 1H ) , 3.63 ( t , J = 5.1 Hz , 4H ) , 3.12 ( t , J = 5.1 Hz , 4H ) , 3.( ddd , J = 9.4 , 5.6 , 1.4 Hz , 2H ) , 2.82 ( d , J = 0.9 Hz , 3H ) , 1.84 ( q , J = 7.8 Hz , 2H ) , 1.52 ( s , 9H ) , 1.01 ( td , J = 7.4 , 1.4 Hz , 3H ) . = [ 000512 ] N- { 2 - fluoro - 3- [ 2 - methyl - 5- ( 2 - { [ 5- ( piperazin - 1 - yl ) pyridin - 2- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] phenyl } propane - 1 - sulfonamide O = S ) = ( ZI IN N N HN N.

F N [ 000513 ] LCMS : C26H29FN8O2S2 requires : 568.18 , found : m / z = 569.51 [ M + H ] * .

General Procedure for SnAr Coupling Followed by Deprotection ( Version ) [ 000514 ] Synthesis of N- ( 3- ( 5- ( 2 - ( ( 2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4- yl ) -2- ( tert - butyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide O = S HN NH HN F N N N - 487 - 1100573566 5 AMERICAS O = S HN HN F N N -S O = HN - S = O N.

N CI + N₂H Attorney Docket No .: 121843.002NU - 3200 PCT || O = S HN NH HN F N N N ' [ 000515 ] Step - 1 : tert - butyl - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -2 - azaspiro [ 3.3 ] heptane- - carboxylate To a solution of N- { 3- [ 2 - tert - butyl - 5- ( 2 - chloropyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 800.00 mg , 1.7058 mmol ) and triethylamine ( 0.70 mL , 5.1174 mmol ) in dioxane ( 2.50 mL ) and isopropanol ( 2.50 mL ) was added tert - butyl 6 - amino- - azaspiro [ 3.3 ] heptane - 2 - carboxylate ( 543.19 mg , 2.5587 mmol ) . The reaction mixture was heated at 60 ° C for sixty hours . The reaction mixture was then cooled down and diluted with EtOAc ( 40 mL ) . The organic solution was washed by 20 % citric acid solution , dried over sodium sulfate , filtered , and concentrated under reduced pressure . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with a gradient of 15-90 % EtOAc in hexanes , to provide tert - butyl 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -2 - azaspiro [ 3.3 ] heptane - 2- carboxylate ( 0.86 g , 78.19 % ) . LCMS : C31H41FN6O4S2 required : 644.26 found : m / z = 645.[ M + H ] + . [ 000516 ] Step - 2 : N- ( 3- ( 5- ( 2 - ( ( 2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) -2- ( tert - butyl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide - 488 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT To a solution of tert - butyl 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -2 - azaspiro [ 3.3 ] heptane - 2 - carboxylate ( 860.00 mg , 1.3337 mmol ) in hexafluoro - 2 - propanol ( 4 mL ) was added TFA ( 0.5 mL ) and the reaction was stirred for one hour at room temperature . The solution was concentrated in vacuo . The dried product was dissolved in DCM ( 30 mL ) , washed with sat . NaHCO3 solution , and concentrated in vacuo . The product was lyophilized to provide N- { 3- [ 5- ( 2- { 2 - azaspiro [ 3.3 ] heptan - 6- ylamino } pyrimidin - 4 - yl ) -2 - tert - butyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 0.661 g , 90.99 % ) as a yellow oil . LCMS : C26H33FN6O2S2 , requires : 544.21 , found : m / z = 545.34 [ M + H ] * . [ 000517 ] The following scheme uses the above General Procedure for SnAr Coupling Followed by Deprotection ( Version 2 ) .

F HN N N. CI N HN -S = F N -N . abs N + N₂H abs N C F. HN -S = O S -N . -NH abs [ 000518 ] Tert - butyl ( 3R ) -3 - { [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] methyl } pyrrolidine - 1- carboxylate - 489 - 1100573566 5 AMERICAS NI Attorney Docket No .: 121843.002NU - 3200 PCT HN .

N.

S F N LCMS : C30H41FN6O4S2 requires : 632.26 , found : m / z = 633.30 [ M + H ] * . [ 000519 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 3S ) -pyrrolidin - 3 - ylmethyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide O = == HN . N N.

S F N LCMS : C25H33FN6O2S2 , requires : 532.21 , found : m / z = 533.69 [ M + H ] + . [ 000520 ] The following scheme uses the above General Procedure for SnAr Coupling Followed by Deprotection ( Version 2 ) . - 490 - 1100573566 5 AMERICAS N.

HN ' N₂H N.

N HN F.

CI O = 8- -N N abs -N abs N Attorney Docket No .: 121843.002NU - 3200 PCT F. HN -N . -NH abs N [ 000521 ] Tert - butyl ( 3S ) -3 - { [ ( 4-2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] methyl } pyrrolidine - 1- carboxylate 0 = S = 0 ZI HN N.

F N LCMS : C30H41FN6O4S2 requires : 632.26 , found : m / z = 633.86 [ M + H ] * . [ 000522 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 3R ) -pyrrolidin - 3 - ylmethyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide -491- 1100573566 5 AMERICAS 0 = S = H IN HN Attorney Docket No .: 121843.002NU - 3200 PCT N N.

S F N LCMS : C25H33FN6O2S2 , requires : 532.21 , found : m / z = 533.76 [ M + H ] * . [ 000523 ] The following scheme uses a modified General Procedure for Amide Coupling Followed by Deprotection . [ 000524 ] Synthesis of N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 4 - fluoropiperidine - 4 - carbonyl ) - - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide 0 = 8 . . HN F -N . · N . N -N . NH -492- 1100573566 5 AMERICAS HN- N.

F N.

N H IN -N .

-NH 0 : + HN -8 = F N -N .

N IN N.

Attorney Docket No .: 121843.002NU - 3200 PCT HO F HN . -8 = N. IN -N .

N -N . NH [ 000525 ] Step - 1 : tert - butyl 4- ( 6 - ( ( 4- ( 2- ( tert - butyl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 5 - yl ) pyrimidin - 2 - yl ) amino ) -2 - azaspiro [ 3.3 ] heptane- - carbonyl ) -4 - fluoropiperidine - 1 - carboxylate To a solution of 1- ( tert - butoxycarbonyl ) -4 - fluoropiperidine - 4 - carboxylic acid ( 23.15 mg , 0.09 mmol ) in mmol ) and [ ( dimethylamino ) ( { [ 1,2,3 ] triazolo [ 4,5 - b ] pyridine - 3- yloxy } ) methylidene ] dimethylazanium ; hexafluoro - lambda5 - phosphanuide ( 35.60 mg , 0.09DMF ( 0.4 mL ) was added N , N - diisopropylethylamine ( 40.34 mg , 0.31mmol ) followed by the addition of N- { 3- [ 5- ( 2- { 2 - azaspiro [ 3.3 ] heptan - 6 - ylamino } pyrimidin- - 493 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 4 - yl ) -2 - tert - butyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 34.00 mg , 0.06mmol ) in DMF ( 0.2 mL ) . The reaction was stirred at room temperature for twenty minutes . The reaction mixture was then diluted with EtOAc ( 20 mL ) . The organic solution was washed with water ( 0.5 mL ) twice , dried over sodium sulfate , filtered , and concentrated in vacuo . The product was loaded onto a Redi - Sep prepacked silica gel column eluting with a gradient of 0- % DCM in MeOH to afford tert - butyl 4- { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -2 - azaspiro [ 3.3 ] heptane - 2- carbonyl } -4 - fluoropiperidine - 1 - carboxylate ( 0.046 g , 95.22 % ) . LCMS : C37H49F2N7O5Srequires : 773.32 , found : m / z = 775.04 . [ 000526 ] Step - 2 : N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 4 - fluoropiperidine - 4 - carbonyl ) -2- azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide Tert - butyl 4- { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol- - yl } pyrimidin - 2 - yl ) amino ] -2 - azaspiro [ 3.3 ] heptane - 2 - carbonyl } -4 - fluoropiperidine - 1- carboxylate ( 46.00 mg , 0.0594 mmol ) was dissolved in DCM ( 2 mL ) and 4 N HCl in dioxane ( 0.30 mL , 1.1887 mmol ) was added . The reaction was stirred for one hour and the solvent was removed in vacuo . N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 2- ( 4 - fluoropiperidine - 4 - carbonyl ) -2- azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide was isolated without further purification . LCMS : C32H41F2N7O3S2 requires : 673.27 , found : m / z = 674.84 [ M + H ] * . [ 000527 ] [ 000528 ] General Procedure for Reductive Alkylation Followed by Deprotection Synthesis of N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( azetidin - 3 - yl ) piperidin- - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide HN .

S - NH O = S = OF N NHN - 494 - 1100573566 5 AMERICAS S - NH O = S = O FL NHN N S HN .

O = S = NH -F N₂H N -N Attorney Docket No .: 121843.002NU - 3200 PCT .N .

S - NH O = S = OLL N NHN S ' N N NΣ . N. HN . [ 000529 ] Step - 1 : tert - butyl 3- ( 4- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidin - 1 - yl ) azetidine - 1 - carboxylate To a solution of N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 130.00 mg , 0.2728 mmol ) and tert - butyl 3- oxoazetidine - 1 - carboxylate ( 46.70 mg , 0.2728 mmol ) in DMSO ( 0.50 mL ) and DCM ( 4.mL ) was added triethylamine ( 37.81 Lμ , 27.60 mg , 0.2728 mmol ) followed by sodium triacetoxyborohydride ( 173.43 mg , 0.8183 mmol ) powder in portions . The reaction was stirred at room temperature for sixteen hours . The reaction was diluted with DCM ( 30 mL ) . The organic solution was washed with water ( 1 mL ) , dried over sodium sulfate , filtered , and concentrated in vacuo . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with a gradient of 2-10 % MeOH in DCM to provide tert - butyl 3- ( 4- ( 5- ( 2- aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidin - 1- yl ) azetidine - 1 - carboxylate ( 0.146 g , 84.72 % ) . LCMS : C29H38FN7O4S2 requires 631.24 , found m / z = 632.56 [ M + H ] * . [ 000530 ] Step - 2 : N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( azetidin - 3 - yl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide -495- 1100573566 5 AMERICAS To a solution of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 3- ( 4- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidin - 1 - yl ) azetidine - 1 - carboxylate ( 146.00 mg , 0.2311 mmol ) in DCM ( 2 mL ) was added hydrogen chloride ( 2.00 mL , 0.29 g , 8.0000 mmol ) in dioxane ( 4 M ) . The reaction was stirred for twenty minutes . Solvents were removed under reduced pressure to provide N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( azetidin - 3 - yl ) piperidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide without further purification . LCMS C24H30FN7O2S2 requires : 531.19 ; found : m / z = 532.44 [ M + H ] * . [ 000531 ] General Procedure for Reductive Amination Followed by Deprotection [ 000532 ] Synthesis of N- ( 2 - fluoro - 3- ( 1- ( 4- ( piperazin - 1 - ylmethyl ) phenyl ) -3- ( pyridin- - yl ) -1H - pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide -NH N N = S = NH 0 = 0 = HN- [ 000533 ] Step - 1 : tert - butyl N Brose N = 8 = 4- ( 4- ( 4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) benzyl ) piperazine - 1 - carboxylate To a solution of N- ( 2 - fluoro - 3- [ 1- ( 4 - formylphenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] phenylpropane - 1 - sulfonamide ( 101.20 mg , 0.2179 mmol ) and tert - butyl piperazine - 1- carboxylate ( 44.64 mg , 0.2396 mmol ) in DCM ( 3.0 mL ) was added acetic acid ( 0. - 496 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT mL ) followed by the addition of sodium triacetoxyborohydride ( 138.52 mg , 0.6536 mmol ) . The reaction was stirred for thirty minutes ; however , the starting material did not dissolve . Thus , MeOH ( 0.10 mL ) was added and the starting material started to dissolve . The reaction was stirred for 2.5 hours . The crude product was diluted with DCM ( 30 mL ) , the solution was washed with water and brine , dried over sodium sulfate , filtered , and concentrated in vacuo . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with a gradient of 20-100 % EtOAc in DCM to afford tert - butyl 4 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ) methyl ] piperazine - 1 - carboxylate ( 0.121 g , 70.00 % ) . LCMS : C33H39FN6O4S requires : 634.3 , found : m / z = 635.7 [ M + H ] * . [ 000534 ] Step - 2 : N- ( 2 - fluoro - 3- ( 1- ( 4- ( piperazin - 1 - ylmethyl ) phenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide To a solution of tert - butyl 4 - [ ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ) phenyl ) methyl ] piperazine - 1 - carboxylate ( 121.00 mg , 0.1906 mmol ) in DCM ( 4 mL ) was added TFA ( 1 mL ) . The reaction was stirred for thirty minutes and then TFA and DCM were removed in vacuo . The crude product was loaded onto Redi - Sep prepacked Ccolumn ( 30 g ) eluting with a gradient of 10-90 % acetonitrile in water ( with 0.01 % TFA ) to afford N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - ylmethyl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) propane - 1 - sulfonamide ( 0.1 g , 81.12 % ) as a TFA salt . LCMS : C28H31FN6O2S , requires : 534.22 , found : m / z = 535.57 [ M + H ] * . [ 000535 ] The following scheme uses another modified General Procedure for Amide Coupling Followed by Deprotection . [ 000536 ] Synthesis of N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide HN O = S HN F N N -S NH , - 497 - 1100573566 5 AMERICAS N ﻢﻬﻣ ﺢﻣاﺩ OH -N O = S HN O = S- HN .

F N N NH HN- F N Attorney Docket No .: 121843.002NU - 3200 PCT N NH O = S HN N- HN F N N -S NH [ 000537 ] Step - 1 : tert - butyl 4- ( 4- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) thiazol - 2 - yl ) piperidine - 1 - carbonyl ) piperidine - 1 - carboxylate To a solution of 1- ( tert - butoxycarbonyl ) piperidine - 4 - carboxylic acid ( 81.78 mg , 0.35mmol ) and yloxy } ) methylidene ] dimethylazanium ; [ ( dimethylamino ) ( { [ 1,2,3 ] triazolo [ 4,5 - b ] pyridin - 3- hexafluoro - lambda5 - phosphanuide ( 135.63 mg , 0.3567 mmol ) in DMF ( 1 mL ) was added N , N - diisopropylethylamine ( 256.12 Lµ , 184.41 mg , 1.4268 mmol ) . After stirring the reaction for three minutes , the reaction mixture was added into N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( piperidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 170.00 mg , 0.3567 mmol ) in DMF ( 0.mL ) and the reaction mixture was stirred for twenty minutes . The crude product was diluted with EtOAc ( 10 mL ) , washed with water and brine , dried over sodium sulfate , filtered , and concentrated in vacuo . The crude product was loaded onto Redi - Sep prepacked silica gel column eluting with EtOAc in heptanes , to afford tert - butyl 4- { 4- [ 5- ( 2 - aminopyrimidin - 4 - yl ) - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carboxylate ( 0.145 g , 38.41 % ) . LCMS : C32H42FN7O5S2 requires : 687.3 , found : m / z = 688.7 [ M + H ] * . - 498 - 1100573566 5 AMERICAS [ 000538 ] Step - 2 : Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- ( 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- ( piperidine - 4- carbonyl ) piperidin - 4 - yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide Tert - butyl 4- [ 4- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 2 - yl ] piperidine - 1 - carbonyl } piperidine - 1 - carboxylate ( 145.00 mg , 0.21mmol ) was dissolved in 50 % v / v TFA in DCM ( 4 mL ) and the solution was stirred for thirty minutes . TFA and DCM were then removed in vacuo . The crude product was loaded onto Redi - Sep prepacked C18 column ( 30 g ) eluting with a gradient of 10-90 % acetonitrile in water ( 0.01 % TFA ) to afford N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( piperidine - 4- carbonyl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 0.1 g , 67.6 % ) . LCMS : C27H34FN7O3S2 , requires : 587.2 , found : m / z = 588.6 [ M + H ] * . ' H NMR ( 5MHz , DMSO - do ) 8 9.74 ( s , 1H ) , 8.49 ( d , J = 11.1 Hz , 1H ) , 8.26 ( s , 1H ) , 8.09 ( d , J = 5.3 Hz , 1H ) , 7.55 ( t , J = 7.7 Hz , 1H ) , 7.40 ( t , J = 7.0 Hz , 1H ) , 7.33 ( t , J = 7.9 Hz , 1H ) , 6.84 ( s , 2H ) , 6.12 ( d , J = 5.2 Hz , 1H ) , 4.46 ( d , J = 12.9 Hz , 1H ) , 4.08 ( d , J = 13.5 Hz , 1H ) , 3.26 ( dd , J = 35.6 , 12.8 Hz , 4H ) , 3.06 ( dd , J = 9.0 , 6.3 Hz , 2H ) , 3.02 – 2.86 ( m , 2H ) , 2.76 ( d , J = 19.8 Hz , 2H ) , 2.15 ( dd , J = 25.6 , 12.8 Hz , 2H ) , 1.85 – 1.62 ( m , 8H ) , 1.63 – 1.49 ( m , 1H ) , 1.27 ( q , J 5.8 , 4.7 Hz , 2H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . = = = [ 000539 ] Synthesis of ( R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 4- ( 3 - methylpiperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide ( 12 ) - 499- 1100573566 5 AMERICAS Br Boc HN ( R ) Br BINAP , ₂dP ( dba ) з . ‍rB NaO - t - Bu , toluene , ° C , 16 h Step - Pd ( Amphos ) ₂lC , CSF , dioxane , O₂H , 100 ° C , 2 h Step - N- Boc ( R ) of Pd ( dppf ) Cl2 CH2Cl2 , Attorney Docket No .: 121843.002NU - 3200 PCT -NH Br Boc Br- KOAc , dioxane , Cu ( OAc ) 2 , pyr , MS 4A , O2 , 100 ° C , 16 h 100 ° C , 16 h Step - 2 Step - 0 = 8 = HN NH F N - Boc TMSOTf , DIPEA -F DCM , 0 ° C , 2 h 0 = 3 = Step - 7 RNH Synthesis of Intermedlate 0 = $ = NH F TEA , DCM , NH0 ° C to rt , 4 h = $ = NH Na2CO3 , CH3CN , F Br O₂H , 80 ° C , 2 h Step - Pd ( dppf ) ₂lC - CH2Cl2 , KOAc , dioxane , 100 ° C , 2 h Br Step - -Boc [ 000540 ] Step - 1 : Synthesis of tert - butyl ( R ) -4- ( 4 - bromophenyl ) -2 - methylpiperazine- - carboxylate ( 3 ) [ 000541 ] To a stirred solution of compound 1 ( 4.5 g , 22.47 mmol , 1.0 equiv ) and compound 2 ( 12.25 g , 56.2 mmol , 2.5 equiv ) in toluene ( 300 mL ) was added sodium tert- butoxide ( 6.48 g , 67.4 mmol . 3.0 equiv ) and BINAP ( 0.700 g , 1.123 mmol , 0.05 equiv ) at room temperature . The resulting mixture was purged with N2 for 10 min and then Pd2 ( dba ) 3 ( 1.0g , 1.123 mmol , 0.05 equiv ) was added . The resulting mixture was purged with N2 for another min and then heated at 60 ° C for 16 h . The progress of the reaction was monitored by TLC ( 10 % ethyl acetate : petroleum ether , Rf : ~ 0.8 ) . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound ( 17 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 5-10 % ) as eluent to afford compound 3 ( 6.5 g , 78 % ) as a pale yellow solid . -500- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000542 ] Step - 2 : Synthesis of tert - butyl ( R ) -2 - methyl - 4- ( 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ) piperazine - 1 - carboxylate ( 5 ) [ 000543 ] To a solution of compound 3 ( 6.5 g , 18.30 mmol , 1.0 equiv ) and compound ( 6.97 g , 27.4 mmol , 1.5 equiv ) in 1,4 - dioxane ( 300 mL ) was added potassium acetate ( 3.59 g , 36.6 mmol , 2.0 equiv ) at room temperature . The resulting mixture was purged with N2 for min and then PdCl2 ( dppf ) CH2Cl2 adduct ( 1.494 g , 1.830 mmol , 0.1 equiv ) was added . The resulting mixture was purged with N2 for another 5 min and then heated at 100 ° C for 16 h . The progress of the reaction was monitored by TLC ( 10 % ethyl acetate : petroleum ether , Rf : ~ 0.6 ) . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound ( 14 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 5-7 % ) as eluent to afford compound 5 ( 7 g , 92 % ) as a pale yellow solid . [ 000544 ] Step - 3 : Synthesis of tert - butyl ( R ) -4- ( 4- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ) phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 7 ) [ 000545 ] To a mixture of compound 6 ( 1.5 g , 6.69 mmol , 1.0 equiv ) and compound ( 3.23 g , 8.03 mmol , 1.2 equiv ) in pyridine ( 20 mL ) was added molecular sieves , 4 Å ( 0.731 g , 3.35 mmol , 0.5 equiv ) and copper ( II ) acetate ( 1.824 g , 10.04 mmol , 1.5 equiv ) at room temperature . The resulting mixture was then purged with O2 for 15 min and then heated at 1° C for 16 h . The progress of the reaction was monitored by TLC ( 50 % ethyl acetate : petroleum ether , Rf : ~ 0.3 ) and LCMS . The reaction mixture was then cooled to room temperature , filtered through a Celite pad , and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound ( 10 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-4mesh ) using ethyl acetate : petroleum ether ( 10 % ) as eluent to afford compound 7 ( 1.7g , 47.6 % ) as a yellow gummy liquid . [ 000546 ] Step - 4 : Synthesis of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) propane - 1- sulfonamide ( 10 ) - 501 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000547 ] To a stirred solution of compound 9 ( 1.0 g , 4.46 mmol , 1.0 equiv ) in dichloromethane ( 30 mL ) was added triethylamine ( 2.484 mL , 17.82 mmol , 4.0 equiv ) and propane - 1 - sulfonyl chloride ( 1.003 mL , 8.91 mmol , 2.0 equiv ) at 0 ° C , and the resulting reaction mixture was then warmed and stirred at room temperature for 4 h . Upon completion of the reaction as confirmed by TLC ( 10 % ethyl acetate : petroleum ether , Rf : ~ 0.1 ) the reaction mixture was then concentrated under vacuum to give the crude product which was dissolved in acetonitrlie ( 30 mL ) . To this was added Na2CO3 ( 4.72 g , 44.6 mmol ) in water ( 30 mL ) and the reaction was heated at 80 ° C for 2 h . Then the reaction mixture was concentrated under vacuum and the residue obtained was acidified with aq . citric acid solution . The solid obtained was filtered and dried to give the crude product which was purified via Isolera ( silica gel , 230- 400 mesh ) using ethyl acetate : petroleum ether ( 35-40 % ) as eluent . The pure fractions were concentrated under vacuum and the solid obtained was washed with petroleum ether ( 100 mL ) and dried under vacuum to give compound 10 ( 1.0 g , 63.8 % ) as a white solid . [ 000548 ] Step - 5 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ) propane - 1 - sulfonamide ( 11 ) [ 000549 ] To a mixture of compound 10 ( 1.0 g , 3.02 mmol , 1.0 equiv ) and compound ( 1.152 g , 4.54 mmol , 1.5 equiv ) in 1,4 - dioxane ( 15 mL ) was added potassium acetate ( 1.039 g , 10.59 mmol , 3.5 qeuiv ) and PdCl2 ( dppf ) CH2Cl2 ( 0.247 g , 0.302 mmol , 0.1 equiv ) . The resulting mixture was purged with nitrogen for 10 min and then stirred at 100 ° C for 2 h . Upon completion of the reaction , as confirmed by LCMS , the reaction mixture was filtered through a Celite bed and washed with 1,4 - dioxane ( 25 mL ) . The filtrate was concentrated under vacuum to afford crude compound 11. LCMS : m / z : 294 indicated the corresponding boronic acid of . [ 000550 ] ( R ) -4- ( 4- ( 4- ( 5 - chloro - 2 - fluoro - 3- Step - 6 : Synthesis of tert - butyl ( propylsulfonamido ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) phenyl ) -2- methylpiperazine - 1 - carboxylate ( 8 ) [ 000551 ] To a stirred solution of compound 7 ( 1 g , 2.006 mmol , 1.0 equiv ) and compound ( 3 g , crude ) in 1,4 - dioxane ( 15 mL ) and water ( 4 mL ) was added CSF ( 0.610 g , 4.01 mmol , 2.0 equiv ) and Pd ( amphos ) Cl2 ( 0.142 g , 0.201 mmol , 0.1 equiv ) and the reaction mixture was purged with nitrogen for 10 min . The reaction was then heated at 100 ° C for 2 h . Upon completion of reaction as confirmed by LCMS , the reaction mixture was filtered through a Celite bed and washed with 1,4 - dioxane ( 20 mL ) . The filtrate was concentrated under vacuum -502- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT and the residue was washed with water ( 100 mL ) and extracted with ethyl acetate ( 100 mL ) . The combined organic layer was dried over sodium sulfate , filtered , and concentrated under vacuum to provide the crude product which was purified via Isolera ( silica gel , 230-400 mesh ) using ethyl acetate : petroleum ether ( 30-35 % ) as eluent to afford compound 8 ( 0.480 g , 30 % ) as a yellow solid . [ 000552 ] Step - 7 : Synthesis of ( R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 4- ( 3 - methylpiperazin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide ( 12 ) [ 000553 ] To stirred solution of compound 8 ( 0.480 g , 0.717 mmol , 1.0 equiv ) in DCM ( 10 mL ) was added DIPEA ( 0.260 mL , 1.435 mmol , 2.0 equiv ) and TMS - OTf ( 0.195 mL , 1.076 mmol , 1.5 equiv ) at 0 ° C and the reaction was stirred at room temperature for 2 h . Upon completion of reaction as confirmed by LCMS , the reaction mixture was quenched with water ( 20 mL ) and extracted with DCM ( 2 x 20 mL ) . The combined organic layer was dried over Na2SO4 and concentrated under vacuum provide the crude product which was purified by prep- HPLC ( Column : X Bridge C8 150 , Method : Formic acid : ACN , Rt : 10 min , Flow rate : mL / min ) to provide 12 ( 0.222 g , 51.6 % , Formate salt ) as a yellow solid . LCMS : m / z : 569.( M + H ) * , Rt : 1.329 min , Area : 95.991 % ; Column : X - BRIDGE C8 ( 50 x 4.6mm ) mµ5.3 , Mobile phase : A : 0.1 % TFA in H2O , B : ACN , Flow Rate : 2.0 mL / min . HPLC : Rt : 7.6min , Area : 94.819 % , Column : Atlantis T3 ( 150 x 4.6 ) mm , mμ3 , Mobile phase : A : 0.1 % TFA in water , Mobile phase : B : ACN , Flow : 1.2 mL / min . ' H NMR ( 400 MHz , DMSO - do ) : 8 8.( s , 1H ) , 8.57 ( q , J = 1.60 Hz , 2H ) , 8.15 ( s , 1H ) , 7.83 ( d , J = 9.20 Hz , 2H ) , 7.43 – 7.50 ( m , 4H ) , 7.18 ( d , J = 9.20 Hz , 2H ) , 3.85 ( q , J = 13.20 Hz , 2H ) , 3.40 – 3.33 ( m , 3H ) , 3.14 – 3.06 ( m , 3H ) , 2.94 ( m , 1H ) , 2.74 – 2.68 ( m , 1H ) , 1.69 – 1.63 ( m , 2H ) , 1.26 ( d , J = 6.40 Hz , 3H ) , 0.92 ( t , J = 7.20 Hz , 3H ) . = == [ 000554 ] Synthesis of ( S ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 4- ( 3 - methylpiperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide ( 12 ) -503- 1100573566 5 AMERICAS Br HN ( S ) N Br Boc .Br BINAP , ₂dP ( dba ) 3 , NaO - t - Bu , toluene , ° C , 16 h Step - Boc Br Pd ( Amphos ) Cl2 , CSF , dioxane , O₂H , 100 ° C , 2 h Step - NH.F CI HN TEA , DCM , ° C to rt , 4 h B - B . .Boc Pd ( dppf ) Cl2 CH2Cl2 , KOAc , dioxane , 100 ° C , 16 h Step - Attorney Docket No .: 121843.002NU - 3200 PCT -NH Br -Boc Cu ( OAc ) 2 , pyr , MS 4A , O2 , 100 ° C , 16 h Step - NH N - Boc TMSOTf , DIPEA CI- DCM , 0 ° C , 2h Synthesis of Intermediate NH Na2CO3 , CH3CN , ` гB O₂H , 80 ° C , 2 h Step - B- Step - 4 NH ‚ F Pd ( dppf ) ₂lC - CH2Cl2 , KOAc , dioxane , 100 ° C , 2 h Br Step - ( SINH Step - 1 : Synthesis of tert - butyl ( S ) -4- ( 4 - bromophenyl ) -2 - methylpiperazine- [ 000555 ] - carboxylate ( 3 ) [ 000556 ] To a stirred solution of compound 1 ( 3.5 g , 17.48 mmol , 1.0 equiv ) and compound 2 ( 10.31 g , 43.7 mmol , 2.5 equiv ) in toluene ( 300 mL ) was added sodium tert- butoxide ( 5.04 g , 52.4 mmol . 3.0 equiv ) and BINAP ( 0.544 g , 0.874 mmol , 0.05 equiv ) at room temperature . The resulting mixture was purged with N2 for 10 min and then Pd2 ( dba ) 3 ( 0.8g , 0.874 mmol , 0.05 equiv ) was added . The resulting mixture was then purged with N2 for another 5 min and the reaction was then heated at 60 ° C for 16 h . The progress of the reaction was monitored by TLC ( 10 % ethyl acetate : petroleum ether , Rf : ~ 0.8 ) . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound ( 15 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 5-10 % ) as eluent to afford compound 3 ( 6.2 g , 95 % ) as a pale yellow solid . -504- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000557 ] Step - 2 : Synthesis of tert - butyl ( S ) -2 - methyl - 4- ( 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ) piperazine - 1 - carboxylate ( 5 ) [ 000558 ] To a solution of compound 3 ( 7.7 g , 21.67 mmol , 1.0 equiv ) and compound ( 8.26 g , 32.5 mmol , 1.5 equiv ) in 1,4 - dioxane ( 300 mL ) was added potassium acetate ( 4.25 g , 43.3 mmol , 2.0 equiv ) at room temperature . The resulting mixture was purged with N2 for min and then PdCl2 ( dppf ) CH2Cl2 adduct ( 1.770 g , 2.167 mmol , 0.1 equiv ) was added . The resulting mixture was purged with N2 for another 5 min and the reaction was then heated at 100 ° C for 16 h . The progress of the reaction was monitored by TLC ( 10 % ethyl acetate : petroleum ether , Rf : ~ 0.6 ) . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound ( 16 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 5-7 % ) as eluent to afford compound 5 ( 8.g , 98 % ) as a pale yellow solid . [ 000559 ] Step - 3 : Synthesis of tert - butyl ( S ) -4- ( 4- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H- pyrazol - 1 - yl ) phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 7 ) [ 000560 ] To a mixture of compound 6 ( 2 g , 8.93 mmol , 1.0 equiv ) and compound 5 ( 4.g , 10.71 mmol , 1.2 equiv ) in pyridine ( 25 mL ) was added molecular sieves , 4 Å ( 0.974 g , 4.mmol , 0.5 equiv ) and copper ( II ) acetate ( 2.432 g , 13.39 mmol , 1.5 equiv ) at room temperature . The resulting mixture was purged with O2 for 15 min and then the reaction was heated at 1° C for 16 h . The progress of the reaction was monitored by TLC ( 50 % ethyl acetate : petroleum ether , Rf : ~ 0.3 ) and LCMS . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford a crude compound ( 12 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 15-20 % ) as eluent to afford compound ( 1.5 g , 32 % ) as a yellow gummy liquid . [ 000561 ] Step - 4 : Synthesis of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) propane - 1- sulfonamide ( 10 ) -505- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000562 ] To a stirred solution of compound 9 ( 0.8 g , 3.56 mmol , 1.0 equiv ) in dichloromethane ( 30 mL ) was added triethylamine ( 1.44 g , 14.26 mmol , 4.0 equiv ) and propane - 1 - sulfonyl chloride ( 1.203 mL , 10.69 mmol , 3.0 equiv ) at 0 ° C and the resulting reaction mixture was stirred at room temperature for 4 h . Upon completion of the reaction as confirmed by TLC ( 10 % ethyl acetate : petroleum ether , Rf : ~ 0.1 ) , the reaction mixture was then concentrated under vacuum to give the crude product which was dissolved in acetonitrlie ( mL ) . Na2CO3 ( 3.77 g , 35.6 mmol ) in water ( 30 mL ) was then added and the reaction was then heated at 80 ° C for 2 h . Then the reaction mixture was concentrated under vacuum and the residue obtained was acidified with aq . citric acid solution . The solid obtained was filtered and dried to give the crude product which was purified via Isolera ( silica gel , 230-400 mesh ) using ethyl acetate : petroleum ether ( 35-40 % ) as eluent . The pure fractions were concentrated under vacuum and the solid obtained was washed with petroleum ether ( 25 mL ) and dried under vacuum to give compound 10 ( 1.1 g , 91 % ) as a white solid . [ 000563 ] Step - 5 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ) propane - 1 - sulfonamide ( 11 ) [ 000564 ] To a mixture of compound 10 ( 1.1 g , 3.33 mmol , 1.0 equiv ) and compound ( 1.267 g , 4.99 mmol , 1.5 equiv ) in 1,4 - dioxane ( 15 mL ) was added potassium acetate ( 1.14 g , 11.65 mmol , 3.5 equiv ) and PdCl2 ( dppf ) CH2Cl2 ( 0.272 g , 0.333 mmol , 0.1 equiv ) . The resulting mixture was purged with nitrogen for 10 min and then stirred at 100 ° C for 2 h . Upon completion of the reaction , as confirmed by LCMS , the reaction mixture was filtered through a Celite bed and washed with 1,4 - dioxane ( 25 mL ) . The filtrate was concentrated under vacuum to afford crude compound 11 ( 2.9 g , quant . ) . LCMS : m / z = 294 corresponds to the boronic acid derivative of 11 . [ 000565 ] Step - 6 : Synthesis of tert - butyl ( S ) -4- ( 4- ( 4- ( 5 - chloro - 2 - fluoro - 3- ( propylsulfonamido ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) phenyl ) -2- methylpiperazine - 1 - carboxylate ( 8 ) [ 000566 ] To a stirred solution of compound 7 ( 1.1 g , 2.207 mmol , 1.0 equiv ) and compound 11 ( 2.9 g , crude ) in 1,4 - dioxane ( 15 mL ) and water ( 4 mL ) was added CSF ( 0.6g , 4.41 mmol , 2.0 equiv ) and Pd ( amphos ) Cl2 ( 0.156 g , 0.221 mmol , 0.1 equiv ) and the reaction mixture was purged with nitrogen for 10 min . The reaction was then heated at 100 ° C for 2 h . Upon completion of the reaction , as confirmed by LCMS , the reaction mixture was then filtered through a Celite bed and washed with 1,4 - dioxane ( 20 mL ) . The filtrate was concentrated under - 506 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT vacuum and the residue was washed with water ( 100 mL ) and extracted with ethyl acetate ( 1mL ) . The combined organic layer was dried over sodium sulfate , filtered , and concentrated under vacuum to provide the crude product which was purified via Isolera ( silica gel , 230-4mesh ) using ethyl acetate : petroleum ether ( 30-35 % ) as eluent to afford compound 8 ( 0.580 g , 31.8 % ) as a yellow solid . [ 000567 ] Step - 7 : Synthesis of ( S ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 4- ( 3 - methylpiperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) propane - 1 - sulfonamide ( 12 ) [ 000568 ] To stirred solution of compound 8 ( 0.580 g , 0.867 mmol , 1.0 equiv ) in DCM ( 10 mL ) was added DIPEA ( 0.302 mL , 1.733 mmol , 2.0 equiv ) and TMS - OTf ( 0.473 mL , 2.mmol , 3 equiv ) at 0 ° C and the reaction was then stirred at room temperature for 2 h . Upon completion of then reaction , as confirmed by LCMS , the reaction mixture was then quenched with water ( 20 mL ) and extracted with DCM ( 2 x 20 mL ) . The combined organic layer was dried over Na2SO4 and concentrated under vacuum provide the crude which was purified by prep - HPLC ( Column : Xselect C18 250 mm , Method : Formic acid ( FA ) : ACN , Rt : 10 min , Flow rate : 15 mL / min ) to provide 12 ( 0.156 g , 31.2 % , formate salt ) as a yellow solid . LCMS : Rt : 1.461 min , Area : 99.33 % , m / z = 569.2 ( M + H ) * . Column : BEH C18 ( 50 x 2.1 mm ) 1.7 mμ ; Mobile phase : A : 0.1 % HCOOH in O₂H , B : ACN ; Flow Rate : 0.8 mL / min . HPLC : ťR : 7.6min , Area : 99.93 % ; Method Info : Column : Atlantis T3 ( 150 x 4.6 mm , mμ3 ; Mobile phase : A : 0.1 % TFA in water ; Mobile phase : B : ACN ; Flow : 1.2 mL / min . ' H NMR ( 400 MHz , DMSO - ɛd ) : § 9.00 ( bs , 2H ) , 8.78 ( s , 1H ) , 8.57 ( q , J = 1.60 Hz , 2H ) , 7.83 ( d , J = 9.20 Hz , 2H ) , 7.51 – 7.41 ( m , 4H ) , 7.18 ( d , J = 9.20 Hz , 2H ) , 3.88 – 3.79 ( m , 2H ) , 3.39 – 3.33 ( m , 2H ) , 3.- 3.05 ( m , 3H ) , 2.96 – 2.93 ( m , 1H ) , 2.73 – 2.68 ( m , 1H ) , 1.69 – 1.63 ( m , 2H ) , 1.26 ( d , J = 6.Hz , 3H ) , 0.92 ( t , J = 7.60 Hz , 3H ) . [ 000569 ] - - Synthesis of ( R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ( 11 ) -507- 1100573566 5 AMERICAS Cl CI H HCI N = 8 = " F DIPEA , DCM , -70 ° C to rt , 1 h Step - NH Attorney Docket No .: 121843.002NU - 3200 PCT O = 5 = CI F O = S = CI Br H Br N. N.

" F DMAP , pyr , ° C to 40 ° C , 24 h O = S = NH F Pd ( Amphos ) Cl2 , CSF , dioxane , O₂H , ° C , 6 h Step - Step - ' N ' O = S = Cl NH F N - N TFA , DCM , ° C to rt , 1 h to - F Pd ( dppf ) Cl2 CH2Cl2 , KOAc , dioxane , 90 ° C , 4 h Step - F abs N N - N Step - Boc Synthesis of Common Intermediate -NH N Br Br -Boc Br Boc O = S = NH F -NH [ 000570 ] [ 000571 ] 3OC₂sC , O₂uC , - hydroxyquinoline , DMSO , 100 ° C , 16 h Step - Step - 1 : Synthesis of ( R ) -3 - fluoropyrrolidine - 1 - sulfonyl chloride ( 2 ) To a solution of compound 1 ( 4.5 g , 35.8 mmol , 1.0 equiv ) in DCM ( 90 mL ) was added DIPEA ( 17.78 mL , 108 mmol , 3.0 equiv ) and the solution was cooled to -70 ° C . Sulfuryl dichloride ( 9.67 g , 71.7 mmol , 2.0 equiv ) was then added and the reaction was stirred at -70 ° C for one hour . The reaction was then warmed and stirred at room temperature for one hour . The progress of the reaction was monitored by TLC ( 20 % ethyl acetate : petroleum ether , Rf : ~ 0.6 , KMnO4 active ) . The reaction mixture was then quenched with water ( 200 mL ) , extracted with DCM ( 2 x 200 mL ) , and washed with 1.5 N HCl ( 100 mL ) . The combined organic layer was dried over Na2SO4 and concentrated under vacuum at room temperature to afford compound 2 ( 5 g , 74.4 % ) as an off white solid . -508- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000572 ] Step - 2 : Synthesis fluoropyrrolidine - 1 - sulfonamide ( 4 ) [ 000573 ] of ( R ) -N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) -3- To a solution of compound 2 ( 3 g , 13.38 mmol , 1.0 equiv ) in pyridine ( 4.5 mL ) was added DMAP ( 0.327 g , 2.637 mmol , 0.2 equiv ) followed by compound 3 ( 3.261 g , 17.mmol , 1.3 equiv ) at 0 ° C , and the resulting reaction mixture was then heated to 40 ° C for 24 h . Upon completion of the reaction , as confirmed by LCMS , the reaction mixture was concentrated under vacuum to afford a crude compound ( 5 g ) as a brown gum . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 10-12 % ) as eluent to afford compound 4 ( 1.7 g , 33.8 % ) as a yellow solid . [ 000574 ] Step - 3 : Synthesis of ( R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ( 6 ) [ 000575 ] To a solution of compound 4 ( 1 g , 2.66 mmol , 1.0 equiv ) in 1,4 - dioxane ( mL ) was added compound 5 ( 1.014 g , 3.99 mmol , 1.5 equiv ) and potassium acetate ( 0.523 g , 5.32 mmol , 2.0 equiv ) and the mixture was purged with nitrogen for 15 min . Then PdCl2 ( dppf ) DCM ( 0.195 g , 0.266 mmol , 0.1 equiv ) was added and the reaction was heated to ° C for 4 h . The progress of the reaction was monitored by TLC ( 50 % ethyl acetate : petroleum ether , Rf : ~ 0.4 ) . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 2mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was passed through silica gel ( 100-120 mesh ) , dried over Na2SO4 , and concentrated under vacuum to afford crude compound 6 ( 1.0 g , 89 % ) as a brown liquid . [ 000576 ] Step - 4 : Synthesis of tert - butyl 4- ( 6- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) pyridin - 3 - yl ) piperazine - 1 - carboxylate ( 9 ) [ 000577 ] A mixture of compound 7 ( 0.5 g , 0.0022 mmol , 1.0 equiv ) and 8 ( 0.75 g , 0.00mmol , 1.0 equiv ) in DMSO ( 5 mL ) was treated with cesium carbonate ( 1.45 g , 0.0044 mmol , 2.0 equiv ) , copper ( I ) oxide ( 0.032 g , 0.0002 mmol , 0.1 equiv ) , and 8 - hydroxyquinoline ( 0.0g , 0.0004 mmol , 0.2 equiv ) at room temperature . The reaction mixture was purged with N2 for min and then heated at 100 ° C in a closed vial for 16 h . Similarly , five additional batches were peformed on 0.5 g scale . [ 000578 ] All the batches were then cooled to room temperature , mixed together , and filtered through a Celite pad . The Celite pad was washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The -509- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford a crude compound ( 6 g ) as a brown liquid . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 30-35 % ) as eluent to afford compound ( 3.0 g , 46 % ) as an off - white solid . [ 000579 ] Step - 5 : Synthesis of tert - butyl ( R ) -4- ( 6- ( 4- ( 5 - chloro - 2 - fluoro - 3 - ( ( 3- fluoropyrrolidine ) -1 - sulfonamido ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) pyridin - 3- yl ) piperazine - 1 - carboxylate ( 10 ) [ 000580 ] To a mixture of compound 6 ( 1.0 g , 2.366 mmol , 1.0 equiv ) and compound ( 0.918 g , 1.892 mmol , 0.8 equiv ) in 1,4 - dioxane ( 24 mL ) and H2O ( 6 mL ) was added cesium fluoride ( 0.718 g , 4.732 mmol , 2.0 equiv ) and Pd ( amphos ) Cl2 ( 0.168 g , 0.236 mmol , 0.1 equiv ) at room temperature . The reaction mixture was purged with N2 for 10 min and then heated at ° C for 6 h . Upon completion of reaction , as confirmed by LCMS , the reaction mixture was filtered through a Celite pad and washed with ethyl acetate ( 50 mL ) . The filtrate was diluted with water ( 50 mL ) and extracted with ethyl acetate ( 2 x 50 mL ) . The combined organic layer was dried over Na2SO4 and concentrated under vacuum provide a crude which was purified by prep - HPLC ( Column : SUNFIRE C18 250 x 30 mm , Method : TFA : ACN , Rt : 12 min , Flow rate : 15 mL / min ) to provide compound 10 ( 0.6 g , 37.2 % ) as a yellow solid . [ 000581 ] Step - 6 : Synthesis of ( R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 5- ( piperazin - 1- yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) -3 - fluoropyrrolidine - 1- sulfonamide ( 11 ) [ 000582 ] To a solution of compound 10 ( 0.6 g , 0.856 mmol , 1.0 equiv ) in DCM ( 20 mL ) was added trifluoroacetic acid ( 0.976 g , 8.56 mmol , 10 equiv ) at 0 ° C and the reaction was warmed and stirred at room temperature for 2 h . The progress of the reaction was monitored by TLC ( 100 % ethyl acetate , Rf : ~ 0.2 ) . The reaction mixture was then concentrated under vacuum to give a brown gum , which was washed with petroleum ether ( 3 x 20 mL ) , dried under vacuum , and lyophilized to provide 11 ( 537 mg , 98 % , TFA salt ) as a yellow solid . LCMS : Rt : 1.261 min , Area : 96.8 % , m / z = 601.1 ( M + H ) * . Column : X - BRIDGE C8 ( 50 x 4.6 mm ) 3.mμ ; Mobile phase : A : 0.1 % TFA in O₂H , B : ACN ; Flow Rate : 2.0 mL / min . HPLC : ťR : 7.4min , Area : 95.07 % ; Method Info : Column : Atlantis T3 150 x 4.6 mm , 3 mµ ; Mobile phase : A : 0.1 % TFA in water ; Mobile phase : B : ACN ; Flow : 1.2 mL / min . ' H NMR ( 400 MHz , DMSO- do ) : 10.10 ( s , 1H ) , 8.85 ( s , 3H ) , 8.71 ( d , J = 6.40 Hz , 2H ) , 8.29 ( d , J = 2.80 Hz , 1H ) , 7.99 ( d , J = 9.20 Hz , 1H ) , 7.75 – 7.68 ( m , 3H ) , 7.54 ( q , J = 2.40 Hz , 1H ) , 7.43 ( q , J = 2.40 Hz , 1H ) , 5. -510 - 1100573566 5 AMERICAS - Attorney Docket No .: 121843.002NU - 3200 PCT ( d , J = 52.00 Hz , 2H ) , 3.51 ( q , J = 8.00 Hz , 5H ) , 3.41 – 3.37 ( m , 2H ) , 3.28 ( t , J = 2.40 Hz , 4H ) , 2.17 1.99 ( m , 2H ) . 19F NMR ( 400 MHz , DMSO - do ) : -74.32 , -126.08 , -174.86 .

Synthesis of ethylmethyl [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine ( 7 ) [ 000583 ] NHF CI O = S = N- LL F Br pyr , DMAP , IZ = S = CI Br ° C , 16 h CI Step - Boc ` N ' N N. ﻝا B - B ' N ' O = S = Cl NH Pd ( dppf ) Cl2 CH2Cl2 , KOAc , dioxane , 90 ° C , 3 h Step - SS >> LL Br Cl NH - S - O N N. Common Intermediate N TFA , DCM , " CI NH - S -S = O .N . F N ° C to rt , 2 h N - N Pd ( Amphos ) ₂lC , CSF , dioxane , O₂H , ° C , 6 h Step - N N - N N Step - -N Boc N -NH [ 000584 ] Step - 1 : Synthesis of ethylmethyl [ ( 3 - bromo - 5 - chloro - 2- fluorophenyl ) sulfamoyl ] amine ( 3 ) [ 000585 ] To a solution of compound 1 ( 1 g , 4.46 mmol , 1.0 equiv ) in pyridine ( 1.5 mL ) was added DMAP ( 0.109 g , 0.891 mmol , 0.2 equiv ) followed by compound 2 ( 0.913 g , 17.mmol , 1.3 equiv ) at 0 ° C and the resulting reaction mixture was heated to 40 ° C for 16 h . Upon completion of the reaction , as confirmed by LCMS , the reaction mixture was concentrated under vacuum to afford a crude compound ( 1.5 g ) as a brown gum . The crude compound was purified via Isolera ( silica gel : 230-400 mesh ) using ethyl acetate : petroleum ether ( 7-10 % ) as eluent to afford compound 3 ( 0.85 g , 49.5 % ) as an off - white solid . - 511- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000586 ] Step - 2 : Synthesis of ethylmethyl { [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] sulfamoyl } amine ( 5 ) [ 000587 ] To a solution of compound 3 ( 0.5 g , 1.447 mmol , 1.0 equiv ) in 1,4 - dioxane ( mL ) was added compound 4 ( 0.551 g , 2.17 mmol , 1.5 equiv ) and potassium acetate ( 0.284 g , 2.89 mmol , 2.0 equiv ) at room temperature . The resulting mixture was purged with N2 for min . Then PdCl2 ( dppf ) DCM ( 0.117 g , 0.145 mmol , 0.1 equiv ) was added and the reaction was heated to 90 ° C for 3 h . The progress of the reaction was monitored by TLC ( 50 % ethyl acetate petroleum ether , Rf : ~ 0.2 ) . The reaction mixture was then cooled to room temperature and filtered through a Celite pad and washed with ethyl acetate ( 50 mL ) . The combined organic layer was passed through silica gel ( 100-120 mesh ) , dried over Na2SO4 , and concentrated under vacuum to afford crude compound 5 ( 1.0 g , quant . ) as a brown solid . [ 000588 ] Step - 3 : Synthesis of tert - butyl 4- ( 6- ( 4- ( 5 - chloro - 3 - ( ( N - ethyl - N- methylsulfamoyl ) amino ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) pyridin - 3- yl ) piperazine - 1 - carboxylate ( 6 ) [ 000589 ] To a mixture of compound compound 5 ( 2.0 g , 5.28 mmol , 3.0 equiv ) and tert- butyl 4- ( 6- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) pyridin - 3 - yl ) piperazine - 1 - carboxylate ( common intermediate 9 , 0.85 g , 1.751 mmol , 1.0 equiv ) and in 1,4 - dioxane ( 30 mL ) and water ( 7.5 mL ) was added CsF ( 0.532 g , 3.5 mmol , 2.0 equiv ) and Pd ( Amphos ) Cl2 ( 0.124 g , 0.1mmol , 0.1 equiv ) and the reaction mixture was purged with nitrogen for 10 min . The reaction was then heated at 90 ° C for 6 h . Upon completion of reaction as confirmed by LCMS , the reaction mixture was filtered through a Celite pad and washed with ethyl acetate ( 100 mL ) . The filtrate was diluted with water ( 50 mL ) and extracted with ethyl acetate ( 2 x 100 mL ) . The combined organic layer was dried over Na2SO4 and concentrated under vacuum to provide a crude which was purified by prep - HPLC ( Column : SUNFIRE C18 250 x 30 mm , Method : TFA : ACN , Rt : 12 min , Flow rate : 15 mL / min ) to provide compound 6 ( 0.6 g , 51 % ) as a yellow solid . [ 000590 ] Step - 4 : Synthesis of ethylmethyl [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine ( 7 ) [ 000591 ] To a solution of compound 6 ( 0.6 g , 0.8939 mmol , 1.0 equiv ) in DCM ( 14 mL ) was added trifluoroacetic acid ( 0.70 mL , 8.939 mmol , 10 equiv ) at 0 ° C and the reaction was warmed and stirred at room temperature for 2 h . The progress of the reaction was monitored by TLC ( 100 % ethyl acetate , Rf : ~ 0.2 ) . The reaction mixture was concentrated under vacuum -512- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT to provide a crude product as a brown gum . The crude was washed with petroleum ether ( 3 x mL ) and dried under vacuum to afford a crude compound ( 0.6 g , 92 % ) by LCMS . The crude was purified by prep - HPLC ( Column : SUNFIRE C18 250 x 30 mm , Method : TFA : ACN , Rt : min , Flow rate : 15 mL / min ) and then lyophilized to provide 7 ( 392 mg , 98 % , TFA salt ) as a pale yellow solid . LCMS : Rt : 1.306 min , Area : 99.6 % , m / z = 571.2 ( M + H ) ; Column : X- BRIDGE C8 ( 50 x 4.6 mm ) 3.5 mμ ; Mobile phase : A : 0.1 % TFA in O₂H , B : ACN ; Flow Rate : 2.0 mL / min . HPLC : Rt : 7.527 min , Area : 99.31 % ; Method Info : Column : Atlantis T3 150 x 4.6 mm , 3 mμ ; Mobile phase : A : 0.1 % TFA in water ; Mobile phase : B : ACN ; Flow : 1.mL / min . ' H NMR ( 400 MHz , DMSO - do ) : 9.96 ( s , 1H ) , 8.87 - 8.85 ( m , 3H ) , 8.66 ( d , J = 1.Hz , 2H ) , 8.28 ( d , J = 3.20 Hz , 1H ) , 7.98 ( d , J = 8.80 HZ , 1H ) , 7.73 ( dd , J = 3.20 , 9.00 Hz , 1H ) , 7.58 ( d , J = 1.60 Hz , 2H ) , 7.47 ( dd , J = 2.80 , 6.40 Hz , 1H ) , 7.41 ( dd , J = 2.80 , 5.60 Hz , 1H ) , 3.323.50 ( m , 4H ) , 3.30 ( br s , 4H ) , 3.10 ( q , J = 7.20 Hz , 2H ) , 2.69 ( s , 3H ) , 1.03 ( t , J = 7.Hz , 3H ) . 19F NMR ( 400 MHz , DMSO - do ) : -74.08 , -126.55 . [ 000592 ] Synthesis of – N- ( 5 - chloro - 3- ( 1- ( 4- ( 3,3 - dimethylpiperazin - 1 - yl ) -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1- sulfonamide TFA salt ( 7 ) Br -Br HN N - Boc ₂dP ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - N N - Boc ﻢﻟا N - Boc O = 5 = Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1h Step - 2niP₂B Pd2 ( dba ) 3 , X - Phos , KOAc , methoxycyclopentane , 110 ° C , 2 h Step - Br NH -N N - Boc Cu ( OAc ) 2 , pyr , molecular sieves ( 4A ) , 100 ° C Step - NH NH TFA , DCM , ° C , 1 h OH Step - 6 NH Boc [ 000593 ] Step - 1 : Synthesis of tert - butyl dimethylpiperazine - 1 - carboxylate ( 2 ) [ 000594 ] 4- ( 4 - chloro - 3 - fluorophenyl ) -2,2- To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 3 g , 14.324 mmol , 1 equiv ) and tert - butyl 2,2 - dimethyl - 1 - piperazinecarboxylate ( 3.07 g , 14.324 mmol , 1 equiv ) in toluene ( 60 mL ) was added Pd2 ( dba ) 3 ( 131 mg , 0.143 mmol , 0.01 equiv ) , BINAP ( 178 mg , 0.286 mmol , 0.02 equiv ) , and t - BuONa ( 1.93 g , 20.054 mmol , 1.4 equiv ) . The resulting mixture was stirred - 513 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with petroleum ether ( PE ) : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) -2,2- dimethylpiperazine - 1 - carboxylate ( 2.3 g , 46.84 % ) as an off - white solid . LCMS : C17H24C1FN2O2 requires : 342.2 , found : m / z = 343.3 [ M + H ] * . [ 000595 ] Step - 2 : Synthesis of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -2,2 - dimethylpiperazine - 1 - carboxylate ( 3 ) [ 000596 ] To a mixture of tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) -2,2 - dimethylpiperazine- - carboxylate ( 2.1 g , 6.1253 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 2.38 g , 9.188 mmol , 1.5 equiv ) in methoxycyclopentane ( 30 mL ) was added Pd2 ( dba ) 3 ( 171 mg , 0.188 mmol , 0.03 equiv ) , X- Phos ( 176 mg , 0.376 mmol , 0.06 equiv ) , and KOAc ( 1.75 g , 18.375 mmol , 3 equiv ) . The resulting mixture was then stirred at 110 ° C for 2.0 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- [ 3 - fluoro- 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] - 2,2 - dimethylpiperazine - 1- carboxylate ( 1.3 g , 48.86 % ) as a brown oil . LCMS : C23H36BFN2O4 requires : 434.3 , found : m / z = 435.2 [ M + H ] * . [ 000597 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] - - fluorophenyl } -2,2 - dimethylpiperazine - 1 - carboxylate ( 4 ) [ 000598 ] To a mixture of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] - 2,2 - dimethylpiperazine - 1 - carboxylate ( 1.3 g , 2.993 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.006 g , 4.489 mmol , 1.5 equiv ) in pyridine ( mL ) was added Cu ( OAc ) 2 ( 1.09 g , 5.986 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 1.4 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 20 : 1 ) to afford tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -2,2 - dimethylpiperazine - 1- carboxylate ( 0.45 g , 28.35 % ) as a brown semi - solid . LCMS : C25H29BrFN5O2 requires : 529.1 , found : m / z = 530.2 [ M + H ] * . -514- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000599 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,2- dimethylpiperazine - 1 - carboxylate ( 6 ) [ 000600 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl } -2,2 - dimethylpiperazine - 1 - carboxylate ( 450 mg , 0.8483 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1- sulfonamide ( 1.03 g , 2.545 mmol , 3 equiv ) in dioxane ( 10 mL ) was added CSF ( 258 mg , 1.mmol , 2 equiv ) in O₂H ( 2 mL ) and Pd ( AMPHOS ) 2Cl2 ( 60 mg , 0.085 mmol , 0.1 equiv ) . The resulting mixture was then stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- [ 4- ( 4- { 5- chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3- fluorophenyl ] -2,2 - dimethylpiperazine - 1 - carboxylate ( 170 mg , 27.52 % ) as an off - white solid . LCMS : C35H40C1F2N7O4S requires : 727.3 , found : m / z = 728.3 [ M + H ] * . [ 000601 ] Step - 5 : Synthesis of N- ( 5 - chloro - 3- ( 1- ( 4- ( 3,3 - dimethylpiperazin - 1 - yl ) -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1- sulfonamide TFA salt ( 7 ) [ 000602 ] To a mixture of tert - butyl 4- [ 4- ( 4-5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,2- dimethylpiperazine - 1 - carboxylate ( 170 mg , 0.2334 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- ( 5 - chloro - 3- { 1- [ 4- ( 3,3- dimethylpiperazin - 1 - yl ) -2 - fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid ( 100.0 mg , 68.22 % ) as a yellow solid . LCMS : C30H32C1F2N7O2S requires : 627.2 , found : m / z = 628.3 [ M + H ] * . [ 000603 ] Synthesis of N- ( 3- ( 1- ( 4- ( 3,3 - dimethylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide TFA salt ( 6 ) -515- 1100573566 5 AMERICAS ﻹا HN N - Boc Attorney Docket No .: 121843.002NU - 3200 PCT 2niP₂B Pd2 ( dba ) 3 , X - Phos , KOAC ` Boc methoxycyclopentane , 110 ° C CI- -Br Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - Br NH Br ﻮﻟا LL F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C 1 h Step - Boc Cu ( OAc ) 2 , pyr , molecular sieves 4A , 60 ° C Step - N. NH -F ' N ' Boc TFA , DCM , 0 ° C Step - Step - 8 = -N .

Boc NH OH -F NH [ 000604 ] Step - 1 : Synthesis of tert - butyl dimethylpiperazine - 1 - carboxylate ( 2 ) 4- ( 4 - chloro - 3 - fluorophenyl ) -2,2- [ 000605 ] To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 5 g , 23.873 mmol , 1 equiv ) and tert - butyl 2,2 - dimethylpiperazine - 1 - carboxylate ( 5.12 g , 23.873 mmol , 1 equiv ) in toluene ( 50 mL ) was added Pd2 ( dba ) 3 ( 0.22 g , 0.239 mmol , 0.01 equiv ) , BINAP ( 0.30 g , 0.477 mmol , 0.02 equiv ) , and t - BuONa ( 3.21 g , 33.422 mmol , 1.4 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAC ( 9 : 1 ) to afford tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) -2,2 - dimethylpiperazine- - carboxylate ( 7.8 g , 95.30 % ) as an orange solid . LCMS : C17H24ClFN2O2 requires : 342.2 , found : m / z = 343.3 [ M + H ] * . [ 000606 ] Step - 2 : Synthesis of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -2,2 - dimethylpiperazine - 1 - carboxylate ( 3 ) [ 000607 ] To a mixture of tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) -2,2 - dimethylpiperazine- - carboxylate ( 7.8 g , 22.751 mmol , 1 equiv ) and bis ( pinacolato ) diboron ( B2Pin2 ) ( 8.67 g , 34.127 mmol , 1.5 equiv ) in methoxycyclopentane ( 80 mL ) was added Pd2 ( dba ) 3 ( 0.63 g , 0.6 -516- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT mmol , 0.03 equiv ) , XPhos ( 0.65 g , 1.365 mmol , 0.06 equiv ) , and AcOK ( 6.70 g , 68.253 mmol , equiv ) . The resulting mixture was stirred at 110 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 9 : 1 ) to afford tert - butyl 4- [ 3- fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -2,2 - dimethylpiperazine - 1- carboxylate ( 9 g , 91.07 % ) as an orange solid . LCMS : C23H36BFN2O4 requires : 434.3 , found : m / z 435.2 [ M + H ] * . [ 000608 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] - - fluorophenyl } -2,2 - dimethylpiperazine - 1 - carboxylate ( 4 ) [ 000609 ] To a mixture of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -2,2 - dimethylpiperazine - 1 - carboxylate ( 2 g , 4.604 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.13 g , 5.064 mmol , 1.1 equiv ) in pyridine ( 20 mL ) was added Cu ( OAc ) 2 ( 1.67 g , 9.208 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 2 g ) . The resulting mixture was stirred at 60 ° C overnight under an oxygen atmosphere . The resulting mixture was then diluted with water and extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4- yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -2,2 - dimethylpiperazine - 1 - carboxylate ( 1 g , 40.94 % ) as a white solid . LCMS : C25H29BrFN5O2 requires : 529.2 , found : m / z = 530.1 [ M + H ] * . [ 000610 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,2- dimethylpiperazine - 1 - carboxylate ( 5 ) [ 000611 ] To a mixture of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 586 mg , 1.508 mmol , 1 equiv ) and tert - butyl 4- ( 4- ( 4- bromo - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) -3 - fluorophenyl ) -2,2 - dimethylpiperazine - 1- carboxylate ( 800 mg , 1.508 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl( 107 mg , 0.151 mmol , 0.1 equiv ) and CsF ( 458 mg , 3.016 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) . The crude product was further purified by trituration with EtOAc to afford tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- - 517 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,2- dimethylpiperazine - 1 - carboxylate ( 250 mg , 23.29 % ) as a white solid . LCMS : C35H40F3N7O4S requires : 711.3 , found : m / z = 712.4 [ M + H ] * . [ 000612 ] Step - 5 : Synthesis of N- ( 3- { 1- [ 4- ( 3,3 - dimethylpiperazin - 1 - yl ) -2- fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2,5 - difluorophenyl ) pyrrolidine - 1- sulfonamide TFA salt ( 6 ) [ 000613 ] To a mixture of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,2- dimethylpiperazine - 1 - carboxylate ( 250 mg , 0.351 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under vacuum to afford N- ( 3- ( 1- ( 4- ( 3,3- dimethylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 219 mg , crude ) as a yellow solid . LCMS : C30H32F3N7O2S requires : 611.2 , found : m / z = 612.4 [ M + H ] * . ' H NMR ( 4MHz , Methanol - d4 ) § 8.78 – 8.70 ( m , 2H ) , 8.40 – 8.35 ( m , 1H ) , 8.12 – 8.05 ( m , 2H ) , 7.88 – 7.79 ( m , 1H ) , 7.45 – 7.36 ( m , 1H ) , 7.14 – 7.01 ( m , 3H ) , 3.60 – 3.53 ( m , 2H ) , 3.48 – 3.44 ( m , 2H ) , 3.42 ( s , 2H ) , 3.33 – 3.30 ( m , 3H ) , 1.96 – 1.84 ( m , 5H ) , 1.53 ( s , 6H ) . [ 000614 ] - - Synthesis of N- ( 2,5 - difluoro - 3- ( 1- ( 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide TFA salt ( 5 ) Br NH Br- ' N ' NaH , THF , 0 ° C Step - -Boc Br LL F IZ = S = 2niP₂B , Pd ( dppf ) ₂lC , dioxane , KOAc , 90 ° C Step - ﻢﻟا O = 0 = O = S = ' F N - N TFA , 0 ° C , 1 h Pd ( amphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C 2 h N - N Step - Boc Step - -NH OH -518- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000615 ] Step - 1 : Synthesis difluorophenyl ) cyclopentanesulfonamide ( 2 ) [ 000616 ] of N- ( 3 - bromo - 2,5- To a mixture of NaH ( 1.08 g , 28.8454 mmol , 2 equiv , 60 % ) in THF ( 50 mL ) was added 3 - bromo - 2,5 - difluoroaniline ( 3 g , 14.4227 mmol , 1 equiv ) . The resulting mixture was stirred for one hour at 0 ° C under a nitrogen atmosphere . To the above mixture was added cyclopentanesulfonyl chloride ( 4.86 g , 28.845 mmol , 2 equiv ) at 0 ° C . The resulting mixture was then warmed and stirred at room temperature overnight under a nitrogen atmosphere . The reaction was then quenched by the addition of water at 0 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : DCM ( 1 : 3 ) to afford N- ( 3 - bromo - 2,5- difluorophenyl ) cyclopentanesulfonamide ( 639 mg , 13.02 % ) as an off - white solid . LCMS : C11H12BrF2NO2S requires : 340.0 , found : m / z = 341.1 [ M - H ] ‍ . [ 000617 ] Step - 2 : Synthesis of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 3 ) [ 000618 ] To a mixture of N- ( 3 - bromo - 2,5 - difluorophenyl ) cyclopentanesulfonamide ( 6mg , 1.878 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 953 mg , 3.754 mmol , 2 equiv ) in dioxane ( 10 mL ) was added KOAc ( 369 mg , 3.754 mmol , 2 equiv ) and Pd ( dppf ) C12 ( 137 mg , 0.188 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] cyclopentanesulfonamide ( 620 mg , crude ) as a black oil . LCMS : C17H24BF2NO4S requires : 387.1 , found : m / z = 388.2 [ M + H ] * . [ 000619 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 4 ) [ 000620 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenylpiperazine - 1 - carboxylate ( 700 mg , 1.3933 mmol , 1 equiv ) and N- [ 2,5 - difluoro- 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 540 mg , 1.3933 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 98 mg , 0.139 mmol , 0.1 equiv ) and CsF ( 424 mg , 2.79 mmol , 2 equiv ) in O₂H ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then -519- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3- cyclopentanesulfonamido - 2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenylpiperazine - 1 - carboxylate ( 192 mg , 20.29 % ) as an off - white solid . LCMS : C34H37F3N6O4S requires : 682.3 , found : m / z = 683.1 [ M + H ] * . [ 000621 ] Step - 4 : Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 5 ) [ 000622 ] A mixture of tert - butyl 4- { 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 1mg , 0.281 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was concentrated under reduced pressure and then lyophilized . This resulted in N- ( 2,5 - difluoro- 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid slat ( 161 mg , crude ) as a yellow solid . LCMS : C29H29F3N6O2S requires : 582.2 , found : m / z = 583.3 [ M + H ] * . [ 000623 ] Synthesis of N- ( 2,5 - difluoro - 3- ( 1- ( 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) cyclohexanesulfonamide TFA salt ( 5 ) Br NH Br = ﻱ = NaH , THF , 0 ° C Br Step - Boc Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - LL F 0 = 5 = IZ 0 = 5 = ✓ 2niP₂B , Pd ( dppf ) Cl2 , dioxane , KOAc , 90 ° C Step - TFA 0 ° C , 1 h N - N F [ 000624 ] Step - 1 : Synthesis difluorophenyl ) cyclohexanesulfonamide ( 2 ) Step - Boc ﻝا ד . IZ = 5 = O = 5 = N - N OH -NH of N- ( 3 - bromo - 2,5- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000625 ] To a mixture of NaH ( 1.26 g , 33.653 mmol , 2 equiv , 60 % ) in THF ( 60 mL ) was added 3 - bromo - 2,5 - difluoroaniline ( 3.5 g , 16.826 mmol , 1 equiv ) . The resulting mixture was stirred for one hour at 0 ° C under a nitrogen atmosphere . To the above mixture was added cyclohexanesulfonyl chloride ( 6.18 g , 33.653 mmol , 2 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere . The reaction was then quenched by the addition of water at 0 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : DCM ( 1 : 3 ) to afford N- ( 3 - bromo - 2,5 - difluorophenyl ) cyclohexanesulfonamide ( 1.02 g , 17.1 % ) as an off - white solid . LCMS : C12H14BrF2NO2S requires : 353.0 , found : m / z = 354.4 [ M- H ] ‍ . [ 000626 ] Step - 2 : Synthesis of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] cyclohexanesulfonamide ( 3 ) [ 000627 ] To a mixture of N- ( 3 - bromo - 2,5 - difluorophenyl ) cyclohexanesulfonamide ( 8mg , 1.878 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( 953 mg , 3.754 mmol , 2 equiv ) in dioxane ( 10 mL ) was added KOAC ( 369 mg , 3.754 mmol , 2 equiv ) and Pd ( dppf ) ₂lC ( 137 mg , 0.188 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] cyclohexanesulfonamide ( 650 mg , crude ) as a black oil . LCMS : C18H26BF2NO4S requires : 387.1 , found : m / z = 388.2 [ M + H ] * [ 000628 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- ( 4- ( 3- ( cyclohexanesulfonamido ) -2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) -3 - fluorophenyl ) piperazine - 1- carboxylate ( 4 ) [ 000629 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl } piperazine - 1 - carboxylate ( 751 mg , 1.495 mmol , 1 equiv ) and N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclohexanesulfonamide ( 600 mg , 1.4mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 105 mg , 0.150 mmol , 0.equiv ) and CSF ( 454 mg , 2.99 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 4- ( 4- ( 3- ( cyclohexanesulfonamido ) -2,5- -521- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) -3 - fluorophenyl ) piperazine - 1 - carboxylate ( 188 mg , 18 % ) as an off - white solid . LCMS : C35H39F3N6O4S requires : 696.3 , found : m / z 697.5 [ M + H ] + . [ 000630 ] = Step - 4 : Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) cyclohexanesulfonamide trifluoroacetic acid salt ( 5 ) [ 000631 ] A mixture of tert - butyl 4- ( 4- ( 4- ( 3- ( cyclohexanesulfonamido ) -2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) -3 - fluorophenyl ) piperazine - 1 - carboxylate ( 188 mg , 0.27 mmol , 1 equiv ) in TFA ( 4 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and then lyophilized . This resulted in N- ( 2,5 - difluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) cyclohexanesulfonamide trifluoroacetic acid salt ( 177 mg , crude ) as a yellow solid . LCMS : C30H31F3N6O2S requires : 596.2 , found : m / z = 597.2 [ M + H ] * . [ 000632 ] Synthesis of N- ( 2,5 - difluoro - 3- ( 1- ( 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide TFA salt ( 5 ) Br NH Br 0 = 5 = NaH , THF , 0 ° C Br Step - Boc Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - [ 000633 ] Step - 1 : LL = 5 = IZ O = 5 = ﻢﻴﻟاﺩ 2niP₂B , Pd ( dppf ) ₂lC , dioxane , KOAc , 90 ° C Step - F.

LL IZ = 5 = N TFA , 0 ° C , 1 h N - N N - N OH Synthesis Step - Boc of -NH N- ( 3 - bromo - 2,5- difluorophenyl ) cyclopentanesulfonamide ( 2 ) [ 000634 ] To a mixture of NaH ( 1.08 g , 28.8454 mmol , 2 equiv , 60 % ) in THF ( 50 mL ) was added 3 - bromo - 2,5 - difluoroaniline ( 3 g , 14.4227 mmol , 1 equiv ) . The resulting mixture was stirred for one hour at 0 ° C under a nitrogen atmosphere . To the above mixture was added -522- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT cyclopentanesulfonyl chloride ( 4.86 g , 28.845 mmol , 2 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere . The reaction was then quenched by the addition of water at 0 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : DCM ( 1 : 3 ) to afford N- ( 3 - bromo - 2,5 - difluorophenyl ) cyclopentanesulfonamide ( 639 mg , 13.02 % ) as an off - white solid . LCMS : C11H12BrF2NO2S requires : 340.0 , found : m / z = 341.[ M - H ] . [ 000635 ] Step - 2 : Synthesis of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 3 ) [ 000636 ] To a mixture of N- ( 3 - bromo - 2,5 - difluorophenyl ) cyclopentanesulfonamide ( 6mg , 1.878 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 953 mg , 3.754 mmol , 2 equiv ) in dioxane ( 10 mL ) was added KOAc ( 369 mg , 3.754 mmol , 2 equiv ) and Pd ( dppf ) Cl2 ( 137 mg , 0.188 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] cyclopentanesulfonamide ( 620 mg , crude ) as a black oil . LCMS : C17H24BF2NO4S requires : 387.1 , found : m / z = 388.2 [ M + H ] * . in [ 000637 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 4 ) [ 000638 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenyl } piperazine - 1 - carboxylate ( 800 mg , 1.593 mmol , 1 equiv ) and N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 617 mg , 1.5933 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 112 mg , 0.1mmol , 0.1 equiv ) and CSF ( 486 mg , 3.186 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3- cyclopentanesulfonamido - 2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenyl } piperazine - 1 - carboxylate_ ( 210 mg , 19.3 % ) as an off - white solid . LCMS : C34H37F3N6O4S requires : 682.3 , found : m / z = 683.3 [ M + H ] * . -523- 1100573566 5 AMERICAS [ 000639 ] Step - 4 : Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 2,5 - difluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 5 ) [ 000640 ] A mixture of tert - butyl 4- { 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate_ ( 2mg , 0.307 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and then lyophilized . This resulted in N- ( 2,5- difluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 160 mg , crude ) as a yellow solid . LCMS : C29H29F3N6O2S requires : 582.2 , found : m / z = 583.3 [ M + H ] * . [ 000641 ] Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide TFA salt ( 3 ) 0 Cl B LL F CI 0 = S = IN = S = Br- F Boc N N.

Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - N TFA , 0 ° C , 1 h N - N -F Step - N -N Cl = S = F. N - N OH F F N -NH [ 000642 ] Step - 1 : Boc Synthesis of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3- cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenylpiperazine - 1 - carboxylate ( 2 ) -524- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000643 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenyl } piperazine - 1 - carboxylate ( 996 mg , 1.982 mmol , 1 equiv ) and N- [ 5 - chloro - 2- fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 8mg , 1.982 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2C12 ( 140 mg , 0.1mmol , 0.1 equiv ) and CSF ( 606 mg , 3.964 mmol , 2 equiv ) in O₂H ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3- cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenyl } piperazine - 1 - carboxylate ( 350 mg , 25.3 % ) as an off - white solid . LCMS : C34H37C1F2N6O4S requires : 698.2 , found : m / z = 699.3 [ M + H ] * . [ 000644 ] Step - 2 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 3 ) [ 000645 ] A mixture of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3 - cyclopentanesulfonamido - 2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 3mg , 0.5 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and then lyophilized . This resulted in N- ( 5- chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 276 mg , crude ) as a yellow solid . LCMS : C29H29ClF2N6O2S requires : 598.2 , found : m / z = 599.2 [ M + H ] * . [ 000646 ] Synthesis of ( R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- ( 2 - fluoro - 4- ( 3 - methylpiperazin- - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide TFA salt ( 3 ) -525- 1100573566 5 AMERICAS N CI F N - N IN = S = CI 0 = 8 = 0 + Attorney Docket No .: 121843.002NU - 3200 PCT Boc N N Br- ' N Pd ( AMphos ) 2Cl2 , CSF , dioxane , H2O , 90 ° C , 2 h Step - TFA , 0 ° C , 1h Step - F N -N Boc [ 000647 ] Step - 1 : Synthesis Cl = 8 = .N . IN N N - N F F OH F N -NH of tert - butyl ( 2R ) -4-4- [ 4- ( 5 - chloro - 3- cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl ) -2 - methylpiperazine - 1 - carboxylate ( 2 ) [ 000648 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl ) -2 - methylpiperazine - 1 - carboxylate ( 1.0 g , 1.936 mmol , 1 equiv ) and N- [ 5- chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] cyclopentanesulfonamide ( 782 mg , 1.936 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 136 mg , 0.194 mmol , 0.1 equiv ) and CsF ( 592 mg , 3.872 mmol , equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl ( 2R ) -4- { 4- [ 4- ( 5 - chloro - 3 - cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -2 - methylpiperazine - 1 - carboxylate ( 400 mg , 28.96 % ) as an off - white solid . LCMS : C35H39C1F2N6O4S requires : 712.2 , found : m / z = 713.4 [ M + H ] * . -526- 1100573566 5 AMERICAS [ 000649 ] Step - 2 : Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ) phenyl ] cyclopentanesulfonamide trifluoroacetic acid salt ( 3 ) [ 000650 ] A mixture of tert - butyl ( 2R ) -4- { 4- [ 4- ( 5 - chloro - 3 - cyclopentanesulfonamido - 2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -2 - methylpiperazine - 1- carboxylate ( 400 mg , 0.561 mmol , 1 equiv ) in TFA ( 6 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and then lyophilized . This resulted N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] phenyl } -3- = 613.( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] cyclopentanesulfonamide trifluoroacetic acid salt ( 321 mg , crude ) as a yellow solid . LCMS : C30H31C1F3N6O2S requires : 612.2 , found : m / z [ M + H ] + . [ 000651 ] Synthesis of ( R ) -N- ( 2,5 - difluoro - 3- ( 1- ( 2 - fluoro - 4- ( 3 - methylpiperazin - 1- yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide TFA salt ( 3 ) F. 0 - B F H O = S = C IZ F O = S = N N - N F Br EN -Boc Pd ( AMphos ) 2Cl2 , CSF , dioxane , H2O , 90 ° C , 2 h Step - TFA , 0 ° C , 1 h N -N Boc Step - F. = S = IN ✓ N N - N F F OH F -NH -527- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000652 ] Step - 1 : Synthesis of tert - butyl ( 2R ) -4- { 4- [ 4- ( 3 - cyclopentanesulfonamido- 2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -2 - methylpiperazine - 1- carboxylate ( 2 ) [ 000653 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl ) -2 - methylpiperazine - 1 - carboxylate ( 900mg , 1.743 mmol , 1 equiv ) and N- [ 2,5- difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 675 mg , 1.743 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 122 mg , 0.174 mmol , 0.1 equiv ) and CsF ( 533 mg , 3.486 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl ( 2R ) -4- { 4- [ 4- ( 3- cyclopentanesulfonamido - 2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } - - methylpiperazine - 1 - carboxylate ( 208 mg , 17.13 % ) as an off - white solid . LCMS : C35H39F3N6O4S requires : 696.3 , found : m / z = 697.7 [ M + H ] * . [ 000654 ] Step - 2 : Synthesis of N- [ 2,5 - difluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ) phenyl ] cyclopentanesulfonamide ; trifluoroacetic acid salt ( 3 ) [ 000655 ] A mixture of tert - butyl ( 2R ) -4- { 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -2 - methylpiperazine - 1- carboxylate ( 208 mg , 0.2985 mmol , 1 equiv ) in TFA ( 4 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and then lyophilized . This resulted N- [ 2,5 - difluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ] cyclopentanesulfonamide trifluoroacetic acid salt ( 171 mg , crude ) as a yellow solid . LCMS : C30H31F4N6O2S requires : 596.2 , found : m / z = 597.4 [ M + H ] * . [ 000656 ] Synthesis of N- ( 3- ( 1- ( 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ) -2,5 - difluorophenyl ) cyclopentanesulfonamide TFA salt ( 7 ) -528- 1100573566 5 AMERICAS F LL F Br NH N Br Attorney Docket No .: 121843.002NU - 3200 PCT 3OC₂K , DMSO F NOF NOStep - ﻢﻟا LL O = S = IZ F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - HN - S HN - S Fe , NH4Cl , EtOH , AcOH , F F- H2O , 80 ° C , 0.5 h -F F Step - NONH N - Boc HN - S TSOH , NaNO2 , KI , ACN , O₂H , 0 ° C F HN -F O Step - 5 F HN - S D = S = O -F F -N . 6 F ' N ' .N 、 Boc TFA , 0 ° C , 1 h Pd - PEPPSI - IHeptCI , 3OC₂sC , dioxane , 90 ° C , 4 h Step - HN - S F.

Step - -N LL OH NH [ 000657 ] yl ] pyridine ( 2 ) Step - 1 : Synthesis of 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4 - nitrophenyl ) pyrazol - 3- [ 000658 ] To a mixture of 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 29 g , 129.43 mmol , equiv ) in DMSO ( 200 mL ) was added K2CO3 ( 27 g , 194.1 mmol , 1.5 equiv ) and 1,2,3 - trifluoro- - nitrobenzene ( 27.5 g , 155.32 mmol , 1.2 equiv ) . The resulting mixture was stirred at room temperature for 6 h . The resulting mixture was then extracted with CH2Cl2 . The combined -529- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4- nitrophenyl ) pyrazol - 3 - yl ] pyridine ( 44 g , 89.2 % ) as a white solid . LCMS : C14H7BrF2N4Orequires : 379.9 , found : m / z = 380.9 [ M + H ] + . [ 000659 ] Step - 2 : Synthesis of N- { 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2,5 - difluorophenylcyclopentanesulfonamide ( 3 ) [ 000660 ] To a mixture of 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4 - nitrophenyl ) pyrazol - 3- yl ] pyridine ( 9.0 g , 23.61 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 9.1 g , 23.61 mmol , 1 equiv ) in dioxane ( 100 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 1.63 g , 2.361 mmol , 0.1 equiv ) and CSF ( 7.g , 47.22 mmol , 2 equiv ) in H2O ( 20 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford N- { 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2,5- difluorophenyl } cyclopentanesulfonamide ( 5.3 g , 40 % ) as a yellow solid . LCMS : C25H19F4N5O4S requires : 561.1 , found : m / z = 562.1 [ M + H ] * . [ 000661 ] Step - 3 : Synthesis of N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2,5 - difluorophenyl } cyclopentanesulfonamide ( 4 ) [ 000662 ] A mixture of Fe ( 2.64 g , 47.2 mmol , 5 equiv ) and NH4Cl ( 49 mg , 0.944 mmol , 0.1 equiv ) in AcOH ( 2 mL ) and H2O ( 10 mL ) was stirred at 80 ° C for 5 min . To the above mixture was added N- { 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2,5- difluorophenyl } cyclopentanesulfonamide ( 5.3 g , 9.439 mmol , 1 equiv ) in EtOH ( 100 mL ) . The resulting mixture was stirred at 80 ° C for 0.5 h . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] -2,5 - difluorophenyl } cyclopentanesulfonamide ( 3.7 g , 73.7 % ) as a yellow solid . LCMS : C25H19F4N5O2S requires : 531.1 , found : m / z = 532.2 [ M + H ] * . [ 000663 ] Step - 4 : Synthesis of N- { 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2,5 - difluorophenyl } cyclopentanesulfonamide ( 5 ) [ 000664 ] To a mixture of N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol- - yl ] -2,5 - difluorophenyl } cyclopentanesulfonamide ( 3.7 g , 6.961 mmol , 1 equiv ) and TsOH -530- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 3.64 g , 20.88 mmol , 3 equiv ) in ACN ( 30 mL ) was added NaNO2 ( 1.46 g , 20.88 mmol , equiv ) in H2O ( 3 mL ) and KI ( 4.0 g , 17.40 mmol , 2.5 equiv ) at 0 ° C . The resulting mixture was stirred at 0 ° C for 10 min and was then warmed to room temperature . The mixture was stirred for additional 30 min at room temperature . The mixture was then basified to pH = 8 with saturated aqueous Na2CO3 . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 2 ) to afford N- { 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2,5 - difluorophenyl } cyclopentanesulfonamide ( 770 mg , 17.2 % ) as a brown solid . LCMS : C25H19F4IN4O2S requires : 642.0 , found : m / z = 643.7 [ M + H ] * . [ 000665 ] Step - 5 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3,5 - difluorophenyl } piperazine - 1- carboxylate ( 6 ) [ 000666 ] To a mixture of N- { 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4 - yl ) pyrazol- - yl ] -2,5 - difluorophenyl } cyclopentanesulfonamide ( 770 mg , 1.199 mmol , 1 equiv ) and tert- butyl piperazine - 1 - carboxylate ( 558 mg , 2.998 mmol , 2.5 equiv ) in dioxane ( 10 mL ) was added Pd - PEPPSI - IHeptCl ( 116 mg , 0.12 mmol , 0.1 equiv ) and Cs2CO3 ( 976 mg , 2.998 mmol , 2.equiv ) . The resulting mixture was stirred at 90 ° C for 4 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- { 4- [ 4- ( 3- cyclopentanesulfonamido - 2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3,5- difluorophenyl } piperazine - 1 - carboxylate ( 320 mg , 38.1 % ) as a brown solid . LCMS : C34H36F4N6O4S requires : 700.2 , found : m / z = 701.4 [ M + H ] * . . [ 000667 ] Step - 6 : Synthesis of N- ( 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2,5 - difluorophenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 7 ) [ 000668 ] A mixture of tert - butyl 4- [ 4- [ 4- ( 3 - cyclopentanesulfonamido - 2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3,5 - difluorophenyl } piperazine - 1 - carboxylate ( 320 mg , 0.457 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The product was lyophilized to afford N- ( 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2,5- -531- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT difluorophenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 210 mg , crude ) as a light = yellow solid . LCMS : C29H28F4N6O4S requires : 600.2 , found : m / z = 601.2 [ M + H ] * . [ 000669 ] Synthesis of N- ( 5 - chloro - 3- ( 1- ( 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) cyclopentanesulfonamide TFA salt ( 7 ) Br .

NO ﻢﻟا F 0 = S = Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - HN- CI- HN - S HN - S TsOH , NaNO2 , KI , ACN , O₂H , 0 ° C N - N CI- HN- = S = NHStep - 6 F ' N ' Boc F HN - S CI- TFA , 0 ° C , 1 h Fe , NH4Cl , EtOH , AcOH , O₂H , 80 ° C , 0.5 h Step - NO HN N - Boc Pd - PEPPSI - IHeptCl , Cs2CO3 , dioxane , 90 ° C Step - OH F Step - 7 F .NH [ 000670 ] Step - 1 : Synthesis of N- ( 5 - chloro - 3- ( 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) cyclopentanesulfonamide ( 3 ) [ 000671 ] To a mixture of 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4 - nitrophenyl ) pyrazol - 3- yl ] pyridine ( 9.0 g , 23.61 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 9.53 g , 23.61 mmol , 1 equiv ) in dioxane ( 100 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 1.64 g , 2.361 mmol , 0.1 equiv ) and CSF ( 7.g , 47.22 mmol , 2 equiv ) in H2O ( 20 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford N- ( 5 - chloro - 3- ( 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- -532- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) -2 - fluorophenyl ) cyclopentanesulfonamide_ ( 6.1 g , 44.7 % ) as a yellow solid . LCMS : C25H19C1F3N5O4S requires : 577.1 , found : m / z = 578.1 [ M + H ] * . [ 000672 ] Step - 2 : Synthesis of N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -5 - chloro - 2 - fluorophenyl } cyclopentanesulfonamide ( 4 ) [ 000673 ] A mixture of Fe ( 2.94 g , 52.77 mmol , 5 equiv ) and NH4Cl ( 55 mg , 1.055 mmol , 0.1 equiv ) in AcOH ( 2 mL ) and H2O ( 10 mL ) was stirred at 80 ° C for 5 min . To the above mixture was added N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] -2 - fluorophenyl } cyclopentanesulfonamide ( 6.1 g , 10.55 mmol , 1 equiv ) in EtOH ( 100 mL ) . The resulting mixture was stirred at 80 ° C for 0.5 h . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -5 - chloro - 2 - fluorophenyl } cyclopentanesulfonamide ( 4.05 g , % ) as a yellow solid . LCMS : C25H21CIF3N5O2S requires : 547.1 , found : m / z = 548.2 [ M + H ] * . [ 000674 ] Step - 3 : Synthesis of N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 5 ) [ 000675 ] To a mixture of N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol- - yl ] -5 - chloro - 2 - fluorophenyl } cyclopentanesulfonamide ( 4.0 g , 7.3 mmol , 1 equiv ) and TsOH ( 3.82 g , 21.9 mmol , 3 equiv ) in ACN ( 30 mL ) was added NaNO2 ( 1.53 g , 21.9 mmol , 3 equiv ) in O₂H ( 3 mL ) and KI ( 3.1 g , 18.25 mmol , 2.5 equiv ) at 0 ° C . The resulting mixture was stirred at 0 ° C for 10 min and then the reaction was warmed to room temperature . The mixture was stirred for additional 30 min at room temperature . The mixture was basified to pH = 8 with saturated aqueous Na2CO3 . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 2 ) to afford N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4- iodophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } cyclopentanesulfonamide ( 982 mg , 20.4 % ) as a brown solid . LCMS : C25H19C1F3IN4O2S requires : 657.9 , found : m / z = 658.[ M + H ] + . [ 000676 ] Step - 4 : Synthesis of tert - butyl 4-4- [ 4- ( 5 - chloro - 3- cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3,5- difluorophenyl } piperazine - 1 - carboxylate ( 6 ) -533- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000677 ] To a mixture of N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } cyclopentanesulfonamide ( 982 mg , 1.49 mmol , 1 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 694 mg , 3.725 mmol , 2.5 equiv ) in dioxane ( 10 mL ) was added Pd - PEPPSI - IHeptCl ( 145 mg , 0.149 mmol , 0.1 equiv ) and Cs2CO3 ( 1.21 g , 3.725 mmol , 2.5 equiv ) . The resulting mixture was stirred at 90 ° C for 4 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- { 4- [ 4- ( 5- chloro - 3 - cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3,5- difluorophenylpiperazine - 1 - carboxylate ( 451 mg , 42.2 % ) as a brown solid . LCMS : C34H36C1F3N6O4S requires : 716.2 , found : m / z = 717.3 [ M + H ] * . [ 000678 ] Step - 5 : Synthesis of N- ( 5 - chloro - 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) cyclopentanesulfonamide TFA salt ( 7 ) [ 000679 ] A mixture of afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3 - cyclopentanesulfonamido - 2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3,5 - difluorophenyl } piperazine - 1 - carboxylate ( 451 mg , 0.6288 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated and lyophilized to afford N- ( 5 - chloro - 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2- fluorophenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 310 mg , crude ) as a light yellow solid . LCMS : C29H28CIF3N6O2S requires : 616.2 ; found : m / z = 617.2 [ M + H ] + . [ 000680 ] Synthesis of ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine TFA salt ( 6 ) NH F OH F F -N NH -534- 1100573566 5 AMERICAS B CI- to O = 5 = -Br HO OH PdAMPHOS , CSF , dioxane , O₂H , 90 ° C , 1 h Step - HN N - Boc Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - a N - Boc NH F CI- Br Attorney Docket No .: 121843.002NU - 3200 PCT N - Boc 2niP₂B Pd2 ( dba ) 3 , X - Phos , KOACC , methoxycyclopentane , 110 ° C , 2 h Step - NH Br N - Boc Cu ( OAc ) 2 , pyr , molecular sieves ( 4A ) , 100 ° C Step - OH NH TFA , DCM , 0 ° C N - Boc Step - N NH [ 000681 ] carboxylate ( 2 ) [ 000682 ] Step - 1 : Synthesis of tert - butyl 4- ( 4 - chloro - 2 - fluorophenyl ) piperazine - 1- To a mixture of 1 - bromo - 4 - chloro - 2 - fluorobenzene ( 3 g , 14.324 mmol , 1 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 2.67 g , 14.324 mmol , 1 equiv ) in toluene ( 60 mL ) was added Pd2 ( dba ) 3 ( 131 mg , 0.143 mmol , 0.01 equiv ) , BINAP ( 178 mg , 0.286 mmol , 0.02 equiv ) , and t - BuONa ( 1.93 g , 20.054 mmol , 1.4 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - chloro - 2 - fluorophenyl ) piperazine - 1 - carboxylate ( 2 g , 39.92 % ) as an off - white solid . LCMS : C15H20CIFN2O2 requires : 314.1 , found : m / z = 315.[ M + H ] + . [ 000683 ] Step - 2 : Synthesis of tert - butyl 4- [ 2 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3 ) [ 000684 ] To a mixture of tert - butyl 4- ( 4 - chloro - 2 - fluorophenyl ) piperazine - 1 - carboxylate ( 2 g , 6.353 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 2.42 g , 9.529 mmol , 1.5 equiv ) in methoxycyclopentane ( 30 mL ) was added Pd2 ( dba ) 3 ( 175 mg , 0.191 mmol , 0.03 equiv ) , X - Phos ( 182 mg , 0.381 mmol , -535- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 0.06 equiv ) , and KOAc ( 1.87 g , 19.059 mmol , 3 equiv ) . The resulting mixture was stirred at 110 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- [ 2 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] piperazine - 1 - carboxylate ( 2.5 g , 87.16 % ) as a brown oil . LCMS : C21H32BFN2Orequires : 406.2 , found : m / z = 407.2 [ M + H ] * . [ 000685 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] - - fluorophenyl } piperazine - 1 - carboxylate ( 4 ) [ 000686 ] To a mixture of tert - butyl 4- [ 2 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 2.5 g , 6.153 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 2.07 g , 9.229 mmol , 1.5 equiv ) in pyridine ( 20 mL ) was added Cu ( OAc ) 2 ( 2.24 g , 12.306 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 2.07 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 20 : 1 ) to afford tert - butyl 4- { 4- [ 4 - bromo- 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 2 g , 51.76 % ) as a brown semi - solid . LCMS : C23H25BrFN5O2 requires : 501.1 , found : m / z = 502.1 [ M + H ] * . [ 000687 ] Step - 4 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 5 ) [ 000688 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenylpiperazine - 1 - carboxylate ( 1.5 ) g , 2.986 mmol , 1 equiv ) and 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenylboronic acid ( 824 mg , 2.986 mmol , 1 equiv ) in dioxane ( 10 mL ) was added PdAMPHOS ( 423 mg , 0.597 mmol , 0.2 equiv ) and CSF ( 9mg , 5.972 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by C18 reverse phase column chromatography with ACN : O₂H ( 2 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 5mg , 24.33 % ) as an off - white solid . LCMS : C32H37F2N7O4S requires : 653.3 , found : m / z = 654.[ M + H ] + . -536- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000689 ] Step - 5 : Synthesis of ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 6 ) [ 000690 ] To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 5mg , 0.903 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was warmed and stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure . The product was then lyophilized under vacuum . This resulted in ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ) sulfamoyl ] amine_trifluoroacetic acid salt ( 344.1 mg , crude ) as a yellow solid . LCMS : C27H29F2N7O2S requires : 553.2 , found : m / z = 554.2 [ M + H ] * . ' H NMR ( 400 MHz , CD3OD ) 8 8.79 – 8.73 ( m , 2H ) , 8.66 – 8.62 ( m , 1H ) , 8.20 – 8.14 ( m , 2H ) , 7.91 – 7.83 ( m , 1H ) , 7.83 7.76 ( m , 1H ) , 7.66 - 7.57 ( m , 1H ) , 7.38 - 7.27 ( m , 3H ) , 3.50 -3.39 ( m , 8H ) , 3.33 - 3.( m , 2H ) , 2.86 – 2.82 ( m , 3H ) , 1.18 – 1.10 ( m , 3H ) . - [ 000691 ] Synthesis of ethylmethyl ( 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 6 ) COH NH F F -N NH -537- 1100573566 5 AMERICAS B HO OH PdAMPHOS , CSF , dioxane , O₂H , 90 ° C , 1 h Step - HN N - Boc -Br Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - Br NH N - Boc Cu ( OAc ) 2 , pyr , molecular sieves ( 4A ) , 100 ° C F NH Step - Attorney Docket No .: 121843.002 N - Boc 2niP₂B NU - 3200 PCT Pd2 ( dba ) 3 , X - Phos , KOAC methoxycyclopentane , 110 ° C , 2 h Step - Br N - Boc OH NH TFA , DCM , 0 ° C N - Boc Step - NH [ 000692 ] carboxylate ( 2 ) [ 000693 ] Step - 1 : Synthesis of tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) piperazine - 1- To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 3 g , 14.324 mmol , 1 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 2.67 g , 14.324 mmol , 1 equiv ) in toluene ( 60 mL ) was added Pd2 ( dba ) 3 ( 131 mg , 0.143 mmol , 0.01 equiv ) , BINAP ( 178 mg , 0.286 mmol , 0.02 equiv ) , and t - BuONa ( 1.93 g , 20.054 mmol , 1.4 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) piperazine - 1 - carboxylate ( 2 g , 39.92 % ) as an off - white solid . LCMS : C15H20C1FN2O2 requires : 314.1 , found : m / z 315.[ M + H ] + . = [ 000694 ] Step - 2 : Synthesis of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3 ) [ 000695 ] To a mixture of tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) piperazine - 1 - carboxylate ( 2 g , 6.353 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( 2niP₂B ) ( 2.42 g , 9.529 mmol , 1.5 equiv ) in methoxycyclopentane ( 30 mL ) was added Pd2 ( dba ) 3 ( 175 mg , 0.191 mmol , 0.03 equiv ) , X - Phos ( 182 mg , 0.381 mmol , 0.06 equiv ) and KOAc ( 1.87 g , 19.059 mmol , 3 equiv ) . The resulting mixture was stirred at -538- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 110 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] piperazine - 1 - carboxylate ( 1.5 g , 46.49 % ) as a brown oil . LCMS : C21H32BFN2Orequires : 406.2 , found : m / z = 407.2 [ M + H ] * . = [ 000696 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) -3 - fluorophenyl ) piperazine - 1 - carboxylate ( 4 ) [ 000697 ] To a mixture of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 1.5 g , 3.692 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.24 g , 5.538 mmol , 1.5 equiv ) in pyridine ( 20 mL ) was added Cu ( OAc ) 2 ( 1.34 g , 7.384 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 1.5 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 20 : 1 ) to afford tert - butyl 4- ( 4- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) -3 - fluorophenyl ) piperazine - 1 - carboxylate ( 500 mg , 22.91 % ) as a brown semi - solid . LCMS : C23H25BrFN5O2 requires : 501.1 , found : m / z = 502.1 [ M + H ] * . [ 000698 ] Step - 4 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 5 ) [ 000699 ] To a mixture of tert - butyl 4- ( 4- ( 4 - bromo - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) -3- fluorophenyl ) piperazine - 1 - carboxylate ( 500 mg , 0.995 mmol , 1 equiv ) and 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenylboronic acid ( 275 mg , 0.995 mmol , 1 equiv ) in dioxane ( 10 mL ) was added PdAMPHOS ( 141 mg , 0.199 mmol , 0.2 equiv ) and CSF ( 302.1.990 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 1 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- mg , ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 450 mg , 55.33 % ) as a yellow solid . LCMS : C32H37F2N7O4S requires : 653.3 , found : m / z = 654.3 [ M + H ] * . [ 000700 ] Step - 5 : Synthesis of ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 6 ) -539- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000701 ] To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 4mg , 0.612 mmol , 1 equiv ) in DCM ( 3 mL ) was added TFA ( 1 mL ) at 0 ° C . The resulting mixture was warmed and stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure . The residue was purified by C18 reverse phase column chromatography with ACN : O₂H ( 0.5 % TFA ) ( 1 : 3 ) to afford ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 317.6 mg , 77.28 % ) as a yellow solid . LCMS : C27H29F2N7O2S requires : 553.2 , found : m / z 554.3 [ M + H ] * . H¹ NMR ( 400 MHz , DMSO - do ) 8 9.67 – 9.62 ( m , 1H ) , 8.85 8.81 ( m , 2H ) , 8.66 – 8.60 ( m , 2H ) , 8.46 – 8.41 ( m , 1H ) , 7.80 - 7.71 ( m , 1H ) , 7.57 - 7.– ( m , 2H ) , 7.54 – 7.45 ( m , 1H ) , 7.31 – 7.20 ( m , 2H ) , 7.20 – 7.12 ( m , 1H ) , 7.05 – 6.96 ( m , 1H ) , - == = = 3.55 3.48 ( m , 4H ) , 3.32 - 3.22 ( m , 4H ) , 3.13 -3.03 ( m , 2H ) , 2.70 – 2.66 ( m , 3H ) , 1.05 - 0.( m , 3H ) . [ 000702 ] Synthesis of N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 2R ) -2 - methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide trifluoroacetic acid salt ( 8 ) N N - N IZ TO = S = LL F F N- ( abs -NH OH -540- 1100573566 5 AMERICAS Br HN ( R ) Boc t - BuONa , Pd ( OAc ) 2 , [ P ( t - Bu ) 3 ] BF4 , toluene , 110 ° C Step - 2niP₂B , Pd ( dppf ) ₂lC , O - B . KOAc , dioxane , 80 ° C HO .B Step - O = S = OH F Pd ( AMPHOS ) ₂lC₂ , CSF , dioxane , O₂H , 90 ° C , 2 h Step - 0 = 8 = וו N - S = O Boc Attorney Docket No .: 121843.002NU - 3200 PCT Br tetrabutylammonium tribromide CHCl 3 , 0 ° C Boc Boc Step - TFA , DCM , 0 ° C Step - Br NH Br .

Cu ( OAc ) 2 , pyridine , molecular sieves 4A , 100 ° C Boc Step - Boc Na2CO3 , THF : O₂H : ACN , 50 ° C Step - = S = 0 · N - N OH ( abs -NH HN - S O = S = O H Boc [ 000703 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl ( 3R ) -3 - methyl - 4 - phenylpiperazine - 1- [ 000704 ] To a mixture of bromobenzene ( 2 g , 12.762 mmol , 1.2 equiv ) and tert - butyl ( 3R ) -3 - methylpiperazine - 1 - carboxylate ( 2.13 g , 10.635 mmol , 1 equiv ) in toluene ( 20 mL ) was added [ P ( t - Bu ) 3 ] BF4 ( 0.29 g , 0.851 mmol , 0.08 equiv ) , Pd ( OAc ) 2 ( 0.07 g , 0.319 mmol , 0.equiv ) , and t - BuONa ( 1.43 g , 14.889 mmol , 1.4 equiv ) . The resulting mixture was stirred at 110 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with - 541 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT PE : EtOAc ( 3 : 1 ) to afford tert - butyl ( 3R ) -3 - methyl - 4 - phenylpiperazine - 1 - carboxylate ( 2.5 g , 76.55 % ) as a yellow oil . LCMS : C16H24N2O2 requires : 276.2 , found : m / z = 277.2 [ M + H ] * . [ 000705 ] Synthesis Step - 2 : methylpiperazine - 1 - carboxylate ( 3 ) [ 000706 ] of tert - butyl ( 3R ) -4- ( 4 - bromophenyl ) -3- To a mixture of tert - butyl ( 3R ) -3 - methyl - 4 - phenylpiperazine - 1 - carboxylate ( 2.g , 8.684 mmol , 1 equiv ) in CHCl3 ( 50 mL ) was added tetrabutylammonium tribromide ( 4.g , 8.684 mmol , 1 equiv ) at 0 ° C . The resulting mixture was warmed and stirred at room temperature for 0.5 h . The resulting mixture was then extracted with CHCl3 . The combined organic layers were washed with water , dried over anhydrous Na2SO4 , filtered , and concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 3R ) -4- ( 4 - bromophenyl ) -3 - methylpiperazine- - carboxylate ( 2.5 g , 72.93 % ) as a light yellow oil . LCMS : C16H23BrN2O2 requires : 354.1 , found : m / z = 355.2 [ M + H ] * . [ 000707 ] Step - 3 : Synthesis of tert - butyl ( 3R ) -3 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 4 ) [ 000708 ] To a mixture of tert - butyl ( 3R ) -4- ( 4 - bromophenyl ) -3 - methylpiperazine - 1- carboxylate ( 2.47 g , 6.952 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 5.3 g , 20.856 mmol , 3 equiv ) in 1,4- dioxane ( 50 mL ) was added Pd ( dppf ) Cl2 ( 0.57 g , 0.7 mmol , 0.1 equiv ) and KOAc ( 1.36 g , 13.mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert- butyl ( 3R ) -3 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1- carboxylate ( 2.5 g , 80.44 % ) as a white solid . LCMS : C22H35BN2O4 requires : 402.3 , found : m / z = 403.2 [ M + H ] * . = [ 000709 ] Step - 4 : Synthesis of tert - butyl ( 3R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] phenyl - 3 - methylpiperazine - 1 - carboxylate ( 5 ) [ 000710 ] To a mixture of tert - butyl ( 3R ) -3 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 2.5 g , 6.214 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.95 g , 8.7 mmol , 1.4 equiv ) in pyridine ( 25 mL ) was added Cu ( OAc ) 2 ( 2.26 g , 12.428 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 2.5 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture -542- - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl ( 3R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl - 3 - methylpiperazine - 1 - carboxylate ( 2 g , 58.12 % ) as a light yellow solid . LCMS : C24H28BrN5O2 requires : 497.1 , found : m / z = 498.1 [ M + H ] * . [ 000711 ] Step - 5 : Synthesis of tert - butyl ( 3R ) -4- [ 4- ( 4- { 2 - fluoro - 3- [ N- ( propane - 1- sulfonyl ) -N - propane - 1 - sulfonamido ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -3- methylpiperazine - 1 - carboxylate ( 6 ) [ 000712 ] To a mixture of tert - butyl ( 3R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl - 3 - methylpiperazine - 1 - carboxylate ( 400 mg , 0.803 mmol , 1 equiv ) and 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N - propane - 1 - sulfonamido ] phenylboronic acid ( 884 mg , 2.408 mmol , equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 114 mg , 0.161 mmol , 0.2 equiv ) and CSF ( 244 mg , 1.605 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl ( 3R ) -4- [ 4- ( 4- { 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N- propane - 1 - sulfonamido ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -3 - methylpiperazine - 1- carboxylate ( 400 mg , 53.82 % ) as a dark yellow solid . LCMS : C36H45FN6O6S2 requires : 740.3 , found : m / z = 741.2 [ M + H ] * . [ 000713 ] Step - 6 : Synthesis of tert - butyl of tert - butyl ( 3R ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) -3 - methylpiperazine - 1- carboxylate ( 7 ) [ 000714 ] To a mixture of tert - butyl ( 3R ) -4- [ 4- ( 4- { 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N- propane - 1 - sulfonamido ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -3 - methylpiperazine - 1- carboxylate ( 400 mg , 0.54 mmol , 1 equiv ) in THF ( 10 mL ) and ACN ( 10 mL ) was added Na2CO3 ( 858 mg , 8.1 mmol , 15 equiv ) in H2O ( 10 mL ) . The resulting mixture was stirred at ° C overnight . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl ( 3R ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol- - yl ) phenyl ) -3 - methylpiperazine - 1 - carboxylate ( 310 mg , 78.79 % ) as a yellow solid . LCMS : C33H39FN6O4S requires : 634.3 , found : m / z = 635.2 [ M + H ] * . -543- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000715 ] Step - 7 : Synthesis of yl ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide acid salt ( 8 ) N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 2R ) -2 - methylpiperazin - 1- trifluoroacetic [ 000716 ] To a mixture of tert - butyl ( 3R ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) -3 - methylpiperazine - 1 - carboxylate ( 310 mg , 0.488 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for 2 h . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 2R ) -2- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide trifluoroacetic acid salt ( 309.0 mg , crude ) as a yellow solid . LCMS : C28H31FN6O2S requires : 534.2 , found : m / z = 535.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.78 – 8.72 ( m , 2H ) , 8.60 ( s , 1H ) , 8.24 – 8.17 ( m , 2H ) , 7.98 – 7.89 ( m , 2H ) , 7.65 – 7.56 ( m , 1H ) , 7.45 – 7.23 ( m , 4H ) , 4.16 – 4.08 ( m , 1H ) , 3.58 – 3.44 ( m , 3H ) , 3.41 – 3.34 ( m , 2H ) , 3.31 – 3.26 ( m , 1H ) , 3.– 3.11 ( m , 2H ) , 1.94 – 1.80 ( m , 2H ) , 1.21 – 1.15 ( m , 3H ) , 1.10 – 1.01 ( m , 3H ) . [ 000717 ] – - - Synthesis of N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 2S ) -2 - methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide trifluoroacetic acid salt ( 8 ) N H .N . = S = F OH N - N F F N- abs ) דיי. -NH -544- 1100573566 5 AMERICAS Br 111 ** Br HN- 11111 ( ( s ) N Br Boc t - BuONa , Pd ( OAc ) 2 , [ P ( t - Bu ) 3 ] BF4 , toluene , 110 ° C Step - 2niP₂B , Pd ( dppf ) Cl2 , KOAc , dioxane , 80 ° C Boc Step - N - N Na2CO3 , THF : H2O : ACN , ° C Step - -N Boc O = S = O HN - S Attorney Docket No .: 121843.002NU - 3200 PCT N -N Boc tetrabutylammonium tribromide CHCI 3,0 ° C Step - Boc ﻢﺤﻣﺩ ﻻا O - B .

O = S = .N . = 5 = F .B . HO OH Pd ( AMPHOS ) ₂lC2 , CsF , dioxane , O₂H , 90 ° C , 1 h Step - ' N ' N Boc Br NH Cu ( OAc ) 2 , pyridine , molecular sieves 4A , 100 ° C Step - O = $ = N - S = O || TFA , DCM , 0 ° C Step - ' N ' .N . Boc 0 = S = N - N OH *** Kabs -NH [ 000718 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl ( 3S ) -3 - methyl - 4 - phenylpiperazine - 1- [ 000719 ] To a mixture of bromobenzene ( 2.8 g , 17.975 mmol , 1.2 equiv ) and tert - butyl ( 3S ) -3 - methylpiperazine - 1 - carboxylate ( 3 g , 14.979 mmol , 1 equiv ) in toluene ( 30 mL ) was added [ P ( t - Bu ) 3 ] BF4 ( 348 mg , 1.198 mmol , 0.08 equiv ) , Pd ( OAc ) 2 ( 101 mg , 0.449 mmol , 0.equiv ) , and t - BuOK ( 2 g , 20.971 mmol , 1.4 equiv ) . The resulting mixture was stirred at 110 ° C -545- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT overnight under a nitrogen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl ( 3S ) -3- methyl - 4 - phenylpiperazine - 1 - carboxylate ( 3.5 g , 84.54 % ) as an off - white oil . LCMS : C16H24N2O2 requires : 276.2 , found : m / z = 277.2 [ M + H ] * . [ 000720 ] Synthesis Step - 2 : methylpiperazine - 1 - carboxylate ( 3 ) of tert - butyl ( 3S ) -4- ( 4 - bromophenyl ) -3- [ 000721 ] To a mixture of tert - butyl ( 3S ) -3 - methyl - 4 - phenylpiperazine - 1 - carboxylate ( 3.g , 12.664 mmol , 1 equiv ) in CHCl3 ( 40 mL ) was added tetrabutylammonium tribromide ( 6.g , 12.664 mmol , 1 equiv ) at 0 ° C . The resulting mixture was warmed and stirred at room temperature for 0.5 h . The resulting mixture was then extracted with CHCl3 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert - butyl ( 3S ) -4- ( 4 - bromophenyl ) -3- methylpiperazine - 1 - carboxylate ( 4 g , 80.02 % ) as a white solid . LCMS : 2O₂NrB32H61C requires : 354.2 , found : m / z = 355.2 [ M + H ] * . [ 000722 ] Step - 3 : Synthesis of tert - butyl ( 3S ) -3 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 4 ) [ 000723 ] To a mixture of tert - butyl ( 38 ) -4- ( 4 - bromophenyl ) -3 - methylpiperazine - 1- carboxylate ( 4 g , 11.259 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 8.6 g , 33.777 mmol , 3 equiv ) in 1,4 - dioxane ( 40 mL ) was added Pd ( dppf ) Cl2 ( 917 mg , 1.126 mmol , 0.1 equiv ) and KOAc ( 2.2 g , 22.5mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford tert- butyl ( 38 ) -3 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1- carboxylate ( 4 g , 88.30 % ) as a white solid . LCMS : C22H35BN2O4 requires : 402.2 , found : m / z = 403.2 [ M + H ] * . = [ 000724 ] Step - 4 : Synthesis of tert - butyl ( 3S ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] phenyl - 3 - methylpiperazine - 1 - carboxylate ( 5 ) -546- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000725 ] To a mixture of tert - butyl ( 3S ) -3 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 4 g , 9.942 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 3.1 g , 13.919 mmol , 1.4 equiv ) in pyridine ( 40 mL ) was added Cu ( OAc ) 2 ( 3.6 g , 19.884 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 3.1 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 35 ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } -3 - methylpiperazine - 1 - carboxylate ( 2 g , 36.33 % ) as a light yellow oil . LCMS : C24H28BrN5O2 requires : 497.1 , found : m / z = 498.1 [ M + H ] * . [ 000726 ] Step - 5 : Synthesis of tert - butyl ( 3S ) -4- [ 4- ( 4- { 2 - fluoro - 3- [ N- ( propane - 1- sulfonyl ) -N - propane - 1 - sulfonamido ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -3- methylpiperazine - 1 - carboxylate ( 6 ) [ 000727 ] To a mixture of tert - butyl ( 35 ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl - 3 - methylpiperazine - 1 - carboxylate ( 500 mg , 1.003 mmol , 1 equiv ) and 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N - propane - 1 - sulfonamido ] phenylboronic acid ( 1.5 g , 4.012 mmol , equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 142 mg , 0.201 mmol , 0.2 equiv ) and CSF ( 305 mg , 2.006 mmol , 2 equiv ) in O₂H ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . This resulted in tert - butyl ( 3S ) -4- [ 4- ( 4- { 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) - N - propane - 1 - sulfonamido ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -3 - methylpiperazine- - carboxylate ( 700 mg , crude ) as a dark yellow solid . LCMS : C36H45FN6O6S2 requires : 740.2 , found : m / z = 741.2 [ M + H ] + . [ 000728 ] Step - 6 : Synthesis of tert - butyl ( 3S ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) -3 - methylpiperazine - 1- carboxylate ( 7 ) [ 000729 ] To a mixture of tert - butyl ( 3S ) -4- [ 4- ( 4- ( 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N- propane - 1 - sulfonamido ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -3 - methylpiperazine - 1- carboxylate ( 700 mg , 0.945 mmol , 1 equiv ) was added THF ( 20 mL ) , ACN ( 20 mL ) , and Na2CO3 ( 1.5 g , 14.175 mmol , 15 equiv ) in H2O ( 20 mL ) . The resulting mixture was stirred at ° C overnight . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 3S ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol- -547- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1 - yl ) phenyl ) -3 - methylpiperazine - 1 - carboxylate ( 250 mg , 37.52 % ) as a yellow solid . LCMS : C33H39FN6O4S requires : 634.2 , found : m / z = 635.2 [ M + H ] + . [ 000730 ] Step - 7 : Synthesis of N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 2S ) -2 - methylpiperazin - 1- trifluoroacetic yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide acid salt ( 8 ) [ 000731 ] To a mixture of tert - butyl ( 38 ) -4- ( 4- ( 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) -3 - methylpiperazine - 1 - carboxylate ( 240 mg , 0.378 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was warmed and stirred at room temperature for one hour . The resulting mixture was concentrated under reduced pressure . This resulted in N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 2S ) -2- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide trifluoroacetic acid salt ( 215.5 mg , 87.51 % ) as a yellow solid . LCMS : C28H31FN6O2S requires : 534.2 , found : m / z = 535.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.78 – 8.72 ( m , 2H ) , 8.60 ( s , 1H ) , 8.24 - 8.17 ( m , 2H ) , 7.98 – 7.89 ( m , 2H ) , 7.65 – 7.56 ( m , 1H ) , 7.45 - 7.32 ( m , 2H ) , 7.31 -7.23 ( m , 2H ) , 4.16 – 4.08 ( m , 1H ) , 3.58 – 3.44 ( m , 3H ) , 3.41 – 3.34 ( m , 2H ) , 3.– 3.26 ( m , 1H ) , 3.19 – 3.11 ( m , 2H ) , 1.94 – 1.80 ( m , 2H ) , 1.21 – 1.15 ( m , 3H ) , 1.10 – 1.01 ( m , 3H ) . - - - [ 000732 ] Synthesis of N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide trifluoroacetic acid salt ( 7 ) N N - N O = S = ✓ F ד ד N abs NH OH - 548 - 1100573566 5 AMERICAS 0 = 8 = O = S = O [ 000733 ] HN Boc Br Br ₂dP ( dba ) 3 , BINAP , Cs2CO3 , dioxane , 90 ° C Step - Br NH Cu ( OAc ) 2 , pyridine , molecular sieves 4A , 100 ° C Step - Boc Br Na2CO3 , THF : O₂H : ACN , ° C Step - Step - 1 : Synthesis Br .

Attorney Docket No .: 121843.002NU - 3200 PCT 2niP₂B , Pd ( dppf ) ₂lC , KOAc , dioxane , 80 ° C Step - Boc 0 = 8 = N N -Boc = S = ✓B. HO OH Boc Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - 0 = 5 = NH N TFA , DCM , 0 ° C N - N OH Step - of tert - butyl Boc NH ( 2R ) -4- ( 4 - bromophenyl ) -2- methylpiperazine - 1 - carboxylate ( 2 ) [ 000734 ] To a mixture of tert - butyl ( 2R ) -2 - methylpiperazine - 1 - carboxylate ( 5 g , 24.9mmol , 1 equiv ) and 1,4 - dibromobenzene ( 14.72 g , 62.413 mmol , 2.5 equiv ) in 1,4 - dioxane ( mL ) was added Pd2 ( dba ) 3 ( 1.14 g , 1.248 mmol , 0.05 equiv ) , BINAP ( 0.78 g , 1.248 mmol , 0.equiv ) , and Cs2CO3 ( 12.2 g , 37.447 mmol , 1.5 equiv ) . The resulting mixture was stirred at ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with ACN : H2O ( 1 : 1 ) to afford tert - butyl ( 2R ) -4- ( 4 - bromophenyl ) -2 - methylpiperazine - 1- carboxylate ( 4.97 g , 56 % ) as a white solid . LCMS : C16H23BrN2O2 requires : 354.1 , found : m / z = 355.2 [ M + H ] * . [ 000735 ] Step - 2 : Synthesis of tert - butyl ( 2R ) -2 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3 ) [ 000736 ] To a mixture of tert - butyl ( 2R ) -4- ( 4 - bromophenyl ) -2 - methylpiperazine - 1- carboxylate ( 2 g , 5.629 mmol , 1 equiv ) and B2Pin2 ( 4.29 g , 16.887 mmol , 3 equiv ) in 1,4- dioxane ( 20 mL ) was added Pd ( dppf ) Cl2 ( 412 mg , 0.563 mmol , 0.1 equiv ) and KOAc ( 1.1 g , -549- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 11.258 mmol , 2 equiv ) . The resulting mixture was stirred at 80 ° C overnight under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 2R ) -2 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1- carboxylate ( 2 g , 79.47 % ) as a white solid . LCMS : C22H35BN2O4 requires : 402.3 , found : m / z = 403.2 [ M + H ] * . [ 000737 ] Step - 3 : Synthesis of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] phenyl - 2 - methylpiperazine - 1 - carboxylate ( 4 ) [ 000738 ] To a mixture of tert - butyl ( 2R ) -2 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 2 g , 4.971 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.56 g , 6.959 mmol , 1.4 equiv ) in pyridine ( 20 mL ) was added Cu ( OAc ) 2 ( 1.81 g , 9.942 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 2 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) afford tert - butyl to ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } -2- methylpiperazine - 1 - carboxylate ( 900 mg , 26.52 % ) as a yellow solid . LCMS : C24H28BrN5requires : 497.1 , found : m / z = 498.1 [ M + H ] * . [ 000739 ] Step - 4 : Synthesis of tert - butyl ( 2R ) -4- [ 4- ( 4- { 2 - fluoro - 3- [ N- ( propane - 1- sulfonyl ) -N - propane - 1 - sulfonamido ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2- methylpiperazine - 1 - carboxylate ( 5 ) [ 000740 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 400 mg , 0.803 mmol , 1 equiv ) and 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N - propane - 1 - sulfonamido ] phenylboronic acid ( 1179 mg , 3.21 mmol , equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 114 mg , 0.161 mmol , 0.2 equiv ) and CSF ( 2441 mg , 1.606 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 3 ) to afford tert - butyl ( 2R ) -4- [ 4- ( 4- ( 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N- propane - 1 - sulfonamido ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2 - methylpiperazine - 1- -550- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT carboxylate ( 400 mg , 61.89 % ) as a yellow solid . LCMS : C36H45FN6O6S2 requires : 740.3 , found : m / z = 741.2 [ M + H ] * . [ 000741 ] Step - 5 : Synthesis of tert - butyl ( 2R ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) -2 - methylpiperazine - 1- carboxylate ( 6 ) [ 000742 ] To a mixture of tert - butyl ( 2R ) -4- [ 4- ( 4- ( 2 - fluoro - 3- [ N- ( propane - 1 - sulfonyl ) -N- propane - 1 - sulfonamido ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2 - methylpiperazine - 1- carboxylate ( 400 mg , 0.54 mmol , 1 equiv ) was added THF ( 10 mL ) , ACN ( 10 mL ) , and Na2CO3 ( 858 mg , 8.1 mmol , 15 equiv ) in H2O ( 10 mL ) . The resulting mixture was stirred at ° C overnight . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford tert - butyl ( 2R ) -4- ( 4- { 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) -2 - methylpiperazine - 1- carboxylate ( 220 mg , 57.78 % ) as a yellow solid . LCMS : C33H39FN6O4S requires : 634.3 , found : m / z = 635.2 [ M + H ] * . [ 000743 ] Step - 6 : Synthesis of N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1- trifluoroacetic yl ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide acid salt ( 7 ) [ 000744 ] To a mixture of tert - butyl ( 2R ) -4- ( 4- ( 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 215 mg , 0.339 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for 2 h . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in N- [ 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3- methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] propane - 1 - sulfonamide trifluoroacetic acid salt ( 217.9 mg , crude ) as a yellow solid . LCMS : C28H31FN6O2S requires : 534.2 , found : m / z = 535.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.77 - 8.68 ( m , 2H ) , 8.57 ( s , 1H ) , 8.20 – 8.11 ( m , 2H ) , 7.94 – 7.86 ( m , 2H ) , 7.64 – 7.56 ( m , 1H ) , 7.44 – 7.30 ( m , 2H ) , 7.27 - 7.22 ( m , 2H ) , 4.01 - 3.83 ( m , 2H ) , 3.66 - 3.35 ( m , 2H ) , 3.34 ( s , 1H ) , 3.20 – 3.( m , 3H ) , 2.97 – 2.84 ( m , 1H ) , 1.92 – 1.80 ( m , 2H ) , 1.50 – 1.39 ( m , 3H ) , 1.12 – 1.00 ( m , 3H ) . [ 000745 ] - Synthesis of ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 4 ) -551- 1100573566 5 AMERICAS 0 = $ = B HO OH N PdAMPHOS , CSF , dioxane , O₂H , 90 ° C , 1 h Step - N - Boc 0 = S = Attorney Docket No .: 121843.002NU - 3200 PCT N - N OH F F N N- -NH Br NH Br Cu ( OAc ) 2 , pyridine , molecular sieves ( 4A ) , 100 ° C Step - N - Boc 0 = S = TFA , DCM , 0 ° C N - N N - N OH N Boc Step - -NH [ 000746 ] Step - 1 : Synthesis of tert - butyl 4- { 5- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyridin - 2 - yl } piperazine - 1 - carboxylate ( 2 ) [ 000747 ] To a mixture of tert - butyl 4- [ 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyridin - 2 - yl ] piperazine - 1 - carboxylate ( 2 g , 5.137 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H- pyrazol - 3 - yl ) pyridine ( 1.7 g , 7.705 mmol , 1.5 equiv ) in pyridine ( 20 mL ) was added Cu ( OAc ) ( 1.87 g , 10.274 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 1.7 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 5- [ 4 - bromo - 3- ( pyridin - 4- yl ) pyrazol - 1 - yl ] pyridin - 2 - yl } piperazine - 1 - carboxylate ( 1.5 g , 60.15 % ) as a yellow solid . LCMS : C22H25BrN6O2 requires : 484.1 , found : m / z = 485.1 [ M + H ] * . -552- 1100573566 5 AMERICAS [ 000748 ] Attorney Docket No .: 121843.002NU - 3200 PCT Step - 2 : Synthesis of tert - butyl 4- { 5- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 2 - yl } piperazine - 1 - carboxylate ( 3 ) [ 000749 ] To a mixture of tert - butyl 4- { 5- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin- - yl } piperazine - 1 - carboxylate ( 500 mg , 1.03 mmol , 1 equiv ) and 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenylboronic acid ( 341 mg , 1.236 mmol , 1.2 equiv ) in dioxane ( 5 mL ) was added PdAMPHOS ( 73 mg , 0.103 mmol , 0.1 equiv ) and CsF ( 313 mg , 2.06 mmol , 2 equiv ) in H2O ( 1 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 2 ) to afford tert - butyl 4- { 5- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 2 - yl } piperazine - 1 - carboxylate ( 300 mg , 41.16 % ) as a white solid . LCMS : C31H37FN8O4S requires : 636.3 , found : m / z = 637.3 [ M + H ] + . [ 000750 ] Step - 3 : Synthesis of ethylmethyl [ ( 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin- - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 4 ) [ 000751 ] To a mixture of tert - butyl 4- { 5- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 2 - yl } piperazine - 1 - carboxylate ( 300 mg , 0.471 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in ethylmethyl [ ( 2 - fluoro- 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 233.3 mg , crude ) as a yellow solid . LCMS : C26H29FN8O2S requires : 536 , found : m / z = 537 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.86 –- 8.72 ( m , 3H ) , 8.( s , 1H ) , 8.26 – 8.13 ( m , 3H ) , 7.64 – 7.56 ( m , 1H ) , 7.38 – 7.29 ( m , 2H ) , 7.19 – 7.10 ( m , 1H ) , 3.99 – 3.88 ( m , 4H ) , 3.44 – 3.37 ( m , 4H ) , 3.29 – 3.21 ( m , 2H ) , 2.84 ( s , 3H ) , 1.23 – 1.10 ( m , 3H ) . - - - [ 000752 ] Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) -553- 1100573566 5 AMERICAS Br F. 0 = 8 = 0 + IZ Attorney Docket No .: 121843.002NU - 3200 PCT N ' F N - N OH F F N -NH O = S NO2 NHFe , NH4Cl i ) TEA , DCM F F EtOH , AcOH , O₂H , 80 ° C , 0.5 h Br Step - ii ) Na2CO3 , THF : O₂H : ACN , 50 ° C Step - Br Br N N - N II -S = 2niP₂B , Pd ( dppf ) ₂lC₂ NH dioxane , KOAc , 90 ° C Step - 0 = 5 = ﻢﻟا F -S = NH 0 = 0 = Boc F N - N TFA , DCM , 0 ° C Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - N - N Step - Boc [ 000753 ] Step - 1 : Synthesis of 3 - bromo - 2,5 - difluoroaniline ( 2 ) -NH OH [ 000754 ] To a mixture of Fe ( 5.8 g , 105.045 mmol , 5 equiv ) in AcOH ( 2 mL ) and O₂H ( 10 mL ) was added NH4Cl ( 112 mg , 2.101 mmol , 0.1 equiv ) . The resulting mixture was stirred at 80 ° C for 5 min . To the above mixture was added 1 - bromo - 2,5 - difluoro - 3 - nitrobenzene ( g , 21.009 mmol , 1 equiv ) in EtOH ( 100 mL ) . The resulting mixture was stirred at 80 ° C for 0.h . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 1 ) to afford 3 - bromo- -554- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 2,5 - difluoroaniline ( 4 g , 82.38 % ) as an off - white oil . LCMS : C6H4BrF2N requires : 207.2 , found : m / z = 208.3 [ M + H ] * .

Step - 2 : [ 000755 ] sulfonamide ( 3 ) Synthesis of N- ( 3 - bromo - 2,5 - difluorophenyl ) propane - 1- [ 000756 ] To a mixture of 3 - bromo - 2,5 - difluoroaniline ( 500 mg , 2.404 mmol , 1 equiv ) and TEA ( 729 mg , 7.212 mmol , 3 equiv ) in DCM ( 20 mL ) was added propane - 1 - sulfonyl chloride ( 1.1 g , 7.212 mmol , 3 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure . To the above mixture was then added THF ( 50 mL ) , ACN ( 50 mL ) , and Na2CO3 ( 3.8 g , 36.0mmol , 15 equiv ) in O₂H ( 50 mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford N- ( 3 - bromo - 2,5- difluorophenyl ) propane - 1 - sulfonamide ( 700 mg , 83.43 % ) as a white solid . LCMS : C9H10BrF2NO2S requires : 313.2 , found : m / z = 314.3 [ M + H ] * . [ 000757 ] Step - 3 : Synthesis of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] propane - 1 - sulfonamide ( 4 ) [ 000758 ] To a mixture of N- ( 3 - bromo - 2,5 - difluorophenyl ) propane - 1 - sulfonamide ( 7mg , 2.228 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 1.1 g , 4.456 mmol , 2 equiv ) in 1,4 - dioxane ( 10 mL ) was added Pd ( dppf ) Cl2 ( 181 mg , 0.223 mmol , 0.1 equiv ) and KOAc ( 437 mg , 4.456 mmol , 2 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . After filtration , the filtrate was concentrated under reduced pressure . This resulted in N- [ 2,5 - difluoro- 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] propane - 1 - sulfonamide ( 700 mg , crude ) as a black oil . LCMS : C15H22BF2NO4S requires : 361.2 , found : m / z = 362.2 [ M + H ] * . [ 000759 ] Step - 4 : Synthesis of tert - butyl = 4- ( 4- { 4- [ 2,5 - difluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 5 ) [ 000760 ] To a mixture of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] propane - 1 - sulfonamide ( 700 mg , 1.938 mmol , 3 equiv ) and tert - butyl 4- { 4- [ 4- bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 313 mg , 0.646 mmol , equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 46 mg , 0.065 mmol , 0.1 equiv ) and CSF ( 196 mg , 1.292 mmol , 2 equiv ) in O₂H ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under -555- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 2,5 - difluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 200 mg , 43.61 % ) as a yellow solid . LCMS : C32H36F2N6O4S requires : 638.2 , found : m / z = 639.2 [ M + H ] * . [ 000761 ] Step - 5 : Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000762 ] To a mixture of tert - butyl 4- ( 4- ( 4- [ 2,5 - difluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ) piperazine - 1 - carboxylate ( 200 mg , 0.313 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in N- ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide trifluoroacetic acid salt ( 196.1 mg , crude ) as a yellow solid . LCMS : C27H28F2N6O2S requires : 538.2 , found : m / z = 539.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.77 – 8.71 ( m , 2H ) , 8.59 ( s , 1H ) , 8.16 – 8.09 ( m , 2H ) , 7.94 – 7.85 ( m , 2H ) , 7.46 – 7.37 ( m , 1H ) , 7.28 – 7.20 ( m , 2H ) , 7.197.11 ( m , 1H ) , 3.57 - 3.50 ( m , 4H ) , 3.50 -3.40 ( m , 4H ) , 3.22 - 3.13 ( m , 2H ) , 1.- 1.78 ( m , 2H ) , 1.09 – 1.01 ( m , 3H ) . - = [ 000763 ] Synthesis of [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] -N - ethyl - N - methylamine acid salt ( 3 ) Cl O = S = O IZ F N - N OH F F N -NH trifluoroacetic -556- 1100573566 5 AMERICAS N Attorney Docket No .: 121843.002NU - 3200 PCT Cl NHCl F CI .

N - N N DMAP , pyridine , 40 ° C Step - N N - N N- -N Boc TFA , DCM , 0 ° C Step - N CI .N . [ 000764 ] Step - 1 : Synthesis O = S = IZ N - N O == O ד ד F OH F F N -N Boc N- -NH of tert - butyl 4- [ 4- [ 4- ( 5 - chloro - 3- { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 2 ) [ 000765 ] To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 5 - chloro - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 400 mg , 0.729 mmol , 1 equiv ) and N - ethyl - N - methylsulfamoyl chloride ( 230 mg , 1.458 mmol , 2 equiv ) in pyridine ( 1.6 mL ) was added DMAP ( 107 mg , 0.875 mmol , 1.2 equiv ) . The resulting mixture was stirred at 40 ° C overnight under a nitrogen atmosphere . The residue was purified via C18 reverse phase column chromatography with ACN : H2O ( 4 : 1 ) . The residue was then purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 100 mg , 18.43 % ) as a white solid . LCMS : C32H37C1FN7O4S requires : 669.2 , found : m / z = 670.1 [ M + H ] * . [ 000766 ] Step - 2 : Synthesis of [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] -N - ethyl - N - methylamine acid salt ( 3 ) trifluoroacetic -557- 1100573566 5 AMERICAS [ 000767 ] To a mixture Attorney Docket No .: 121843.002NU - 3200 PCT of tert - butyl 4- [ 4- [ 4- ( 5 - chloro - 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 100 mg , 0.149 mmol , 1 equiv ) in DCM ( 3 mL ) was added TFA ( 1 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) sulfamoyl ] -N - ethyl - N - methylamine trifluoroacetic acid salt ( 81.8 mg , crude ) as a yellow solid . LCMS : C27H29 CIFN7O2S requires : 569.2 , found : m / z = 570.3 . [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.76 – 8.70 ( m , 2H ) , 8.60 – 8.56 ( m , 1H ) , 8.09 – 8.03 ( m , 2H ) , 7.- 7.85 ( m , 2H ) , 7.63 – 7.56 ( m , 1H ) , 7.38 - 7.32 ( m , 1H ) , 7.28 – 7.19 ( m , 2H ) , 3.57 – 3.50 ( m , 4H ) , 3.47 – 3.40 ( m , 4H ) , 3.32 – 3.22 ( m , 2H ) , 2.86 – 2.82 ( m , 3H ) , 1.20 – 1.12 ( m , 3H ) . [ 000768 ] - - - - .

Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) N CI O == O N - N F F. OH F N- -NH -558- 1100573566 5 AMERICAS m N - N N -N Boc B. ﻮﻟا LL CI IZ Attorney Docket No .: 121843.002NU - 3200 PCT Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - CI . = S = N Cl .N .

O = S = ✓O N - N N TFA , DCM , 0 ° C N - N F F OH Step - N N- -N Boc -NH [ 000769 ] Step - 1 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1- carboxylate ( 2 ) [ 000770 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl } piperazine - 1 - carboxylate ( 400 mg , 0.796 mmol , 1 equiv ) and N- [ 5 - chloro - 2- fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 9mg , 2.388 mmol , 3 equiv ) in dioxane ( 10 mL ) was added CsF ( 242 mg , 1.592 mmol , 2 equiv ) in O₂H ( 2 mL ) and Pd ( AMPHOS ) 2Cl2 ( 59 mg , 0.08 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1:10 ) to afford tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1- carboxylate ( 260 mg , 46.64 % ) as a brown solid . LCMS : C33H36ClF2N7O4S requires : 699.2 , found : m / z = 700.2 [ M + H ] * . -559- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000771 ] Step - 2 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000772 ] To a mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1- carboxylate ( 210 mg , 0.300 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 137.6 mg , 61.48 % ) as a yellow solid . LCMS : C28H28C1F2N7O2S requires : 599.2 , found : m / z = 600.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.70 ( s , 2H ) , 8.36 ( s , 1H ) , 7.99 – 7.93 ( m , 2H ) , 7.84 ( s , 1H ) , 7.63 ( s , 1H ) , 7.30 ( s , 1H ) , 7.14 – 7.04 ( m , 2H ) , 3.59 ( s , 4H ) , 3.( s , 4H ) , 3.34 3.28 ( m , 4H ) , 1.96 – 1.86 ( m , 4H ) . [ 000773 ] - - Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) N H CI .N . = S = IZ OH F N - N F N- -NH -560- 1100573566 5 AMERICAS CI Br HN Boc Pd2 ( dba ) 3 , XantPhos , t - BuONa , toluene , 100 ° C ﻭﻻا LL 0 = 5 = Step - Attorney Docket No .: 121843.002NU - 3200 PCT CI -Boc ₂B Pin2 , Pd ( OAc ) 2 , XPhos , KOAc , dioxane , 90 ° C Step - Br Boc NH ' N ' Br .

CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - Cu ( OAc ) 2 , pyridine , molecular sieves 4A , 100 ° C CI .

Step - 0 = 5 = ✓ N. N- -Boc 0 = 5 = N TFA , DCM , 0 ° C OH N - N N N - N Step - -N Boc -NH [ 000774 ] carboxylate ( 2 ) Step - 1 : Synthesis of tert - butyl 4- ( 6 - chloropyridin - 3 - yl ) piperazine - 1- [ 000775 ] To a mixture of 5 - bromo - 2 - chloropyridine ( 5 g , 25.982 mmol , 1 equiv ) and tert- butyl piperazine - 1 - carboxylate ( 4.8 g , 25.982 mmol , 1 equiv ) in toluene ( 150 mL ) was added XantPhos ( 902 mg , 1.559 mmol , 0.06 equiv ) , Pd2 ( dba ) 3 ( 476 mg , 0.520 mmol , 0.02 equiv ) , and t - BuOK ( 3.8 g , 38.973 mmol , 1.5 equiv ) . The resulting mixture was stirred at 100 ° C overnight under a nitrogen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with waterand dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4- ( 6- chloropyridin - 3 - yl ) piperazine - 1 - carboxylate ( 7 g , 81.43 % ) as a white solid . LCMS : C14H20CIN3O2 requires : 297.1 , found : m / z = 298.2 [ M + H ] * . [ 000776 ] Step - 2 : Synthesis of tert - butyl 4- [ 6- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 3 ) - 561 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000777 ] To a mixture of tert - butyl 4- ( 6 - chloropyridin - 3 - yl ) piperazine - 1 - carboxylate ( g , 6.716 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) -1,3,2 - dioxaborolane ( 2niP₂B ) ( 1.9 g , 7.388 mmol , 1.1 equiv ) in 1,4 - dioxane ( 40 mL ) was added Pd ( OAc ) 2 ( 181 mg , 0.806 mmol , 0.12 equiv ) , XPhos ( 576 mg , 1.209 mmol , 0.18 equiv ) , and KOAc ( 2 g , 20.148 mmol , 3 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . After filtration , the filtrate was concentrated under reduced pressure . This resulted in tert - butyl 4- [ 6- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) pyridin - 3 - yl ] piperazine - 1- carboxylate ( 3 g , crude ) as a black oil . LCMS : C20H32BN3O4 requires : 389.3 , found : m / z 390.2 [ M + H ] * . [ 000778 ] = Step - 3 : Synthesis of tert - butyl 4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 4 ) [ 000779 ] To a mixture of tert - butyl 4- [ 6- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 3 g , 7.706 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H- pyrazol - 3 - yl ) pyridine ( 2.4 g , 10.801 mmol , 1.4 equiv ) in pyridine ( 30 mL ) was added Cu ( OAc ) 2 ( 2.8 g , 15.412 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 2.4 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 6- [ 4 - bromo - 3- ( pyridin - 4- yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 230 mg , 5.23 % ) as a yellow solid . LCMS : C22H25BrN6O2 requires : 484.1 , found : m / z = 485.1 [ M + H ] * . [ 000780 ] Step - 4 : Synthesis of tert - butyl 4- ( 6- { 4- [ 5 - chloro - 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } pyridin - 3 - yl ) piperazine - 1 - carboxylate ( 5 ) [ 000781 ] To a mixture of tert - butyl 4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin- - yl } piperazine - 1 - carboxylate ( 220 mg , 0.453 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] propane - 1 - sulfonamide ( 514 mg , 1.3mmol , 3 equiv ) in dioxane ( 5 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 32 mg , 0.045 mmol , 0.equiv ) and CSF ( 138 mg , 0.906 mmol , 2 equiv ) in O₂H ( 1 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 6- { 4- [ 5 - chloro - 2 - fluoro - 3- -562- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( propane - 1 - sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 3 - yl ) piperazine - 1- carboxylate ( 150 mg , 45.39 % ) as a white solid . LCMS : C31H35CIFN7O4S : 655.2 , found : m / z = 656.2 [ M + H ] + . [ 000782 ] Step - 5 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin- - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) propane - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000783 ] To a mixture of tert - butyl 4- ( 6- { 4- [ 5 - chloro - 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } pyridin - 3 - yl ) piperazine - 1 - carboxylate ( 145 mg , 0.221 mmol , 1 equiv ) in DCM ( 6 mL ) was added TFA ( 2 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in N- ( 5- chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) propane - 1 - sulfonamide trifluoroacetic acid salt ( 125.4 mg , crude ) as a yellow solid . LCMS : C26H27C1FN7O2S requires : 555.2 , found : m / z = 556.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.85 ( s , 1H ) , 8.76 – 8.70 ( m , 2H ) , 8.35 – 8.24 ( m , 1H ) , 8.14 – 8.03 ( m , 3H ) , 7.81 – 7.69 ( m , 1H ) , 7.67 – 7.58 ( m , 1H ) , 7.44 – 7.31 ( m , 1H ) , 3.63 – 3.54 ( m , 4H ) , 3.51 – 3.( m , 4H ) , 3.20 – 3.12 ( m , 2H ) , 1.91 – 1.78 ( m , 2H ) , 1.09 – 1.00 ( m , 3H ) . [ 000784 ] – - = – Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) N Cl N - N H IN N. : S = F ד ד OH F LL F N -NH -563- 1100573566 5 AMERICAS F Br NH CI HCI Br- 0 = 5 = DMAP , pyridine , 40 ° C Step - Br Boc LL ﻢﻫ Attorney Docket No .: 121843.002NU - 3200 PCT 2niP₂B , Pd ( dppf ) 2Cldioxane , KOAc , ° C , 1 h Step - Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h TFA , DCM , 0 ° C Step - N Step - 0 = 5 = ﻭﻻا N N - N N - N OH -NH TO = S = CI N. = 5 = Boc [ 000785 ] Step - 1 : Synthesis of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) pyrrolidine - 1- sulfonamide ( 2 ) [ 000786 ] To a mixture of 3 - bromo - 5 - chloro - 2 - fluoroaniline hydrochloride ( 2 g , 7.6mmol , 1 equiv ) and pyrrolidine - 1 - sulfonyl chloride ( 2.6 g , 15.33 mmol , 2 equiv ) in pyridine ( mL ) was added DMAP ( 1.12 g , 9.198 mmol , 1.2 equiv ) . The resulting mixture was stirred at ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) pyrrolidine - 1- sulfonamide ( 2 g , 65.66 % ) as a yellow solid . LCMS : C10H11BrClFN2O2S requires : 355.9 , found : m / z = 357.1 [ M + H ] * . [ 000787 ] Step - 2 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 3 ) [ 000788 ] To a mixture of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) pyrrolidine - 1- sulfonamide ( 2 g , 5.593 mmol , 1 equiv ) and bis ( pinacolato ) diboron ( 2niP₂B ) ( 2.84 g , 11.1 -564- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT mmol , 2 equiv ) in dioxane ( 30 mL ) was added KOAc ( 1.1 g , 11.186 mmol , 2 equiv ) and Pd ( dppf ) Cl2 ( 0.41 g , 0.559 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for h under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5- tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 2 g , crude ) as a black oil . LCMS : C16H23BCIFN2O4S requires : 404.1 , found : m / z = 405.2 [ M + H ] * . [ 000789 ] Step - 3 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 5 ) [ 000790 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 800 mg , 1.652 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro- 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 2 g , 4.9mmol , 3 equiv ) in dioxane ( 20 mL ) was added CsF ( 502 mg , 3.304 mmol , 2 equiv ) in O₂H ( mL ) and Pd ( AMPHOS ) 2Cl2 ( 117 mg , 0.165 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for 1 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3mg , 26.40 % ) as an off - white solid . LCMS : C33H37C1FN7O4S requires : 681.2 , found : m / z = 682.2 [ M + H ] + . [ 000791 ] Step - 4 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000792 ] To a mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3mg , 0.528 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 161.0 mg , 61.45 % ) as a yellow solid . LCMS : C28H29C1FN7O2S requires : 581.2 ;, found : m / z = 582.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.78 – 8.72 ( m , 2H ) , 8.59 ( s , 1H ) , 8.15 - 8.08 ( m , 2H ) , 7. -565- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT – 7.85 ( m , 2H ) , 7.64 ( s , 1H ) , 7.36 ( s , 1H ) , 7.28 – 7.19 ( m , 2H ) , 3.54 ( s , 4H ) , 3.44 ( s , 4H ) , 3.( s , 2H ) , 3.35 ( s , 2H ) 1.98 – 1.85 ( m , 4H ) . [ 000793 ] Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) methanesulfonamide trifluoroacetic acid salt ( 4 ) Cl NH F N N - N F N -N Cl N Boc CI = h = C IN N. = S = F N - N F OH pyridine , DCM , 0 ° C O == O IN F Step - N - N N- -N N -NH N O = S = N. O = 5 = F N - N F CI -N Boc IZ Na2CO3 , THF , MeCN , O₂H , 50 ° C Step - N TFA , DCM , 0 ° C N - N F OH F Step - 3 Boc [ 000794 ] Step - 1 Synthesis of tert - butyl -NH 4- ( 4-4- [ 5 - chloro - 2 - fluoro - 3- ( N- methanesulfonylmethanesulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3- fluorophenyl ) piperazine - 1 - carboxylate ( 2 ) [ 000795 ] To a mixture of tert - butyl 4- { 4- [ 4- ( 3 - amino - 5 - chloro - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 400 mg , 0.705 mmol , -566- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT equiv ) and pyridine ( 837 mg , 10.575 mmol , 15 equiv ) in DCM ( 10 mL ) was added methanesulfonic anhydride ( 737 mg , 4.23 mmol , 6 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . This resulted in tert - butyl 4- ( 4- { 4- [ 5 - chloro - 2 - fluoro - 3- ( N - methanesulfonylmethanesulfonamido ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ) piperazine - 1 - carboxylate ( 385 mg , crude ) as a yellow solid . LCMS : C31H33C1F2N6O6S2 requires : 722.2 , found : m / z = 723.2 [ M + H ] * . . [ 000796 ] Step - 2 Synthesis of tert - butyl 4-4- [ 4- ( 5 - chloro - 2 - fluoro - 3- methanesulfonamidophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1- carboxylate ( 3 ) [ 000797 ] To a mixture of tert - butyl 4- ( 4- ( 4- [ 5 - chloro - 2 - fluoro - 3- ( N- methanesulfonylmethanesulfonamido ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3- fluorophenyl ) piperazine - 1 - carboxylate ( 375 mg , 0.519 mmol , 1 equiv ) in THF ( 5 mL ) and MeCN ( 5 mL ) was added Na2CO3 ( 824 mg , 7.785 mmol , 15 equiv ) in O₂H ( 5 mL ) . The resulting mixture was stirred at 50 ° C overnight . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3- methanesulfonamidophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1- carboxylate ( 250 mg , 74.74 % ) as an off - white solid . LCMS : C30H31ClF2N6O4S requires : 644.2 , found : m / z = 645.2 [ M + H ] + . [ 000798 ] Step - 3 Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) methanesulfonamide trifluoroacetic acid salt ( 4 ) [ 000799 ] To a mixture of tert - butyl 4-4- [ 4- ( 5 - chloro - 2 - fluoro - 3- methanesulfonamidophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1- carboxylate ( 380 mg , 0.589 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure and subjected to lyophilization . This resulted in N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) methanesulfonamide trifluoroacetic acid salt ( 390.8 mg , crude ) as a yellow solid . LCMS : C25H23ClF2N6O2S requires : 544.1 , found : m / z = 545.2 [ M + H ] * . ' H NMR ( 400 MHz , - 567 - 1100573566 5 AMERICAS - Attorney Docket No .: 121843.002NU - 3200 PCT Methanol - d4 ) 8 8.77 – 8.71 ( m , 2H ) , 8.40 ( s , 1H ) , 8.11 – 8.05 ( m , 2H ) , 7.85 ( s , 1H ) , 7.62 ( s , 1H ) , 7.40 ( s , 1H ) , 7.15 – 7.02 ( m , 2H ) , 3.59 ( s , 4H ) , 3.43 ( s , 4H ) , 3.08 ( s , 3H ) . [ 000800 ] Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) LL CI CI H .N . 0 = S = IZ ` N 0 = S = F F. N - N F F Br .

N -NH OH CI O = S = O IN N F N N- Boc N - N EN Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - Cl TFA , DCM , 0 ° C Step - N IZ N - N = S = F ע . N ד ד F OH F N -NH ‍N -N Boc 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000801 ] Step - 1 : Synthesis of tert - butyl 4- [ 6- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 3 - yl ] piperazine - 1- carboxylate ( 2 ) [ 000802 ] To a mixture of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 1 g , 2.472 mmol , 3 equiv ) and tert - butyl ( 400 mg , 4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } piperazine - 1 - carboxylate 0.824 mmol , 1 equiv ) in dioxane ( 10 mL ) was added CsF ( 83.87 mg , 0.552 mmol , 0.67 equiv ) in O₂H ( 2 mL ) and Pd ( AMPHOS ) 2Cl2 ( 58.35 mg , 0.082 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for 1 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 6- ( 4- { 5 - chloro - 2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 3 - yl ] piperazine- - carboxylate ( 600 mg , 35.52 % ) as a yellow solid . LCMS : C32H36C1FN8O4S requires : 682.2 , found : m / z = 683.2 [ M + H ] * . [ 000803 ] Step - 2 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin- - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000804 ] To a mixture of tert - butyl 4- [ 6- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 3 - yl ] piperazine - 1 - carboxylate ( 590 mg , 0.864 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 1 ) to afford N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 509.mg , 84.06 % ) as a yellow solid . LCMS : C27H28C1FN8O2S requires : 582.1 , found : m / z = 583.[ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.84 ( s , 1H ) , 8.77 – 8.71 ( m , 2H ) , 8.29 ( s , 1H ) , 8.10 - 8.02 ( m , 3H ) , 7.73 ( s , 1H ) , 7.64 ( s , 1H ) , 7.32 ( s , 1H ) , 3.76 ( s , 4H ) , 3.59 ( s , 4H ) , 3.46 ( s , 2H ) , 3.33 ( s , 2H ) , 1.98 – 1.85 ( m , 4H ) . [ 000805 ] Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) -569- 1100573566 5 AMERICAS IN N N - N O == DMAP , pyr , 40 ° C Br Cl F. NHF Br Br Step - IL- -LL Attorney Docket No .: 121843.002NU - 3200 PCT F N -NH 0 = 8 = N IN OH ﻝا 2niP₂B , Pd ( dppf ) 2Cl2 , dioxane , KOAc , 90 ° C Step - F.

LL = S = IN N ' N - Boc N TFA , DCM , 0 ° C N - N N - N OH Step - Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h [ 000806 ] Step - Step - 1 : Synthesis of Boc -NH N- ( 3 - bromo - 2,5 - difluorophenyl ) pyrrolidine - 1- sulfonamide ( 2 ) [ 000807 ] To a mixture of 3 - bromo - 2,5 - difluoroaniline ( 2.5 g , 12.019 mmol , 1 equiv ) and pyrrolidine - 1 - sulfonyl chloride ( 4.08 g , 24.038 mmol , 2 equiv ) in pyridine ( 4 mL ) was added DMAP ( 1.76 g , 14.423 mmol , 1.2 equiv ) . The resulting mixture was stirred at 40 ° C for 2 days under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford N- ( 3 - bromo - 2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide ( 2.8 g , 54.63 % ) as a white solid . LCMS : C10H11BrF2N2O2S requires : 340.0 , found : m / z = 341.1 [ M + H ] * .

Step - 2 : Synthesis of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 3 ) [ 000808 ] -570- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000809 ] To a mixture of N- ( 3 - bromo - 2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide ( 500 mg , 1.466 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 744 mg , 2.932 mmol , 2 equiv ) in 1,4- dioxane ( 10 mL ) was added Pd ( dppf ) Cl2 ( 120 mg , 0.147 mmol , 0.1 equiv ) and KOAc ( 288 mg , 2.932 mmol , 2 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan- - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 500 mg , 87.88 % ) C16H23BF2N2O4S requires : 388.1 , found : m / z = 389.2 [ M + H ] * . [ 000810 ] a black oil . LCMS : Step - 3 : Synthesis of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 4 ) [ 000811 ] To a mixture of N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 500 mg , 1.29 mmol , 1 equiv ) and tert - butyl 4- { 4- [ 4- bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 625 mg , 1.29 mmol , equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 91 mg , 0.129 mmol , 0.1 equiv ) and CsF ( 392 mg , 2.58 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 4mg , 40.51 % ) as an off - white solid . LCMS : C33H37F2N7O4S requires : 665.3 , found : m / z = 666.[ M + H ] + . [ 000812 ] Step - 4 : Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) [ 000813 ] To a mixture of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 4mg , 0.601 mmol , 1 equiv ) in DCM ( 9 mL ) was added TFA ( 3 mL ) at 0 ° C . The resulting mixture was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 4 ) to afford N- ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 212.6 mg , 51.70 % ) as a yellow solid . LCMS : C28H29F2N7O2S requires : 565.2 , found : m / z - 571 - 1100573566 5 AMERICAS = Attorney Docket No .: 121843.002NU - 3200 PCT 566.3 [ M + H ] * . H¹ NMR ( 400 MHz , Methanol - d4 ) 8 8.79 – 8.69 ( m , 2H ) , 8.57 ( s , 1H ) , 8.– 8.03 ( m , 2H ) , 7.95 – 7.86 ( m , 2H ) , 7.48 – 7.37 ( m , 1H ) , 7.30 – 7.20 ( m , 2H ) , 7.14 – 7.03 ( m , - 1H ) , 3.60 – 3.49 ( m , 4H ) , 3.44 ( m , 4H ) , 3.35 ( m , 2H ) , 3.31 ( m , 2H ) , 2.06 – 1.80 ( m , 4H ) . [ 000814 ] Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) HN - S CI Tabs F F. N FF OH · N . N N NH -572- 1100573566 5 AMERICAS HN HCI D = S = O CI - S - CI CI abs TEA , DCM , -30 ° C abs F F Step - HN - S 2niP₂B , Pd ( dppf ) 2Cl2 , CI- dioxane , KOAc , 90 ° C abs F B - O Step - Cl HN - S LO Attorney Docket No .: 121843.002NU - 3200 PCT Br NHHCI CI DMAP , pyr , 40 ° C Common Intermediate Step - Br HN - S N CI- abs F Br N N -N N - Boc Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - HN - S N CI- abs TFA , 0 ° C N Step - ' N ' Boc abs F. OH F ' N ' NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000815 ] Step - 1 : Synthesis of ( 3R ) -3 - fluoropyrrolidine - 1 - sulfonyl chloride ( 2 ) [ 000816 ] To a mixture of ( 3R ) -3 - fluoropyrrolidine hydrochloride ( 20 g , 159.274 mmol , equiv ) in DCM ( 400 mL ) was added TEA ( 67 mL , 477.822 mmol , 3 equiv ) . To the above mixture was then added sulfonyl chloride ( 26 mL , 318.548 mmol , 2 equiv ) in DCM ( 100 mL ) dropwise over 30 min at -30 ° C . The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere . The resulting mixture was then diluted with HCl ( 1 N ) ( 300 mL ) . The resulting mixture was extracted with DCM . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . This resulted in ( 3R ) -3 - fluoropyrrolidine - 1 - sulfonyl chloride ( 20 g , crude ) as a dark yellow solid . LCMS : C4H7C1FNO2S requires : 187.0 , found : 188.6 . [ 000817 ] Step - 2 : Synthesis fluoropyrrolidine - 1 - sulfonamide ( 3 ) of ( 3R ) -N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) -3- [ 000818 ] To a mixture of 3 - bromo - 5 - chloro - 2 - fluoroaniline hydrochloride ( 5 g , 19.1mmol , 1 equiv ) and ( 3R ) -3 - fluoropyrrolidine - 1 - sulfonyl chloride ( 7.19 g , 38.326 mmol , 2 equiv ) in pyridine ( 8 mL ) was added DMAP ( 2.81 g , 22.996 mmol , 1.2 equiv ) . The resulting mixture was stirred at 40 ° C for 2 days under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford ( 3R ) -N- ( 3 - bromo - 5 - chloro - 2- fluorophenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ( 5 g , 57.66 % ) as a brown solid . LCMS : C10H10BrClF2N2O2S requires : 373.9 , found : m / z = 373.1 [ M - H ] . [ 000819 ] Step - 3 : Synthesis of ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 4 ) [ 000820 ] To a mixture of ( 3R ) -N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) -3- fluoropyrrolidine - 1 - sulfonamide ( 2 g , 5.325 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 2.7 g , 10.6mmol , 2 equiv ) in 1,4 - dioxane ( 20 mL ) was added Pd ( dppf ) Cl2 ( 434 mg , 0.533 mmol , 0.1 equiv ) and KOAc ( 1.05 g , 10.65 mmol , 2 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5- tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 2 g , crude ) as a black oil . LCMS : C16H22BCIF2N2O4S requires : 422.1 , found : m / z = 423.2 [ M + H ] + . -574- 1100573566 5 AMERICAS [ 000821 ] Attorney Docket No .: 121843.002NU - 3200 PCT Step - 4 : Synthesis of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 5 ) [ 000822 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 2.4 g , 4.955 mmol , 1 equiv ) and ( 3R ) -N- [ 5 - chloro - 2- fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine - 1- sulfonamide ( 2.09 g , 4.955 mmol , 1 equiv ) in dioxane ( 40 mL ) was added Pd ( AMPHOS ) 2Cl( 0.35 g , 0.496 mmol , 0.1 equiv ) and CsF ( 1.51 g , 9.91 mmol , 2 equiv ) in O₂H ( 8 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2- fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 1.1 g , 26.95 % ) as a yellow solid . LCMS : C33H36C1F2N7O4S requires : 699.2 , found : m / z = 700.3 [ M + H ] * . [ 000823 ] Step - 5 : Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- ( 1- [ 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000824 ] To a mixture of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 1.1 g , 1.571 mmol , 1 equiv ) was added TFA ( 10 mL ) at ° C . The resulting mixture was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with ACN : O₂H ( 1 : 4 ) to afford ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 1.0020 g , 87.71 % ) as a yellow solid . LCMS : C28H28C1F2N7O2S requires : 599.2 , found : m / z = 600.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol- d4 ) 8 8.74 – 8.67 ( m , 2H ) , 8.54 ( s , 1H ) , 8.04 – 7.96 ( m , 2H ) , 7.92 – 7.84 ( m , 2H ) , 7.72 – 7.( m , 1H ) , 7.37 – 7.31 ( m , 1H ) , 7.28 – 7.19 ( m , 2H ) , 5.28 ( m , 1H ) , 3.66 – 3.49 ( m , 7H ) , 3.49 – 3.38 ( m , 5H ) , 2.33 – 1.98 ( m , 2H ) . - [ 000825 ] Synthesis of ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) -575- 1100573566 5 AMERICAS Br N HN- CI ( R ) Boc O == ₁O .N . IZ Attorney Docket No .: 121843.002NU - 3200 PCT F abs F N - N F OH F -LL F Br Pd2 ( dba ) 3 , Cs2CO3 , ` I Xantphos , 1,4 - dioxane , 90 ° C ﻝا O - B N | | O = S - N Cl NH F F Step - -N Boc N N abs NH Boc Br . NH Cu ( OAc ) 2 , molecular sieves 4A , pyridine , 100 ° C N - N Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - Step - O = S = Boc 2niP₂B , Pd ( dppf ) ₂lC , KOAc , dioxane , 90 ° C Step - Br N - N N TFA , rt Step - N - N Boc O = S = abs abs NH OH -576- 1100573566 5 AMERICAS [ 000826 ] Step - 1 : Synthesis Attorney Docket No .: 121843.002NU - 3200 PCT ( 2R ) -4- ( 4 - bromophenyl ) -2- of tert - butyl methylpiperazine - 1 - carboxylate ( 2 ) [ 000827 ] To a mixture of 4 - bromoiodobenzene ( 10 g , 35.347 mmol , 1 equiv ) and tert- butyl ( 2R ) -2 - methylpiperazine - 1 - carboxylate ( 8.5 g , 42.416 mmol , 1.2 equiv ) in 1,4 - dioxane ( 150 mL ) was added Pd2 ( dba ) 3 ( 1.6 g , 1.767 mmol , 0.05 equiv ) , Xantphos ( 2.1 g , 3.535 mmol , 0.1 equiv ) , and Cs2CO3 ( 17.3 g , 53.020 mmol , 1.5 equiv ) . The resulting mixture was stirred at ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by reverse phase flash chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl ( 2R ) -4- ( 4 - bromophenyl ) -2 - methylpiperazine - 1- carboxylate ( 3 g , 23.89 % ) as a brown solid . LCMS : C16H23BrN2O2 requires : 354.0 , found : m / z = 355.2 [ M + H ] * . [ 000828 ] Step - 2 : Synthesis of tert - butyl ( 2R ) -2 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3 ) : [ 000829 ] To a mixture of tert - butyl ( 2R ) -4- ( 4 - bromophenyl ) -2 - methylpiperazine - 1- carboxylate ( 3 g , 8.444 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 4.3 g , 16.888 mmol , 2 equiv ) in 1,4 - dioxane ( 35 mL ) was added Pd ( dppf ) Cl2 ( 0.7 g , 0.844 mmol , 0.1 equiv ) and KOAc ( 1.7 g , 16.888 mmol , equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in tert - butyl ( 2R ) -2 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) phenyl ] piperazine - 1 - carboxylate ( 3 g , crude ) as a brown solid . LCMS : C22H35BN2Orequires : 402.2 , found : m / z = 403.2 [ M + H ] * . [ 000830 ] Step - 3 : Synthesis of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] phenyl } -2 - methylpiperazine - 1 - carboxylate ( 4 ) [ 000831 ] To a mixture of tert - butyl ( 2R ) -2 - methyl - 4- [ 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3 g , 7.456 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 2 g , 8.947 mmol , 1.2 equiv ) in pyridine ( 40 mL ) was added Cu ( OAc ) 2 ( 2.7 g , 14.912 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 3 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 2 ) to afford - 577- 1100573566 5 AMERICAS tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT ( 2R ) -4- [ 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl ) -2 - methylpiperazine - 1- carboxylate ( 900 mg , 21.80 % ) as an orange oil . LCMS : C24H28BrN5O2 requires : 497.1 , found : m / z = 498.1 [ M + H ] * . [ 000832 ] Step - 4 : Synthesis of tert - butyl ( 2R ) -4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } -2- methylpiperazine - 1 - carboxylate ( 5 ) [ 000833 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 900 mg , 1.806 mmol , 1 equiv ) and ( 3R ) -N- [ 5- chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine- - sulfonamide ( 763 mg , 1.806 mmol , 1 equiv ) in dioxane ( 15 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 128 mg , 0.181 mmol , 0.1 equiv ) and CSF ( 549 mg , 3.612 mmol , 2 equiv ) in O₂H ( 3 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 5 : 1 ) to afford tert - butyl ( 2R ) -4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin - 1- ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl ) -2 - methylpiperazine - 1- carboxylate ( 460 mg , 19.62 % ) as a brown solid . LCMS : C34H38CIF2N7O4S requires : 713.2 , found : m / z = 714.2 [ M + H ] * . [ 000834 ] Step - 5 : Synthesis of ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] -3 - fluoropyrrolidine- - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000835 ] A mixture of tert - butyl ( 2R ) -4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl ) -2- methylpiperazine - 1 - carboxylate ( 600 mg , 0.840 mmol , 1 equiv ) in TFA ( 6 mL ) was stirred at room temperature for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : Xcelect CSH F - pheny OBD Column 19 x 250 mm ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 20 mL / min ; Gradient : 35 % B to 50 % B in 15 min ; Wave Length : 254/220 nm to afford ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 136.2 mg , 20.04 % ) as a yellow solid . LCMS : C29H30C1F2N7O2S requires : 613.1 , found : m / z = 614.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.73 – 8. -578- 1100573566 5 AMERICAS = Attorney Docket No .: 121843.002NU - 3200 PCT ( m , 2H ) , 8.57 8.52 ( m , 1H ) , 8.05 - 7.99 ( m , 2H ) , 7.93 - 7.85 ( m , 2H ) , 7.71 – 7.64 ( m , 1H ) , - 7.377.31 ( m , 1H ) , 7.27 – 7.20 ( m , 2H ) , 5.37 – 5.18 ( m , 1H ) , 3.99 – 3.86 ( m , 2H ) , 3.68 – 3.- - ( m , 4H ) , 3.38 – 3.33 ( m , 3H ) , 3.14 – 3.06 ( m , 1H ) , 2.95 – 2.84 ( m , 1H ) , 2.30 – 2.03 ( m , 2H ) , 1.48 1.42 ( m , 3H ) . - [ 000836 ] Synthesis of ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 5 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) CI IZ .N .

N - N F abs F LL labs NH OH -579- 1100573566 5 AMERICAS Br .

N HN- Br BN . Boc Pd2 ( dba ) 3 , Xantphos , t - BuONa , toluene , 110 ° C , 2 h Step - CI .

N - N Br N - N EN O == ✓O IN F N- -N F abs N.

Boc Boc Attorney Docket No .: 121843.002NU - 3200 PCT N -N Boc Br NH N ' N K2CO3 , Cul , TMEDA , DMF , 120 ° C O = S - N labs Cl NH F F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h TFA , 0 ° C , 1 h Step - Step - Step - CI IZ = S = ` N abs N F F. N - N OH F LO N abs NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 2R ) -4- ( 6 - bromopyridin - 3 - yl ) -2- [ 000837 ] Step - 1 : Synthesis of tert - butyl methylpiperazine - 1 - carboxylate ( 2 ) [ 000838 ] To a mixture of 2 - bromo - 5 - iodopyridine ( 18.3 g , 64.410 mmol , 1.29 equiv ) and tert - butyl ( 2R ) -2 - methylpiperazine - 1 - carboxylate ( 10 g , 49.930 mmol , 1 equiv ) in toluene ( 2mL ) was added t - BuONa ( 14.4 g , 149.790 mmol , 3 equiv ) , Xantphos ( 3.47 g , 5.992 mmol , 0.equiv ) , and Pd2 ( dba ) 3 ( 2.3 g , 2.497 mmol , 0.05 equiv ) . The resulting mixture was stirred at 110 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl ( 2R ) -4- ( 6 - bromopyridin - 3 - yl ) -2 - methylpiperazine - 1- carboxylate ( 11 g , 55.6 % ) as a yellow solid . LCMS : C15H22BrN3O2 requires : 355.0 , found : m / z = 356.1 [ M + H ] * . [ 000839 ] Step - 2 : Synthesis of tert - butyl ( 2R ) -4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] pyridin - 3 - yl } -2 - methylpiperazine - 1 - carboxylate ( 3 ) [ 000840 ] To a mixture of tert - butyl ( 2R ) -4- ( 6 - bromopyridin - 3 - yl ) -2 - methylpiperazine - 1- carboxylate ( 6 g , 16.888 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 5.7 g , 25.332 mmol , 1.5 equiv ) in DMF ( 80 mL ) was added K2CO3 ( 7.0 g , 50.664 mmol , 3 equiv ) , TMEDA ( 0.79 g , 6.755 mmol , 0.4 equiv ) , and CuI ( 640 mg , 3.378 mmol , 0.2 equiv ) . The resulting mixture was stirred at 120 ° C overnight under a nitrogen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 3 ) to afford tert - butyl ( 2R ) -4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } -2- methylpiperazine - 1 - carboxylate ( 5 g , 53.35 % ) as a brown solid . LCMS : C23H27BrN6Orequires : 498.1 , found : m / z = 499.2 [ M + H ] * . = [ 000841 ] Step - 3 : Synthesis of tert - butyl ( 2R ) -4- { 6- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } - - methylpiperazine - 1 - carboxylate ( 4 ) : [ 000842 ] To a mixture of tert - butyl ( 2R ) -4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyridin - 3 - yl ) -2 - methylpiperazine - 1 - carboxylate ( 1.2 g , 2.403 mmol , 1 equiv ) and ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3- fluoropyrrolidine - 1 - sulfonamide ( 3.1 g , 7.209 mmol , 3 equiv ) in dioxane ( 15 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 170 mg , 0.240 mmol , 0.1 equiv ) and CsF ( 730 mg , 4.806 mmol , 2 equiv ) - 581 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT in H2O ( 3 mL ) . The resulting mixture was stirred at 90 ° C for 1 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl ( 2R ) -4- { 6- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin- - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl ) -2 - methylpiperazine - 1 - carboxylate ( 690 mg , 35.33 % ) as a yellow solid . LCMS : C33H37ClF2N8O4S requires : 714.2 , found : m / z = 715.2 [ M + H ] * . [ 000843 ] Step - 4 : Synthesis of ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 5 - [ ( 3R ) -3- methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] -3- fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) [ 000844 ] A mixture of tert - butyl ( 2R ) -4- { 6- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } -2- methylpiperazine - 1 - carboxylate ( 680 mg , 0.951 mmol , 1 equiv ) in TFA ( 7 mL ) was stirred at ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The residue was purified by C18 reverse phase flash chromatography eluted with ACN : H2O ( 4 : 1 ) to afford ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 5 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 427.6 mg , 59.09 % ) as a yellow solid . LCMS : C28H29C1F2N8O2S requires : 614.1 , found : m / z = 615.1 [ M + H ] * . ' H NMR ( 300 MHz , Methanol - d4 ) 8 8.86 – 8.80 ( m , 1H ) , 8.79 – 8.71 ( m , 2H ) , 8.33 8.26 ( m , 1H ) , 8.16 – 8.04 ( m , 3H ) , 7.79 – 7.65 ( m , 2H ) , 7.37 - 7.29 ( m , 1H ) , 5.40 – 5.( m , 1H ) , 4.05 – 3.90 ( m , 2H ) , 3.65 – 3.35 ( m , 7H ) , 3.26 – 3.11 ( m , 1H ) , 3.03 – 2.89 ( m , 1H ) , - - 2.33 1.98 ( m , 2H ) , 1.50 1.41 ( m , 3H ) . [ 000845 ] - Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2- yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) HN - S Cl F N. abs ד ד F F OH NH 1100573566 5 AMERICAS Cl = 5 = 0 + IZ abs F Br Attorney Docket No .: 121843.002NU - 3200 PCT HN - S N CI- N N. Boc Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - HN - S Cl -F abs TFA , 0 ° C Step - ' N ' .NH abs F .N . Boc OH [ 000846 ] Step - 1 : Synthesis of tert - butyl 4- { 6- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3- yl } piperazine - 1 - carboxylate ( 2 ) [ 000847 ] To a mixture of ( 3R ) -N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 1.9 g , 4.495 mmol , 1 equiv ) and tert - butyl 4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } piperazine - 1- carboxylate ( 2.2 g , 4.495 mmol , 1 equiv ) in dioxane ( 30 mL ) was added CSF ( 1.37 g , 8.mmol , 2 equiv ) in H2O ( 6 mL ) and Pd ( AMPHOS ) 2Cl2 ( 0.32 g , 0.449 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 3 ) to afford tert - butyl 4- { 6- [ 4- ( 5 - chloro - 2 - fluoro - 3- { [ ( 3R ) -3 - fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin- - yl } piperazine - 1 - carboxylate ( 1.5 g , 45.21 % ) as an off - white solid . LCMS : C32H35ClF2N8O4S requires : 700.2 , found : m / z = 701.2 [ M + H ] * . [ 000848 ] Step - 2 : Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000849 ] A mixture of tert - butyl 4- { 6- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin- - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } piperazine - 1- -583- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT carboxylate ( 1 g , 1.426 mmol , 1 equiv ) in TFA ( 10 mL ) was stirred at 0 ° C for 2 h . The resulting mixture was then concentrated under vacuum . The residue was purified by reverse phase flash chromatography eluted with ACN : H2O ( 1 : 4 ) to afford ( 3R ) -N- ( 5 - chloro - 2 - fluoro- 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) -3- fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 468.7 mg , 53.04 % ) as a yellow solid . LCMS : C27H27C1F2N8O2S requires : 600.2 , found : m / z = 601.1 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.81 ( s , 1H ) , 8.76 - 8.68 ( m , 2H ) , 8.31 - 8.25 ( m , 1H ) , 8.138.06 ( m , 3H ) , 7.76 – 7.63 ( m , 2H ) , 7.35 – 7.27 ( m , 1H ) , 5.39 – 5.17 ( m , 1H ) , 3.65 – 3.48 ( m , 7H ) , 3.47 – 3.( m , 5H ) , 2.31 – 1.94 ( m , 2H ) . = [ 000850 ] Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) HN - S CI- N -N . OH F F N abs NH > -584- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Br 2000- ' N ' Boc ﻝا B. F IN Ayto CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - TFA , 0 ° C Step - HN - S Cl ' N ' Cl OH F abs NH HN - S ' N ' abs N Boc [ 000851 ] Step - 1 : Synthesis of tert - butyl ( 2R ) -4- [ 4- ( 4- ( 5 - chloro - 2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2- methylpiperazine - 1 - carboxylate ( 2 ) [ 000852 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 500 mg , 1.003 mmol , 1 equiv ) and N- [ 5 - chloro- - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 406 mg , 1.003 mmol , 1 equiv ) in dioxane ( 15 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 71 mg , 0.mmol , 0.1 equiv ) and CSF ( 305 mg , 2.006 mmol , 2 equiv ) in H2O ( 3 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 2 : 1 ) to afford tert - butyl ( 2R ) -4- [ 4- ( 4- { 5 - chloro- - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2- methylpiperazine - 1 - carboxylate ( 300 mg , 30.07 % ) as a brown oil . LCMS : C34H39C1FN7O4S requires : 695.2 , found : m / z = 696.2 [ M + H ] * . [ 000853 ] Step - 2 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin- - yl ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) -585 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000854 ] A mixture of tert - butyl ( 2R ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2 - methylpiperazine - 1- carboxylate ( 280 mg , 0.402 mmol , 1 equiv ) in TFA ( 3 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : Xselect CSH C18 OBD Column 30 x 150mm 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 5 % B to 5 % B in 2 min , 10 % B to 25 % B in 15 min ; Wave Length : 254/220 nm to afford N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 188.8 mg , 22.73 % ) as a yellow solid . LCMS : C29H31 CIFN7O2S requires : 595.1 , found : m / z = 596.2 [ M + H ] * . ' H NMR ( 300 MHz , Methanol - d4 ) § 8.80 – 8.72 ( m , 2H ) , 8.63 – 8.57 ( m , 1H ) , 8.19 – 8.11 ( m , 2H ) , 7.94 – 7.85 ( m , 2H ) , 7.69 – 7.59 ( m , 1H ) , 7.41 – 7.32 ( m , 1H ) , 7.- 7.19 ( m , 2H ) , 4.00 -3.86 ( m , 2H ) , 3.61 - 3.51 ( m , 2H ) , 3.50 -3.43 ( m , 2H ) , 3.43 - 3.28 ( m , 3H ) , 3.21 – 3.02 ( m , 1H ) , 2.97 – 2.84 ( m , 1H ) , 1.99 – 1.84 ( m , 4H ) , 1.57 – 1.41 ( m , 3H ) . _ – [ 000855 ] Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 5 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) HN - S CI- N.

' N ' ד ד abs NH OH - 586 - 1100573566 5 AMERICAS Br Boc ﺱﻻاﺩ LL F Attorney Docket No .: 121843.002NU - 3200 PCT HN - S ' N ' CI- -F = 5 = N. IN CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - TFA , rt , 2 h Step - CI HN - S N - N . N abs NH ' N ' abs N. POTTE Boc OH ( 2R ) -4- [ 6- ( 4- { 5 - chloro - 2 - fluoro - 3- [ 000856 ] Step - 1 : Synthesis of tert - butyl [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 3 - yl ] -2- methylpiperazine - 1 - carboxylate ( 2 ) [ 000857 ] To a mixture of tert - butyl ( 2R ) -4- { 6- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyridin - 3 - yl ) -2 - methylpiperazine - 1 - carboxylate ( 700 mg , 1.402 mmol , 1 equiv ) and N- [ 5- chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1- sulfonamide ( 567 mg , 1.402 mmol , 1 equiv ) in dioxane ( 20 mL ) was added Pd ( AMPHOS ) 2Cl( 99 mg , 0.140 mmol , 0.1 equiv ) and CsF ( 430 mg , 2.804 mmol , 2 equiv ) in H2O ( 4 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 2 : 1 ) to afford tert - butyl ( 2R ) -4- [ 6- ( 4- { 5- chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ) pyridin - 3 - yl ] -2 - methylpiperazine - 1 - carboxylate ( 400 mg , 34.79 % ) as a brown solid . LCMS : C33H38C1FN8O4S requires : 696.2 , found : m / z = 697.2 [ M + H ] * . [ 000858 ] Step - 2 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 5 - [ ( 3R ) -3 - methylpiperazin- - yl ] pyridin - 2 - yl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) - 587 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000859 ] A mixture of tert - butyl ( 2R ) -4- [ 6- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 3 - yl ] -2 - methylpiperazine - 1- carboxylate ( 390 mg , 0.559 mmol , 1 equiv ) in TFA ( 4 mL ) was stirred at room temperature for h . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XBridge Prep Phenyl OBD Column19 x 250 mm ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 25 mL / min ; Gradient : 23 % B to 33 % B in 10 min ; Wave Length : 254/297 nm to afford N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 5 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 246.8 mg , 60.49 % ) as a yellow solid . LCMS : C28H30C1FN8O2S requires : 596.1 , found : m / z = 597.2 [ M + H ] * . H¹ NMR ( 300 MHz , Methanol - d4 ) 8 8.88 - 8.82 ( m , 1H ) , 8.81 - 8.73 ( m , 2H ) , 8.33 – 8.27 ( m , 1H ) , 8.16 – 8.06 ( m , 3H ) , 7.80 – 7.70 ( m , 1H ) , 7.69 – 7.60 ( m , 1H ) , 7.38 – 7.29 ( m , 1H ) , 4.– 3.90 ( m , 2H ) , 3.59 – 3.53 ( m , 2H ) , 3.46 – 3.35 ( m , 3H ) , 3.34 – 3.28 ( m , 2H ) , 3.26 – 3.09 ( m , – = = - 1H ) , 3.03 - 2.89 ( m , 1H ) , 1.99 – 1.86 ( m , 4H ) , 1.56 – 1.42 ( m , 3H ) . [ 000860 ] Synthesis of - N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 5 ) N CI N - N 0 = S = F F N -NH OH - 588- 1100573566 5 AMERICAS FL Br F CI NH0 = S = NaH , THF , 0 ° C Step - Br 0 - m -B .

Cl LL O = S = IN Attorney Docket No .: 121843.002NU - 3200 PCT CI Br O = 5² = IN 2niP₂B , Pd ( dppf ) ₂lC dioxane , KOAc , 90 ° C Step - N Boc CI Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - F = 8 = 0 + N N - N TFA , 0 ° C , 1 h Step - N -N Boc Synthesis CI O = 5 = IZ F N F. N - N OH F N -NH [ 000861 ] Step - 1 : fluorophenyl ) cyclopentanesulfonamide ( 2 ) of N- ( 3 - bromo - 5 - chloro - 2- [ 000862 ] To a mixture of NaH ( 1 g , 26.730 mmol , 2 equiv , 60 % ) in THF ( 50 mL ) was added 3 - bromo - 5 - chloro - 2 - fluoroaniline ( 3 g , 13.365 mmol , 1 equiv ) . The resulting mixture was then stirred for one hour at 0 ° C under a nitrogen atmosphere . To the above mixture was then added cyclopentanesulfonyl chloride ( 4.5 g , 26.730 mmol , 2 equiv ) at 0 ° C . The resulting mixture was then stirred at room temperature overnight under a nitrogen atmosphere . The reaction was then quenched by the addition of water at 0 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : DCM ( 1 : 3 ) to afford N- ( 3 - bromo - 5 - chloro - 2- -589- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT fluorophenyl ) cyclopentanesulfonamide ( 630 mg , 11.90 % ) as an off - white solid . LCMS : C11H12BrClFNO2Srequires : 354.9 , found : m / z = 354.1 [ M - H ] . [ 000863 ] Step - 2 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 3 ) [ 000864 ] To a mixture of N- ( 3 - bromo - 5 - chloro - 2- fluorophenyl ) cyclopentanesulfonamide ( 630 mg , 1.767 mmol , 1 equiv ) and 4,4,5,5- tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( 2niP₂B ) ( 897 mg , 3.534 mmol , 2 equiv ) in dioxane ( 10 mL ) was added KOAc ( 347 mg , 3.534 mmol , equiv ) and Pd ( dppf ) Cl2 ( 129.26 mg , 0.177 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 600 mg , crude ) as a black oil . LCMS : C17H24BCIFNO4S requires : 403.1 , found : m / z = 404.2 [ M + H ] * . [ 000865 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- ( 4- ( 5 - chloro - 3- ( cyclopentanesulfonamido ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1- yl ) phenyl ) piperazine - 1 - carboxylate ( 4 ) [ 000866 ] To a mixture of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] cyclopentanesulfonamide ( 600 mg , 1.486 mmol , 1 equiv ) and tert- butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 720 mg , 1.486 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 105 mg , 0.149 mmol , 0.1 equiv ) and CSF ( 452 mg , 2.972 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3- cyclopentanesulfonamido - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1- carboxylate ( 200 mg , 17.78 % ) as an off - white solid . LCMS : C34H38C1FN6O4S requires : 680.2 , found : m / z = 681.1 [ M + H ] * . [ 000867 ] Step - 4 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 5 ) [ 000868 ] A mixture of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 3 - cyclopentanesulfonamido - 2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 200 mg , 0.2mmol , 1 equiv ) in TFA ( 2 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then -590- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT concentrated under reduced pressure and lyophilized . This resulted in N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) cyclopentanesulfonamide trifluoroacetic acid salt ( 126.1 mg , crude ) as a yellow solid . LCMS : C29H30C1FN6O2S requires : 580.1 , found : m / z = 581.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.78 – 8.72 ( m , 2H ) , 8.62 – 8.58 ( m , 1H ) , 8.17 – 8.11 ( m , 2H ) , 7.94 – 7.86 ( m , 2H ) , 7.71 – 7.63 ( m , 1H ) , 7.46 – 7.- = ( m , 1H ) , 7.28 – 7.20 ( m , 2H ) , 3.72 – 3.59 ( m , 1H ) , 3.58 – 3.50 ( m , 4H ) , 3.47 – 3.40 ( m , 4H ) , 2.09 – 1.91 ( m , 4H ) , 1.83 – 1.78 ( m , 2H ) , 1.69 – 1.65 ( m , 2H ) . [ 000869 ] Synthesis of rac- ( 2R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) butane - 2 - sulfonamide trifluoroacetic acid salt ( 5 ) N Cl = S = .N . IN F & F. OH N - N F F N -NH -591- 1100573566 5 AMERICAS F Br NH 2niP₂B , Pd ( dppf ) ₂lC dioxane , KOAc , 90 ° C Step - N CI .N .

N - N 0 = S = B.

N Cl = S = NaH , DMF , rt Step - ד . IZ Attorney Docket No .: 121843.002NU - 3200 PCT Br LL O == IZ CI Br EN Boc CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - -N Boc TFA , 0 ° C , 1h Step - N CI 70 = S = & F N - N OH F F N -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000870 ] Step - 1 : Synthesis of sulfonamide ( 2 ) N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) butane - 2- [ 000871 ] To a mixture of NaH ( 891 mg , 22.276 mmol , 2 equiv , 60 % ) in DMF ( 50 mL ) was added 3 - bromo - 5 - chloro - 2 - fluoroaniline ( 2.5 g , 11.138 mmol , 1 equiv ) . The resulting mixture was stirred at 0 ° C for one hour under a nitrogen atmosphere . To the above mixture was added butane - 2 - sulfonyl chloride ( 3.5 g , 22.276 mmol , 2 equiv ) at 0 ° C . The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere . The reaction was then quenched with water at 0 ° C . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : CH2Cl2 ( 1 : 1 ) to afford N- ( 3 - bromo - 5 - chloro- - fluorophenyl ) butane - 2 - sulfonamide ( 650 mg , 15.24 % ) as a brown semi - solid . LCMS : C10H12BrClFNO2S Srequires : 342.9 , found : m / z = 342.0 [ M - H ] . [ 000872 ] Step - 2 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] butane - 2 - sulfonamide ( 3 ) [ 000873 ] To a mixture of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) butane - 2 - sulfonamide ( 650 mg , 1.886 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 958 mg , 3.772 mmol , 2 equiv ) in dioxane ( 10 mL ) was added Pd ( dppf ) Cl2 ( 138 mg , 0.189 mmol , 0.1 equiv ) and KOAc ( 370 mg , 3.7mmol , 2 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] butane - 2 - sulfonamide ( 650 mg , crude ) as a black oil . LCMS : C16H24BCIFNO4S requires : 391.1 , found : m / z = 392.2 [ M + H ] * . [ 000874 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- { 4- [ 3- ( butane - 2 - sulfonamido ) -5 - chloro- - fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 4 ) [ 000875 ] To a mixture of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] butane - 2 - sulfonamide ( 650 mg , 1.659 mmol , 1 equiv ) and tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 804 mg , 1.6mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 118 mg , 0.166 mmol , 0.equiv ) and CSF ( 504 mg , 3.318 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then -593- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 3- ( butane - 2- sulfonamido ) -5 - chloro - 2 - fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1- carboxylate ( 250 mg , 20.94 % ) as an off - white solid . LCMS : C33H38C1FN6O4S requires : 668.2 , found : m / z = 669.1 [ M + H ] * . [ 000876 ] Step - 4 : Synthesis of rac- ( 2R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) butane - 2 - sulfonamide trifluoroacetic acid salt ( 5 ) [ 000877 ] A mixture of tert - butyl 4- ( 4- { 4- [ 3- ( butane - 2 - sulfonamido ) -5 - chloro - 2- fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 250 mg , 0.3mmol , 1 equiv ) in TFA ( 3 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and lyophilized . This resulted in rac- ( 2R ) -N- ( 5 - chloro - 2- fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) butane - 2- sulfonamide trifluoroacetic acid salt ( 151.9 mg , crude ) as a yellow solid . LCMS : C28H30C1FN6O2S requires : 568.1 , found : m / z = 569.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol- d4 ) 8 8.79 – 8.73 ( m , 2H ) , 8.63 – 8.58 ( m , 1H ) , 8.18 – 8.11 ( m , 2H ) , 7.94 – 7.86 ( m , 2H ) , 7.– 7.63 ( m , 1H ) , 7.45 – 7.38 ( m , 1H ) , 7.28 – 7.20 ( m , 2H ) , 3.57 – 3.50 ( m , 4H ) , 3.50 – 3.40 ( m , 4H ) , 3.17 – 3.05 ( m , 1H ) , 2.13 – 1.98 ( m , 1H ) , 1.68 – 1.52 ( m , 1H ) , 1.40 – 1.31 ( m , 3H ) , 1. – -0.99 ( m , 3H ) . - = [ 000878 ] Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoroazetidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) HN - S N CI- · F F N OH N. F N NH -594- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT CI - S - CI HCI HN- O = S = O NH.F HN - S CI Br N CI- TEA , ACN , ° C , 0.5 h NaH , THF , F ° C , 0.5 h LL F Br Step - 1 Step - HN - S N- 2niP₂B , Pd ( dppf ) 2Cl2 , CI- dioxane , KOAc , 90 ° C CI- - Step - HN - S F N -Boc N N. Br- Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - HN - S N F COH - CI- F TFA , 0 ° C , 1 h Step - N N. N ' N ' N. ` Boc N NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000879 ] [ 000880 ] Step - 1 : Synthesis of 3 - fluoroazetidine - 1 - sulfonyl chloride ( 2 ) To a mixture of sulfonyl chloride ( 9.0 g , 67.240 mmol , 2.5 equiv ) in ACN ( mL ) was added 3 - fluoroazetidine hydrochloride ( 3 g , 26.896 mmol , 1 equiv ) and TEA ( 7.2 g , 71.274 mmol , 2.65 equiv ) at 0 ° C . The resulting mixture was stirred at 50 ° C for 30 min . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in 3 - fluoroazetidine - 1 - sulfonyl chloride ( 3 g , crude ) as an off - white solid . LCMS : C3H5CIFNO2S requires : 172.9 , found : m / z = 173.8 [ M + H ] * [ 000881 ] Step - 2 : Synthesis of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) -3- fluoroazetidine - 1 - sulfonamide ( 3 ) [ 000882 ] To a mixture of NaH ( 400 mg , 16.706 mmol , 2 equiv ) in THF ( 100 mL ) was added 3 - bromo - 5 - chloro - 2 - fluoroaniline ( 1.9 g , 8.353 mmol , 1 equiv ) at 0 ° C under nitrogen atmosphere . The resulting mixture was stirred at 0 ° C for 30 min under a nitrogen atmosphere . To the above mixture was added 3 - fluoroazetidine - 1 - sulfonyl chloride ( 2.9 g , 16.706 mmol , equiv ) at 0 ° C under a nitrogen atmosphere . The resulting mixture was then stirred at 50 ° C overnight under a nitrogen atmosphere . The reaction was then quenched with saturated aqueous NH4Cl at 0 ° C . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford N- ( 3- bromo - 5 - chloro - 2 - fluorophenyl ) -3 - fluoroazetidine - 1 - sulfonamide ( 500 mg , 13.24 % ) as a brown solid . LCMS : C9H8BrClF2N2O2S requires : 359.9 , found : m / z = 358.9 [ M - H ] ‍ . [ 000883 ] Step - 3 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - fluoroazetidine - 1 - sulfonamide ( 4 ) [ 000884 ] To a mixture of N- ( 3 - bromo - 5 - chloro - 2 - fluorophenyl ) -3 - fluoroazetidine - 1- sulfonamide ( 450 mg , 1.245 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 632 mg , 2.490 mmol , 2 equiv ) in dioxane ( 10 mL ) was added KOAc ( 244 mg , 2.490 mmol , 2 equiv ) and Pd ( dppf ) Cl2 ( 101 mg , 0.125 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - fluoroazetidine - 1 - sulfonamide ( 450 mg , crude ) as a black oil . LCMS : C15H20BC1F2N2O4S requires : 408.1 , found : m / z = 409.2 [ M + H ] * . -596- 1100573566 5 AMERICAS [ 000885 ] Step - 4 : Synthesis of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 4- [ 4- ( 4-5 - chloro - 2 - fluoro - 3 - [ ( 3- fluoroazetidin - 1 - ylsulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ) phenyl ] piperazine - 1 - carboxylate ( 5 ) [ 000886 ] To a mixture of N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - fluoroazetidine - 1 - sulfonamide ( 450 mg , 1.101 mmol , 3 equiv ) and tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 178 mg , 0.367 mmol , 1 equiv ) in dioxane ( 5 mL ) was added CSF ( 112 mg , 0.734 mmol , equiv ) in H2O ( 1 mL ) and Pd ( AMPHOS ) 2Cl2 ( 26 mg , 0.037 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 3 : 2 ) to afford tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2- fluoro - 3 - [ ( 3 - fluoroazetidin - 1 - ylsulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ) phenyl ] piperazine - 1 - carboxylate ( 380 mg , 90.52 % ) as a black solid . LCMS : C32H34C1F2N7O4S requires : 685.2 , found : m / z = 686.2 [ M + H ] * . [ 000887 ] Step - 5 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoroazetidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000888 ] A mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( 3 - fluoroazetidin - 1- ylsulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3mg , 0.554 mmol , 1 equiv ) in TFA ( 4 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Fluoro Phenyl 30 x 150 mm , 5 mµ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : % B to 40 % B in 12min ; Wave Length : 254/220 nm to afford N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoroazetidine - 1- sulfonamide trifluoroacetic acid salt ( 220.8 mg , 21.01 % ) as a yellow solid . LCMS : C27H26C1F2N7O2S requires : 585.2 ,, found : m / z 586.1 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 88.74 – 8.68 ( m , 2H ) , 8.59 - 8.54 ( m , 1H ) , 8.05 - 7.99 ( m , 2H ) , 7.94 – 7.84 ( m , 2H ) , 7.68 – 7.61 ( m , 1H ) , 7.42 – 7.35 ( m , 1H ) , 7.27 – 7.19 ( m , 2H ) , 5.40 – 5.30 ( m , 1H ) , 4.- == - 4.11 ( m , 2H ) , 4.08 – 3.94 ( m , 2H ) , 3.57 – 3.50 ( m , 4H ) , 3.50 – 3.40 ( m , 4H ) . [ 000889 ] = - Synthesis of ethylmethyl [ ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 5 ) -597- 1100573566 5 AMERICAS F Br NH F 0 .

Attorney Docket No .: 121843.002NU - 3200 PCT O = S - N NH -F F F OH N - N . N NH CI N - S = O DMAP , pyr , 40 ° C Step - ' N ' Z - S = O O = S - NH F N.

O = 8 - N F- NH -F N.

LL F -B ' N ' N Boc ' N ' O = S - NH F 2niP₂B , Pd ( dppf ) 2Cl Br dioxane , KOAc , 90 ° C Step - F Br N- -N N - Boc Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h TFA , 0 ° C , 1 h Step - Step - 0 . O = S - N NH -F F. OH ' N ' .NH -598- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 [ 000890 ] Step - 1 : Synthesis difluorophenyl ) sulfamoyl ] ( ethyl ) methylamine ( 2 ) [ 000891 ] of NU - 3200 PCT [ ( 3 - bromo - 2,5- To a mixture of 3 - bromo - 2,5 - difluoroaniline ( 1.5 g , 7.211 mmol , 1 equiv ) and N - ethyl - N - methylsulfamoyl chloride ( 2.84 g , 18.027 mmol , 2.5 equiv ) in pyridine ( 2 mL ) was added DMAP ( 1.06 g , 8.653 mmol , 1.2 equiv ) . The resulting mixture was stirred at 40 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford [ ( 3 - bromo - 2,5 - difluorophenyl ) sulfamoyl ] ( ethyl ) methylamine ( 1.4 g , 58.98 % ) as a brown yellow solid . LCMS : S2O2N2FrB₁₁HC requires : 328.0 , found : m / z = 329.[ M + H ] + . [ 000892 ] Step - 2 : Synthesis of ethylmethyl { [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] sulfamoyl } amine ( 3 ) [ 000893 ] To a mixture of [ ( 3 - bromo - 2,5 - difluorophenyl ) sulfamoyl ] ( ethyl ) methylamine ( 700 mg , 2.127 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 1.08 g , 4.254 mmol , 2 equiv ) in 1,4 - dioxane ( 10 mL ) was added Pd ( dppf ) Cl2 ( 156 mg , 0.213 mmol , 0.1 equiv ) and KOAc ( 417 mg , 4.2mmol , 2 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The filtrate was concentrated under reduced pressure . This resulted in ethylmethyl { [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] sulfamoyl } amine ( 700 mg , crude ) as a black oil . LCMS : C15H23BF2N2O4S requires : 376.1 , found : m / z = 377.2 [ M + H ] * . [ 000894 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - 2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 4 ) [ 000895 ] To a a mixture of ethylmethyl { [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] sulfamoyl } amine_ ( 649 mg , 1.724 mmol , 1 equiv ) and tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenylpiperazine - 1 - carboxylate ( 835 mg , 1.7mmol , 1 equiv ) in dioxane ( 25 mL ) was added CSF ( 524 mg , 3.448 mmol , 2 equiv ) in O₂H ( mL ) and Pd ( AMPHOS ) 2Cl2 ( 122 mg , 0.172 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography DCM : EtOAc ( 2 : 3 ) to afford tert - butyl eluted with { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- 4- { 4- [ 4- ( 3- -599- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ] phenylpiperazine - 1 - carboxylate ( 0.55 g , 48.81 % ) as a yellow solid . LCMS : C32H37F2N7O4S requires : 653.3 , found : m / z = 654.3 [ M + H ] * . [ 000896 ] of ethylmethyl [ ( 2,5 - difluoro - 3- { 1- [ 4- ( piperazin - 1- Step - 4 : Synthesis yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 5 ) [ 000897 ] A mixture of tert - butyl 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] phenyl } piperazine - 1 - carboxylate ( 0.55 g , 0.8mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure and lyophilized . This resulted in ethylmethyl [ ( 2,5- difluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- . yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 301.9 mg , crude ) as a yellow solid . LCMS : C27H29F2N7O2S requires : 553.2 , found : m / z = 554.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.79 – 8.73 ( m , 2H ) , 8.62 – 8.57 ( m , 1H ) , 8.18 – 8.12 ( m , 2H ) , 7.95 – 7.86 ( m , 2H ) , 7.42 - 7.32 ( m , 1H ) , 7.28 – 7.20 ( m , 2H ) , 7.14 – 7.05 ( m , 1H ) , 3.57 – 3.50 ( m , 4H ) , 3.– 3.40 ( m , 4H ) , 3.33 - 3.23 ( m , 2H ) , 2.87 – 2.83 ( m , 3H ) , 1.20 – 1.11 ( m , 3H ) [ 000898 ] Synthesis of = - ethylmethyl [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 3 ) CI O = O = S- N. NH OH F N.

' N ' NH -600 - 1100573566 5 AMERICAS IN LL CI Br- Boc 2000 .

Pd ( AMphos ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - Attorney Docket No .: 121843.002 O = - $ = N. NH CI- -F NU - 3200 PCT TFA , 0 ° C , 1 h CI- Step - [ 000899 ] Step - 1 : Synthesis 0 = 8- -N . NH OH NH ﻢﻤﺠﻤﻫ of tert - butyl .N .

' N ' N Boc 4- { 6- [ 4- ( 5 - chloro - 3- { [ ethyl ( methyl ) sulfamoyl ] amino - 2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin- - yl } piperazine - 1 - carboxylate ( 2 ) [ 000900 ] To a mixture of ethylmethyl { [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] sulfamoyl } amine ( 1 g , 2.547 mmol , 1 equiv ) and tert - butyl 4- { 6- [ 4- bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 1.2 g , 2.547 mmol , equiv ) in dioxane ( 20 mL ) was added Pd ( AMphos ) 2Cl2 ( 180 mg , 0.255 mmol , 0.1 equiv ) and CSF ( 774 mg , 5.094 mmol , 2 equiv ) in H2O ( 4 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc 4- { 6- [ 4- ( 5 - chloro - 3- ( 1 : 1 ) to afford tert - butyl { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3- ylpiperazine - 1 - carboxylate ( 500 mg , 23.40 % ) as a brown semi - solid . LCMS : C31H36C1FN8O4S requires : 670.2 , found : m / z = 671.3 [ M + H ] * . [ 000901 ] Step - 2 : Synthesis of ethylmethyl [ ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1- yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) sulfamoyl ] amine trifluoroacetic acid salt ( 3 ) - 601 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000902 ] A mixture of tert - butyl 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin - 3 - yl } piperazine - 1 - carboxylate ( 500 mg , 0.745 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred for one hour at 0 ° C . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XBridge Prep Phenyl OBD Column19 x 250 mm ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : 25 mL / min ; Gradient : 40 % B to 55 % B in 10 min ; Wave Length : 254/220 nm to afford ethylmethyl [ ( 5- chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyridin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) sulfamoyl ] amine_trifluoroacetic acid salt ( 222.9 mg , 43.50 % ) as a yellow solid . LCMS : C26H28C1FN8O2S requires : 570.1 , found : m / z = 571.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.88 – 8.84 ( m , 1H ) , 8.81 – 8.75 ( m , 2H ) , 8.33 – 8.27 ( m , 1H ) , 8.21 – 8.07 ( m , 3H ) , 7.77 – 7.70 ( m , 1H ) , 7.64 – 7.57 ( m , 1H ) , 7.37 - 7.31 ( m , 1H ) , 3.67 – 3.56 ( m , 4H ) , 3.- 3.42 ( m , 4H ) , 3.33 - 3.23 ( m , 2H ) , 2.87 – 2.83 ( m , 3H ) , 1.21 – 1.12 ( m , 3H ) .

- - – Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000903 ] CI IZ = S = F abs N F N - N F F F -LL F N- -NH OH -602- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT HN - S N CI- Br N B - O abs N - N N -N Boc Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - CI CI .

O = S = IZ N N F N - N N abs F TFA , 0 ° C , 1 h N - N F F OH Step - F N -NH N- -N Boc [ 000904 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenylpiperazine - 1 - carboxylate ( 2 ) [ 000905 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl } piperazine - 1 - carboxylate ( 1.5 g , 2.986 mmol , 1 equiv ) and ( 3R ) -N- [ 5 - chloro - 2- fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine - 1- sulfonamide ( 1.3 g , 2.986 mmol , 1 equiv ) in dioxane ( 20 mL ) was added Pd ( AMPHOS ) 2Cl( 211 mg , 0.299 mmol , 0.1 equiv ) and CsF ( 907 mg , 5.972 mmol , 2 equiv ) in H2O ( 4 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 5- chloro - 2 - fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 900 mg , 31.48 % ) as a brown semi- solid . LCMS : C33H35CIF3N7O4S requires : 717.2 , found : m / z = 718.3 [ M + H ] * . -603- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000906 ] Step - 2 : Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin- - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid ( 3 ) [ 000907 ] A mixture of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin- - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1- carboxylate ( 900 mg , 1.253 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by reverse phase flash chromatography with the following conditions : Column : Xselect CSH C18 OBD Column 30 x 150mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 5 % B to 5 % B in 2 min , 10 % B to % B in 15 min ; Wave Length : 254/220 nm to afford ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2- fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ) -3 - fluoropyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 485.3 mg , 51.84 % ) as a yellow solid . LCMS : C28H27C1F3N7O2S requires : 617.1 , found : m / z = 618.1 [ M + H ] * . ' H NMR ( 300 MHz , Methanol- d4 ) 8 8.77 – 8.69 ( m , 2H ) , 8.39 – 8.32 ( m , 1H ) , 8.11 – 8.00 ( m , 2H ) , 7.90 – 7.78 ( m , 1H ) , 7.– 7.64 ( m , 1H ) , 7.36 – 7.27 ( m , 1H ) , 7.15 - 7.00 ( m , 2H ) , 5.48 - 5.06 ( m , 1H ) , 3.68 – 3.49 ( m , 6H ) , 3.533.38 ( m , 6H ) , 2.41 – 1.96 ( m , 2H ) . [ 000908 ] - - Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoroazetidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) Cl HN - S ד ד F ' N ' NH OH -604- 1100573566 5 AMERICAS CI- HN - S -F F Br . F Attorney Docket No .: 121843.002NU - 3200 PCT HN - S ' N ' CI- F N. Boc F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - ' N ' N Boc HN - S Cl -F TFA , 0 ° C , 1 h F F Step - N -N . OH ' N ' NH - 605 - 1100573566 5 AMERICAS [ 000909 ] Step - 1 : Synthesis of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( 3- fluoroazetidin - 1 - ylsulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3- fluorophenylpiperazine - 1 - carboxylate ( 2 ) added [ 000910 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenylpiperazine - 1 - carboxylate ( 830 mg , 1.652 mmol , 1 equiv ) in dioxane ( 10 mL ) was N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3- fluoroazetidine - 1 - sulfonamide ( 2.1 g , 4.956 mmol , 3 equiv ) , CsF ( 502 mg , 3.304 mmol , equiv ) in H2O ( 2 mL ) , and Pd ( AMPHOS ) 2Cl2 ( 117 mg , 0.165 mmol , 0.1 equiv ) at room temperature . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert- butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( 3 - fluoroazetidin - 1 - ylsulfonyl ) amino ] phenyl ) -3- ( pyridin- - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1 - carboxylate ( 550 mg , 41.60 % ) as a yellow solid . LCMS : C32H33C1F3N7O4S requires : 703.2 , found : m / z = 704.2 [ M + H ] * . [ 000911 ] Step - 2 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoroazetidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000912 ] A mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( 3 - fluoroazetidin - 1- ylsulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1- carboxylate ( 500 mg , 0.710 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Fluoro Phenyl x 150 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : mL / min ; Gradient : 5 % B to 40 % B in 12min ; Wave Length : 254/220 nm to afford N- ( 5- chloro - 2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) -3 - fluoroazetidine - 1 - sulfonamide trifluoroacetic acid salt ( 264.2 mg , 50.88 % ) as a yellow solid . LCMS : C27H25CIF3N7O2S requires : 603.1 ;, found : m / z = 604.2 [ M + H ] * . ' H NMR ( 300 MHz , Methanol - d4 ) 88.81 - 8.72 ( m , 2H ) , 8.41 – 8.37 ( m , 1H ) , 8.10 - 8.05 ( m , 2H ) , 7.– 7.79 ( m , 1H ) , 7.69 – 7.63 ( m , 1H ) , 7.40 – 7.33 ( m , 1H ) , 7.14 – 7.01 ( m , 2H ) , 5.42 – 5.14 ( m , 1H ) , 4.25 – 4.10 ( m , 2H ) , 4.09 – 3.91 ( m , 2H ) , 3.67 – 3.54 ( m , 4H ) , 3.48 – 3.38 ( m , 4H ) . - - - 606 - 1100573566 5 AMERICAS [ 000913 ] Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) HN - S N CI- abs F B - O N HN - S abs CI- F OH F F N -N . F sodo Br F N .NH HN - S Labs F N Cl F .N . Boc joda do Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - F N Boc HN - S abs Cl F TFA , 0 ° C , 1 h F OH F N N. F Step - N NH [ 000914 ] Step - 1 : Synthesis of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3- fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenylpiperazine - 1 - carboxylate ( 2 ) [ 000915 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenylpiperazine - 1 - carboxylate ( 900 mg , 1.791 mmol , 1 equiv ) and ( 3R ) -N- [ 5 - chloro- - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - fluoropyrrolidine - 1- -607- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT sulfonamide ( 757 mg , 1.791 mmol , 1 equiv ) in dioxane ( 10 mL ) was added CSF ( 544 mg , 3.5mmol , 2 equiv ) and Pd ( AMPHOS ) 2Cl2 ( 127 mg , 0.179 mmol , 0.1 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2- fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin - 1 - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] -2 - fluorophenyl } piperazine - 1 - carboxylate ( 660 mg , 51.30 % ) as a white solid . LCMS : C33H35C1F3N7O4S requires : 717.2 , found : m / z = 718.3 [ M + H ] * . [ 000916 ] Step - 2 : Synthesis of ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin- - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000917 ] A mixture of tert - butyl 4- { 4- [ 4- ( 5 - chloro - 2 - fluoro - 3 - { [ ( 3R ) -3 - fluoropyrrolidin- - ylsulfonyl ] amino } phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2 - fluorophenyl } piperazine - 1- carboxylate ( 660 mg , 0.919 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , 30 x 150 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 5 % B to 40 % B in 12 min ; Wave Length : 254/220 nm to provide ( 3R ) -N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } phenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 295.8 mg , = 618.40.13 % ) as a yellow solid . LCMS : C28H27ClF3N7O2S requires : 617.2 , found : m / z [ M + H ] * . ' H NMR ( 300 MHz , Methanol - d4 ) 8 8.83 - 8.68 ( m , 2H ) , 8.64 ( s , 1H ) , 8.18 - 8.( m , 2H ) , 7.90 – 7.74 ( m , 2H ) , 7.74 – 7.65 ( m , 1H ) , 7.41 – 7.26 ( m , 2H ) , 5.41 – 5.14 ( m , 1H ) , 3.63 – 3.38 ( m , 12H ) , 2.33 – 1.93 ( m , 2H ) . [ 000918 ] - Synthesis of N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( ( 5 ) - 608 - 1100573566 5 AMERICAS F NH OH F NH F Br N F Cl- = Attorney Docket No .: 121843.002NU - 3200 PCT DMAP , pyr , 40 ° C Step - NH CNH F F Br F Br 2niP₂B , Pd ( dppf ) Cl2 , -SP = C NH F N - N F N N. Boc dioxane , KOAc , 90 ° C F ` B ' F Step - Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - 0 . O = 8- · N . NH .

-F F NH TFA , rt , 2 h F -F OH Step - F O = S - N · N . N F N .N . Boc N. N F NH -609- 1100573566 5 AMERICAS [ 000919 ] Step - 1 : Synthesis fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 2 ) [ 000920 ] Attorney Docket No .: 121843.002NU - 3200 PCT of N- [ 3 - bromo - 5- ( difluoromethyl ) -2- To a mixture of 3 - bromo - 5- ( difluoromethyl ) -2 - fluoroaniline ( 1.8 g , 7.4mmol , 1 equiv ) and pyrrolidine - 1 - sulfonyl chloride ( 2.3 g , 13.498 mmol , 1.8 equiv ) in pyridine ( 3 mL ) was added DMAP ( 1.1 g , 8.999 mmol , 1.2 equiv ) . The resulting mixture was stirred at ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford N- [ 3 - bromo - 5- ( difluoromethyl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide ( 1 g , 26.44 % ) as a yellow solid . LCMS : C11H12BrF3N2O2S requires : 371.9 , found : m / z = 373.0 [ M + H ] * . - [ 000921 ] Step - 2 : Synthesis of N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 3 ) [ 000922 ] To a mixture of N- [ 3 - bromo - 5- ( difluoromethyl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide ( 900 mg , 2.412 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 1225 mg , 4.824 mmol , 2 equiv ) in dioxane ( 10 mL ) was added KOAc ( 473 mg , 4.824 mmol , 2 equiv ) and Pd ( dppf ) Cl2 ( 197 mg , 0.241 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then filtered . The resulting mixture was concentrated under reduced pressure to afford N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 900 mg , crude ) as a black oil . LCMS : C11H12BrF3N2O2S requires : 420.2 ;, found : m / z = 421.1 [ M + H ] * . [ 000923 ] Step - 3 : Synthesis of tert - butyl 4- ( 4- { 4- [ 5- ( difluoromethyl ) -2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3- fluorophenyl ) piperazine - 1 - carboxylate ( 4 ) [ 000924 ] To a mixture of N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 2.3 g , 5.572 mmol , 2.8 equiv ) and tert- butyl 4- [ 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } piperazine - 1 - carboxylate ( 1 g , 1.990 mmol , 1 equiv ) in 1,4 - dioxane ( 40 mL ) was added CsF ( 605 mg , 3.980 mmol , equiv ) in H2O ( 8 mL ) and Pd ( AMPHOS ) 2Cl2 ( 141 mg , 0.199 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 5- ( difluoromethyl ) - -610 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3- fluorophenyl ) piperazine - 1 - carboxylate ( 560 mg , 39.31 % ) as a yellow solid . LCMS : C34H37F4N7O4S requires : 715.3 , found : m / z = 716.1 [ M + H ] * . [ 000925 ] Step - 4 : Synthesis of of N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) [ 000926 ] A mixture of tert - butyl 4- ( 4- { 4- [ 5- ( difluoromethyl ) -2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } -3 - fluorophenyl ) piperazine - 1- carboxylate ( 470 mg , 0.657 mmol , 1 equiv ) in TFA ( 7 mL ) was stirred at room temperature for h . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : Xcelect CSH F - pheny OBD Column 19 x 250 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : 25 mL / min ; Gradient : 28 % B to 43 % B in 30 min ; Wave Length : 254/2nmto provide N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 293.mg , 61.19 % ) as a yellow solid . LCMS : C29H29F4N7O2S requires : 615.2 , found : m / z = 616.[ M + H ] * . ' H NMR ( 300 MHz , Methanol - d4 ) 8 8.70 – 8.63 ( m , 2H ) , 8.38 – 8.34 ( m , 1H ) , 7.93 – 7.77 ( m , 4H ) , 7.49 – 7.41 ( m , 1H ) , 7.13 – 6.99 ( m , 2H ) , 6.85 – 6.62 ( m , 1H ) , 3.63 – 3.55 ( m , 4H ) , 3.48 – 3.40 ( m , 4H ) , 3.34 ( s , 4H ) , 1.93 – 1.84 ( m , 4H ) . [ 000927 ] = Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) N HN - S N CI- F OH F ' N ' NH -611- 1100573566 5 AMERICAS ﻡﻻاﺩ O = S = IZ Br N Attorney Docket No .: 121843.002NU - 3200 PCT HN - S N CI- -F .N . Boc Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - N OH HN - S CI TFA , 0 ° C , 1 h F F ד ד Step - N ' N ' NH ' N ' N 、 Boc -612- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000928 ] Step - 1 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2 - fluorophenyl ] piperazine - 1- carboxylate ( 2 ) [ 000929 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2- fluorophenyl } piperazine - 1 - carboxylate ( 1 g , 1.990 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro- 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 805 mg , 1.990 mmol , 1 equiv ) in dioxane ( 10 mL ) was added CSF ( 604 mg , 3.980 mmol , 2 equiv ) and Pd ( AMPHOS ) 2Cl2 ( 141 mg , 0.199 mmol , 0.1 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 1 : 1 ) to afford tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2- fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2- fluorophenyl ] piperazine - 1 - carboxylate ( 700 mg , 40.18 % ) as a white solid . LCMS : C33H36C1F2N7O4S requires : 699.2 , found : m / z = 700.2 [ M + H ] + . [ 000930 ] Step - 2 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000931 ] A mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2 - fluorophenyl ] piperazine - 1- carboxylate ( 700 mg , 1.000 mmol , 1 equiv ) in TFA ( 7 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , 19 x 250 mm , 5 mµ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : 25 mL / min ; Gradient : 35 % B to 50 % B in 11 min ; Wave Length : 254/220 nm to provide N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 3 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 381.0 mg , 52.94 % ) as a yellow solid . LCMS : C28H28ClF2N7O2S requires : 599.2 , found : m / z = 600.2 [ M + H ] * . ' H NMR ( 300 MHz , Methanol - d4 ) 8 8.80 – 8.70 ( m , 2H ) , 8.66 ( s , 1H ) , 8.13 - 8.04 ( m , 2H ) , 7.- 7.73 ( m , 2H ) , 7.68 – 7.61 ( m , 1H ) , 7.41 – 7.24 ( m , 2H ) , 3.53 – 3.39 ( m , 8H ) , 3.36 – 3.34 ( m , 2H ) , 3.32 – 3.29 ( m , 2H ) , 2.02 – 1.63 ( m , 4H ) . = - 613 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000932 ] Synthesis of N- ( 5 - chloro - 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 7 ) HN - S CI- OH F F ' N ' NH -614- 1100573566 5 AMERICAS F. F F NO Br- NH EN K2CO3 , DMSO , rt , 5 h Step - - Br N F Attorney Docket No .: 121843.002NU - 3200 PCT 2 F NO ﻢﻟا LL CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - HN - S HN - S Fe , NH4Cl , EtOH , CI- CI- F AcOH , O₂H , 80 ° C , 0.5 h Step - NO HN - S TsOH , NaNO2 , KI , ACN , O₂H , 0 ° C , 10 min CI- Cl- HN- Step - HO = S = O -N F N Boc F F TFA , 0 ° C , 1 h Step - N. -N .

F ₂HN Ina HN N - Boc Pd - PEPPSI - IHeptCI , Cs2CO3 , dioxane , 90 ° C , 4 h Step - HN - S CI- OH ' N ' NH -615 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000933 ] yl ] pyridine ( 2 ) Step - 1 : Synthesis of 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4 - nitrophenyl ) pyrazol - 3- [ 000934 ] To a mixture of 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 5.8 g , 25.886 mmol , equiv ) in DMSO ( 50 mL ) was added K2CO3 ( 5.4 g , 38.829 mmol , 1.5 equiv ) and 1,2,3- trifluoro - 5 - nitrobenzene ( 5.5 g , 31.063 mmol , 1.2 equiv ) . The resulting mixture was stirred at room temperature for 5 h . The resulting mixture was then extracted with CH2Cl2 . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4- nitrophenyl ) pyrazol - 3 - yl ] pyridine ( 9 g , 82.10 % ) as a white solid . LCMS : C14H7BrF2N4Orequires : 379.9 , found : m / z = 380.9 [ M + H ] * . [ 000935 ] Step - 2 : Synthesis of N - 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 3 ) [ 000936 ] To a mixture of 4- [ 4 - bromo - 1- ( 2,6 - difluoro - 4 - nitrophenyl ) pyrazol - 3- yl ] pyridine ( 8.8 g , 23.089 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 9.3 g , 23.089 mmol , 1 equiv ) in dioxane ( 100 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 1.6 g , 2.309 mmol , 0.1 equiv ) and CsF ( 7.g , 46.178 mmol , 2 equiv ) in H2O ( 20 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2- fluorophenyl } pyrrolidine - 1 - sulfonamide ( 5.65 g , 33.81 % ) as a yellow solid . LCMS : C24H18C1F3N6O4S requires : 578.1 , found : m / z = 579.1 [ M + H ] + . [ 000937 ] Step - 3 : Synthesis of N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -5 - chloro - 2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 4 ) [ 000938 ] A mixture of Fe ( 2.7 g , 48.365 mmol , 5 equiv ) and NH4Cl ( 50 mg , 0.967 mmol , 0.1 equiv ) in AcOH ( 2 mL ) and H2O ( 10 mL ) was stirred at 80 ° C for 5 min . To the above mixture was added N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - nitrophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 5.6 g , 9.673 mmol , 1 equiv ) in EtOH ( 100 mL ) . The resulting mixture was stirred at 80 ° C for 0.5 h . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4- - 616 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl ) pyrazol - 4 - yl ] -5 - chloro - 2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 4.33 g , 65.24 % ) as a yellow solid . LCMS : C24H20C1F3N6O2S requires : 548.1 , found : m / z = 549.2 [ M + H ] * . [ 000939 ] Step - 4 : Synthesis of N - 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 5 ) [ 000940 ] To a mixture of N- { 3- [ 1- ( 4 - amino - 2,6 - difluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol- - yl ] -5 - chloro - 2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 3.7 g , 6.685 mmol , 1 equiv ) and TSOH ( 3.5 g , 20.055 mmol , 3 equiv ) in ACN ( 30 mL ) was added NaNO2 ( 1.4 g , 20.055 mmol , equiv ) in H2O ( 3 mL ) and KI ( 2.8 g , 16.712 mmol , 2.5 equiv ) at 0 ° C . The resulting mixture was stirred at 0 ° C for 10 min and then was warmed to room temperature . The mixture was stirred at room temperature for an additional 30 min . The mixture was then basified to pH = with saturated aqueous Na2CO3 . The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 2 ) to afford N- { 5 - chloro - 3- [ 1- ( 2,6- difluoro - 4 - iodophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1- sulfonamide ( 850 mg , 15.42 % ) as a brown solid . LCMS : C24H18C1F3IN5O2S requires : 658.9 , found : m / z = 659.9 [ M + H ] * . = [ 000941 ] Step - 5 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3,5 - difluorophenyl ] piperazine - 1- carboxylate ( 6 ) [ 000942 ] To a mixture of N- { 5 - chloro - 3- [ 1- ( 2,6 - difluoro - 4 - iodophenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 700 mg , 1.061 mmol , 1 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 494 mg , 2.652 mmol , 2.5 equiv ) in dioxane ( 10 mL ) was added Pd - PEPPSI - IHeptCl ( 103 mg , 0.106 mmol , 0.1 equiv ) and Cs2CO3 ( 864 mg , 2.6mmol , 2.5 equiv ) . The resulting mixture was stirred at 90 ° C for 4 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4- yl ) pyrazol - 1 - yl ) -3,5 - difluorophenyl ] piperazine - 1 - carboxylate ( 430 mg , 44.02 % ) as a brown solid . LCMS : C33H35C1F3N7O4S requires : 717.2 , found : m / z = 718.4 [ M + H ] * . -617- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000943 ] Step - 6 : Synthesis of N- ( 5 - chloro - 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 7 ) [ 000944 ] A mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3,5 - difluorophenyl ] piperazine - 1- carboxylate ( 430 mg , 0.599 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , x 150 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : mL / min ; Gradient : 5 % B to 50 % B in 12 min ; Wave Length : 254/220 nm to afford N- ( 5 - chloro- 3- { 1- [ 2,6 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 163.9 mg , 37.09 % ) as a light yellow solid . LCMS : C28H27CIF3 requires : 617.2 , found : m / z = 618.2 [ M + H ] * . ' H NMR ( 4MHz , Methanol - d4 ) 8 8.75 – 8.69 ( m , 2H ) , 8.28 – 8.24 ( m , 1H ) , 8.00 – 7.94 ( m , 2H ) , 7.67 – 7.60 ( m , 1H ) , 7.33 – 7.27 ( m , 1H ) , 6.99 – 6.90 ( m , 2H ) , 3.68 – 3.61 ( m , 4H ) , 3.45 – 3.38 ( m , - - 4H ) , 3.34 3.28 ( m , 4H ) , 1.96 – 1.85 ( m , 4H ) . [ 000945 ] – – Synthesis of N- ( 5 - chloro - 3- { 1- [ 2,5 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) HN - S N CI- -F N -N . LL OH LL F F N NH - 618 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Br HN N - Boc Br F ' N ' F Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Boc CI- HN - S Br Step - F 3 F ' N ' Boc N -N . .F 4 F ' N ' .N . Boc B. F LL Br NH FN K2CO3 , Cul , TMEDA , DMF , 120 ° C , 2 d Step - IZ CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - HN - S N CI- -F TFA , 0 ° C , 1 h ד ד F. OH F F Step - 4 N - N F N NH [ 000946 ] Step - 1 : Synthesis of tert - butyl 4- ( 4 - bromo - 2,5 - difluorophenyl ) piperazine- - carboxylate ( 2 ) [ 000947 ] To a mixture of 1 - bromo - 2,5 - difluoro - 4 - iodobenzene ( 14.5 g , 45.471 mmol , equiv ) and tert - butyl piperazine - 1 - carboxylate ( 10.6 g , 56.839 mmol , 1.25 equiv ) in toluene ( 150 mL ) was added t - BuONa ( 8.7 g , 90.942 mmol , 2 equiv ) , BINAP ( 5.7 g , 9.094 mmol , 0.equiv ) , and Pd2 ( dba ) 3 ( 4.2 g , 4.547 mmol , 0.1 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl 4- ( 4 - bromo - 2,5 - difluorophenyl ) piperazine - 1 - carboxylate ( 11 g , 51.30 % ) as a light yellow solid . LCMS : C15H19BrF2N2O2 requires : 376.0 , found : m / z = 377.[ M + H ] * . - 619 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000948 ] Step - 2 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] - 2,5 - difluorophenyl } piperazine - 1 - carboxylate ( 3 ) [ 000949 ] To a mixture of tert - butyl 4- ( 4 - bromo - 2,5 - difluorophenyl ) piperazine - 1- carboxylate ( 11 g , 29.160 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 7.2 g , 32.076 mmol , 1.1 equiv ) in DMF ( 150 mL ) was added K2CO3 ( 12.1 g , 87.480 mmol , 3 equiv ) , Cul ( 1.1 g , 5.832 mmol , 0.2 equiv ) , and TMEDA ( 1.4 g , 11.664 mmol , 0.4 equiv ) . The resulting mixture was stirred at 120 ° C for two days under a nitrogen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) . The residue was purified by trituration with EtOAc . This resulted in tert - butyl 4- { 4- [ 4- bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2,5 - difluorophenyl } piperazine - 1 - carboxylate ( 900 mg , 5.34 % ) as a brown solid . LCMS : C23H24BrF2N5O2 requires : 519.1 , found : m / z = 520.3 [ M + H ] * . [ 000950 ] Step - 3 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2,5 - difluorophenyl ] piperazine - 1- carboxylate ( 4 ) [ 000951 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2,5- difluorophenylpiperazine - 1 - carboxylate ( 900 mg , 1.730 mmol , 1 equiv ) and N- [ 5 - chloro - 2- fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 7mg , 1.730 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 245 mg , 0.3mmol , 0.2 equiv ) and CsF ( 525 mg , 3.460 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 1 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 3 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2,5 - difluorophenyl ] piperazine - 1 - carboxylate ( 550 mg , 42.07 % ) as a white solid . LCMS : C33H35C1F3N7O4S requires : 717.2 , found : m / z = 718.3 [ M + H ] * . [ 000952 ] Step - 4 : Synthesis of N- ( 5 - chloro - 3- { 1- [ 2,5 - difluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 5 ) [ 000953 ] A mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2,5 - difluorophenyl ] piperazine - 1- -620- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT carboxylate ( 550 mg , 0.766 mmol , 1 equiv ) in TFA ( 6 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum and lyophilized . This resulted in N- ( 5 - chloro - 3- { 1- [ 2,5 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 345.2 mg , crude ) as a yellow solid . LCMS : C28H27C1F3N7O2S requires : 617.1 , found : m / z = 618.2 [ M + H ] * . ' H NMR ( 4MHz , Methanol - d4 ) 8 8.82 - 8.75 ( m , 2H ) , 8.51 - 8.46 ( m , 1H ) , 8.17 – 8.10 ( m , 2H ) , 7.7.81 ( m , 1H ) , 7.68 – 7.61 ( m , 1H ) , 7.37 – 7.31 ( m , 1H ) , 7.29 – 7.18 ( m , 1H ) , 3.50 – 3.44 ( m , 8H ) , 3.38 – 3.29 ( m , 4H ) , 1.97 – 1.86 ( m , 4H ) . [ 000954 ] – Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyrimidin - 2 - yl ] - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 7 ) N CI- - HN - S -F OH F F ' N ' NH -621 - 1100573566 5 AMERICAS HO .N .

Br .N . IZ ' N ' Boc Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 80 ° C Step - TfO .N . O₂fT , TEA , ' N ' .N . DCM , rt , 2 h Boc Step - Br N. N.

` N ' N Boc .N .

Attorney Docket No .: 121843.002NU - 3200 PCT ' N ' N- KOH , t - BuOH , 70 ° C Step - Boc ' N ' .N . Boc F Br NH N N K2CO3 , Cul , TMEDA , DMF , 90 ° C , 1 h Step - = S = CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , H2O , 90 ° C , 1h Step - HN - S N Cl HN - S CI- TFA , 0 ° C , 2h N. Step - N Boc F OH ' N ' NH [ 000955 ] carboxylate ( 2 ) [ 000956 ] Step - 1 : Synthesis of tert - butyl 4- ( 2 - methoxypyrimidin - 5 - yl ) piperazine - 1- To a mixture of 5 - bromo - 2 - methoxypyrimidine ( 7.5 g , 39.680 mmol , 1 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 7.39 g , 39.680 mmol , 1 equiv ) in toluene ( 30 mL ) was added BINAP ( 0.49 g , 0.794 mmol , 0.02 equiv ) , t - BuONa ( 7.63 g , 79.360 mmol , 2 equiv ) , and Pd2 ( dba ) 3 ( 0.47 g , 0.518 mmol , 0.01 equiv ) . The resulting mixture was stirred at 80 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under -622- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 2 - methoxypyrimidin - 5 - yl ) piperazine - 1 - carboxylate ( 4.3 g , 25.36 % ) as a yellow solid . LCMS : C14H22N4O3 requires : 294.2 , found : m / z = 295.2 [ M + H ] * . [ 000957 ] carboxylate ( 3 ) Step - 2 : Synthesis of tert - butyl 4- ( 2 - hydroxypyrimidin - 5 - yl ) piperazine - 1- = [ 000958 ] To a mixture of tert - butyl 4- ( 2 - methoxypyrimidin - 5 - yl ) piperazine - 1- carboxylate ( 3.21 g , 10.905 mmol , 1 equiv ) in t - BuOH ( 30 mL ) was added KOH ( 0.86 g , 15.267 mmol , 1.4 equiv ) . The resulting mixture was stirred at 70 ° C overnight . The mixture was then neutralized to pH 7 with aqueous HCl ( 2 M ) . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with CH2Cl2 : MeOH ( 10 : 1 ) to afford tert - butyl 4- ( 2 - hydroxypyrimidin - 5 - yl ) piperazine- - carboxylate ( 2.61 g , 85.38 % ) as a yellow solid . LCMS : C13H20N4O3 requires : 280.2 , found : m / z = 281.2 [ M + H ] * . [ 000959 ] Step - 3 : Synthesis of tert - butyl 4- [ 2- ( trifluoromethanesulfonyloxy ) pyrimidin - 5 - yl ] piperazine - 1 - carboxylate ( 4 ) [ 000960 ] To a mixture of tert - butyl 4- ( 2 - hydroxypyrimidin - 5 - yl ) piperazine - 1- carboxylate ( 2.41 g , 8.597 mmol , 1 equiv ) in DCM ( 7 mL ) was added TEA ( 2.61 g , 25.7mmol , 3 equiv ) and O₂fT ( 4.85 g , 17.194 mmol , 2 equiv ) at 0 ° C . The resulting mixture was then warmed and stirred at room temperature for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4- [ 2- ( trifluoromethanesulfonyloxy ) pyrimidin - 5 - yl ] piperazine - 1 - carboxylate ( 1.4159 g , 37.94 % ) as a light brown solid . LCMS : C14H19F3N4O5S requires : 412.1 , found : m / z = 413.1 [ M + H ] * .

Step - 4 : Synthesis of tert - butyl 4- { 2- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyrimidin - 5 - yl } piperazine - 1 - carboxylate ( 5 ) [ 000961 ] [ 000962 ] To a mixture of tert - butyl 4- [ 2- ( trifluoromethanesulfonyloxy ) pyrimidin - 5- yl ] piperazine - 1 - carboxylate ( 3 g , 7.275 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3- yl ) pyridine ( 2.5 g , 10.913 mmol , 1.5 equiv ) in DMF ( 40 mL ) was added K2CO3 ( 3.0 g , 21.8mmol , 3 equiv ) , CuI ( 277 mg , 1.455 mmol , 0.2 equiv ) , and TMEDA ( 338 mg , 2.910 mmol , 0.equiv ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was -623- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with EtOAc : MeOH ( 19 : 1 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl 4- { 2- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyrimidin- - ylpiperazine - 1 - carboxylate ( 900 mg , 22.89 % ) as a brown solid . LCMS : C21H24BrN7Orequires : 485.1 , found : m / z = 486.3 [ M + H ] + . [ 000963 ] Step - 5 : Synthesis of tert - butyl 4- [ 2- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyrimidin - 5 - yl ] piperazine - 1- carboxylate ( 6 ) [ 000964 ] To a mixture of tert - butyl 4- { 2- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyrimidin - 5 - yl } piperazine - 1 - carboxylate ( 900 mg , 1.850 mmol , 1 equiv ) and N- [ 5 - chloro- - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 749 mg , 1.850 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 131 mg , 0.185 mmol , 0.1 equiv ) and CsF ( 562 mg , 3.700 mmol , 2 equiv ) in O₂H ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with EtOAc : MeOH ( 9 : 1 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl 4- [ 2- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyrimidin - 5 - yl ] piperazine - 1- carboxylate ( 700 mg , 44.23 % ) as a brown semi - solid . LCMS : C31H35ClFN9O4S requires : 683.2 , found : m / z = 684.3 [ M + H ] * . [ 000965 ] Step - 6 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1-5- ( piperazin - 1- yl ) pyrimidin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 7 ) [ 000966 ] A mixture of tert - butyl 4- [ 2- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyrimidin - 5 - yl ] piperazine - 1- carboxylate ( 700 mg , 1.023 mmol , 1 equiv ) in TFA ( 7 mL ) was stirred at 0 ° C for 2 h . The resulting mixture was then concentrated under vacuum . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , x 250 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : mL / min ; Gradient : 33 % B to 48 % B in 10 min ; Wave Length : 254/220 nm to afford N- ( 5- chloro - 2 - fluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyrimidin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 342.5 mg , 46.67 % ) as a yellow -624- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT solid . LCMS : C26H27CIFN9O2S requires : 583.2 , found : m / z = 584.1 [ M + H ] * . ' H NMR ( 3MHz , Methanol - d4 ) 8 8.98 - 8.91 ( m , 1H ) , 8.84 – 8.76 ( m , 2H ) , 8.75 -8.65 ( m , 2H ) , 8.22 – 8.14 ( m , 2H ) , 7.69 – 7.60 ( m , 1H ) , 7.40 – 7.30 ( m , 1H ) , 3.73 – 3.64 ( m , 4H ) , 3.53 – 3.43 ( m , 4H ) , 3.38 – 3.28 ( m , 4H ) , 1.97 – 1.86 ( m , 4H ) . [ 000967 ] Synthesis - - of N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- { 1- [ 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) F F NH .F 0 = 8- O = N. NH F -F F F F F OH N ' N NH Br N -N N - Boc Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , H2O , 90 ° C , 1.5 h TFA , 0 ° C , 1 h Step - Step - F 0 . O = S - N F 0 . O = S - N NH -F N. N N NH F -F COH F N N NH N. - Boc -625- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000968 ] Step - 1 : Synthesis of tert - butyl 4- ( 4- { 4- [ 5- ( difluoromethyl ) -2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine- - carboxylate ( 2 ) [ 000969 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenylpiperazine - 1 - carboxylate ( 1.2 g , 2.477 mmol , 1 equiv ) and N- [ 5- ( difluoromethyl ) - - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 1.04 g , 2.477 mmol , 1 equiv ) in dioxane ( 40 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 175 mg , 0.248 mmol , 0.1 equiv ) and CsF ( 753 mg , 4.954 mmol , 2 equiv ) in O₂H ( 8 mL ) . The resulting mixture was stirred at 90 ° C for 1.5 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : EtOAc ( 1 : 1 ) to afford tert - butyl 4- ( 4- { 4- [ 5- ( difluoromethyl ) -2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ] -3- ( pyridin - 4 - yl ) pyrazol- - yl } phenyl ) piperazine - 1 - carboxylate ( 450 mg , 20.83 % ) as an off - white solid . LCMS : C34H38F3N7O4S requires : 697.3 , found : m / z = 698.3 [ M + H ] * . [ 000970 ] Step - 2 : Synthesis of N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- { 1- [ 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000971 ] A mixture of tert - butyl 4- ( 4- { 4- [ 5- ( difluoromethyl ) -2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl } phenyl ) piperazine - 1 - carboxylate ( 4mg , 0.631 mmol , 1 equiv ) in TFA ( 3 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , 30 x 150 mm , mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 5 % B to 40 % B in 12 min ; Wave Length : 254/220 nm to afford N- [ 5- ( difluoromethyl ) -2 - fluoro - 3- { 1- [ 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 304.1 mg , 67.56 % ) as a yellow solid . LCMS : C29H30F3N7O2S requires : 597.2 , found : m / z 598.2 [ M + H ] * . ' H NMR ( 4= MHz , Methanol - d4 ) 8 8.83 - 8.70 ( m , 2H ) , 8.62 ( s , 1H ) , 8.21 - 8.07 ( m , 2H ) , 7.98 – 7.87 ( m , 2H ) , 7.86 – 7.76 ( m , 1H ) , 7.60 – 7.49 ( m , 1H ) , 7.35 – 7.19 ( m , 2H ) , 7.06 – 6.66 ( m , 1H ) , 3.- – 3.50 ( m , 4H ) , 3.49 – 3.40 ( m , 4H ) , 3.36 – 3.28 ( m , 4H ) , 2.02 – 1.82 ( m , 4H ) . -626- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000972 ] Synthesis of N- ( 5 - chloro - 3- { 1- [ 4- ( 1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide acid salt ( 6 ) trifluoroacetic · N . O = S NH F CI- F OH -F N.

N NH 1100573566 5 AMERICAS CI- F -Br Attorney Docket No .: 121843.002NU - 3200 PCT HN N - Boc Cl Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - 2niP₂B , Pd2 ( dba ) 3 , X - Phos , KOAc , methoxycyclopentane , 110 ° C , 3 h Step - to Br ﻢﻄﺒﻫ N N - Boc N O = S - N bc N N - Boc N - Boc LL Br- NH Cu ( OAc ) 2 , pyr , molecular sieves 4A , 100 ° C Step - O = S = IZ N ' CI Pd ( AMPHOS ) 2Cl2 , CSF dioxane , H2O , 90 ° C , 2 h Step - O = = 8- CI- NH -F NH F. OH TFA , 0 ° C , 1 h F -F CI- F Step - N N - Boc 5700- [ 000973 ] N N NH Step - 1 : Synthesis of tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) -1,4 - diazepane- - carboxylate ( 2 ) [ 000974 ] To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 21 g , 100.267 mmol , equiv ) and tert - butyl 1,4 - diazepane - 1 - carboxylate ( 25.10 g , 125.334 mmol , 1.25 equiv ) in toluene ( 200 mL ) was added BINAP ( 12.49 g , 20.053 mmol , 0.2 equiv ) , t - BuONa ( 19.27 g , 200.534 mmol , 2 equiv ) , and Pd2 ( dba ) 3 ( 9.18 g , 10.027 mmol , 0.1 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column -628- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) - 1,4 - diazepane - 1 - carboxylate ( 30 g , 90.99 % ) as a brown oil . LCMS : C16H22C1FN2O2 requires : 328.1 , found : m / z = 329.3 [ M + H ] * . [ 000975 ] Step - 2 : Synthesis of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -1,4 - diazepane - 1 - carboxylate ( 3 ) [ 000976 ] To a mixture of tert - butyl 4- ( 4 - chloro - 3 - fluorophenyl ) -1,4 - diazepane - 1- carboxylate ( 27 g , 82.114 mmol , 1 equiv ) and bis ( pinacolato ) diboron ( 2niP₂B ) ( 31.28 g , 123.171 mmol , 1.5 equiv ) in methoxycyclopentane ( 300 mL ) was added AcOK ( 24.18 g , 246.342 mmol , 3 equiv ) , XPhos ( 2.35 g , 4.927 mmol , 0.06 equiv ) , and Pd2 ( dba ) 3 ( 2.26 g , 2.4mmol , 0.03 equiv ) . The resulting mixture was stirred at 110 ° C for 3 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert- butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -1,4 - diazepane - 1- carboxylate ( 12 g , 34.77 % ) as a white solid . LCMS : C22H34BFN2O4 requires : 420.3 , found : m / z = 421.1 [ M + H ] * . [ 000977 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] - - fluorophenyl } -1,4 - diazepane - 1 - carboxylate ( 4 ) [ 000978 ] To a mixture of tert - butyl 4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -1,4 - diazepane - 1 - carboxylate ( 12 g , 28.549 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 7.04 g , 31.404 mmol , 1.1 equiv ) in pyridine ( 120 mL ) was added Cu ( OAc ) 2 ( 10.37 g , 57.098 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 12 g ) . The resulting mixture was stirred at 100 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 3 ) to afford tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl ) -1,4- diazepane - 1 - carboxylate ( 3 g , 20.35 % ) as a white solid . LCMS : C24H27BrFN5O2 requires : 515.1 , found : m / z = 516.3 [ M + H ] + . [ 000979 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -1,4 - diazepane - 1- carboxylate ( 5 ) - 629 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 000980 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl - 1,4 - diazepane - 1 - carboxylate ( 1 g , 1.936 mmol , 1 equiv ) and N- [ 5 - chloro - 2- fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 0.78 g , 1.936 mmol , 1 equiv ) in dioxane ( 10 mL ) was added CsF ( 0.59 g , 3.872 mmol , 2 equiv ) and Pd ( AMPHOS ) 2Cl2 ( 0.14 g , 0.194 mmol , 0.1 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -1,4- diazepane - 1 - carboxylate ( 700 mg , 50.61 % ) as a grey solid . LCMS : C34H38ClF2N7O4S requires : 713.2 , found : m / z = 714.3 [ M + H ] * [ 000981 ] Step - 5 : Synthesis of N- ( 5 - chloro - 3- { 1- [ 4- ( 1,4 - diazepan - 1 - yl ) -2- fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 000982 ] A mixture of tert - butyl 4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -1,4 - diazepane - 1- carboxylate ( 700 mg , 0.980 mmol , 1 equiv ) in TFA ( 10 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , 30 x 150 mm , 5 mµ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : 60 mL / min ; Gradient : 5 % B to 40 % B in 12 min ; Wave Length : 254/220 nm to afford N- ( 5 - chloro - 3- { 1- [ 4- ( 1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 347.2 mg , 48.65 % ) as 614.3 [ M + H ] * . ' H a yellow solid . LCMS : C29H30C1F2N7O2S requires : 613.2 , found : m / z = NMR ( 300 MHz , Methanol - d4 ) 8 8.79 – 8.70 ( m , 2H ) , 8.35 - 8.28 ( m , 1H ) , 8.13 - 8.04 ( m , 2H ) , 7.82 – 7.69 ( m , 1H ) , 7.67 – 7.58 ( m , 1H ) , 7.37 – 7.28 ( m , 1H ) , 6.93 – 6.79 ( m , 2H ) , 3.- - - - 3.85 ( m , 2H ) , 3.75 -3.65 ( m , 2H ) , 3.51 - 3.42 ( m , 2H ) , 3.38 - 3.33 ( m , 4H ) , 3.33 - 3.29 ( m , 2H ) , 2.33 – 2.19 ( m , 2H ) , 1.98 – 1.84 ( m , 4H ) . [ 000983 ] Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) -630- 1100573566 5 AMERICAS CI- N - Boc 2200- HN - S N Attorney Docket No .: 121843.002NU - 3200 PCT OH F -N . F LL F IZ ' N ' NH CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1.5 h TFA , 0 ° C , 1 h Step - Step - HN - S Cl N HN - S CI- F N ' N ' N .、 Boc F OH -N . ' N ' NH [ 000984 ] Step - 1 : Synthesis of tert - butyl 4- [ 5- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 2 - yl ] piperazine - 1- carboxylate ( 2 ) [ 000985 ] To a mixture of tert - butyl 4- { 5- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] pyridin- - yl } piperazine - 1 - carboxylate ( 1.2 g , 2.472 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 1 g , 2.4mmol , 1 equiv ) in dioxane ( 40 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 0.18 g , 0.247 mmol , 0.equiv ) and CSF ( 0.75 g , 4.944 mmol , 2 equiv ) in O₂H ( 8 mL ) . The resulting mixture was stirred at 90 ° C for 1.5 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with DCM : EtOAc ( 1 : 1 ) to afford tert - butyl 4- [ 5- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- -631- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 2 - yl ] piperazine - 1 - carboxylate ( 700 mg , 33.15 % ) as an off - white solid . LCMS : C32H36C1FN8O4S requires : 682.2 , found : m / z = = 683.2 [ M + H ] * . [ 000986 ] Step - 2 : Synthesis of N- ( 5 - chloro - 2 - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin- - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000987 ] A mixture of tert - butyl 4- [ 5- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyridin - 2 - yl ] piperazine - 1 - carboxylate ( 690 mg , 1.01 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , x 150 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : ACN ; Flow rate : mL / min ; Gradient : 5 % B to 40 % B in 12 min ; Wave Length : 254/220 nm to afford N- ( 5 - chloro- - fluoro - 3- { 1- [ 6- ( piperazin - 1 - yl ) pyridin - 3 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 462.3 mg , 64.42 % ) as a yellow solid . LCMS : C27H28C1FN8O2S requires : 582.2 , found : m / z = 583.3 [ M + H ] * . ' H NMR ( 4MHz , Methanol - d4 ) 8 8.86 - 8.72 ( m , 3H ) , 8.61 ( s , 1H ) , 8.24 – 8.18 ( m , 1H ) , 8.17 - 8.11 ( m , 2H ) , 7.70 – 7.61 ( m , 1H ) , 7.42 – 7.33 ( m , 1H ) , 7.13 ( m , 1H ) , 4.05 – 3.86 ( m , 4H ) , 3.42 – 3.( m , 4H ) , 3.35 3.30 ( m , 4H ) , 2.00 – 1.84 ( m , 4H ) . [ 000988 ] - - Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyrimidin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) F HN - S -F F. OH ' N ' .NH -632- 1100573566 5 AMERICAS Br N. ﻡﻻاﺩ F IN Attorney Docket No .: 121843.002NU - 3200 PCT HN - S -F ' N ' Pd ( AMphos ) 2Cl2 , CSF , dioxane , H2O , 90 ° C , 1 h Boc ' N ' Step - .N 、 Boc HN - S TFA , 0 ° C , 1 h OH Step - N ' N ' NH [ 000989 ] Step - 1 : Synthesis of tert - butyl 4- [ 2- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyrimidin - 5 - yl ] piperazine - 1- carboxylate ( 2 ) [ 000990 ] To a mixture of tert - butyl 4- { 2- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] pyrimidin - 5 - yl } piperazine - 1 - carboxylate ( 900 mg , 1.850 mmol , 1 equiv ) and N- [ 2,5- difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 718 mg , 1.850 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMphos ) 2Cl2 ( 131 mg , 0.1mmol , 0.1 equiv ) and CSF ( 562 mg , 3.700 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with EtOAc : MeOH ( 9 : 1 ) to afford tert - butyl 4- [ 2- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyrimidin - 5 - yl ] piperazine - 1- carboxylate ( 700 mg , 45.32 % ) as a brown solid . LCMS : C31H35F2N9O4S requires : 667.2 , found : m / z = 668.3 [ M + H ] * . [ 000991 ] Step - 2 : Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyrimidin - 2- yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 000992 ] A mixture of tert - butyl 4- [ 2- ( 4- ( 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) pyrimidin - 5 - yl ] piperazine - 1- -633- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT carboxylate ( 700 mg , 1.048 mmol , 1 equiv ) in TFA ( 7 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , x 250 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : mL / min ; Gradient : 30 % B to 45 % B in 10 min ; Wave Length : 254/220 nm to afford N- ( 2,5- difluoro - 3- { 1- [ 5- ( piperazin - 1 - yl ) pyrimidin - 2 - yl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 320.0 mg , 44.24 % ) as a yellow solid . LCMS : C26H27F2N9O2S requires : 567.2 , found : m / z 568.2 [ M + H ] * . ' H NMR ( 4= = MHz , Methanol - d4 ) 8 8.97 – 8.92 ( m , 1H ) , 8.84 – 8.78 ( m , 2H ) , 8.71 – 8.66 ( m , 2H ) , 8.8.17 ( m , 2H ) , 7.47 - 7.38 ( m , 1H ) , 7.13 – 7.04 ( m , 1H ) , 3.72 – 3.65 ( m , 4H ) , 3.51 - 3.44 ( m , 4H ) , 3.40 – 3.35 ( m , 4H ) , 1.96 – 1.85 ( m , 4H ) . [ 000993 ] - Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) HN - S N OH -N . F ' N ' NH -634- 1100573566 5 AMERICAS Br N - N N -N Boc ﻝا FL - B IZ Attorney Docket No .: 121843.002NU - 3200 PCT Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h Step - HN - S N F TFA , 0 ° C , 1 h N Step - HN - S · F N N Boc F OH F F ' N ' .NH [ 000994 ] Step - 1 : Synthesis of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1- carboxylate ( 2 ) [ 000995 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl } piperazine - 1 - carboxylate ( 900 mg , 1.791 mmol , 1 equiv ) and N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 695 mg , 1.791 mmol , 1 equiv ) in dioxane ( 10 mL ) was added CSF ( 544 mg , 3.582 mmol , 2 equiv ) and Pd ( AMPHOS ) 2Cl2 ( 126 mg , 0.179 mmol , 0.1 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 3 ) to afford tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3- fluorophenyl ] piperazine - 1 - carboxylate ( 600 mg , 48.98 % ) as a yellow solid . LCMS : C33H36F3N7O4S requires : 683.2 , found : m / z = 684.3 [ M + H ] * . [ 000996 ] Step - 2 : Synthesis of N- ( 2,5 - difluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1- yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) -635- 1100573566 5 AMERICAS [ 000997 ] A mixture of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] piperazine - 1- carboxylate ( 600 mg , 0.878 mmol , 1 equiv ) in TFA ( 6 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : XSelect CSH Prep C18 OBD Column , 19 x 250 mm , 5 mµ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : 25 mL / min ; Gradient : 30 % B to 45 % B in 12 min ; Wave Length : 254/220 nm to afford N- ( 2,5 - difluoro - 3- { 1- [ 2 - fluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4- yl } phenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 284.0 mg , 46.39 % ) as a yellow solid . LCMS : C28H28F3N7O2S requires : 583.2 , found : m / z = 584.1 [ M + H ] * . ' H NMR ( 3MHz , Methanol - d4 ) 8 8.80 - 8.72 ( m , 2H ) , 8.41 - 8.34 ( m , 1H ) , 8.16 – 8.08 ( m , 2H ) , 7.90- 7.78 ( m , 1H ) , 7.47 - 7.35 ( m , 1H ) , 7.14 – 7.01 ( m , 3H ) , 3.65 - 3.55 ( m , 4H ) , 3.47 - 3.38 ( m , 4H ) , 3.383.33 ( m , 4H ) , 1.98 – 1.84 ( m , 4H ) . [ 000998 ] - = Synthesis of N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R , 5R ) -3,5 - dimethylpiperazin - 1 - yl ] -2- fluorophenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ; trifluoroacetic acid ( 6 ) CI IZ = √ = F N - N F OH F N- abs abs NH -636- 1100573566 5 AMERICAS F CI- Attorney Docket No .: 121843.002NU - 3200 PCT HN F ( R ) ( R ) -N Cl Boc -Br Pd2 ( dba ) ³ , BINAP , t - BuONa , toluene , 60 ° C 2niP₂B , Pd2 ( dba ) 3 , X - Phos , KOAC methoxycyclopentane , 110 ° C , 3 h Step - CI Br Step - F N N - N F N -N Boc IN O = 0 : F > CI- Boc ' N ' N. Boc Br NH EN Cu ( OAc ) 2 , molecular sieves 4A , pyridine , 60 ° C Step - HN - S B - N Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h N Step - CI IZ O = S : = N - N F TFA , 0 ° C , 1 h Step - N- -N Boc N - N LL F. COH F F N- abs abs NH [ 000999 ] Step - 1 : Synthesis of tert - butyl ( 2R , 6R ) -4- ( 4 - chloro - 3 - fluorophenyl ) -2,6- dimethylpiperazine - 1 - carboxylate ( 2 ) -637- 1100573566 5 AMERICAS [ 0001000 ] Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 4.9 g , 23.331 mmol , equiv ) and tert - butyl ( 2R , 6R ) -2,6 - dimethylpiperazine - 1 - carboxylate ( 5 g , 23.331 mmol , equiv ) in toluene ( 60 mL ) was added Pd2 ( dba ) 3 ( 214 mg , 0.233 mmol , 0.01 equiv ) , t - BuONa ( 3.4 g , 32.663 mmol , 1.4 equiv ) , and BINAP ( 291 mg , 0.467 mmol , 0.02 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 10 : 1 ) to afford tert - butyl ( 2R , 6R ) -4- ( 4 - chloro - 3- fluorophenyl ) -2,6 - dimethylpiperazine - 1 - carboxylate ( 5 g , 56.26 % ) as a brown solid . LCMS : C17H24C1FN2O2 requires : 342.1 , found : m / z = 343.2 [ M + H ] * . [ 0001001 ] Step - 2 : Synthesis of tert - butyl ( 2R , 6R ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl- 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -2,6 - dimethylpiperazine - 1 - carboxylate ( 3 ) [ 0001002 ] To a mixture of tert - butyl ( 2R , 6R ) -4- ( 4 - chloro - 3 - fluorophenyl ) -2,6- dimethylpiperazine - 1 - carboxylate ( 5 g , 14.584 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 5.6 g , 21.8mmol , 1.5 equiv ) in methoxycyclopentane ( 70 mL ) was added Pd2 ( dba ) 3 ( 401 mg , 0.438 mmol , 0.03 equiv ) , KOAc ( 4.3 g , 43.752 mmol , 3 equiv ) , and XPhos ( 417 mg , 0.875 mmol , 0.equiv ) . The resulting mixture was stirred at 110 ° C for 3 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 9 : 1 ) to afford tert - butyl ( 2R , 6R ) -4- [ 3 - fluoro- 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -2,6 - dimethylpiperazine - 1 - carboxylate ( 5 g , 71.04 % ) as a brown solid . LCMS : C23H36BFN2O4 requires : 434.3 , found : m / z = 435.[ M + H ] + . [ 0001003 ] Step - 3 : Synthesis of tert - butyl ( 2R , 6R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4- yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } -2,6 - dimethylpiperazine - 1 - carboxylate ( 4 ) [ 0001004 ] To a mixture of tert - butyl ( 2R , 6R ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -2,6 - dimethylpiperazine - 1 - carboxylate ( 3.5 g , 8.058 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 2 g , 8.864 mmol , 1.1 equiv ) in pyridine ( 40 mL ) was added Cu ( OAc ) 2 ( 2.9 g , 16.116 mmol , 2 equiv ) and molecular sieves type 4A ( 3.5 g ) . The resulting mixture was stirred at 60 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc -638- 1100573566 5 AMERICAS ( 1 : 1 ) to afford tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT ( 2R , 6R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl } -2,6 - dimethylpiperazine - 1 - carboxylate ( 1.5 g , 31.58 % ) as an off - white solid . LCMS : C25H29BrFN5O2 requires : 529.2 , found : m / z = 530.4 [ M + H ] * . [ 0001005 ] Step - 4 : Synthesis of tert - butyl ( 2R , 6R ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] - 2,6 - dimethylpiperazine - 1 - carboxylate ( 5 ) [ 0001006 ] To a mixture of tert - butyl ( 2R , 6R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] -3 - fluorophenyl ) -2,6 - dimethylpiperazine - 1 - carboxylate ( 500 mg , 0.943 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1- sulfonamide ( 382 mg , 0.943 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl( 67 mg , 0.094 mmol , 0.1 equiv ) and CsF ( 286 mg , 1.886 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl ( 2R , 6R ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,6- dimethylpiperazine - 1 - carboxylate ( 190 mg , 26.29 % ) as a white solid . LCMS : C35H40C1F2N7O4S requires : 727.2 , found : m / z = 728.3 [ M + H ] * . [ 0001007 ] Step - 5 : Synthesis of N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R , 5R ) -3,5 - dimethylpiperazin - 1- yl ] -2 - fluorophenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 6 ) [ 0001008 ] A mixture of tert - butyl ( 2R , 6R ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,6- dimethylpiperazine - 1 - carboxylate ( 190 mg , 0.261 mmol , 1 equiv ) in TFA ( 2 mL ) was stirred at 0 ° C for one hour . The resulting mixture was concentrated under vacuum and lyophilized . This resulted in N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R , 5R ) -3,5 - dimethylpiperazin - 1 - yl ] -2 - fluorophenyl } -3- – = ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 133.3 mg , crude ) as a yellow solid . LCMS : C30H32ClF2N7O2S requires : 627.2 , found : m / z 628.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) § 8.80 – 8.71 ( m , 2H ) , 8.41 – 8.32 ( m , 1H ) , 8.15 – 8.09 ( m , 2H ) , 7.87 – 7.78 ( m , 1H ) , 7.67 – 7.60 ( m , 1H ) , 7.37 – 7.30 ( m , 1H ) , 7.13 – 7.( m , 2H ) , 3.90 – 3.78 ( m , 2H ) , 3.70 – 3.61 ( m , 2H ) , 3.41 – 3.33 ( m , 3H ) , 3.33 – 3.28 ( m , 3H ) , 1.96 – 1.85 ( m , 4H ) , 1.52 – 1.46 ( m , 6H ) . - - - - -639- 1100573566 5 AMERICAS [ 0001009 ] Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 2S ) -2- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 6 ) CI- N O = S = NH OH F N F N - N N Labs -NH - 640 - 1100573566 5 AMERICAS CI- Attorney Docket No .: 121843.002 HN F Cl -N 、 Boc -Br N Pd2 ( dba ) 3 , BINAP , t - BuONa , 2niP₂B , Pd2 ( dba ) 3 , X - Phos , KOAC methoxycyclopentane , 110 ° C 3 h Step - N Br N N - N CI IN F = S = N - N F toluene , 60 ° C F Step - N- 1111 * -N Boc ' N ' N Boc NU - 3200 PCT Boc Br NH EN Cu ( OAc ) 2 , molecular sieves 4A , pyr , 60 ° C Step - F H .N . = S = CI Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , H2O , 90 ° C , 1 h TFA , 0 ° C , 1 h Step - N- -N Boc Step - CN O = S = NH Cl OH F F N - N IL F N Labs -NH [ 0001010 ] Step - 1 : Synthesis of tert - butyl ( 3S ) -4- ( 4 - chloro - 3 - fluorophenyl ) -3- methylpiperazine - 1 - carboxylate ( 2 ) - 641 - 1100573566 5 AMERICAS [ 0001011 ] Attorney Docket No .: 121843.002NU - 3200 PCT To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 8 g , 38.197 mmol , 1 equiv ) and tert - butyl ( 3S ) -3 - methylpiperazine - 1 - carboxylate ( 7.7 g , 38.197 mmol , 1 equiv ) in toluene ( 100 mL ) was added Pd2 ( dba ) 3 ( 350 mg , 0.382 mmol , 0.01 equiv ) , t - BuONa ( 5.1 g , 53.4mmol , 1.4 equiv ) , and BINAP ( 476 mg , 0.764 mmol , 0.02 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 5 : 1 ) to afford tert - butyl ( 3S ) -4- ( 4 - chloro - 3 - fluorophenyl ) -3- methylpiperazine - 1 - carboxylate ( 8 g , 37.82 % ) as a yellow oil . LCMS : C16H22CIFN2O2 requires : 328.1 , found : m / z = 329.2 [ M + H ] * . [ 0001012 ] Step - 2 : Synthesis of tert - butyl ( 3S ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - methylpiperazine - 1 - carboxylate ( 3 ) [ 0001013 ] To a mixture of tert - butyl ( 38 ) -4- ( 4 - chloro - 3 - fluorophenyl ) -3- methylpiperazine - 1 - carboxylate ( 5 g , 15.206 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 5.8 g , 22.8mmol , 1.5 equiv ) in methoxycyclopentane ( 70 mL ) was added Pd2 ( dba ) 3 ( 418 mg , 0.456 mmol , 0.03 equiv ) , KOAc ( 4.5 g , 45.618 mmol , 3 equiv ) , and XPhos ( 435 mg , 0.912 mmol , 0.equiv ) . The resulting mixture was stirred at 110 ° C for 3 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 9 : 1 ) to afford tert - butyl ( 3S ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - methylpiperazine - 1 - carboxylate ( 5 g , 70.40 % ) as a brown solid . LCMS : C22H34BFN2O4 requires : 420.2 , found : m / z = 421.3 [ M + H ] * . [ 0001014 ] Step - 3 : Synthesis of tert - butyl ( 3S ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] -3 - fluorophenyl } -3 - methylpiperazine - 1 - carboxylate ( 4 ) : [ 0001015 ] To a mixture of tert - butyl ( 3S ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - methylpiperazine - 1 - carboxylate ( 2.5 g , 5.948 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.5 g , 6.543 mmol , 1.1 equiv ) in pyridine ( 30 mL ) was added Cu ( OAc ) 2 ( 2.2 g , 11.896 mmol , 2 equiv ) and molecular sieves type 4A ( 2.5 g ) . The resulting mixture was stirred at 60 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl ( 3S ) - -642- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } -3 - methylpiperazine - 1- carboxylate ( 1 g , 29.30 % ) as an off - white semi - solid . LCMS : C24H27BrFN5O2 requires : 515.1 , found : m / z = 516.3 [ M + H ] * . . [ 0001016 ] Step - 4 : Synthesis of tert - butyl ( 3S ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -3- methylpiperazine - 1 - carboxylate ( 5 ) : [ 0001017 ] To a mixture of tert - butyl ( 3S ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl - 3 - methylpiperazine - 1 - carboxylate ( 500 mg , 0.968 mmol , 1 equiv ) and N- [ 5- chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1- sulfonamide ( 392 mg , 0.968 mmol , 1 equiv ) in dioxane ( 10 mL ) was added Pd ( AMPHOS ) 2Cl( 69 mg , 0.097 mmol , 0.1 equiv ) and CsF ( 294 mg , 1.936 mmol , 2 equiv ) in H2O ( 2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) . The residue was purified by trituration with EtOAc . This resulted in tert - butyl ( 3S ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -3 - methylpiperazine - 1- carboxylate ( 200 mg , 27.48 % ) as a white solid . LCMS : C34H38CIF2N7O4S requires : 713.2 , found : m / z = 714.3 [ M + H ] * . [ 0001018 ] Step - 5 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 2S ) -2- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 6 ) [ 0001019 ] A mixture of tert - butyl ( 3S ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -3 - methylpiperazine - 1- carboxylate ( 200 mg , 0.280 mmol , 1 equiv ) in TFA ( 2 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum and lyophilized . This resulted in N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 2S ) -2 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4- = yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 144.3 mg , crude ) as a yellow solid . LCMS : C29H30C1F2N7O2S requires : 613.1 , found : m / z = 614.2 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.78 – 8.72 ( m , 2H ) , 8.41 - 8.36 ( m , 1H ) , 8.11 - 8.04 ( m , 2H ) , 7.89 - 7.80 ( m , 1H ) , 7.67 – 7.29 ( m , 2H ) , 7.12 – 7.00 ( m , 2H ) , 4.39 – 4.31 ( m , 1H ) , 3.– 3.66 ( m , 1H ) , 3.54 – 3.34 ( m , 4H ) , 3.34 – 3.33 ( m , 3H ) , 3.33 – 3.24 ( m , 2H ) , 1.96 – 1.85 ( m , 4H ) , 1.36 – 1.23 ( m , 3H ) . - - - -643- 1100573566 5 AMERICAS [ 0001020 ] Synthesis of Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 2R ) -2- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 6 ) CI N N - N 0 = S = IZ F LL F F. OH F N ( abs -NH -644- 1100573566 5 AMERICAS HN Attorney Docket No .: 121843.002NU - 3200 PCT CI F -Br ( R ) CI -N . Boc Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - 2niP₂B , Pd2 ( dba ) 3 , X - Phos , KOAC methoxycyclopentane , 110 ° C , 3 h Step - -B .

N N Br N - N = S = Cl IZ F LL LL F -N FL N .N . Boc N N. Boc Br NH N Cu ( OAc ) 2 , pyridine , molecular sieves 4A , 60 ° C Step - F IN .N . = #to CI ' N ' Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Boc TFA , 0 ° C , 1h N - N F LO Step - -N Boc Step - = S = 0 · CI IZ F N - N F OH F N abs -NH 1100573566 5 AMERICAS [ 0001021 ] Step - 1 : Synthesis of tert - butyl methylpiperazine - 1 - carboxylate ( 2 ) [ 0001022 ] Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -4- ( 4 - chloro - 3 - fluorophenyl ) -3- To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 8 g , 38.197 mmol , 1 equiv ) and tert - butyl ( 3R ) -3 - methylpiperazine - 1 - carboxylate ( 7.65 g , 38.197 mmol , 1 equiv ) in toluene ( 80 mL ) was added BINAP ( 0.48 g , 0.764 mmol , 0.02 equiv ) , t - BuONa ( 5.14 g , 53.4mmol , 1.4 equiv ) , and Pd2 ( dba ) 3 ( 0.35 g , 0.382 mmol , 0.01 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert - butyl ( 3R ) -4- ( 4 - chloro - 3- fluorophenyl ) -3 - methylpiperazine - 1 - carboxylate ( 6 g , 47.77 % ) as a yellow oil . LCMS : C16H22CIFN2O2 requires : 328.1 , found : m / z = 329.0 [ M + H ] * . [ 0001023 ] Step - 2 : Synthesis of tert - butyl ( 3R ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - methylpiperazine - 1 - carboxylate ( 3 ) [ 0001024 ] To a mixture of tert - butyl ( 3R ) -4- ( 4 - chloro - 3 - fluorophenyl ) -3- methylpiperazine - 1 - carboxylate ( 6 g , 18.248 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 6.95 g , 27.3mmol , 1.5 equiv ) in methoxycyclopentane ( 60 mL ) was added AcOK ( 5.37 g , 54.744 mmol , equiv ) , XPhos ( 0.52 g , 1.095 mmol , 0.06 equiv ) , and Pd2 ( dba ) 3 ( 0.5 g , 0.547 mmol , 0.03 equiv ) . The resulting mixture was stirred at 110 ° C for 3 h under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 8 : 1 ) to afford tert - butyl ( 3R ) -4- [ 3 - fluoro - 4- ( 4 , 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -3 - methylpiperazine - 1 - carboxylate ( 6 g , 78.23 % ) as a yellow solid . LCMS : C22H34BFN2O4 requires : 420.3 , found : m / z = 421.1 [ M + H ] * . [ 0001025 ] Step - 3 : Synthesis of tert - butyl ( 3R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] -3 - fluorophenyl } -3 - methylpiperazine - 1 - carboxylate ( 4 ) [ 0001026 ] To a mixture of tert - butyl ( 3R ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -3 - methylpiperazine - 1 - carboxylate ( 3 g , 7.137 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 1.76 g , 7.851 mmol , 1.1 equiv ) in pyridine ( 30 mL ) was added Cu ( OAc ) 2 ( 2.59 g , 14.274 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 3 g ) . The resulting mixture was stirred at 60 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . - 646 - - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 3R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } -3- methylpiperazine - 1 - carboxylate ( 2 g , 54.26 % ) as a white solid . LCMS : C24H27BrFN5= requires : 515.1 , found : m / z = 516.1 [ M + H ] + . [ 0001027 ] Step - 4 : Synthesis of tert - butyl ( 3R ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -3- methylpiperazine - 1 - carboxylate ( 5 ) [ 0001028 ] To a stirred solution of tert - butyl ( 3R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] -3 - fluorophenyl } -3 - methylpiperazine - 1 - carboxylate ( 500 mg , 0.968 mmol , 1 equiv ) and N- [ 5 - chloro - 2 - fluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1- sulfonamide ( 391 mg , 0.968 mmol , 1 equiv ) in dioxane ( 5 mL ) was added Pd ( AMPHOS ) 2Cl( 68 mg , 0.097 mmol , 0.1 equiv ) and CSF ( 294 mg , 1.936 mmol , 2 equiv ) in H2O ( 1 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 4 ) to afford tert - butyl ( 3R ) -4- [ 4- ( 4- { 5- chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3- fluorophenyl ] -3 - methylpiperazine - 1 - carboxylate ( 450 mg , 65.07 % ) as a white solid . LCMS : C34H38C1F2N7O4S requires : 713.2 , found : m / z = 714.0 [ M + H ] * . [ 0001029 ] Step - 5 : Synthesis of N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 2R ) -2- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 6 ) [ 0001030 ] A mixture of tert - butyl ( 3R ) -4- [ 4- ( 4- { 5 - chloro - 2 - fluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -3 - methylpiperazine - 1- carboxylate ( 450 mg , 0.630 mmol , 1 equiv ) in TFA ( 5 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under reduced pressure . The crude product was purified by prep - HPLC with the following conditions : Column : Xcelect CSH F - pheny OBD Column 19 x 250 mm , 5 mμ ; Mobile Phase A : Water ( 0.05 % TFA ) , Mobile Phase B : MeOH ; Flow rate : 25 mL / min ; Gradient : 30 % B to 45 % B in 12 min ; Wave Length : 254/220 nm to afford N- [ 5 - chloro - 2 - fluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 2R ) -2 - methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 149.mg , 32.57 % ) as a yellow solid . LCMS : C29H30C1F2N7O2S requires : 613.2 , found : m / z = 614.[ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.78 - 8.69 ( m , 2H ) , 8.41 - 8.36 ( m , 1H ) , 8.11 – -647- - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 - - - NU - 3200 PCT – 8.01 ( m , 2H ) , 7.89 – 7.80 ( m , 1H ) , 7.67 – 7.60 ( m , 1H ) , 7.36 – 7.29 ( m , 1H ) , 7.12 – 7.01 ( m , 2H ) , 4.39 - 4.30 ( m , 1H ) , 3.75 – 3.65 ( m , 1H ) , 3.54 – 3.44 ( m , 2H ) , 3.43 – 3.38 ( m , 2H ) , 3.– 3.34 ( m , 2H ) , 3.33 ( s , 2H ) , 3.32 ( s , 1H ) , 1.98 – 1.84 ( m , 4H ) , 1.33 – 1.20 ( m , 3H ) . [ 0001031 ] Synthesis of N- [ 3- ( 1- { 4 - [ ( 3R , 5R ) -3,5 - dimethylpiperazin - 1 - yl ] -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2,5 - difluorophenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 3 ) F. IZ ) = 59 = ✓ F N N N - N F OH F N abs abs NH Br N N - N F B FL IN O == C F IN N N N - N F F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h N -N Boc Step - TFA , 0 ° C , 1 h Step - N N. IZ = S = F N - N F F F abs abs NH N abs > abs N OH Boc 1100573566 5 AMERICAS [ 0001032 ] Step - 1 : Synthesis of tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT ( 2R , 6R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] - 2,6 - dimethylpiperazine - 1 - carboxylate ( 2 ) [ 0001033 ] To a mixture of tert - butyl ( 2R , 6R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] -3 - fluorophenyl ) -2,6 - dimethylpiperazine - 1 - carboxylate ( 500 mg , 0.943 mmol , 1 equiv ) and N- [ 2,5 - difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1- sulfonamide ( 366 mg , 0.943 mmol , 1 equiv ) in dioxane ( 7.5 mL ) was added Pd ( AMPHOS ) 2Cl( 67 mg , 0.094 mmol , 0.1 equiv ) and CsF ( 286 mg , 1.886 mmol , 2 equiv ) in O₂H ( 1.5 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 2 ) to afford tert - butyl ( 2R , 6R ) -4- [ 4- ( 4- { 2,5- difluoro - 3 - [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3- fluorophenyl ] -2,6 - dimethylpiperazine - 1 - carboxylate ( 300 mg , 42.48 % ) as a white solid . LCMS : C35H40F3N7O4S requires : 711.3 , found : m / z = 712.3 [ M + H ] * . [ 0001034 ] Step - 2 : Synthesis of N- [ 3- ( 1- { 4 - [ ( 3R , 5R ) -3,5 - dimethylpiperazin - 1 - yl ] -2- fluorophenyl - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) -2,5 - difluorophenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 3 ) [ 0001035 ] A mixture of tert - butyl ( 2R , 6R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2,6- dimethylpiperazine - 1 - carboxylate ( 30 mg , 0.042 mmol , 1 equiv ) in TFA ( 1 mL ) was stirred at ° C for one hour . The resulting mixture was concentrated under vacuum and lyophilized . This resulted in N- [ 3- ( 1- { 4 - [ ( 3R , 5R ) -3,5 - dimethylpiperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4- - yl ) pyrazol - 4 - yl ) -2,5 - difluorophenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 16 mg , crude ) as a yellow solid . LCMS : C30H32F3N7O2S requires : 611.2 , found : m / z = 612.3 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.83 – 8.72 ( m , 2H ) , 8.42 – 8.34 ( m , 1H ) , 8.18 – 8.09 ( m , 2H ) , 7.90 7.78 ( m , 1H ) , 7.50 -7.36 ( m , 1H ) , 7.15 – 7.00 ( m , 3H ) , 3.92 – 3.76 ( m , 2H ) , 3.– 3.59 ( m , 2H ) , 3.41 – 3.34 ( m , 2H ) , 3.33 – 3.28 ( m , 4H ) , 2.00 – 1.80 ( m , 4H ) , 1.59 – 1.42 ( m , 6H ) . - [ 0001036 ] Synthesis of N- ( 3- { 1- [ 2,3 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4- yl ) pyrazol - 4 - yl } -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) -649 - 1100573566 5 AMERICAS N F O == O IZ Attorney Docket No .: 121843.002NU - 3200 PCT F F N - N F OH F N -NH - 650- 1100573566 5 AMERICAS Br F F -Br 2niP₂B , Pd ( dppf ) ₂lC , KOAc , dioxane , 90 ° C Step - N F F HN N Attorney Docket No .: 121843.002NU - 3200 PCT Boc Pd2 ( dba ) 3 , BINAP , t - BuONA , toluene , 85 ° C Step - * F N .N . Boc Br F Br B.

N - N F = S = N - N F N- -F N -N Boc -N Boc LL F -F -N Boc Br NH Cu ( OAc ) 2 , pyr , molecular sieves 4A , 60 ° C IN .N . ` ' N ' Step - F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 1 h Step - TFA , 0 ° C , 1 h Step - F. .N . D = S = F N N - N F OH F N -NH 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001037 ] Step - 1 : Synthesis of tert - butyl 4- ( 4 - bromo - 2,3 - difluorophenyl ) piperazine- - carboxylate ( 2 ) [ 0001038 ] To a mixture of 1,4 - dibromo - 2,3 - difluorobenzene ( 8 g , 29.424 mmol , 1 equiv ) and tert - butyl piperazine - 1 - carboxylate ( 6.03 g , 32.366 mmol , 1.1 equiv ) in toluene ( 150 mL ) was added BINAP ( 1.1 g , 1.765 mmol , 0.06 equiv ) , t - BuONa ( 3.39 g , 35.309 mmol , 1.2 equiv ) , and Pd2 ( dba ) 3 ( 1.62 g , 1.769 mmol , 0.06 equiv ) . The resulting mixture was stirred at 85 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 3 : 1 ) to afford tert - butyl 4- ( 4 - bromo - 2,3 - difluorophenyl ) piperazine - 1 - carboxylate ( 8 g , 72.07 % ) as an orange solid . LCMS : C15H19BrF2N2O2 requires : 376.1 , found : m / z = 377.[ M + H ] + . [ 0001039 ] Step - 2 : Synthesis of tert - butyl 4- [ 2,3 - difluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 3 ) [ 0001040 ] To a mixture of tert - butyl 4- ( 4 - bromo - 2,3 - difluorophenyl ) piperazine - 1- carboxylate ( 6 g , 15.905 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 8.08 g , 31.810 mmol , 2 equiv ) in 1,4- dioxane ( 100 mL ) was added AcOK ( 3.12 g , 31.810 mmol , 2 equiv ) and Pd ( dppf ) Cl2 ( 1.3 g , 1.591 mmol , 0.1 equiv ) . The resulting mixture was stirred at 90 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 4 : 1 ) to afford tert- butyl 4- [ 2,3 - difluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] piperazine - 1- carboxylate ( 5.6 g , 82.98 % ) as an orange solid . LCMS : C21H31BF2N2O4 requires : 424.2 , found : m / z = 425.3 [ M + H ] * . [ 0001041 ] Step - 3 : Synthesis of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] - 2,3 - difluorophenyl } piperazine - 1 - carboxylate ( 4 ) [ 0001042 ] To a mixture of tert - butyl 4- [ 2,3 - difluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] piperazine - 1 - carboxylate ( 5.6 g , 13.198 mmol , 1 equiv ) and 4- ( 4- bromo - 1H - pyrazol - 3 - yl ) pyridine ( 3.25 g , 14.518 mmol , 1.1 equiv ) in pyridine ( 50 mL ) was added Cu ( OAc ) 2 ( 4.79 g , 26.396 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 5.6 g ) . The resulting mixture was stirred at 60 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced -652- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2,3- difluorophenylpiperazine - 1 - carboxylate ( 700 mg , 10.19 % ) as a white solid . LCMS : C23H24BrF2N5O2 requires : 519.1 , found : m / z = 520.1 [ M + H ] * . [ 0001043 ] Step - 4 : Synthesis of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2,3 - difluorophenyl ] piperazine - 1- carboxylate ( 5 ) [ 0001044 ] To a mixture of tert - butyl 4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -2,3- difluorophenylpiperazine - 1 - carboxylate ( 600 mg , 1.153 mmol , 1 equiv ) and N- [ 2,5 - difluoro- 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 447 mg , 1.153 mmol , 1 equiv ) in dioxane ( 5 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 81 mg , 0.115 mmol , 0.1 equiv ) and CSF ( 350 mg , 2.306 mmol , 2 equiv ) in H2O ( 1 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 3 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2,3 - difluorophenyl ] piperazine - 1- carboxylate ( 400 mg , 49.44 % ) as a white solid . LCMS : C33H35F4N7O4S requires : 701.2 , found : m / z = 702.3 [ M + H ] * . [ 0001045 ] Step - 5 : Synthesis of N- ( 3- { 1- [ 2,3 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2,5 - difluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) [ 0001046 ] A mixture of tert - butyl 4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -2,3 - difluorophenyl ] piperazine - 1- carboxylate ( 400 mg , 0.570 mmol , 1 equiv ) in TFA ( 4 mL ) was stirred at 0 ° C for hone hour . The resulting mixture was then concentrated under vacuum and lyophilized . This resulted in N- ( 3- { 1- [ 2,3 - difluoro - 4- ( piperazin - 1 - yl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl } -2,5- difluorophenyl ) pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 376.6 mg , crude ) as a yellow solid . LCMS : C28H27F4N7O2S requires : 601.2 , found : m / z = 602.3 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.89 – 8.77 ( m , 2H ) , 8.51 – 8.46 ( m , 1H ) , 8.21 – 8.14 ( m , 2H ) , 7.7.70 ( m , 1H ) , 7.47 – 7.37 ( m , 1H ) , 7.19 – 7.05 ( m , 2H ) , 3.52 – 3.43 ( m , 8H ) , 3.37 – 3.35 ( m , 1H ) , 3.34 - 3.33 ( m , 3H ) , 1.98 – 1.86 ( m , 4H ) . - – – -653- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001047 ] Synthesis of N- [ 2,5 - difluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] phenyl } - 3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) Br N abs N Boc F- .N . IZ N - N TO = U = F N IZ F OH F N abs NH 0 = S = N - N = S = Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H , 90 ° C , 2 h N Step - abs N Boc TO = S = O F F TFA , 0 ° C , 1 h N OH F N - N Step - N abs NH [ 0001048 ] Step - 1 : Synthesis of tert - butyl ( 2R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2 - methylpiperazine - 1- carboxylate ( 2 ) [ 0001049 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1- yl ] phenyl ) -2 - methylpiperazine - 1 - carboxylate ( 80 mg , 0.161 mmol , 1 equiv ) and N- [ 2,5- difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide -654- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 62 mg , 0.161 mmol , 1 equiv ) in dioxane ( 1 mL ) was added Pd ( AMPHOS ) 2Cl2 ( 11 mg , 0.0mmol , 0.1 equiv ) and CSF ( 49 mg , 0.322 mmol , 2 equiv ) in O₂H ( 0.2 mL ) . The resulting mixture was stirred at 90 ° C for 2 h under a nitrogen atmosphere . The resulting mixture was then concentrated under vacuum . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 3 ) . The residue was then purified by trituration with EtOAc . This resulted in tert - butyl ( 2R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2 - methylpiperazine - 1- carboxylate ( 20 mg , 17.41 % ) as an off - white solid . LCMS : C34H39F2N7O4S requires : 679.2 , found : m / z = 680.4 [ M + H ] * . [ 0001050 ] Step - 2 : Synthesis of N- [ 2,5 - difluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 3 ) [ 0001051 ] A mixture of tert - butyl ( 2R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) phenyl ] -2 - methylpiperazine - 1- carboxylate ( 20 mg , 0.029 mmol , 1 equiv ) in TFA ( 1 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum and lyophilized . This resulted in N- [ 2,5 - difluoro - 3- ( 1- { 4 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 11 mg , crude ) as a yellow solid . 580.3 [ M + H ] . H¹ NMR ( 400 MHz , LCMS : C29H31F2N7O2S requires : 579.2 , found : m / z = - Methanol - d4 ) 8 8.81 – 8.75 ( m , 2H ) , 8.62 – 8.58 ( m , 1H ) , 8.23 – 8.16 ( m , 2H ) , 7.94 – 7.86 ( m , 2H ) , 7.46 -7.37 ( m , 1H ) , 7.29 – 7.20 ( m , 2H ) , 7.14 – 7.06 ( m , 1H ) , 4.00 – 3.86 ( m , 2H ) , 3.– 3.50 ( m , 2H ) , 3.41 – 3.29 ( m , 5H ) , 3.19 – 3.07 ( m , 1H ) , 2.96 – 2.85 ( m , 1H ) , 1.98 – 1.85 ( m , 4H ) , 1.48 – 1.42 ( m , 3H ) . [ 0001052 ] Synthesis of N- [ 2,5 - difluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3 - methylpiperazin - 1- yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 6 ) -655- 1100573566 5 AMERICAS F O == OH IZ F Attorney Docket No .: 121843.002NU - 3200 PCT N - N OH F N abs NH -656- 1100573566 5 AMERICAS CI- F Br HN Attorney Docket No .: 121843.002NU - 3200 PCT RN CI Boc Pd2 ( dba ) 3 , BINAP , t - BuONa , toluene , 60 ° C Step - 2niP₂B , Pd2 ( dba ) 3 , X - Phos , KOAc , methoxycyclopentane , 110 ° C Step - F.

N IZ Br N - N .

F F LL F ' N ' abs N > - Boc B ' N ' abs N ..... Boc LL Br NH N Cu ( OAc ) 2 , pyr , molecular sieves 4A , 60 ° C ﻱ Step - N abs N Boc F Pd ( AMPHOS ) 2Cl2 , CSF , dioxane , O₂H 90 ° C , 1 h Step - N N - N N abs N. Boc TFA , 0 ° C , 1h N Step - IZ F F TO = S = N F F OH N - N . F N abs NH - 657- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 2R ) -4- ( 4 - chloro - 3 - fluorophenyl ) -2- [ 0001053 ] Step - 1 : Synthesis of tert - butyl methylpiperazine - 1 - carboxylate ( 2 ) [ 0001054 ] To a mixture of 4 - bromo - 1 - chloro - 2 - fluorobenzene ( 8 g , 38.197 mmol , 1 equiv ) and tert - butyl ( 2R ) -2 - methylpiperazine - 1 - carboxylate ( 7.65 g , 38.196 mmol , 1 equiv ) in toluene ( 80 mL ) was added BINAP ( 0.48 g , 0.764 mmol , 0.02 equiv ) , t - BuONa ( 5.14 g , 53.4mmol , 1.4 equiv ) , and Pd2 ( dba ) 3 ( 0.35 g , 0.382 mmol , 0.01 equiv ) . The resulting mixture was stirred at 60 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 2R ) -4- ( 4 - chloro - 3- fluorophenyl ) -2 - methylpiperazine - 1 - carboxylate ( 10 g , 79.62 % ) as a white solid . LCMS : C16H22CIFN2O2 requires : 328.1 , found : m / z = 329.0 [ M + H ] * . [ 0001055 ] Step - 2 : Synthesis of tert - butyl ( 2R ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -2 - methylpiperazine - 1 - carboxylate ( 3 ) [ 0001056 ] To a mixture of tert - butyl ( 2R ) -4- ( 4 - chloro - 3 - fluorophenyl ) -2- methylpiperazine - 1 - carboxylate ( 10 g , 30.413 mmol , 1 equiv ) and 4,4,5,5 - tetramethyl - 2- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -1,3,2 - dioxaborolane ( B2Pin2 ) ( 11.58 g , 45.6mmol , 1.5 equiv ) in methoxycyclopentane ( 100 mL ) was added XPhos ( 0.87 g , 1.825 mmol , 0.06 equiv ) , AcOK ( 8.95 g , 91.239 mmol , 3 equiv ) , and Pd2 ( dba ) 3 ( 0.84 g , 0.912 mmol , 0.equiv ) . The resulting mixture was stirred at 110 ° C overnight under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 9 : 1 ) to afford tert - butyl ( 2R ) -4- [ 3- fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] -2 - methylpiperazine - 1- carboxylate ( 12 g , 93.87 % ) as a brown oil . LCMS : C22H34BFN2O4 requires : 420.3 , found : m / z = 421.1 [ M + H ] * . [ 0001057 ] Step - 3 : Synthesis of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol- - yl ] -3 - fluorophenyl } -2 - methylpiperazine - 1 - carboxylate ( 4 ) [ 0001058 ] To a mixture of tert - butyl ( 2R ) -4- [ 3 - fluoro - 4- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) phenyl ] -2 - methylpiperazine - 1 - carboxylate ( 5 g , 11.895 mmol , 1 equiv ) and 4- ( 4 - bromo - 1H - pyrazol - 3 - yl ) pyridine ( 2.93 g , 13.085 mmol , 1.1 equiv ) in pyridine ( 50 mL ) was added Cu ( OAc ) 2 ( 4.32 g , 23.790 mmol , 2 equiv ) and molecular sieves ( 4A ) ( 5 g ) . The resulting mixture was stirred at 60 ° C overnight under an oxygen atmosphere . The resulting mixture was then extracted with EtOAc . The combined organic layers were washed with water -658- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT and dried over anhydrous Na2SO4 . After filtration , the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 1 : 1 ) to afford tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3 - fluorophenyl } - - methylpiperazine - 1 - carboxylate ( 2.1 g , 34.19 % ) as a white solid . LCMS : C24H27BrFN5O requires : 515.1 , found : m / z = 516.1 [ M + H ] * . [ 0001059 ] Step - 4 : Synthesis of tert - butyl ( 2R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2- methylpiperazine - 1 - carboxylate ( 5 ) [ 0001060 ] To a mixture of tert - butyl ( 2R ) -4- { 4- [ 4 - bromo - 3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ] -3- fluorophenyl ) -2 - methylpiperazine - 1 - carboxylate ( 55 mg , 0.107 mmol , 1 equiv ) and N- [ 2,5- difluoro - 3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide ( 41 mg , 0.107 mmol , 1 equiv ) in dioxane ( 1 mL ) was added CSF ( 32 mg , 0.214 mmol , 2 equiv ) and Pd ( AMPHOS ) 2Cl2 ( 8 mg , 0.011 mmol , 0.1 equiv ) in H2O ( 0.2 mL ) . The resulting mixture was stirred at 90 ° C for one hour under a nitrogen atmosphere . The resulting mixture was then concentrated under reduced pressure . The residue was purified by silica gel column chromatography eluted with PE : EtOAc ( 2 : 3 ) to afford tert - butyl ( 2R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3- [ ( pyrrolidine - 1 - sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2- methylpiperazine - 1 - carboxylate ( 20 mg , 26.91 % ) as a yellow oil . LCMS : C34H38F3N7O4S requires : 697.3 , found : m / z = 698.4 [ M + H ] * . = [ 0001061 ] Step - 5 : Synthesis of N- [ 2,5 - difluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3- methylpiperazin - 1 - yl ] phenyl } -3- ( pyridin - 4 - yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1- sulfonamide trifluoroacetic acid salt ( 6 ) [ 0001062 ] A mixture of tert - butyl ( 2R ) -4- [ 4- ( 4- { 2,5 - difluoro - 3 - [ ( pyrrolidine - 1- sulfonyl ) amino ] phenyl ) -3- ( pyridin - 4 - yl ) pyrazol - 1 - yl ) -3 - fluorophenyl ] -2 - methylpiperazine - 1- carboxylate ( 20 mg , 0.029 mmol , 1 equiv ) in TFA ( 1 mL ) was stirred at 0 ° C for one hour . The resulting mixture was then concentrated under vacuum and lyophilized . This resulted in N- [ 2,5 - difluoro - 3- ( 1- { 2 - fluoro - 4 - [ ( 3R ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) phenyl ] pyrrolidine - 1 - sulfonamide trifluoroacetic acid salt ( 14 mg , crude ) as a yellow solid . LCMS : C29H30F3N7O2S requires : 597.2 , found : m / z = 598.3 [ M + H ] * . ' H NMR ( 400 MHz , Methanol - d4 ) 8 8.83 - 8.72 ( m , 2H ) , 8.43 – 8.34 ( m , 1H ) , 8.19 – 8.09 ( m , 2H ) , 7.– 7.78 ( m , 1H ) , 7.49 – 7.38 ( m , 1H ) , 7.19 – 7.00 ( m , 3H ) , 4.09 – 3.90 ( m , 2H ) , 3.64 – 3.49 ( m , -659- 1100573566 5 AMERICAS - = Attorney Docket No .: 121843.002NU - 3200 PCT 2H ) , 3.40 -3.34 ( m , 3H ) , 3.32 – 3.29 ( m , 2H ) , 3.25 – 3.11 ( m , 1H ) , 3.03 - 2.87 ( m , 1H ) , 2.– 1.84 ( m , 4H ) , 1.53 – 1.39 ( m , 3H ) . - [ 0001063 ] Synthesis of ( 1R , 4r ) -4 - ( ( 6 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) -3,4- dihydroisoquinolin - 2 ( 1H ) -yl ) methyl ) cyclohexane - 1 - carboxylic acid & ' N ' H OH ' N ' abs abs toi & & NH abs abs OH [ 0001064 ] Step - 1 : Synthesis of tert - butyl ( 1r , 4r ) -4 - formylcyclohexane - 1 - carboxylate To a solution of tert - butyl ( 1r , 4r ) -4- ( hydroxymethyl ) cyclohexane - 1 - carboxylate ( 300.00 mg , 1.3999 mmol ) in DMSO ( 1 mL ) was added triethylamine ( 1.97 mL , 1416.57 mg , 13.99mmol ) followed by the addition of sulfur trioxide pyridine complex ( 1.11 g , 6.9994 mmol ) in DMSO ( 2 mL ) . The reaction mixture was stirred for 16 h . Additional sulfur trioxide pyridine complex ( 0.56 g , 3.5mmol ) in DMSO ( 0.5 mL ) and triethylamine ( 0.985 mL , 7 mmol ) was added after 16 h . The reaction was complete as indicated by TLC . i - PrOH ( 0.5 mL ) was added to the reaction mixture . After stirring for three hours , the reaction mixture was concentrated under reduced pressure . The crude material was used in the next step without purification . [ 0001065 ] Step - 2 : tert - butyl ( 1R , 4r ) -4 - ( ( 6 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) -3,4- dihydroisoquinolin - 2 ( 1H ) -yl ) methyl ) cyclohexane - 1 - carboxylate To a solution of rac- ( 3R ) -3- ( 1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) piperidine - 2,6 - dione ( 100.mg , 0.4093 mmol ) and tert - butyl ( 1r , 4r ) -4 - formylcyclohexane - 1 - carboxylate ( 86.90 mg , 0.4093 mmol ) in 2 ml DMSO ( 2 mL ) was added triethylamine ( 57.5 Lμ , 0.41 mmol ) and sodium triacetoxyborohydride ( 0.26 g , 1.2280 mmol ) and the reaction mixture was stirred for thirty minutes . EtOAc ( 30 mL ) was added and the organic solution was washed with water and brine , dried over sodium sulfate , filtered , and concentrated . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with MeOH in DCM ( 0-10 % ) , to provide -660 - 1100573566 5 AMERICAS tert - butyl Attorney Docket No .: 121843.002NU - 3200 PCT ( 1R , 4r ) -4 - ( ( 6 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) - yl ) methyl ) cyclohexane - 1 - carboxylate ( 0.18 g , 99.81 % ) . LCMS C26H36N2O4 requires : 440.3 , = found : m / z = 441.7 [ M + H ] * . [ 0001066 ] Step - 3 : ( 1R , 4r ) -4 - ( ( 6 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) -3,4- dihydroisoquinolin - 2 ( 1H ) -yl ) methyl ) cyclohexane - 1 - carboxylic acid To a solution of tert - butyl ( 1R , 4r ) -4 - ( ( 6 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) -3,4- dihydroisoquinolin - 2 ( 1H ) -yl ) methyl ) cyclohexane - 1 - carboxylate ( 180.00 mg , 0.4085 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.5 mL ) and the reaction was stirred for one hour . TFA and DCM were evaporated under reduced pressure and the crude product was pumped to dryness to afford ( 1R , 4r ) -4 - ( ( 6 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) -3,4 - dihydroisoquinolin - 2 ( 1H ) - yl ) methyl ) cyclohexane - 1 - carboxylic acid in quantitative yield . LCMS C22H28N2O4 requires : 384.2 , found m / z = 385.6 [ M + H ] * . [ 0001067 ] Synthesis of rac- ( R ) -1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carboxylic acid N IZ ++ HN & OH -N OH ( N N & N [ 0001068 ] Step - 1 : rac - tert - butyl ( R ) -1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carboxylate To a solution of rac- ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carboxylic acid ( 214.00 mg , 0.6743 mmol ) and [ ( dimethylamino ) ( { [ 1,2,3 ] triazolo [ 4,5 - b ] pyridin - 3- - 661 - 1100573566 5 AMERICAS yloxy } ) methylidene ] dimethylazanium ; Attorney Docket No .: 121843.002NU - 3200 PCT hexafluoro - lambda5 - phosphanuide ( 282.05 mg , 0.7418 mmol ) in DMF ( 2 mL ) was added N , N - diisopropylethylamine ( 435.79 mg , 3.37mmol ) . Then tert - butyl 4 - methylpiperidine - 4 - carboxylate ( 147.83 mg , 0.7418 mmol ) in DMF ( 1 mL ) was added . After stirring for one hour , the crude product was dissolved in ethyl acetate ( 40 mL ) and the solution was then washed with water and brine , dried over sodium sulfate , filtered , and concentrated . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with MeOH in DCM ( 0-6 % ) to afford rac - tert - butyl ( R ) -1- ( 1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carboxylate ( 0.236 g , 70.19 % ) . LCMS : C27H38N4O5 requires : 498.6 , found : m / z = 499.6 [ M + H ] * . [ 0001069 ] Step - 2 : rac- ( R ) -1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carboxylic acid rac - tert - butyl ( R ) -1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) -4- methylpiperidine - 4 - carboxylate ( 0.236 g , 0.4733mmol ) was dissolved in DCM ( 4 mL ) and then trifluoroacetic acid ( 2 mL ) was added . The solution was stirred for three hours . TFA and DCM were evaporated under reduced pressure . The crude product was loaded onto a Redi - Sep prepacked HP C18 ( 30 grams ) column eluting with acetonitrile in water ( 5 % -80 % ) to afford rac- ( R ) -1- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbonyl ) -4- methylpiperidine - 4 - carboxylic acid ( 0.132 g , 44.23 % ) . LCMS : C23H30N4O5 required : 442.5 , found : m / z = 443.6 [ M + H ] * . = [ 0001070 ] Synthesis of rac- ( R ) -1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) acetyl ) -4 - methylpiperidine - 4 - carboxylic acid IN + HN & OH .N . & OH ( N -662- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001071 ] Step - 1 : rac - tert - butyl ( R ) -1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) acetyl ) -4 - methylpiperidine - 4 - carboxylate To a solution of rac- ( R ) -2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetic acid ( 200.90 mg , 0.6063 mmol ) and [ ( dimethylamino ) ( { [ 1,2,3 ] triazolo [ 4,5 - b ] pyridine - 3- yloxy } ) methylidene ] dimethylazanium ; hexafluoro - lambda5 - phosphanuide ( 253.58 mg , 0.6669 mmol ) in DMF ( 2 mL ) was added N , N - diisopropylethylamine ( 391.79 mg , 3.03mmol ) . Then tert - butyl 4 - methylpiperidine - 4 - carboxylate ( 122.03 mg , 0.6123 mmol ) in DMF ( 1 mL ) was added . After stirring for one hour , the crude product was dissolved in ethyl acetate , washed with water and brine , dried over Na2SO4 , filtered , and concentrated . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with MeOH in DCM ( 0-6 % ) to afford the desired product which was contaminated with tert - butyl 4 - methylpiperidine - 4- carboxylate . The crude product was dissolved in DCM , washed with NH4Cl solution three times , dried over Na2SO4 , filtered , and concentrated . The product was used in the next step without rac - tert - butyl ( R ) -1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) acetyl ) -4 - methylpiperidine - 4 - carboxylate ( 0.26g , 83.65 % ) . LCMS : C28H40N4O5 requires : 512.3 , found : m / z = 513.3 [ M + H ] * . purification . [ 0001072 ] Step - 2 : rac- ( R ) -1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin- - yl ) acetyl ) -4 - methylpiperidine - 4 - carboxylic acid rac - tert - butyl ( R ) -1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) -4- methylpiperidine - 4 - carboxylate ( 260.00 mg , 0.5072 mmol ) was dissolved in DCM ( 3 mL ) and trifluoroacetic acid ( 2 mL ) was added . The solution was then stirred for three hours . TFA and DCM were evaporated under reduced pressure . The crude product was loaded onto a Redi - Sep prepacked HP C18 ( 30 grams ) column eluting with acetonitrile in water ( 0 % -60 % ) to afford rac- ( R ) -1- ( 2- ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) acetyl ) -4- methylpiperidine - 4 - carboxylic acid ( 0.19 g , 82.06 % ) as white solid . LCMS : C24H32N4Orequired : 456.2 , found : m / z = 457.3 [ M + H ] * . [ 0001073 ] Synthesis of methylpiperidine - 4 - carboxylic acid rac- ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4- -663- 1100573566 5 AMERICAS F so IN N. & + HN HCI Attorney Docket No .: 121843.002NU - 3200 PCT N N ﻢﻤﻤﻤﻣ & N N sood & [ 0001074 ] Step - 1 : rac - tert - butyl ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4- methylpiperidine - 4 - carboxylate A mixture of rac- ( R ) -3- ( 6 - fluoropyridin - 3 - yl ) piperidine - 2,6 - dione ( 200.00 mg , 0.96mmol ) , tert - butyl 4 - methylpiperidine - 4 - carboxylate hydrochloride ( 452.95 mg , 1.92mmol ) , and N , N - diisopropylethylamine ( 671.14 Lµ , 496.65 mg , 3.8426 mmol ) in DMSO ( 2.00 mL ) was heated at 120 ° C for sixteen hours . The crude product was then cooled down and water ( 5 mL ) was added . The solution was then extracted with EtOAc twice . The organic solution was dried over sodium sulfate , filtered , and concentrated . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with EtOAc : heptane ( 10-100 % ) to provide rac - tert - butyl ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidine - 4- carboxylate ( 0.3 g , 80.59 % ) . LCMS : C21H29N3O4 required : 387.2 , found : m / z = 388.5 [ M + H ] * . [ 0001075 ] Step - 2 : methylpiperidine - 4 - carboxylic acid rac- ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4- rac - tert - butyl ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4 - methylpiperidine - 4- carboxylate ( 300.00 mg , 0.7742 mmol ) was dissolved in DCM ( 2 mL ) and then TFA ( 2 mL ) was added . The reaction was then stirred for three hours . TFA and DCM were evaporated . The crude product was loaded onto a Redi - Sep prepacked HP C18 ( 30 grams ) column eluting with acetonitrile : water ( 0-90 % ) to afford rac- ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -4- - -664 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT methylpiperidine - 4 - carboxylic acid ( 0.21 g , 81.85 % ) as white solid . LCMS C17H21N3Orequires : 331.2 , found : m / z = 332.4 [ M + H ] + . [ 0001076 ] Synthesis of rac- ( R ) -2- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -2- azaspiro [ 3.3 ] heptane - 6 - carbaldehyde IN H -N . & F + HN- NH NH & & N N OH N -OH H [ 0001077 ] Step - 1 : rac- ( R ) -3- ( 6- ( 6- ( hydroxymethyl ) -2 - azaspiro [ 3.3 ] heptan - 2- yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione 1.20A mixture of rac- ( R ) -3- ( 6 - fluoropyridin - 3 - yl ) piperidine - 2,6 - dione ( 250.00 mg , mmol ) , ( 2 - azaspiro [ 3.3 ] heptan - 6 - yl ) methanol ( 413.57 mg , 1.2008 mmol ) , and N.N- diisopropylethylamine ( 1.05 mL , 776.01 mg , 6.0041 mmol ) in DMSO ( 2.00 mL ) was heated at 120 ° C for sixteen hours . The reaction mixture was lyophilized to remove DMSO . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with MeOH in DCM ( 3-20 % ) to provide rac- ( R ) -3- ( 6- ( 6- ( hydroxymethyl ) -2 - azaspiro [ 3.3 ] heptan - 2- yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione ( 0.12 g , 31.69 % ) . LCMS : C17H21N3O3 required : 315.2 , found : m / z = 316.5 [ M + H ] * . ' H NMR ( 500 MHz , CDC13 ) 8 8.14 – 7.86 ( m , 2H ) , 6.30 ( d , J = 8.6 Hz , 1H ) , 4.06 ( d , J = 9.8 Hz , 2H ) , 3.96 ( d , J = 7.4 Hz , 2H ) , 3.65 ( dq , J = 15.8 , 8.8 , 7.0 Hz , 4H ) , 3.52 ( s , 2H ) , 2.80 ( dt , J = 17.7 , 4.8 Hz , 1H ) , 2.74 – 2.58 ( m , 2H ) , 2.52 – 2.12 ( m , 7H ) , 2.11 1.99 ( m , 3H ) , 1.56 - 1.31 ( m , 3H ) . [ 0001078 ] Step - 2 : rac- ( R ) -2- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -2- azaspiro [ 3.3 ] heptane - 6 - carbaldehyde rac- ( R ) -3- ( 6- [ 6- ( hydroxymethyl ) -2 - azaspiro [ 3.3 ] heptan - 2 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione ( 45.00 mg , 0.1427 mmol ) was dissolved in DMSO ( 0.5 mL ) and then triethylamine ( 0. -665- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT mL , 0.29 g , 2.8538 mmol ) and sulfur trioxide pyridine complex ( 227.10 mg , 1.4269 mmol ) were added . After stirring for 30 min , TLC showed no more starting material left . The solution was dissolved in DCM ( 30 mL ) . The solution was washed with water and brine , dried over sodium sulfate , filtered , and concentrated . The crude product was used in the next step without purification . LCMS : C17H19N3O3 , requires : 313.36 , found m / z = 314.33 [ M + H ] * . [ 0001079 ] Synthesis of 3- ( 4- ( 2,6 - diazaspiro [ 3.3 ] heptan - 2 - yl ) phenyl ) piperidine - 2,6- dione Br HN- -N .NH ﻢﺤﻤﺤﻣﺩ ﻢﻤﻤﻣ HN N [ 0001080 ] Step - 1 : tert - butyl diazaspiro [ 3.3 ] heptane - 2 - carboxylate 6- ( 4- ( 2,6 - bis ( benzyloxy ) pyridin - 3 - yl ) phenyl ) -2,6- To a 20 mLvial was added 2,6 - bis ( benzyloxy ) -3- ( 4 - bromophenyl ) pyridine ( 500.00 mg , 1.12mmol ) , tert - butyl 2,6 - diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 244.31 mg , 1.2322 mmol ) , 1,3- bis [ 2,6 - bis ( pentan - 3 - yl ) phenyl ] -2H - imidazole , 3 - chloropyridine , palladium chloride ( 44.mg , 0.0560 mmol ) , and cesium carbonate ( 1094.96 mg , 3.3606 mmol ) . Dioxane ( 4.00 mL ) was then added and the mixture was purged with nitrogen gas for three minutes . Then the suspension was heated at 100 ° C for sixteen hours . The crude reaction was diluted with EtOAc , washed with water twice , dried over Na2SO4 , filtered , and concentrated . The crude product was loaded onto a Redi - Sep prepacked silica gel column ( 40g column ) eluting with EtOAc : hexane ( 0-70 % ) 6- ( 4- ( 2,6 - bis ( benzyloxy ) pyridin - 3 - yl ) phenyl ) -2,6- to provide tert - butyl -666 - - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 0.443 g , 70.15 % ) . LCMS : C35H37N3O4 , requires : 563.70 , found : m / z = 564.52 [ M + H ] * . [ 0001081 ] Step - 2 : tert - butyl 6- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) -2,6- diazaspiro [ 3.3 ] heptane - 2 - carboxylate To a mixture of tert - butyl 6- ( 4- ( 2,6 - bis ( benzyloxy ) pyridin - 3 - yl ) phenyl ) -2,6- diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 443.00 mg , 0.7859 mmol ) and palladium on carbon ( 150.00 mg ) in THF ( 10.00 mL ) was added isopropanol ( 3.00 mL ) and the reaction mixture was stirred under a hydrogen balloon for 24 h . Pd / C solids were then filtered and the filtrate was washed with 10 % MeOH in DCM and concentrated . The crude product was loaded onto a Redi - Sep prepacked silica gel column eluting with EtOAc in hexanes ( 70-100 % ) to afford tert - butyl 6- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) -2,6 - diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 0.22 g , 72.62 % ) . LCMS : C21H27N3O4 , requires : 385.2 , found m / z = 386.4 [ M + H ] * . [ 0001082 ] Step - 3 : 3- ( 4- ( 2,6 - diazaspiro [ 3.3 ] heptan - 2 - yl ) phenyl ) piperidine - 2,6 - dione To a solution of tert - butyl 6- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) -2,6 - diazaspiro [ 3.3 ] heptane- - carboxylate ( 150.00 mg , 0.3881 mmol ) in DCM ( 2.00 mL ) was added trifluoroacetic acid ( mL ) . After stirring for one hour , TFA and DCM were evaporated . The product was lyophilized to dryness to provide 3- ( 4- ( 2,6 - diazaspiro [ 3.3 ] heptan - 2 - yl ) phenyl ) piperidine - 2,6 - dione in quantitative yield . LCMS C16H19N3O2 requires : 285.1 , found : m / z = 286.3 [ M + H ] * . [ 0001083 ] Synthesis of 3- ( 6- { 2,6 - diazaspiro [ 3.3 ] heptan - 2 - yl } pyridin - 3 - yl ) piperidine- 2,6 - dione synthesis - 667 - 1100573566 5 AMERICAS F + HN DIEA , DMSO -N Step - Attorney Docket No .: 121843.002NU - 3200 PCT NH TFA , DCM Step - NH [ 0001084 ] Step - 1 : Synthesis of tert - butyl 6- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) - 2,6 - diazaspiro [ 3.3 ] heptane - 2 - carboxylate To a solution of 3- ( 6 - fluoropyridin - 3 - yl ) piperidine - 2,6 - dione ( 250.00 mg , 1.2008 mmol ) and tert - butyl 2,6 - diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 238.08 mg , 1.2008 mmol ) in DMSO ( 2.mL ) , was added N , N - diisopropylethylamine ( 0.85 mL , 0.62 g , 4.8033 mmol ) and the solution was heated at 120 ° C for four hours . The crude product was lyophilized to remove DMSO . The resulting crude oil was loaded onto a Redi - Sep prepacked silica gel column eluting with 0-10 % MeOH in EtOAc to afford tert - butyl 6- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) - 2,6 - diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 0.15 g , 32.32 % ) . LCMS : C21H29N3O4 required : 386.2 , found : m / z = 386.5 [ M + H ] * . [ 0001085 ] Step - 2 : Synthesis of 3- ( 6- { 2,6 - diazaspiro [ 3.3 ] heptan - 2 - yl } pyridin - 3- yl ) piperidine - 2,6 - dione To a solution of tert - butyl 6- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) -2,6- diazaspiro [ 3.3 ] heptane - 2 - carboxylate ( 150.00 mg , 0.3881 mmol ) in DCM ( 2.00 mL ) was added trifluoroacetic acid ( 2 mL ) and the resulting mixture was stirred for one hour . Solvent was removed under reduced pressure , and the product was lyophilized to afford 3- ( 6- { 2,6- diazaspiro [ 3.3 ] heptan - 2 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione as a TFA salt in quantitative yield . LCMS : C15H18N4O2 required : 286.1 , found : m / z = 286.3 [ M + H ] * . [ 0001086 ] Amide Bond Formation Between the Hook Amines and the Harness Acids [ 0001087 ] FluidX barcoded tubes containing harness acid stocks in NMP ( 0.1 M , eq = lomμ ) were retrieved from the Hamilton Storage Q20 unit and placed onto the deck of a 1.3m - 668 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Hamilton Robotics Vantage . The hook amines were dissolved in NMP ( 0.1 M ) containing DIEA ( 0.15 M , 1.5 equiv ) in V - bottom 20 mL vials and placed into vial racks onto the deck . Transfers of 100 Lμ from the harness acid stocks into corresponding wells of 96 deep well plates were performed , followed by addition of each of DIEA ( 0.15 M , 1.5 equiv ) and HATU ( 0.1 M , 1 equiv ) cocktails from 60 mL troughs . The plates were shaken ten minutes at 600 rpm for activation . Transfers of 100 Lµ from the hook stocks into corresponding wells of the same plates were performed and then the plates were sealed and shaken overnight at 600 rpm for amide bond formation . Finally , these plates were submitted for RP - HPLC purification . [ 0001088 ] [ 0001089 ] Reductive Amination Between the Hook Amines and the Harness Aldehydes FluidX barcoded tubes containing harness aldehyde stocks in NMP ( 0.1 M , eq = 10 lomμ ) were retrieved from the Hamilton Storage Q20 unit and placed onto the deck of a 1.3m Hamilton Robotics Vantage . The hook amines were dissolved in dry NMP ( 0.1 M ) containing DIEA ( 0.2 M , 2 equiv ) and AcOH ( 0.2 equiv , 0.02 M ) in V - bottom 20 mL vials and placed into vial racks onto the deck . Transfers of 100 Lμ from the harness stocks into corresponding wells of 96 deep well plates were performed , followed by transfers of 100 Lμ from the hook stocks into corresponding wells of the same 96 deep well plates . The plates were then shaken ninety minutes at 600 rpm for Schiff base formation . Additional plates dry - loaded with polymer - supported BH3CN ( 20 mg , 4 equiv ) in each well were placed on the deck and the reactions were transferred into these corresponding plates using the 96 pipettor head . The plates were then sealed and shaken overnight at 600 rpm for the reductive amination to occur . The plates were then unsealed , and the reaction mixture was separated from the polymer - supported BH3CN by decantation followed by washing cycles with fresh solvent from 60 mL troughs to recover only the liquid phase into new plates . Finally , these plates were submitted for RP- HPLC purification . [ 0001090 ] Synthesis of 1- ( 4- ( 2.6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidine - 4- carbaldehyde ( HA - 3 ) -669- 1100573566 5 AMERICAS Br HN .OH Br L - proline , Cul , 3OC₂K DMSO , 90 ° C , 12 h Step Attorney Docket No .: 121843.002NU - 3200 PCT BnO N OBn Pd ( dppf ) Cl2 DCM , 3OC₂K dioxane , O₂H OH 110 ° C , 12 h Step BnO .

Pd / C , Pd ( OH ) 2 / C , ₂H ( 50 psi ) AcOH , THF , EtOH , 80 ° C , 12 h HN . DMP , DMSO HN . ° C , 12 h ' N ' Step 3 .OH Step OBn .OH [ 0001091 ] Step - 1 : Synthesis of ( 1- ( 4 - bromo - 2 - fluorophenyl ) piperidin - 4 - yl ) methanol [ 0001092 ] To a solution of 4 - bromo - 2 - fluoro - iodobenzene ( 42.1 g , 365 mmol , 1.10 equiv ) and piperidin - 4 - ylmethanol ( 100 g , 332 mmol , 1.00 equiv ) in DMSO ( 1000 mL ) was added L- proline ( 17.4 g , 132 mmol , 0.400 equiv ) , K2CO3 ( 91.8 g , 664 mmol , 2.00 equiv ) and CuI ( 12.g , 66.4 mmol , 0.200 equiv ) under a nitrogen atmosphere . The reaction was stirred at 90 ° C for h . The reaction mixture was then cooled to 20 ° C and poured into saturated NH4Cl solution ( 1000 mL ) . The product was extracted with ethyl acetate ( 1000 mL x 3 ) and the combined organic layers were washed with brine ( 1000 mL ) , dried over Na2SO4 , filtered , and concentrated . The residue was purified by column chromatography ( SiO2 , petroleum ether : ethyl acetate = 10 : 1 to 0 : 1 , Rf = 0.55 ) . The desired product ( 10.7 g , 35.6 mmol , 10.7 % yield ) was obtained as a yellow solid . LCMS : m / z = 290.0 ( M + H ) * . [ 0001093 ] Step - 2 : Synthesis of ( 1- ( 4- ( 2,6 - bis ( benzyloxy ) pyridin - 3 - yl ) -2- fluorophenyl ) piperidin - 4 - yl ) methanol [ 0001094 ] To a solution of ( 1- ( 4 - bromo - 2 - fluorophenyl ) piperidin - 4 - yl ) methanol ( 11.6 g , 38.6 mmol , 1.00 equiv ) , 2,6 - bis ( benzyloxy ) -3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyridine ( 17.7 g , 42.4 mmol , 1.10 equiv ) , K2CO3 ( 16.0 g , 115 mmol , 3.00 equiv ) in dioxane ( 116 mL ) and H2O ( 23 mL ) was added Pd ( dppf ) Cl2 CH2Cl2 ( 3.15 g , 3.86 mmol , 0.100 equiv ) under a nitrogen atmosphere . Then the reaction mixture was stirred at 110 ° C for 12 h . The mixture was then cooled to 25 ° C . Then the reaction mixture was poured into H2O ( 300 mL ) and was extracted with EtOAc ( 200 mL x 3 ) . The combined organic layers were washed with brine ( 200 mL ) , dried over Na2SO4 , and concentrated . The crude product was purified by MPLC ( SiO2 , petroleum ether : ethyl acetate = 100 : 1 to 5 : 1 ) , Rf = 0.5 ( petroleum ether : ethyl acetate 1 : 1 ) . ( 1- ( 4- ( 2,6 - bis ( benzyloxy ) pyridin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4 - yl ) methanol = -670- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( 10.7 g , 20.5 mmol , 53.2 % yield ) was obtained as a light yellow solid . LCMS : m / z = 499.( M + H ) + . [ 0001095 ] Step - 3 : Synthesis of yl ) phenyl ) piperidine - 2,6 - dione [ 0001096 ] To a solution of 3- ( 3 - fluoro - 4- ( 4- ( hydroxymethyl ) piperidin - 1- ( 1- ( 4- ( 2,6 - bis ( benzyloxy ) pyridin - 3 - yl ) -2- fluorophenyl ) piperidin - 4 - yl ) methanol ( 11.6 g , 23.2 mmol , 1.00 equiv ) in THF ( 120 mL ) and EtOH ( 120 mL ) was added AcOH ( 4.19 g , 69.8 mmol , 3.99 mL , 3.00 equiv ) , Pd / C ( 2.90 g , % purity ) and Pd ( OH ) 2 / C ( 3.01 g , 4.29 mmol , 20 % purity ) under a nitrogen atmosphere . The suspension was degassed under vacuum and purged with H2 several times . The mixture was stirred under H2 ( 50 psi ) at 80 ° C for 12 h . The reaction was then cooled to 20 ° C and filtered . The filtrate was concentrated . The desired product ( 8.40 g , crude ) was obtained as a yellow solid and used in the next step without further purification . LCMS : m / z = 321.2 ( M + H ) * . [ 0001097 ] Synthesis Step - 4 : fluorophenyl ) piperidine - 4 - carbaldehyde of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2- [ 0001098 ] To a solution of 3- ( 3 - fluoro - 4- ( 4- ( hydroxymethyl ) piperidin - 1- yl ) phenyl ) piperidine - 2,6 - dione ( 8.40 g , 26.2 mmol , 1.00 equiv ) in DMSO ( 90.0 mL ) was added DMP ( 22.2 g , 52.4 mmol , 16.2 mL , 2.00 equiv ) in portions . The reaction was stirred at 25 ° C for 12 h . The pH of the reaction mixture then was adjusted to pH = 10 with saturated aqueous Na2CO3 and the aqueous layer was extracted with ethyl acetate ( 400 mL x 4 ) . The combined organic layers were washed with Na2S2O3 solution ( 500 mL x 2 ) and brine ( 1000 mL ) , dried over Na2SO4 , filtered , and concentrated under vacuum . The crude product was triturated with ethyl acetate ( 100 mL ) at 25 ° C for 12 h . 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2- fluorophenyl ) piperidine - 4 - carbaldehyde ( 2.50 g , 7.60 mmol , 28.9 % yield ) was obtained as a yellow solid . LCMS : m / z = 317.1 ( M - H ) * . ' H NMR ( 400 MHz , DMSO - do ) § 10.8 ( s , 1H ) , 9.( s , 1H ) , 7.06 - 6.90 ( s , 3H ) , 3.83 – 3.76 ( m , 1H ) , 3.29 – 3.24 ( m , 2H ) , 2.76 ( t , J = 10.0 Hz , 2H ) , 2.69 – 2.60 ( m , 1H ) , 2.48 – 2.41 ( m , 2H ) , 2.24 – 2.13 ( m , 1H ) , 2.04 – 1.91 ( m , 3H ) , 1.71 – 1.( m , 2H ) . - - - [ 0001099 ] Synthesis of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - fluorophenyl ) piperidine - 4- carbaldehyde ( HA - 4 ) - 671 - 1100573566 5 AMERICAS HN . LL ' N ' Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001100 ] HA - 4 was synthesized following the same procedure as HA - 3 except substituting 4 - bromo - 2 - fluoro - 1 - iodobenzene with 1 - bromo - 2 - fluoro - 4 - iodobenzene in Step to give 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3 - fluorophenyl ) piperidine - 4 - carbaldehyde . LCMS : m / z = 317.1 ( M - H ) * . ' H NMR ( 400 MHz , DMSO - do ) 8 10.79 ( s , 1H ) , 9.62 ( s , 1H ) , 7.07 ( t , J = 8.Hz , 1H ) , 6.77 – 6.69 ( m , 2H ) , 3.91 – 3.84 ( m , 1H ) , 3.67 – 3.59 ( m , 2H ) , 2.91 18.2− ( m , 2H ) , 2.76 – 2.65 ( m , 1H ) , 2.56 – 2.52 ( m , 1H ) , 2.49 – 2.45 ( m , 1H ) , 2.20 70.2− ( m , 1H ) , 1.97 68.1− ( m , 3H ) , 1.61 – 1.49 ( m , 2H ) . [ 0001101 ] - Synthesis of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3,5 - difluorophenyl ) piperidine- - carbaldehyde ( HA - 5 ) HN BnO Br BnO OBn Br L - proline , Cul , Cs2CO3 Pd ( dppf ) Cl2 DCM , 3OC₂K OBn DMSO , 75-85 ° C , 16 h F dioxane , O₂H 100 ° C , 12 h Step 1 Step Pd / C , Pd ( OH ) 2 / C , ₂H ( 50 psi ) THF , 25 ° C , 12 h Step HN . N HCI , THF HN . ° C , 1 h Step [ 0001102 ] Step 1 : _ Synthesis ( dimethoxymethyl ) piperidine of 1- ( 4 - bromo - 3,5 - difluorophenyl ) -4- [ 0001103 ] 2 - bromo - 1,3 - difluoro - 5 - iodobenzene ( 56.3 g , 176 mmol , 1.00 equiv ) , 4- ( dimethoxymethyl ) piperidine ( 30.9 g , 194 mmol , 1.10 equiv ) , L - proline ( 8.13 g , 70.6 mmol , 0.40 equiv ) , Cs2CO3 ( 115 g , 353 mmol , 2.00 equiv ) , and CuI ( 6.72 g , 35.3 mmol , 0.20 equiv ) was stirred in DMSO ( 350 mL ) at 20 ° C and purged with N2 three times . The mixture was then stirred at 85 ° C for 16 h under a nitrogen atmosphere . LCMS showed 60.5 % of the desired mass ( ₁R = 0.715 min ) was detected . TLC ( Petroleum ether : Ethyl acetate = 10 : 1 ) showed that - bromo - 1,3 - difluoro - 5 - iodobenzene ( Rf = 0.8 ) was consumed and a major spot ( Rf = 0.3 ) was t -672- 1100573566 5 AMERICAS = Attorney Docket No .: 121843.002NU - 3200 PCT = detected . The reaction was then added to water ( 800 mL ) and extracted with ethyl acetate ( 3mL x 3 ) . The combined organic layers were washed with brine ( 1.00 L x 1 ) , dried over Na2SO4 , filtered , and concentrated . The residue was purified by column chromatography ( SiO2 , Ethyl acetate : Petroleum ether = 0 : 1 to 1:20 ; Ethyl acetate : Petroleum ether = 1:10 , Rf = 0.3 ) . Then the combined fractions were concentrated under vacuum . 1- ( 4 - bromo - 3,5 - difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( 30.0 g , 84.1 mmol , 48.5 % yield , 98.2 % purity ) was obtained as a light - yellow solid . LCMS : m / z = 350.2 ( M + H ) * . ' H NMR ( 400 MHz , CDC13 ) 86.47 ( d , J = 10.0 Hz , 2H ) , 4.07 ( d , J = 6.8 Hz , 1H ) , 3.74 – 3.62 ( m , 2H ) , 3.38 ( s , 6H ) , 2.84 86.2− ( m , 2H ) , 1.89 – 1.77 ( m , 3H ) , 1.52 03.1− ( m , 2H ) . - [ 0001104 ] Step 2 : Synthesis of 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,6 - difluorophenyl ) pyridine [ 0001105 ] 1- ( 4 - bromo - 3,5 - difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( 20.0 g , 57. = mmol , 1.00 equiv ) , 2,6 - bis ( benzyloxy ) -3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyridine ( 30.9 g , 74.2 mmol , 1.30 equiv ) , K2CO3 ( 23.6 g , 171 mmol , 3.00 equiv ) , and Pd ( dppf ) Cl2 DCM ( 2.51 g , 3.43 mmol , 0.06 equiv ) was added to dioxane ( 200 mL ) and O₂H ( 40 mL ) at 20 ° C and purged with nitrogen three times . The mixture was then stirred at 100 ° C for 16 h under a nitrogen atmosphere . LCMS showed 67.7 % of the desired mass ( ₁R = 0.7min ) was detected . TLC ( Petroleum ether : Ethyl acetate = 10 : 1 ) showed that 1- ( 4 - bromo - 3,5- difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( Rf = 0.3 ) was consumed and a major spot ( Rf = 0.25 ) was detected . The reaction was then added to water ( 1.00 L ) and extracted with ethyl acetate ( 300 mL x 3 ) . The combined organic layers were washed with brine ( 1.00 L x 1 ) , dried over Na2SO4 , filtered , and concentrated . The residue was purified by column chromatography ( SiO2 , Ethyl acetate : Petroleum ether = 0 : 1 to 1:20 ; Ethyl acetate : Petroleum ether = 1:10 , Rf 0.3 ) . Then the fractions were concentrated under vacuum . 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,6 - difluorophenyl ) pyridine ( 20.0 g , 34.0 mmol , 59.6 % yield , 95.5 % purity ) was obtained as a yellow solid . LCMS : m / z = 561.3 ( M + H ) * . ' H NMR ( 400 MHz , CDC13 ) 8 7.56 – 7.29 ( m , 11H ) , 6.50 – 6.44 ( m , 3H ) , 5.39 - 5.32 ( m , 4H ) , 4.09 ( d , J = 7.0 Hz , 1H ) , 3.75 – 3.71 ( m , 2H ) , 3.39 ( s , 6H ) , 2.79 – 2.73 ( m , 2H ) , 1.93 27.1− ( m , 3H ) , 1.56 ( s , 2H ) . [ 0001106 ] Step 3 : Synthesis difluorophenyl ) piperidine - 2,6 - dione == of 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,6- -673 - 1100573566 5 AMERICAS [ 0001107 ] Attorney Docket No .: 121843.002NU - 3200 PCT To a solution of 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) - 2,6 - difluorophenyl ) pyridine ( 5.00 g , 8.92 mmol , 1.00 equiv ) in THF ( 50.0 mL ) was added Pd / C ( 1.50 g , 1.41 mmol , 10 % purity ) and Pd ( OH ) 2 / C ( 1.50 g , 3.20 mmol , 30 % purity ) under a nitrogen atmosphere . The suspension was degassed and purged with H2 three times . The mixture was then stirred under H2 ( 50 psi ) at 25 ° C for 12 h . LCMS showed that the desired peak ( ₁R = 0.568 min ) was detected and the starting material was consumed completely . The mixture was then filtered and concentrated . 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,6- difluorophenyl ) piperidine - 2,6 - dione ( 2.40 g , 6.28 mmol , 70.3 % yield ) was obtained as an off- white solid . LCMS : m / z = 383.2 ( M + H ) * . ' H NMR ( 400 MHz , CDC13 ) § 8.04 ( s , 1H ) , 6.42 ( d , J = 12.1 Hz , 2H ) , 4.07 ( d , J = 6.6 Hz , 1H ) , 4.01 – 3.88 ( m , 1H ) , 3.69 ( br d , J = 12.6 Hz , 2H ) , 3.38 ( s , 6H ) , 2.88 – 2.61 ( m , 4H ) , 2.41 – 2.24 ( m , 1H ) , 2.21 – 2.06 ( m , 1H ) , 1.92 – 1.77 ( m , 3H ) , 1.52 – 1.31 ( m , 2H ) . = - - - [ 0001108 ] Step : Synthesis of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3,5- difluorophenyl ) piperidine - 4 - carbaldehyde [ 0001109 ] To a solution of 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,6- = difluorophenyl ) piperidine - 2,6 - dione ( 20.0 g , 52.3 mmol , 1.00 equiv ) in THF ( 460 mL ) was added HCl ( 2 N , 465 mL , 17.8 equiv ) dropwise slowly . The reaction solution was then stirred at 70 ° C for one hour . LCMS showed 100 % of the desired mass ( Rt 0.535 min ) was detected . The reaction mixture was then treated with saturated NaHCO3 solution until pH = 7 , extracted with methyl tetrahydrofuran ( 500 mL x 3 ) , dried over Na2SO4 , filtered , and concentrated to provide a crude product . The crude was triturated with MTBE ( 30.0 mL ) at ° C for 30 min . 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -3,5 - difluorophenyl ) piperidine - 4 - carbaldehyde ( 15.4 g , 42.9 mmol , 84.2 % yield , 96.2 % purity ) was obtained as a white solid . LCMS : m / z 337.2 ( M + H ) * . H¹ NMR ( 400 MHz , DMSO - do ) & 10.88 ( s , 1H ) , 9.62 ( s , 1H ) , 6.64 ( d , J = 12.Hz , 2H ) , 4.10 – 4.00 ( m , 1H ) , 3.73 – 3.62 ( m , 2H ) , 2.99 - 2.87 ( m , 2H ) , 2.85 - 2.72 ( m , 1H ) , - 2.61 – 2.50 ( m , 2H ) , 2.19 – 2.05 ( m , 1H ) , 2.01 – 1.83 ( m , 3H ) , 1.62 – 1.46 ( m , 2H ) . = [ 0001110 ] = Synthesis of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2,5 - difluorophenyl ) piperidine- - carbaldehyde ( HA - 6 ) -674- 1100573566 5 AMERICAS Br- HN Pd2 ( dba ) 3 , Xantphos t - BuOK , toluene , 100 ° C , 12 h Step Br LL Attorney Docket No .: 121843.002NU - 3200 PCT BnO OBn ے Pd ( dppf ) Cl2 DCM , CS2COdioxane , O₂H 25-100 ° C , 12 h Step BnO HN . Pd / C , Pd ( OH ) 2 / C , ₂H ( 50 psi ) 2 N HCI , THF HN THF , 25 ° C , 12 h Step 70 ° C , 1 h Step [ 0001111 ] Step : Synthesis of ( dimethoxymethyl ) piperidine OBn 1- ( 4 - bromo - 2,5 - difluorophenyl ) -4- [ 0001112 ] To a solution of 1 - bromo - 2,5 - difluoro - 4 - iodobenzene ( 30.0 g , 94.1 mmol , 1.equiv ) , 4- ( dimethoxymethyl ) piperidine ( 18.0 g , 113 mmol , 1.20 equiv ) , Xantphos ( 10.9 g , 18.mmol , 0.200 equiv ) , and t - BuOK ( 13.7 g , 122 mmol , 1.30 equiv ) in toluene ( 210 mL ) was added Pd2 ( dba ) 3 ( 8.61 g , 9.41 mmol , 0.100 equiv ) under N2 . The reaction was then stirred at 100 ° C for 12 h . The mixture was then diluted with H2O ( 500 mL ) and extracted with EtOAc ( 500 mL x 2 ) . The combined organic layer was washed with brine ( 500 mL ) , dried over Na2SO4 , filtered , and concentrated under reduced pressure . The crude was purified by column chromatography ( SiO2 , Petroleum ether : Ethyl acetate = 0 : 1 to 10 : 1 ; Petroleum ether : Ethyl 0.4 ) and concentrated to provide 1- ( 4 - bromo - 2,5 - difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( 15.3 g , 40.3 mmol , 42.8 % yield , 92.2 % purity ) as a yellow oil . LCMS : m / z = 352.0 ( M + H ) * . ' H NMR ( 400 MHz , CDCl3 ) § 7.18 ( dd , J = 6.4 , 11.6 Hz , 1H ) , 6.71 ( dd , J = 7.6 , 10.4 Hz , 1H ) , 4.10 ( d , J = 7.2 Hz , 1H ) , 3.46 ( d , J = 11.6 Hz , 2H ) , 3.( s , 6H ) , 2.62 ( dt , J = 2.0 , 12.0 Hz , 2H ) , 1.85 ( br d , J = 13.2 Hz , 2H ) , 1.81 – 1.69 ( m , 1H ) , 1.- 1.43 ( m , 2H ) . acetate = , Rf = = - [ 0001113 ] Step : Synthesis of ( dimethoxymethyl ) piperidin - 1 - yl ) -2,5 - difluorophenyl ) pyridine [ 0001114 ] To a solution of 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- 1- ( 4 - bromo - 2,5 - difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( 15.3 g , 40.3 mmol , 1.00 equiv ) in dioxane ( 300 mL ) and O₂H ( 60.0 mL ) was added 2,6 - bis ( benzyloxy ) -3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyridine ( 23.8 g , 52.4 mmol , 1.30 equiv ) , C $ 2CO3 ( 32.8 g , 101 mmol , 2.50 equiv ) , and Pd ( dppf ) C12 CH2Cl2 ( 1.64 g , 2.01 mmol , 0.05 equiv ) at 25 ° C under N2 . The reaction mixture -675- 1100573566 5 AMERICAS = = Attorney Docket No .: 121843.002NU - 3200 PCT was then stirred at 100 ° C for 12 h . The mixture was then poured into H2O ( 100 mL ) and extracted with EtOAc ( 50.0 mL x 3 ) . The combined organic layer was washed with brine ( 1mL ) , dried over Na2SO4 , filtered , and concentrated under reduced pressure . The crude was purified by MPLC ( SiO2 , Petroleum ether : Ethyl acetate = 1 : 0 to 10 : 1 ; Petroleum ether : Ethyl acetate 5 : 1 , Rf 0.4 ) and concentrated to provide 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,5 - difluorophenyl ) pyridine ( 21.5 g , 37.0 mmol , 91.9 % yield , 96.5 % purity ) as a yellow oil . LCMS : m / z = 561.3 ( M + H ) * . ' H NMR ( 400 MHz , CDCl3 ) § 7.54 ( dd , J = 1.2 , 8.0 Hz , 1H ) , 7.45 – 7.41 ( m , 2H ) , 7.40 – 7.28 ( m , 8H ) , 7.09 ( dd , J = 7.2 , 13.2 Hz , 1H ) , 6.78 – 6.65 ( m , 1H ) , 6.46 ( d , J = 8.0 Hz , 1H ) , 5.41 ( s , 2H ) , 5.36 ( s , 2H ) , 4.12 ( d , J = 7.2 Hz , 1H ) , 3.54 ( d , J = 12.0 Hz , 2H ) , 3.40 ( s , 6H ) , 2.66 ( br t , J = 11.6 Hz , 2H ) , 2.06 ( s , 1H ) , 1.87 ( br d , J = 12.8 Hz , 2H ) , 1.81 37.1− ( m , 1H ) , 1.58 – 1.47 ( m , 2H ) . = [ 0001115 ] - Step 3 : Synthesis of 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,5- difluorophenyl ) piperidine - 2,6 - dione [ 0001116 ] To a solution of 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) - 2,5 - difluorophenyl ) pyridine ( 21.5 g , 37.0 mmol , 1.00 equiv ) in THF ( 360 mL ) was added Pd / C ( 6.45 g , 10 % purity ) and Pd ( OH ) 2 / C ( 6.45 g , 20 % purity ) under N2 . The suspension was then degassed and purged with H2 three times . The mixture was then stirred under H2 ( 50 psi ) at ° C for 12 h . LCMS showed the starting material was consumed and desired mass ( ₁R = 0.7min ) was formed . The mixture was then filtered through celite and the filtrate was concentrated under reduced pressure . The crude was triturated with MTBE ( 100 mL ) at 25 ° C for 0.5 h , filtered , and the cake was dried under reduced pressure pressure to provide 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,5 - difluorophenyl ) piperidine - 2,6 - dione ( 14.0 g , 36.mmol , 98.9 % yield , 100 % purity ) as a white solid . LCMS : m / z = 383.1 ( M + H ) * . ' H NMR ( 400 MHz , CDCl3 ) § 8.20 – 8.01 ( m , 1H ) , 6.82 ( dd , J = 6.8 , 12.4 Hz , 1H ) , 6.69 ( dd , J = 7.2 , 11.6 Hz , 1H ) , 4.10 ( d , J = 7.2 Hz , 1H ) , 3.81 ( dd , J = 5.6 , 11.2 Hz , 1H ) , 3.49 ( br d , J = 11.2 Hz , 2H ) , 3.38 ( s , 6H ) , 2.86 – 2.75 ( m , 1H ) , 2.74 – 2.56 ( m , 3H ) , 2.33 – 2.13 ( m , 2H ) , 1.84 ( br d , J = 13.2 Hz , 2H ) , 1.77 – 1.71 ( m , 1H ) , 1.58 – 1.43 ( m , 2H ) . = – [ 0001117 ] Step : Synthesis of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2,5- difluorophenyl ) piperidine - 4 - carbaldehyde [ 0001118 ] To a solution of 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,5- difluorophenyl ) piperidine - 2,6 - dione ( 10.0 g , 26.2 mmol , 1.00 equiv ) in THF ( 250 mL ) was added HCl ( 2 N , 233 mL , 17.8 equiv ) . The reaction solution was then stirred at 70 ° C for one -676 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT hour . The reaction mixture was then cooled to 25 ° C and saturated NaHCO3 solution was added until pH = 7. The mixture was then extratcted with EtOAc ( 300 mL x 3 ) and the combined organic layer was washed with brine ( 500 mL ) , dried over Na2SO4 , filtered , and concentrated to provide = 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2,5 - difluorophenyl ) piperidine - 4 - carbaldehyde ( 7.g , 22.8 mmol , 87.1 % yield , 99.7 % purity ) as an off - white solid . LCMS : m / z = 337.1 ( M + H ) * . ' H NMR ( 400 MHz , CDCl3 ) § 9.72 ( s , 1H ) , 8.12 ( br s , 1H ) , 6.84 ( dd , J = 6.8 , 12.4 Hz , 1H ) , 6.68 ( dd , J = 7.2 , 11.6 Hz , 1H ) , 3.82 ( dd , J = 5.6 , 11.2 Hz , 1H ) , 3.48 - 3.34 ( m , 2H ) , 2.92 - 2.75 ( m , 3H ) , 2.74 – 2.61 ( m , 1H ) , 2.49 – 2.36 ( m , 1H ) , 2.33 – 2.14 ( m , 2H ) , 2.10 – 2.00 ( m , 2H ) , 1.94 – 1.78 ( m , 2H ) . [ 0001119 ] – Synthesis of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2,3 - difluorophenyl ) piperidine- - carbaldehyde ( HA - 7 ) F Br HN ₂dP ( dba ) 3 , BINAP t - BuONa , toluene , 20-100 ° C , 16 h Step Br F BnO OBn Pd ( dppf ) ₂lC DCM , 3OC₂sC dioxane , O₂H 100 ° C , 12 h Step HN F Pd / C , Pd ( OH ) 2 / C , ₂H ( 50 psi ) 2 N HCI , THF HN . THF , 25 ° C , 12 h Step 70 ° C , 1 h Step BnO OBn N [ 0001120 ] Step 1 : Synthesis of ( dimethoxymethyl ) piperidine [ 0001121 ] 1- ( 4 - bromo - 2,3 - difluorophenyl ) -4- 1 - Bromo - 2,3 - difluoro - 4 - iodobenzene ( 20.0 g , 62.7 mmol , 1.00 equiv ) , 4- ( dimethoxymethyl ) piperidine ( 10.9 g , 68.9 mmol , 1.10 equiv ) , BINAP ( 1.56 g , 2.51 mmol , 0.04 equiv ) , t - BuONa ( 12.0 g , 125 mmol , 2.00 equiv ) , and Pd2 ( dba ) 3 ( 1.15 g , 1.25 mmol , 0.equiv ) was added to toluene ( 200 mL ) at 20 ° C and the mixture was purged with N2 three times . The mixture was then stirred at 100 ° C for 16 h . The mixture was then concentrated directly via vacuum . The residue was purified by column chromatography ( SiO2 , Ethyl acetate : Petroleum ether = 0 : 1 to 1:20 ; Ethyl acetate : Petroleum ether = 1:10 , Rf = 0.30 ) . Then the fractions were concentrated under vacuum . 1- ( 4 - bromo - 2,3 - difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( 14.0 g , 31.5 mmol , 50.3 % yield , 79.0 % purity ) was obtained as a yellow solid . LCMS : m / z = 350.1 ( M + H ) * . ' H NMR ( 400 MHz , CDC13 ) 8 7.21 – 7.12 ( m , = - -677 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1H ) , 6.67 – 6.55 ( m , 1H ) , 4.10 ( d , J = 7.1 Hz , 1H ) , 3.46 ( br d , J = 12.0 Hz , 2H ) , 3.38 ( s , 6H ) , 2.73 – 2.60 ( td , 2H ) , 1.85 ( br d , J = 13.9 Hz , 2H ) , 1.56 – 1.43 ( m , 2H ) , 1.26 ( t , 1H ) . [ 0001122 ] Step : Synthesis of 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,3 - difluorophenyl ) pyridine [ 0001123 ] 1- ( 4 - bromo - 2,3 - difluorophenyl ) -4- ( dimethoxymethyl ) piperidine ( 13.0 g , 29.mmol , 1.00 equiv ) , 2,6 - bis ( benzyloxy ) -3- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) pyridine ( 16.1 g , 38.6 mmol , 1.30 equiv ) , Cs2CO3 ( 24.1 g , 74.2 mmol , 2.50 equiv ) , and Pd ( dppf ) Cl2 CH2Cl2 ( 1.21 g , 1.48 mmol , 0.05 equiv ) was added into dioxane ( 260 mL ) and O₂H ( 52.0 mL ) at 20 ° C and the mixture was purged with N2 three times . The mixture was then stirred at 100 ° C for 16 h under a nitrogen atmosphere . The residue was then added to water ( 200 mL ) and extracted with ethyl acetate ( 60.0 mL x 3 ) . The combined organic layers were washed with brine ( 100 mL x 1 ) , dried over Na2SO4 , filtered , and concentrated . The residue was purified by column chromatography ( SiO2 , Ethyl acetate : Petroleum ether = 0 : 1 to 1:20 ; Ethyl acetate : Petroleum ether = 1:10 , Rf = 0.25 ) . Then the fractions were concentrated under 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,3- difluorophenyl ) pyridine ( 8.80 g , 13.8 mmol , 46.5 % yield , 88.0 % purity ) was obtained as a yellow solid . LCMS : m / z = 561.3 ( M + H ) * . ' H NMR ( 400 MHz , CDCl3 ) 8 7.56 – 7.29 ( m , 11H ) , 7.10 – 6.95 ( m , 1H ) , 6.46 ( d , J = 8.1 Hz , 1H ) , 5.46 – 5.23 ( m , 4H ) , 4.12 ( d , J = 7.2 Hz , 1H ) , 3.54 ( br d , J = 11.9 Hz , 2H ) , 3.40 ( s , 6H ) , 2.71 ( t , J = 11.4 Hz , 2H ) , 1.87 ( br d , J = 12.Hz , 2H ) , 1.81 – 1.71 ( m , 1H ) , 1.64 - 1.48 ( m , 3H ) . vacuum . [ 0001124 ] - == = = Step 3 : Synthesis of 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,3- difluorophenyl ) piperidine - 2,6 - dione [ 0001125 ] To a solution of 2,6 - bis ( benzyloxy ) -3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) - 2,3 - difluorophenyl ) pyridine ( 43.0 g , 76.7 mmol , 1.00 equiv ) in THF ( 430 mL ) was added Pd / C ( 12.9 g , 12.1 mmol , 10 % purity ) and Pd ( OH ) 2 / C ( 12.9 g , 27.5 mmol , 30 % purity ) under a nitrogen atmosphere . The suspension was then degassed and purged with H2 three times . The mixture was then stirred under H2 ( 50 psi ) at 25 ° C for 6 h . The mixture was then filtered and concentrated . The crude was triturated with MTBE ( 20.0 mL ) at 25 ° C for 30 min , filtered , and the cake was dried under reduced pressure to provide 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1- yl ) -2,3 - difluorophenyl ) piperidine - 2,6 - dione ( 8.00 g , 20.9 mmol , 88.8 % yield ) as a white solid . LCMS : m / z = 383.1 ( M + H ) * . ' H NMR ( 400 MHz , DMSO - do ) & 10.92 ( s , 1H ) , 7.18 – 6.69 ( m , 2H ) , 4.16 ( d , J = 6.5 Hz , 1H ) , 4.11 – 4.00 ( m , 1H ) , 3.47 – 3.38 ( m , 3H ) , 3.32 ( s , 6H ) , - 678 - 1100573566 5 AMERICAS - Attorney Docket No .: 121843.002NU - 3200 PCT 2.85 – 2.64 ( m , 3H ) , 2.30 – 2.13 ( m , 1H ) , 2.10 – 1.95 ( m , 1H ) , 1.84 – 1.68 ( m , 3H ) , 1.52 – 1.( m , 2H ) . = = [ 0001126 ] Step : Synthesis of difluorophenyl ) piperidine - 4 - carbaldehyde [ 0001127 ] To a solution of 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2,3- 3- ( 4- ( 4- ( dimethoxymethyl ) piperidin - 1 - yl ) -2,3- difluorophenyl ) piperidine - 2,6 - dione ( 4.00 g , 10.4 mmol , 1.00 equiv ) in THF ( 93.0 mL ) was = added HCl ( 2.00 N , 93.1 mL , 17.8 equiv ) dropwise slowly . After addition , the reaction solution was then stirred at 70 ° C for one hour . The reaction mixture was then treated with saturated NaHCO3 solution until pH = 7 , extracted with EtOAc ( 30.0 mL x 3 ) , dried over Na2SO4 , filtered , and concentrated to provide crude material . The crude was triturated with EtOAc ( 10.mL ) at 25 ° C for 30 min . 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2,3 - difluorophenyl ) piperidine - 4- carbaldehyde ( 2.00 g , 5.86 mmol , 56.0 % yield , 98.4 % purity ) was obtained as a white solid . LCMS : m / z = 337.2 ( M + H ) * . ' H NMR ( 400 MHz , DMSO - do ) § 10.88 ( s , 1H ) , 9.64 ( s , 1H ) , 6.99 ( br t , J = 7.5 Hz , 1H ) , 6.82 ( br t , J = 7.9 Hz , 1H ) , 4.12 – 3.94 ( m , 1H ) , 3.35 – 3.( m , 2H ) , 2.88 – 2.67 ( m , 3H ) , 2.55 ( br d , J = 3.1 Hz , 1H ) , 2.49 – 2.43 ( m , 1H ) , 2.26 – 2.09 ( m , 1H ) , 2.05 – 1.88 ( m , 3H ) , 1.73 – 1.56 ( m , 2H ) . [ 0001128 ] Synthesis of 1- ( 5- ( 2,4 - dioxotetrahydropyrimidin - 1 ( 2H ) -yl ) 679 yridine - 2- yl ) piperidine - 4 - carbaldehyde ( HA - 8 ) - 679 - 1100573566 5 AMERICAS HO Attorney Docket No .: 121843.002NU - 3200 PCT NONO2 NHN .OH N F ₂H , Pd / C , MeOH : EtOH N N DIPEA , DMSO Dioxane OH Step 1 Step 2 Step HO HO NH NH HN OH NH ' N ' Urea , AcOH .N 4OS₂H DMP , DCM N N Step 4 .N . Step 5 .N . Step 6 .N .

HO [ 0001129 ] Step - 1 : Synthesis of ( 1- ( 5 - nitropyridin - 2 - yl ) piperidin - 4 - yl ) methanol == [ 0001130 ] A mixture of 2 - fluoro - 4 - nitropyridine ( 20 g , 0.140 mol , 1 equiv ) , piperidin - 4- ylmethanol ( 24.318 g , 0.211 mol , 1.5 equiv ) , and DIPEA ( 27.29 mL , 0.211 mol , 1.5 equiv ) in anhydrous DMSO ( 50 mL , 2.82 M ) was stirred at 90 ° C overnight . Then the reaction mixture was poured into ice water . The resulting precipitate was filtered and purified by flash chromatography ( DCM : MeOH 9 : 1 ) to provide [ 1- ( 5 - nitropyridin - 2 - yl ) piperidin - 4- yl ] methanol ( 33.37 g , 47 % yield ) as a yellow solid . LCMS : m / z = 237.7 ( M + H ) * . ' H NMR ( 300 MHz , CDC13 ) 8 9.05 ( d , J = 2.8 Hz , 1H ) , 8.20 ( dd , J = 9.6 , 2.8 Hz , 1H ) , 6.60 ( d , J = 9.Hz , 1H ) , 4.59 ( d , J = 13.4 Hz , 2H ) , 3.57 ( d , J = 5.9 Hz , 2H ) , 3.11 – 2.95 ( m , 2H ) , 1.98 – 1.( m , 3H ) , 1.31 ( tdd , J = 14.3 , 11.8 , 4.2 Hz , 2H ) . [ 0001131 ] [ 0001132 ] = Step - 2 : Synthesis of ( 1- ( 5 - aminopyridin - 2 - yl ) piperidin - 4 - yl ) methanol [ 1- ( 5 - nitropyridin - 2 - yl ) piperidin - 4 - yl ] methanol ( 15.5 g , 0.065 mol , 1 equiv ) was dissolved in a mixture of EtOH : MeOH ( 1 : 1 ) ( 250 mL , 0.26 M ) , degassed , and charged with Pd / C ( 50 % wet , 2.32 g , 15 % weight ) . The reaction mixture was then evacuated and backfilled with H2 ( balloon , 1 atm ) and left to stir overnight . The reaction was then filtered through a celite pad and concentrated to provide [ 1- ( 5 - aminopyridin - 2 - yl ) piperidin - 4- yl ] methanol ( 5.85 g , 45 % yield ) as a pale yellow oil , which was used in the next step without - 680 - 1100573566 5 AMERICAS – Attorney Docket No .: 121843.002NU - 3200 PCT additional purification . LCMS : m / z = 208.25 ( M + H ) * . ' H NMR ( 300 MHz , DMSO - do ) 8 7.( dd , J = 2.9 , 0.7 Hz , 1H ) , 6.89 ( dd , J = 8.8 , 2.9 Hz , 1H ) , 6.61 ( dd , J = 8.9 , 0.8 Hz , 1H ) , 4.56 – 4.39 ( m , 3H ) , 4.02 – 3.89 ( m , 2H ) , 3.26 ( dd , J = 6.3 , 5.3 Hz , 2H ) , 2.60 – 2.52 ( m , 2H ) , 1.76 – 1.62 ( m , 2H ) , 1.49 ( s , 1H ) , 1.12 ( dd , J = 12.2 , 4.0 Hz , 2H ) . = [ 0001133 ] Step - 3 : Synthesis of 3 - ( ( 6- ( 4- ( hydroxymethyl ) piperidin - 1 - yl ) pyridin - 3- yl ) amino ) propanoic acid [ 0001134 ] A pressure vessel was charged with [ 1- ( 5 - aminopyridin - 2 - yl ) piperidin - 4 - yl ] methanol ( 5.8g , 27.9 mmol , 1 equiv ) and acrylic acid ( 1.9 mL , 27.9 mmol , 1 equiv ) dissolved in 1,4 - dioxane ( 58 mL , 0.5 M ) . The reaction mixture was then stirred at 90 ° C . After 16 h , % of the starting amine was still present . Additional acrylic acid ( 0.25 equiv ) was added and the reaction mixture was stirred at 90 ° C for another 16 h . Then the mixture was concentrated , the obtained residue was diluted with EtOAc and refluxed , and the solution was then decanted . The residue ( black gum ) was redissolved in MeOH and concentrated to yield 3 - ( { 6- [ 4- ( hydroxymethyl ) piperidin - 1 - yl ] pyridin - 3 - yl ) amino ) propanoic acid ( 6.4 g , 78 % yield ) . LCMS : m / z = 280.25 ( M + H ) * ; 278.0 ( M - H ) * . ' H NMR ( 300 MHz , DMSO - òd ) § 7.59 ( d , J = 2.9 Hz , 1H ) , 6.93 ( dd , J = 8.9 , 3.0 Hz , 1H ) , 6.68 ( d , J = 8.9 Hz , 1H ) , 4.00 ( dt , J = 12.8 , 3.3 Hz , 2H ) , 3.39 ( t , J = 7.1 Hz , 1H ) , 3.26 ( d , J = 6.3 Hz , 3H ) , 2.63 – 2.53 ( m , 2H ) , 2.47 – 2.29 ( m , 3H ) , 1.67 ( s , 2H ) , 1.13 ( dd , J = 12.2 , 4.0 Hz , 2H ) . [ 0001135 ] Step - 4 and Step - 5 : Synthesis of ( 1- ( 5- ( 2,4 - dioxotetrahydropyrimidin- ( 2H ) -yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl acetate and 1- ( 6- ( 4- ( hydroxymethyl ) piperidin - 1 - yl ) pyridin - 3 - yl ) dihydropyrimidine - 2,4 ( 1H , 3H ) -dione [ 0001136 ] 3 - ( { 6- [ 4- ( hydroxymethyl ) piperidin - 1 - yl ] pyridin - 3 - yl ) amino ) propanoic acid ( 6.4 g , 21.76 mmol , 1.0 equiv ) , and urea ( 2.614 g , 43.53 mmol , 2.0 equiv ) were dissolved in glacial acetic acid ( 64 mL , 10 vol ) and left to stir at 90 ° C for 48 h . The reaction mixture was then concentrated and the obtained residue was dissolved in EtOH ( 100 mL ) , followed by the addition of H2SO4 ( 0.012 mL , 0.022 mmol , 0.01 equiv ) and the mixture was stirred at room temperature for 48 h . The reaction mixture pH was adjusted to 10-11 with KHSO4 , concentrated , and purified by silica gel chromatography ( DCM : MeOH = 9 : 1 ) . The obtained material was further triturated with DCM to provide 1- { 6- [ 4- ( hydroxymethyl ) piperidin - 1- yl ] pyridin - 3 - yl } -1,3 - diazinane - 2,4 - dione ( 1.28 g , 18 % yield ) . LCMS : m / z = 305.05 ( M + H ) * . H¹ NMR ( 300 MHz , DMSO - εd ) 8 10.34 ( s , 1H ) , 8.04 ( d , J = 2.7 Hz , 1H ) , 7.47 ( dd , J = 9.0 , 2.Hz , 1H ) , 6.84 ( d , J = 9.1 Hz , 1H ) , 4.47 ( t , J = 5.3 Hz , 1H ) , 4.29 ( d , J = 13.0 Hz , 2H ) , 3.70 ( t , J - 681 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT = : 6.7 Hz , 2H ) , 3.27 ( t , J = 5.7 Hz , 2H ) , 2.83 – 2.65 ( m , 4H ) , 1.77 – 1.54 ( m , 3H ) , 1.( m , 2H ) . - - 1. [ 0001137 ] Step - 6 : Synthesis of 1- ( 5- ( 2,4 - dioxotetrahydropyrimidin - 1 ( 2H ) -yl ) pyridin- - yl ) piperidine - 4 - carbaldehyde [ 0001138 ] To a solution of 1- { 6- [ 4- ( hydroxymethyl ) piperidin - 1 - yl ] pyridin - 3 - yl } -1,3- diazinane - 2,4- dione ( 0.715 g , 2.3 mmol , 1 equiv ) dissolved in anhydrous DCM ( 0.3 M ) was added Dess - Martin periodinane ( 1.073 g , 2.53 mmol , 1.1 equiv ) in anhydrous DCM ( 0.15 M ) dropwise at 0 ° C . The reaction mixture was then warmed and left to stir at room temperature for one hour . The reaction was monitored by TLC and LCMS . The reaction mixture was then diluted with sat . aq . Na2S2O3 and the organic layer was separated and washed with sat . aq . NaHCO3 . The aqueous layers were combined and back - extracted several times with DCM . The combined organic phase was dried over Na2SO4 and concentrated to provide 1- [ 5- ( 2,4 - dioxo- 1,3 - diazinan - 1 - yl ) pyridin - 2 - yl ] piperidine - 4 - carbaldehyde ( 0.56 g , yield 77 % ) as a beige solid . The product tends to form a stable hydrate . LCMS : ESI ( + ) m / z = = 305.11 [ M + H ] * . ' H NMR ( 300 MHz , DMSO ɛd ) § 10.35 ( s , 1H ) , 9.63 ( d , J = 0.9 Hz , 1H ) , 8.08 - 8.03 ( m , 1H ) , 7.50 ( dd , J = 9.0 , 2.8 Hz , 1H ) , 6.88 ( d , J = 9.1 Hz , 1H ) , 4.13 ( dt , J = 13.2 , 4.1 Hz , 2H ) , 3.70 ( t , J = 6.Hz , 2H ) , 3.11 – 2.99 ( m , 2H ) , 2.71 ( d , J = 6.7 Hz , 2H ) , 2.66 – 2.55 ( m , 1H ) , 1.90 ( dd , J = 13.3 , 3.9 Hz , 2H ) , 1.55 – 1.42 ( m , 2H ) . [ 0001139 ] SFC Separation of Harnesses – N SFC or N N Soo or2 / [ 0001140 ] ( R ) -1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbaldehyde and ( S ) -1- ( 4- ( 2,6- dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbaldehyde ( HA - XX , peak 1 and HA - XX , peak 2 ) [ 0001141 ] Racemic 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperidine - 4 - carbaldehyde was purified by prep - SFC ( column : DAICEL CHIRALPAK AD ( 250 mm x 30 mm , 10 mμ ) ; mobile phase : [ Neu - IPA ] ; B % : 65 % -65 % , 4.5 ; 650 min ) to give peak 1 ( 13.64 g , 45.41 mmol , 48.7 % -682- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yield ) as yellow solid and crude peak 2. Crude peak 2 was purified by prep - SFC ( column : DAICEL CHIRALPAK AD ( 250 mm x 30 mm , 10 mμ ) ; mobile phase : [ IPA - ACN ] ; B % : 65 % - % , 4 ; 580 min ) to give peak 2 ( 8.13 g , 27.07 mmol , 29.04 % yield ) as an off - white solid . [ 0001142 ] HA - XX ( peak 1 ) : [ 0001143 ] = LCMS : m / z = 299.1 ( M - H ) ¯ . [ 0001144 ] SFC : ee % = 98.3 % under 220 nm . [ 0001145 ] – ' H NMR : ( 400 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.63 ( s , 1H ) , 7.04 ( d , J = 8.Hz , 2H ) , 6.90 ( d , J = 8.8 Hz , 2H ) , 3.75 – 3.68 ( m , 1H ) , 3.62 – 3.52 ( m , 2H ) , 2.86 – 2.75 ( m , 2H ) , 2.68 – 2.57 ( m , 1H ) , 2.49 – 2.40 ( m , 2H ) , 2.18 – 2.08 ( m , 1H ) , 2.05 – 1.88 ( m , 3H ) , 1.– 1.51 ( m , 2H ) .

HA - XX ( peak 2 ) : [ 0001146 ] [ 0001147 ] = LCMS : m / z = 299.1 ( M - H ) . [ 0001148 ] SFC : ee % = 100 % under 220 nm . - [ 0001149 ] ' H NMR ( 400 MHz , DMSO - d6 ) 8 10.75 ( s , 1H ) , 9.63 ( s , 1H ) , 7.07 - 7.01 ( m , 2H ) , 6.89 ( d , J = 8.8 Hz , 2H ) , 3.75 – 3.68 ( m , 1H ) , 3.61 – 3.53 ( m , 2H ) , 2.85 – 2.75 ( m , 2H ) , 2.68 – 2.58 ( m , 1H ) , 2.49 – 2.42 ( m , 2H ) , 2.19 – 2.07 ( m , 1H ) , 2.05 – 1.87 ( m , 3H ) , 1.64 – 1.( m , 2H ) .

N SFC or N N N Soo or2 / [ 0001150 ] ( R ) -1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbaldehyde and ( S ) -1- ( 5- ( 2,6- dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbaldehyde ( HA - XX , peak 1 and HA - XX , peak 2 ) [ 0001151 ] Racemic 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidine - 4 - carbaldehyde was purified by SFC ( column : REGIS ( s , s ) WHELK - O1 ( 250 mm x 50 mm , 10 mμ ) ; mobile phase : [ IPA - ACN ] ; B % : 60 % -60 % , B2.7 ; 300 min ) and concentrated under vacuum to provide a residue . The residue was triturated with ethyl acetate ( 60.0 mL ) at 20 ° C for 2 h , filtered , and -683- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT the filter cake was concentrated under vacuum to provide HA - XX , peak 1 ( 17.79 g , 58.3 mmol , 40.5 % yield ) and HA - XX , peak 2 , HA - 33 ( 16.05 g , 52.6 mmol , 36.5 % yield ) as white solids . [ 0001152 ] HA - XX ( peak 1 ) : [ 0001153 ] LCMS : m / z = 320.0 ( M + 19 ) + . [ 0001154 ] H NMR ( 400 MHz , DMSO - do ) 8 10.79 ( s , 1H ) , 9.61 ( s , 1H ) , 7.94 ( d , J = 2.Hz , 1H ) , 7.38 ( dd , J = 2.4 , 8.8 Hz , 1H ) , 6.82 ( d , J = 8.8 Hz , 1H ) , 4.13 – 4.08 ( m , 2H ) , 3.73 – - 3.70 ( m , 1H ) , 3.04 – 2.97 ( m , 2H ) , 2.67 – 2.53 ( m , 3H ) , 2.22 – 2.12 ( m , 1H ) , 2.00 – 1.93 ( m , - 1H ) , 1.901.85 ( m , 2H ) , 1.49 – 1.45 ( m , 2H ) . - [ 0001155 ] SFC : 100 % ee under 220 nm . [ 0001156 ] HA - XX ( peak 2 ) : [ 0001157 ] LCMS : m / z = 320.0 ( M + 19 ) + . [ 0001158 ] ' H NMR ( 400 MHz , DMSO - do ) d 10.79 ( s , 1H ) , 9.61 ( s , 1H ) , 7.94 ( d , J = 2.Hz , 1H ) , 7.38 ( dd , J = 2.4 , 8.8 Hz , 1H ) , 6.82 ( d , J = 8.8 Hz , 1H ) , 4.13 – 4.09 ( m , 2H ) , 3.74 – 3.70 ( m , 1H ) , 3.04 – 2.97 ( m , 2H ) , 2.67 – 2.53 ( m , 3H ) , 2.22 – 2.12 ( m , IH ) , 2.00 – 1.93 ( m , 1H ) , 1.901.85 ( m , 2H ) , 1.49 – 1.46 ( m , 2H ) . - - - [ 0001159 ] SFC : 100 % ee under 220 nm . [ 0001160 ] General Procedures for Synthesis of Final Exemplary Chimeric Targeting Molecules ( CTMs ) [ 0001161 ] Reductive Amination Example [ 0001162 ] Synthesis of rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide - 684 - 1100573566 5 AMERICAS O = 5 = F- HN N.

.N .

Attorney Docket No .: 121843.002NU - 3200 PCT & [ 0001163 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 93 mg , 0.153 mmol ) and rac - 1- { 4- [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4 - carbaldehyde ( 57 mg , 1.25 equiv ) were combined in DCE ( 0.1 M ) and DIEA ( 0.08 mL , 3 equiv ) and the reaction mixture was stirred for fifteen minutes , followed by the addition of STAB ( 89 mg , 2.75 equiv ) . The reaction was then stirred for 4 h , followed by concentration by rotary evaporator . The reaction was then diluted with DMF ( 0.5 mL ) , filtered through a syringe filter , and purified by HPLC to provide the desired product ( 32 mg , 22 % ) . LCMS : C48H57FN8O4S2 requires : 892.4 , found : m / z = 893.[ M + H ] + . [ 0001164 ] Amide Coupling Examples [ 0001165 ] Synthesis of rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2 - ( { 2 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -1,3 - dioxoisoindol - 5 - yl } oxy ) acetyl ] piperidin - 4- ylphenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide ﻝا S. ZI ' N ' N F HN = 5 = N N & NH -685- 1100573566 5 AMERICAS [ 0001166 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 20 mg , 0.033 mmol ) , rac - ( { 2 - [ ( 3R ) - 2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxoisoindol - 5 - yl ) oxy ) acetic acid ( 12 mg , 1.1 equiv ) and HATU ( 13 mg , 1.1 equiv ) in DMF ( 0.2 M ) and DIEA ( 0.023 mL , 4 equiv ) was stirred at rt for h , followed by filtration by syringe filter and purification by HPLC to provide the desired product ( 13 mg , 39 % ) . LCMS : C46H47FN8O8S2 requires : 922.3 , found : m / z = 923.5 [ M + H ] * . [ 0001167 ] Synthesis of rac - N- { 3- [ 1- ( 4- { 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperazine - 1 - carbonylphenyl ) -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide NH HO -NH < & 1 ° N -NH ( & [ 0001168 ] N- ( 2 - fluoro - 3- { 1- [ 4- ( piperazine - 1 - carbonyl ) phenyl ] -3- ( pyridin - 4 - yl ) pyrazol- - yl ) phenyl ) propane - 1 - sulfonamide ( 20 mg , 0.0336 mmol ) , rac- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetic acid ( 12 mg , 1.1 equiv ) , and HATU ( mg , 1.1 equiv ) in DMF ( 0.2 M ) and DIEA ( 0.023 mL , 4 equiv ) was stirred at rt for 4 h . Filtration by syringe filter and purification by HPLC provided the desired product ( 23 mg , 66 % ) . LCMS : C45H48FN9O6S requires : 861.3 , found : m / z = 862.2 [ M + H ] + . [ 0001169 ] Synthesis of rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin- - yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl } -3- ( pyridin - 4- yl ) pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide -NH -NH & OH & - 686 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001170 ] N- { 2 - fluoro - 3- [ 1- ( piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) pyrazol - 4- yl ] phenylpropane - 1 - sulfonamide ( 10 mg , 0.023 mmol ) , rac - 1- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4 - carboxylic acid ( 10 mg , 1.03 equiv ) , and HATU ( 9 mg , 1.05 equiv ) in DMF ( 0.1 M ) and DIEA ( 0.02 mL , 5 equiv ) was stirred at rt for 4 h . Filtration by syringe filter and purification by HPLC provided the desired product ( 5.4 mg , 27 % ) . LCMS : C44H52FN9O6S requires : 853.4 , found : m / z = 854.7 [ M + H ] * . [ 0001171 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 1 ) = LCMS : C43H48FN9O4S requires : 805.4 , found : m / z = 806.2 [ M + H ] * . [ 0001172 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 2 ) = ' H NMR ( 500 MHz , DMSO - do ) 8 10.88 ( s , 1H ) , 9.69 ( s , 1H ) , 9.50 ( s , 1H ) , 8.77 ( s , 1H ) , 8.( d , J = 5.4 Hz , 2H ) , 7.94 ( d , J = 2.4 Hz , 1H ) , 7.87 ( d , J = 8.8 Hz , 2H ) , 7.63 ( d , J = 5.7 Hz , 3H ) , 7.49 ( td , J = 7.7 , 1.9 Hz , 1H ) , 7.40 - 7.34 ( m , 1H ) , 7.31 ( t , J = 7.8 Hz , 1H ) , 7.25 – 7.17 ( m , 2H ) , 4.28 ( d , J = 13.0 Hz , 2H ) , 3.94 ( d , J = 10.9 Hz , 3H ) , 3.89 – 3.79 ( m , 1H ) , 3.25 – 3.10 ( m , 6H ) , 3.09 – 2.94 ( m , 4H ) , 2.75 – 2.60 ( m , 1H ) , 2.32 – 2.13 ( m , 2H ) , 2.03 – 1.92 ( m , 1H ) , 1.( d , J = 12.9 Hz , 2H ) , 1.75 – 1.60 ( m , 2H ) , 1.28 ( d , J = 11.4 Hz , 1H ) , 0.92 ( t , J = 7.4 Hz , 3H ) .

– LCMS : C43H48FN9O4S requires : 805.4 , found : m / z = 806.3 [ M + H ] * . [ 0001173 ] rac - N- { 3- [ 1- ( 6- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 3 ) = LCMS : C42H47FN10O4S requires : 806.3 , found : m / z = 807.2 [ M + H ] + . [ 0001174 ] N- { 3- [ 1- ( 6- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 4 ) LCMS : C43H48FN9O4S requires : 805.4 , found : m / z = 806.2 [ M + H ] * . - 687 - 1100573566 5 AMERICAS [ 0001175 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 1- ( 4 - { [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] oxyphenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 5 ) . LCMS : C44H47FN8O6S requires : 834.3 , found : m / z = 835.2 [ M + H ] * . [ 0001176 ] rac - N- { 3- [ 1- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 6 ) LCMS : C44H54FN9O5S requires : 839.4 , found : m / z = 840.3 [ M + H ] * . [ 0001177 ] rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 7 ) LCMS : C44H52FN9O6S requires : 853.4 , found : m / z = 854.7 [ M + H ] * . [ 0001178 ] rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 8 ) LCMS : C45H54FN9O6S requires : 867.4 , found : m / z = 868.2 [ M + H ] * . [ 0001179 ] rac - N- [ 3- ( 1- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 9 ) LCMS : C45H53FN8O6S requires : 852.4 , found : m / z = 853.2 [ M + H ] * . [ 0001180 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 10 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.68 ( s , 1H ) , 8.71 ( s , 1H ) , 8.55 ( d , J = 5.2 Hz , 2H ) , 7.83 ( s , 2H ) , 7.45 ( dd , J = 16.5 , 6.4 Hz , 3H ) , 7.32 ( dt , J = 26.2 , 7.4 Hz , 2H ) , 7.24 - 7.( m , 4H ) , 6.92 ( d , J = 8.2 Hz , 2H ) , 3.73 ( dd , J = 11.1 , 5.0 Hz , 1H ) , 3.21 ( s , 6H ) , 3.02 ( dd , J = -688- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 9.1 , 6.3 Hz , 2H ) , 2.65 ( t , J = 15.4 Hz , 3H ) , 2.32 – 2.07 ( m , 1H ) , 2.02 ( dd , J = 13.0 , 5.6 Hz , 1H ) , - 1.85 ( d , J = 12.4 Hz , 2H ) , 1.69 ( q , J = 7.6 Hz , 2H ) , 0.92 ( t , J = 7.4 Hz , 3H ) .

LCMS : C44H49FN8O4S requires : 804.4 , found : m / z = 805.7 [ M + H ] * . [ 0001181 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazine - 1 - carbonyl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 11 ) LCMS : C45H49FN8O5S requires : 832.4 , found : m / z = 833.2 [ M + H ] * . [ 0001182 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazine - 1 - carbonyl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 12 ) LCMS : C45H49FN8O5S requires : 832.4 , found : m / z = 833.3 [ M + H ] * . [ 0001183 ] rac - N- { 3- [ 1- ( 4- { 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) acetyl ] piperazine - 1 - carbonyl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 13 ) LCMS : C45H48FN9O6S requires : 861.3 , found : m / z = 862.2 [ M + H ] * . [ 0001184 ] rac - N- [ 3- ( 1- { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperazine - 1 - carbonyl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 14 ) LCMS : C45H47FN8O6S requires : 846.3 , found : m / z = 847.2 [ M + H ] * . [ 0001185 ] N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide ( 15 ) LCMS : C45H50FN7O4S requires : 803.4 , found : m / z = 804.2 [ M + H ] * . - 689 - 1100573566 5 AMERICAS [ 0001186 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 16 ) - ' H NMR ( 500 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.69 ( s , 1H ) , 8.69 ( d , J = 3.0 Hz , 1H ) , 8.57 - 8.52 ( m , 2H ) , 8.15 ( s , 1H ) , 7.79 ( d , J = 8.7 Hz , 2H ) , 7.50 – 7.44 ( m , 1H ) , 7.47 – 7.41 ( m , 2H ) , 7.377.31 ( m , 1H ) , 7.29 ( t , J = 7.8 Hz , 1H ) , 7.13 - 7.08 ( m , 2H ) , 7.05 ( d , J = 8.2 Hz , 2H ) , 6.90 ( d , J = 8.3 Hz , 2H ) , 5.77 ( s , 1H ) , 3.73 ( dd , J = 10.9 , 4.9 Hz , 1H ) , 3.68 ( d , J 11.8 Hz , 2H ) , 3.24 ( d , J = 4.8 Hz , 3H ) , 3.02 ( dd , J = 8.7 , 6.6 Hz , 2H ) , 2.67 ( d , J = 11.7 Hz , 2H ) , 2.= = ( d , J = 7.1 Hz , 2H ) , 2.18 – 2.07 ( m , 1H ) , 2.02 ( dt , J = 13.3 , 4.9 Hz , 1H ) , 1.83 ( d , J = 12.5 Hz , 2H ) , 1.74 – 1.64 ( m , 3H ) , 1.30 – 1.19 ( m , 2H ) , 0.91 ( t , J = 7.4 Hz , 3H ) . - LCMS : C44H49FN8O4S requires : 804.4 , found : m / z = 805.2 [ M + H ] * . [ 0001187 ] rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } -4- methylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 17 ) LCMS : C44H50FN9O4S requires : 819.4 , found : m / z = 820.2 [ M + H ] * . [ 0001188 ] rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2- fluorophenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 18 ) 1H NMR ( 500 MHz , DMSO - d6 ) 8 10.83 ( s , 1H ) , 9.70 ( s , 1H ) , 9.43 ( s , 1H ) , 8.80 ( s , 1H ) , 8.( d , J = 5.6 Hz , 2H ) , 7.89 ( d , J = 8.7 Hz , 2H ) , 7.69 ( d , J = 5.5 Hz , 2H ) , 7.50 ( td , J = 7.7 , 1.9 Hz , – 1H ) , 7.41 – 7.36 ( m , 1H ) , 7.32 ( t , J = 7.8 Hz , 1H ) , 7.22 ( d , J = 8.8 Hz , 2H ) , 7.08 – 6.95 ( m , 3H ) , 3.95 ( d , J = 11.6 Hz , 2H ) , 3.82 ( dd , J = 11.8 , 4.9 Hz , 1H ) , 3.73 – 3.62 ( m , 2H ) , 3.40 ( d , J = = = 11.5 Hz , 2H ) , 3.30 – 3.11 ( m , 6H ) , 3.10 – 3.01 ( m , 2H ) , 2.78 – 2.60 ( m , 3H ) , 2.21 ( dd , J 12.4 , 4.2 Hz , 1H ) , 2.06 – 1.95 ( m , 2H ) , 1.95 – 1.84 ( m , 2H ) , 1.70 ( q , J = 7.6 Hz , 2H ) , 1.56 – 1.36 ( m , 2H ) , 0.93 ( t , J = 7.4 Hz , 3H ) .

LCMS : C44H48F2N8O4S requires : 822.3 , found : m / z = 823.2 [ M + H ] * . [ 0001189 ] rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- fluorophenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 19 ) -690- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C44H48F2N8O4S requires : 822.4 , found : m / z = 823.2 [ M + H ] * . [ 0001190 ] rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 20 ) = ' H NMR ( 500 MHz , DMSO - do ) 8 10.90 ( s , 1H ) , 9.70 ( s , 1H ) , 9.53 ( s , 1H ) , 8.80 ( s , 1H ) , 8.( d , J = 5.4 Hz , 2H ) , 7.95 ( d , J = 2.3 Hz , 1H ) , 7.89 ( d , J = 8.6 Hz , 2H ) , 7.67 ( d , J = 5.5 Hz , 3H ) , 7.55 - 7.46 ( m , 1H ) , 7.35 ( dt , J = 29.6 , 7.5 Hz , 2H ) , 7.22 ( d , J = 8.7 Hz , 2H ) , 7.16 ( s , 1H ) , 4.( d , J = 13.1 Hz , 2H ) , 3.95 ( d , J = 11.1 Hz , 2H ) , 3.86 ( dd , J = 12.6 , 4.9 Hz , 1H ) , 3.67 ( d , J 10.4 Hz , 2H ) , 3.31 – 3.10 ( m , 6H ) , 3.11 – 2.94 ( m , 3H ) , 2.77 – 2.63 ( m , 1H ) , 2.25 ( ddd , J = 19.8 , 14.4 , 7.6 Hz , 2H ) , 1.98 ( dq , J = 13.1 , 4.8 , 4.3 Hz , 1H ) , 1.89 ( d , J = 12.8 Hz , 2H ) , 1.70 ( q , J = 7.6 Hz , 2H ) , 1.30 ( q , J = 12.9 , 12.3 Hz , 2H ) , 0.93 ( t , J = 7.4 Hz , 3H ) .

= LCMS : C43H48FN9O4S requires : 805.4 , found : m / z = 806.2 [ M + H ] * . = [ 0001191 ] rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenylpiperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 21 ) LCMS : C44H49FN8O4S requires : 804.4 , found : m / z = 805.2 [ M + H ] * . [ 0001192 ] rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2- fluorophenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 22 ) LCMS : C45H49F2N7O4S requires : 821.4 , found : m / z = 822.2 [ M + H ] + . [ 0001193 ] rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- fluorophenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 23 ) LCMS : C45H49F2N7O4S requires : 821.4 , found : m / z = 822.2 [ M + H ] * . [ 0001194 ] rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 24 ) -691- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS : C44H49FN8O4S requires : 804.4 , found : m / z = 805.2 [ M + H ] * . [ 0001195 ] NU - 3200 PCT rac - N- { 3- [ 1- ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2 - fluorophenyl } propane- - sulfonamide ( 25 ) LCMS : C45H50FN7O4S requires : 803.4 , found : m / z = 804.3 [ M + H ] * . [ 0001196 ] rac - N- [ 3- ( 1- { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] propane- - sulfonamide ( 26 ) LCMS : C44H47FN8O5S requires : 818.3 , found : m / z = 819.2 [ M + H ] * . [ 0001197 ] ( 3R ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- ylmethyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 27 ) LCMS : C42H49FN12O4S2 requires : 868.3 , found : m / z = 869.2 [ M + H ] * . [ 0001198 ] rac- ( 3R ) -3- [ 2- ( 2- { 4- [ 4 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) -2- fluorophenyl ] piperazin - 1 - yl } -2 - oxoethyl ) -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ] piperidine - 2,6- dione ( 28 ) LCMS : C46H52F2N10O5S2 requires : 926.4 , found : m / z = 927.2 [ M + H ] * . [ 0001199 ] ( 3R ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- yl } methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 29 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 1H ) , 9.70 ( s , 1H ) , 9.56 ( s , 1H ) , 8.35 ( d , J = 5.2 Hz , 1H ) , 7.99 ( d , J = 2.9 Hz , 1H ) , 7.95 ( d , J = 2.4 Hz , 1H ) , 7.83 ( d , J = 9.0 Hz , 1H ) , 7.55 ( t , J = 7.Hz , 1H ) , 7.44 – 7.25 ( m , 4H ) , 6.80 ( d , J = 8.8 Hz , 1H ) , 6.44 ( d , J = 5.2 Hz , 1H ) , 4.28 ( d , J 12.7 Hz , 2H ) , 3.73 ( dd , J = 12.2 , 4.9 Hz , 1H ) , 3.14 ( s , 4H ) , 3.06 ( q , J = 7.1 Hz , 2H ) , 2.80 ( t , J = = · 12.4 Hz , 2H ) , 2.75 – 2.61 ( m , 5H ) , 2.40 – 2.34 ( m , 1H ) , 2.31 – 2.12 ( m , 3H ) , 2.05 – 1.92 ( m , -692- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1H ) , 1.80 ( d , J = 12.7 Hz , 3H ) , 1.48 ( s , 10H ) , 1.25 ( s , 2H ) , 1.19 – 1.05 ( m , 2H ) , 1.00 ( t , J = 7.Hz , 3H ) .

LCMS : C45H55FN12O4S2 requires : 910.4 , found : m / z = 911.2 [ M + H ] * . [ 0001200 ] rac- ( 3R ) -3- { 6- [ 6 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 2 - yl ] pyridin - 3- yl } piperidine - 2,6 - dione ( 30 ) LCMS : C46H55FN12O4S2 requires : 922.4 , found : m / z = 923.2 [ M + H ] * . [ 0001201 ] rac - N- [ 3- ( 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } -4- fluoropiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 31 ) LCMS : C44H49F2N9O4S2 requires : 869.3 , found : m / z = 870.3 [ M + H ] * . [ 0001202 ] rac - N- [ 3- ( 5- { 2 - [ ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) -4- methylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 32 ) LCMS : C44H51FN10O4S2 requires : 866.4 , found : m / z = 867.3 [ M + H ] * . [ 0001203 ] rac- ( 3S ) -3- { 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- yl } methyl ) -4 - fluoropiperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione ( 33 ) LCMS : C43H49F2N11O4S2 requires : 885.3 , found : m / z = 886.2 [ M + H ] * . [ 0001204 ] rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- ylmethyl ) -4 - methylpiperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 34 ) LCMS : C43H51FN12O4S2 requires : 882.4 , found : m / z = 883.2 [ M + H ] * . -693- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001205 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 35 ) LCMS : C47H56FN9O4S2 requires : 893.4 , found : m / z = 894.2 [ M + H ] * . [ 0001206 ] rac- ( 3S ) -3- [ 4- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) phenyl ] piperidine - 2,6 - dione ( 36 ) LCMS : C46H54FN11O5S2 requires : 923.4 , found : m / z = 924.2 [ M + H ] * . [ 0001207 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4- yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 37 ) LCMS : C48H55FN8O5S2 requires : 906.4 , found : m / z = 907.2 [ M + H ] * . [ 0001208 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidine - 4 - carbonyl ) piperazin - 1 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4- yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 38 ) LCMS : C47H54FN9O5S2 requires : 907.4 , found : m / z = 908.7 [ M + H ] + . [ 0001209 ] rac- ( 3R ) -3- { 6- [ 4- ( 2- { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl } - - oxoethyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 39 ) LCMS : C43H49FN12O5S2 requires : 896.3 , found : m / z = 897.2 [ M + H ] * . [ 0001210 ] rac- ( 3S ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazine - 1- carbonyl } piperidin - 1 - yl ) pyridin - 3 - yl ] piperidine - 2,6 - dione ( 40 ) LCMS : C43H47FN12O5S2 requires : 882.3 , found : m / z = 883.2 [ M + H ] * . -694- 1100573566 5 AMERICAS [ 0001211 ] Attorney Docket No .: 121843.002NU - 3200 PCT ( 3R ) -3- ( 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- yl } methyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione ( 41 ) LCMS : C43H50FN11O4S2 requires : 867.3 , found : m / z = 868.2 [ M + H ] * . [ 0001212 ] rac- ( 3S ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } -4 - methylpiperidin - 1 - yl ) pyridin - 3- yl ] piperidine - 2,6 - dione ( 42 ) LCMS : C46H55FN12O5S2 requires : 938.4 , found : m / z = 939.0 [ M + H ] * . [ 0001213 ] rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -2 - methyl - 1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- yl } methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 43 ) LCMS : C42H49FN12O4S2 requires : 868.3 , found : m / z = 868.3 [ M + H ] * . [ 0001214 ] rac - N- { 3- [ 5- ( 2 - { [ 4- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 4 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -2- methyl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 44 ) LCMS : C46H52FN9O5S2 requires : 893.4 , found : m / z = 894.4 [ M + H ] * . [ 0001215 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4- yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 45 ) LCMS : C46H54F2N10O4S2 requires : 912.4 , found : m / z = 913.6 [ M + H ] * . [ 0001216 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 4- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 4 - yl ] acetyl } piperazin - 1 - yl ) -3 - fluorophenyl ] amino } pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 46 ) LCMS : C48H56F2N10O5S2 requires : 954.4 , found : m / z = 955.2 [ M + H ] * . -695- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001217 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 47 ) = ' H NMR ( 500 MHz , DMSO - εd ) 8 10.88 ( s , 1H ) , 9.73 ( s , 1H ) , 9.55 ( s , 1H ) , 9.32 ( s , 1H ) , 8.( d , J = 5.2 Hz , 1H ) , 7.95 ( s , 1H ) , 7.55 ( d , J = 8.3 Hz , 3H ) , 7.47 ( t , J = 6.9 Hz , 1H ) , 7.37 ( t , J 7.9 Hz , 1H ) , 7.09 ( s , 1H ) , 6.94 ( d , J = 8.7 Hz , 2H ) , 6.40 ( d , J = 5.1 Hz , 1H ) , 4.29 ( d , J = 13.Hz , 2H ) , 3.83 ( s , 2H ) , 3.73 ( d , J = 12.7 Hz , 2H ) , 3.64 ( d , J = 11.7 Hz , 2H ) , 3.27 – 3.09 ( m , 3H ) , 3.09 - 2.94 ( m , 5H ) , 2.77 – 2.62 ( m , 2H ) , 2.32 – 2.12 ( m , 2H ) , 1.99 ( dt , J = 11.5 , 5.6 Hz , 1H ) , 1.88 ( d , J = 12.5 Hz , 2H ) , 1.68 ( p , J = 7.6 Hz , 2H ) , 1.37 – 1.21 ( m , 3H ) , 0.91 ( t , J = 7.4 Hz , 3H ) .

- LCMS : C46H55FN10O4S2 requires : 894.4 , found : m / z = 895.2 [ M + H ] * . [ 0001218 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 48 ) LCMS : C47H54F2N10O5S2 requires : 940.4 , found : m / z = 941.3 [ M + H ] * . [ 0001219 ] rac - N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 4- ( 4 - ( ( R ) -1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3- yl ) pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) amino ) pyrimidin - 4- yl ) thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 49 ) LCMS : C45H50F2N10O5S2 requires : 912.3 , found : m / z = 913.6 [ M + H ] * . [ 0001220 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - fluoro - 4- { 4 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) oxy ) cyclohexanecarbonyl ] piperazin - 1- yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 50 ) LCMS : C47H53F2N9O6S2 requires : 941.4 , found : m / z = 942.1 [ M + H ] * . [ 0001221 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,2,3,4 - tetrahydroisoquinolin - 2 - yl } acetyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) amino ) pyrimidin - 4- yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 51 ) - 696 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS : C46H51F2N9O5S2 requires : 911.3 , found : m / z = 912.2 [ M + H ] * .

NU - 3200 PCT [ 0001222 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 4- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] amino } -2 - fluorophenyl ) -4 - hydroxypiperidin - 4 - yl ] acetyl } piperazin - 1 - yl ) -3- fluorophenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 52 ) LCMS : C48H55F3N10O6S2 requires : 988.4 , found : m / z = 989.2 [ M + H ] * . [ 0001223 ] rac- ( 3S ) -3- [ 6- ( 3- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } azetidin - 1 - yl ) pyridin - 3 - yl ] piperidine - 2,6 - dione ( 53 ) LCMS : C43H49FN12O5S2 requires : 896.3 , found : m / z = 897.2 [ M + H ] * . [ 0001224 ] rac - N- [ 3- ( 5- { 2 - [ ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol- - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 54 ) LCMS : C44H50FN9O4S2 requires : 851.3 , found : m / z = 852.2 [ M + H ] * . [ 0001225 ] rac - N- ( 3- { 5- [ 2 - ( { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -2 - methyl - 1,3 - thiazol- - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 55 ) LCMS : C44H48FN9O5S2 requires : 865.3 , found : m / z = 866.2 [ M + H ] * . [ 0001226 ] rac- ( 3R ) -3- [ 6- ( 4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } piperidin - 1 - yl ) pyridin - 3 - yl ] piperidine - 2,6- dione ( 56 ) LCMS : C45H53FN12O5S2 requires : 924.4 , found : m / z = 925.7 [ M + H ] * . -697- 1100573566 5 AMERICAS [ 0001227 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) amino ) pyrimidin - 4- yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 57 ) LCMS : C46H52F2N10O5S2 requires : 926.4 , found : m / z = 927.2 [ M + H ] * . [ 0001228 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 58 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.46 ( s , 1H ) , 8.28 ( d , J = 5.2 Hz , 1H ) , 7.56 ( t , = 8.2 Hz , = J = 7.6 Hz , 1H ) , 7.47 ( dd , J = 23.0 , 7.7 Hz , 3H ) , 7.36 ( t , J = 7.9 Hz , 1H ) , 7.04 ( d , J 2H ) , 6.88 ( dd , J = 18.3 , 8.5 Hz , 4H ) , 6.35 ( d , J = 5.1 Hz , 1H ) , 3.79 – 3.62 ( m , 3H ) , 3.08 ( t , J - 4.9 Hz , 4H ) , 3.01 ( t , J = 7.7 Hz , 2H ) , 2.72 – 2.58 ( m , 4H ) , 2.24 ( d , J = 7.2 Hz , 2H ) , 2.20 – 2.( m , 1H ) , 2.02 ( dt , J = 13.4 , 5.1 Hz , 1H ) , 1.82 ( d , J = 12.7 Hz , 2H ) , 1.69 ( dt , J = 15.2 , 7.4 Hz , 3H ) , 1.30 – 1.17 ( m , 2H ) , 0.91 ( t , J = 7.4 Hz , 3H ) .

= LCMS : C47H56FN9O4S2 requires : 893.4 , found : m / z = 894.4 [ M + H ] * . [ 0001229 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 59 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.80 ( s , 1H ) , 9.73 ( s , 1H ) , 9.56 ( s , 1H ) , 9.34 ( s , 1H ) , 8.( d , J = 5.2 Hz , 1H ) , 7.55 ( d , J = 8.3 Hz , 3H ) , 7.47 ( t , J = 7.0 Hz , 1H ) , 7.37 ( t , J = 7.9 Hz , 1H ) , 7.17 - 7.05 ( m , 2H ) , 7.05 – 6.84 ( m , 4H ) , 6.40 ( d , J = 5.1 Hz , 1H ) , 3.90 – 3.69 ( m , 6H ) , 3.( d , J = 11.5 Hz , 2H ) , 3.18 ( q , J = 8.9 , 6.8 Hz , 4H ) , 3.10 – 2.95 ( m , 4H ) , 2.80 ( s , 2H ) , 2.65 ( td , J = 11.9 , 5.5 Hz , 1H ) , 2.22 – 1.96 ( m , 3H ) , 1.89 ( d , J = 12.3 Hz , 2H ) , 1.67 ( q , J = 7.5 Hz , 2H ) , 1.48 ( s , 9H ) , 1.38 ( t , J = 15.5 Hz , 1H ) , 1.27 ( q , J = 5.8 , 4.7 Hz , 1H ) , 0.91 ( t , J = 7.4 Hz , 3H ) .

- = LCMS : C47H56FN9O4S2 requires : 893.4 , found : m / z = 894.2 [ M + H ] * . [ 0001230 ] N- [ 3- ( 5- { 2 - [ ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenylpiperidin - 4- yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 60 ) LCMS : C43H49FN10O4S2 requires : 852.3 , found : m / z = 853.2 [ M + H ] * . - 698 - 1100573566 5 AMERICAS [ 0001231 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 5- { 2 - [ ( 5- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 61 ) LCMS : C43H49FN10O4S2 requires : 852.3 , found : m / z = 853.2 [ M + H ] [ 0001232 ] rac - N- [ 3- ( 5- { 2 - [ ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 62 ) LCMS : C42H48FN11O4S2 requires : 853.3 , found : m / z = 854.2 [ M + H ] * . [ 0001233 ] N- [ 3- ( 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 63 ) LCMS : C45H51FN8O4S2 requires : 850.3 , found : m / z = 851.2 [ M + H ] * . [ 0001234 ] N- [ 3- ( 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenylpiperidin - 4- yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -2 - methyl - 1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 64 ) = LCMS : C45H51FN8O4S2 requires : 850.3 , found : m / z = 851.2 [ M + H ] * . [ 0001235 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidine - 4 - carbonyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 65 ) LCMS : C47H53F2N9O5S2 requires : 925.4 , found : m / z = 926.2 [ M + H ] * . [ 0001236 ] 5- ( 4 - { [ 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl ) methyl ) piperidin - 1- yl ] methyl } piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 66 ) LCMS : C46H57FN12O5S2 requires : 940.4 , found : m / z = 941.2 [ M + H ] * . - 699 - 1100573566 5 AMERICAS [ 0001237 ] Attorney Docket No .: 121843.002NU - 3200 PCT - { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl } piperidin - 1 - yl ) methyl ] piperidin - 1- yl } -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 67 ) LCMS : C45H55FN12O5S2 requires : 926.4 , found : m / z = 927.3 [ M + H ] * . [ 0001238 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) -4 - methylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 68 ) LCMS : C48H58FN9O5S2 requires : 923.4 , found : m / z = 924.3 [ M + H ] * . [ 0001239 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 69 ) LCMS : C47H56FN9O5S2 requires : 909.4 , found : m / z = 910.6 [ M + H ] * . [ 0001240 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 70 ) LCMS : C47H56FN9O5S2 requires : 909.4 , found : m / z = 910.3 [ M + H ] + . [ 0001241 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1- oxo - 1,2 - dihydroisoquinolin - 6 - yl } piperidin - 4 - yl ) methyl ] piperidin - 4- yloxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 71 ) LCMS : C51H58FN9O6S2 requires : 975.4 , found : m / z = 976.5 [ M + H ] * . [ 0001242 ] N- ( 3- ( 2- ( tert - butyl ) -5- ( 2 - ( ( 3 - ( ( 1 - ( ( ( 1R , ‍r4 ) -4- ( 4 - ( ( RS ) -2,6 - dioxopiperidin - 3- yl ) phenoxy ) cyclohexyl ) methyl ) piperidin - 4 - yl ) oxy ) phenyl ) amino ) pyrimidin - 4 - yl ) thiazol - 4- yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 72 ) LCMS : C49H58FN7O6S2 requires : 923.4 , found : m / z = 924.2 [ M + H ] + . -700- 1100573566 5 AMERICAS [ 0001243 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) -4 - methylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4- yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 73 ) = LCMS : C48H58FN9O4S2 requires : 907.4 , found : m / z = 908.9 [ M + H ] * . [ 0001244 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 74 ) LCMS : C47H56FN9O4S2 requires : 893.4 , found : m / z = 894.2 [ M + H ] * . [ 0001245 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 75 ) LCMS : C47H56FN9O4S2 requires : 893.4 , found : m / z = 894.2 [ M + H ] * . [ 0001246 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3- { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1- oxo - 1,2 - dihydroisoquinolin - 6 - yl } piperidin - 4 - yl ) methyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 76 ) LCMS : C51H58FN9O4S2 requires : 959.4 , found : m / z = 960.3 [ M + H ] * . [ 0001247 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 77 ) LCMS : C44H54FN11O4S2 requires : 883.4 , found : m / z = 884.3 [ M + H ] * . [ 0001248 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 78 ) LCMS : C44H54FN11O4S2 requires : 883.4 , found : m / z = 884.6 [ M + H ] * . - 701- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001249 ] rac - 5- { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl } piperidin - 1- yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 79 ) LCMS : C45H55FN12O5S2 requires : 926.4 , found : m / z = 927.2 [ M + H ] * . [ 0001250 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1- oxo - 1,2 - dihydroisoquinolin - 6 - yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) -1H - pyrazol - 4- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 80 ) LCMS : C48H56FN11O5S2 requires : 949.4 , found : m / z = 950.3 [ M + H ] * . [ 0001251 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4- yl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 81 ) LCMS : C45H56FN11O4S2 requires : 897.4 , found : m / z = 898.2 [ M + H ] * . [ 0001252 ] rac - 5- ( 4 - { [ 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1- ylmethyl ) piperidin - 1 - yl ] methyl } piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2- carboxamide ( 82 ) LCMS : C46H57FN12O5S2 requires : 940.4 , found : m / z = 941.3 [ M + H ] * . [ 0001253 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1- oxo - 1,2 - dihydroisoquinolin - 6 - yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol- - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 83 ) LCMS : C49H58FN11O5S2 requires : 963.4 , found : m / z = 964.2 [ M + H ] * . [ 0001254 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexyl ] methyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin - 4- yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 84 ) LCMS : C47H58FN9O5S2 requires : 911.4 , found : m / z = 912.2 [ M + H ] * . -702- 1100573566 5 AMERICAS [ 0001255 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo- 1,2 - dihydroisoquinolin - 6 - yl } piperidin - 4 - yl ) methyl ] -1,2,3,4 - tetrahydroisoquinolin - 6- yl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 85 ) . LCMS : C49H54FN9O5S2 requires : 931.4 , found : m / z = 932.3 [ M + H ] + . [ 0001256 ] ( 2S , 4R ) -1 - [ ( 28 ) -2- [ 5- ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidin - 1 - yl ) -5- oxopentanamido ] -3,3 - dimethylbutanoyl ] -4 - hydroxy - N - [ ( 1S ) -1- [ 4- ( 4 - methyl - 1,3 - thiazol - 5- yl ) phenyl ] ethyl ] pyrrolidine - 2 - carboxamide ( 86 ) LCMS : C59H73FN10O7S3 requires : 1148.5 , found : m / z = 1149.3 [ M + H ] * . [ 0001257 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 87 ) LCMS : C47H55F2N9O4S2 requires : 911.4 , found : m / z = 912.6 [ M + H ] * . [ 0001258 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 88 ) LCMS : C47H55F2N9O4S2 requires : 911.4 , found : m / z = 912.3 [ M + H ] * . [ 0001259 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 89 ) LCMS : C48H57FN8O4S2 requires : 892.4 , found : m / z = 893.2 [ M + H ] * . [ 0001260 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 90 ) LCMS : C48H57FN8O4S2 requires : 892.4 , found : m / z = 893.2 [ M + H ] * . -703- 1100573566 5 AMERICAS [ 0001261 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 91 ) LCMS : C48H55FN8O6S2 requires : 922.4 , found : m / z = 923.3 [ M + H ] * . [ 0001262 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 92 ) LCMS : C48H55FN8O6S2 requires : 922.4 , found : m / z = 923.2 [ M + H ] * . [ 0001263 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpiperazin - 1 - yl ) acetyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 93 ) LCMS : C47H55FN1006S2 requires : 938.4 , found : m / z = 939.5 [ M + H ] * . [ 0001264 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 94 ) LCMS : C46H52FN9O6S2 requires : 909.3 , found : m / z = 910.2 [ M + H ] * . [ 0001265 ] rac - 5- [ 4- ( 4- { 3 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenoxy } piperidine - 1- carbonyl ) piperidin - 1 - yl ] -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 95 ) LCMS : C48H55FN10O7S2 requires : 966.4 , found : m / z = 967.2 [ M + H ] * . [ 0001266 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3 - [ ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 1 - yl ] acetyl } piperidin - 4 - yl ) oxy ] phenyl ) amino ) pyrimidin - 4 - yl ] - 1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 96 ) LCMS : C49H58FN9O6S2 requires : 951.4 , found : m / z = 952.2 [ M + H ] * . -704- 1100573566 5 AMERICAS [ 0001267 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 11,4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) oxy ) cyclohexanecarbonyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 97 ) LCMS : C48H55FN8O7S2 requires : 938.4 , found : m / z = 939.2 [ M + H ] * . [ 0001268 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3 - ( { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl ) oxy ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 98 ) LCMS : C49H56FN7O7S2 requires : 937.4 , found : m / z = 955.6 [ M + NH4 ] * . [ 0001269 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - { [ 1- ( 1- { 3 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ] oxy } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 99 ) LCMS : C48H55FN8O6S2 requires : 922.4 , found : m / z = 923.7 [ M + H ] * . [ 0001270 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - { [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] oxy } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 100 ) LCMS : C47H54FN9O6S2 requires : 923.4 , found : m / z = 924.3 [ M + H ] * . [ 0001271 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3 - { [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,2,3,4 - tetrahydroisoquinolin - 2 - yl } acetyl ) piperidin - 4 - yl ] oxyphenyl ) amino ] pyrimidin - 4 - yl } - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 101 ) LCMS : C47H53FN8O6S2 requires : 908.4 , found : m / z = 909.0 [ M + H ] + . [ 0001272 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 3- { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } pyrrolidine - 3 - carbonyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 102 ) LCMS : C46H52FN9O5S2 requires : 893.4 , found : m / z = 894.2 [ M + H ] * . -705- 1100573566 5 AMERICAS [ 0001273 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 3- ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 1 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 103 ) LCMS : C49H58FN9O5S2 requires : 935.4 , found : m / z = 936.2 [ M + H ] * . [ 0001274 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 3- [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - acetyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- 1,2,3,4 - tetrahydroisoquinolin - 2 - yl } thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 104 ) LCMS : C47H53FN8O5S2 requires : 892.4 , found : m / z = 893.2 [ M + H ] * . [ 0001275 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 105 ) LCMS : C45H53FN10O5S2 requires : 896.4 , found : m / z = 897.0 [ M + H ] * . [ 0001276 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } pyrrolidine - 3 - carbonyl ] piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 106 ) LCMS : C43H50FN11O5S2 requires : 883.3 , found : m / z = 884.3 [ M + H ] * . [ 0001277 ] rac - 5- [ 4- ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1 - yl } piperidine - 1- carbonyl ) piperidin - 1 - yl ] -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 107 ) LCMS : C45H53FN12O6S2 requires : 940.4 , found : m / z = 941.3 [ M + H ] * . [ 0001278 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1- ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 1 - yl ] acetyl } piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 108 ) LCMS : C46H56FN11O5S2 requires : 925.4 , found : m / z = 926.1 [ M + H ] * . - 706 - 1100573566 5 AMERICAS [ 0001279 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) oxy ) cyclohexanecarbonyl ] piperidin - 4 - yl ) -1H - pyrazol - 4 - yl ) amino ] pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 109 ) LCMS : C45H53FN11O6S2 requires : 912.4 , found : m / z = 913.2 [ M + H ] * . [ 0001280 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1- { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl } -1H - pyrazol - 4 - yl ) amino ] pyrimidin - 4 - yl } - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 110 ) LCMS : C46H54FN9O6S2 requires : 911.4 , found : m / z = 912.2 [ M + H ] * . [ 0001281 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin- - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 111 ) LCMS : C46H55FN10O5S2 requires : 910.4 , found : m / z = 911.4 [ M + H ] * . [ 0001282 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4 - yl ) amino ) pyrimidin- - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 112 ) LCMS : C46H55FN10O5S2 requires : 910.4 , found : m / z = 911.4 [ M + H ] * . [ 0001283 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperazin - 1 - yl ) acetyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 113 ) LCMS : C45H55FN12O5S2 requires : 926.4 , found : m / z = 927.2 [ M + H ] * . [ 0001284 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpyrrolidine - 3 - carbonyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 114 ) LCMS : C44H52FN11O5S2 requires : 897.4 , found : m / z = 898.4 [ M + H ] * . [ 0001285 ] rac - 5- { 4- [ 4 - ( { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1H - pyrazol - 1- -707- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT yl } methyl ) piperidine - 1 - carbonyl ] piperidin - 1 - yl } -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2- carboxamide ( 115 ) LCMS : C46H55FN12O6S2 requires : 954.4 , found : m / z = 955.3 [ M + H ] * . [ 0001286 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 - [ ( 1- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 1 - yl ] acetyl } piperidin - 4 - yl ) methyl ] -1H - pyrazol - 4- yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 116 ) LCMS : C47H58FN11O5S2 requires : 939.4 , found : m / z = 940.5 [ M + H ] * . [ 0001287 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) oxy ) cyclohexanecarbonyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 117 ) LCMS : C46H55FN10O6S2 requires : 926.4 , found : m / z = 927.2 [ M + H ] * . [ 0001288 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 1 - ( { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl ) methyl ) -1H - pyrazol - 4 - yl ] amino } pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 118 ) LCMS : C47H56FN9O6S2 requires : 925.4 , found : m / z = 926.2 [ M + H ] + . [ 0001289 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 1 - { [ 1- ( 2- { 6 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,2,3,4 - tetrahydroisoquinolin - 2 - yl ) acetyl ) piperidin - 4 - yl ] methyl ) -1H - pyrazol - 4- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 119 ) LCMS : C45H53FN10O5S2 requires : 896.4 , found : m / z = 897.5 [ M + H ] * . [ 0001290 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpiperazin - 1 - yl ) acetyl ] -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ) pyrimidin - 4- yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 120 ) LCMS : C45H51FN10O5S2 requires : 894.3 , found : m / z = 895.2 [ M + H ] * . [ 0001291 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } pyrrolidine - 3 - carbonyl ] -1,2,3,4 - tetrahydroisoquinolin - 6 - yl } amino ) pyrimidin- - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 121 ) LCMS : C44H48FN9O5S2 requires : 865.3 , found : m / z = 866.3 [ M + H ] * . [ 0001292 ] rac - 5- ( 4- { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -1,2,3,4 - tetrahydroisoquinoline - 2 - carbonyl } piperidin- - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 122 ) - 708- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C46H51FN10O6S2 requires : 922.3 , found : m / z = 923.1 [ M + H ] * . [ 0001293 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 1 - yl ] acetyl } -1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) amino ] pyrimidin- - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 123 ) LCMS : C47H54FN9O5S2 requires : 907.4 , found : m / z = 908.2 [ M + H ] * . [ 0001294 ] Rac- ( 35 ) -3- ( 2 - { [ ( 1r , 4r ) -4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } cyclohexyl ] methyl } -1,2,3,4- tetrahydroisoquinolin - 7 - yl ) piperidine - 2,6 - dione ( 124 ) LCMS : C51H62FN11O5S2 requires : 991.4 , found : m / z = 992.3 [ M + H ] * . [ 0001295 ] Rac- ( 35 ) -3- ( 2 - { [ ( 1r , 4r ) -4- { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- ylamino ) pyridin - 3 - yl ] piperazine - 1 - carbonyl } cyclohexyl ] methyl } -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) piperidine - 2,6 - dione ( 125 ) LCMS : C51H62FN11O5S2 requires : 991.4 , found : m / z = 992.2 [ M + H ] * . [ 0001296 ] rac- ( 3S ) -3- { 6- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2- yl ) amino ) pyridin - 3 - yl ] piperazin - 1 - yl ) methyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6- dione ( 126 ) = ' H NMR ( 500 MHz , CD3CN ) 8 10.30 ( s , 1H ) , 8.82 ( s , 1H ) , 8.50 ( d , J = 5.4 Hz , 1H ) , 7.( d , J = 2.3 Hz , 1H ) , 7.91 ( dd , J = 9.7 , 2.9 Hz , 1H ) , 7.80 ( dd , J = 9.6 , 2.3 Hz , 1H ) , 7.69 ( d , J 9.6 Hz , 1H ) , 7.63 – 7.55 ( m , 2H ) , 7.49 ( dd , J = 14.5 , 7.6 Hz , 2H ) , 7.37 ( t , J = 7.9 Hz , 1H ) , 7.( d , J = 9.5 Hz , 1H ) , 4.22 ( d , J = 13.7 Hz , 2H ) , 3.83 ( dd , J = 12.7 , 5.1 Hz , 1H ) , 3.24 ( t , J = 12.Hz , 2H ) , 3.17 ( q , J = 7.1 Hz , 2H ) , 3.08 ( d , J = 6.8 Hz , 2H ) , 2.76 ( s , 3H ) , 2.74 – 2.69 ( m , 2H ) , 2.40 – 2.09 ( m , 2H ) , 2.09 – 2.02 ( m , 2H ) , 1.54 ( s , 9H ) , 1.50 – 1.40 ( m , 2H ) , 1.09 ( t , J = 7.1 Hz , 3H ) .

LCMS : C45H55FN12O4S2 requires : 910.4 , found : m / z = 911.2 [ M + H ] * . - 709 - 1100573566 5 AMERICAS [ 0001297 ] Attorney Docket No .: 121843.002NU - 3200 PCT ( 3S ) -3- ( 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl ) amino ) pyridin - 3 - yl ] piperazin - 1- ylmethyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione ( 127 ) ' H NMR ( 500 MHz , DMSO - ɖ ) § 10.79 ( s , 1H ) , 9.69 ( s , 1H ) , 9.32 ( s , 1H ) , 8.41 ( s , 1H ) , 8.( s , 1H ) , 7.84 ( s , 1H ) , 7.55 ( t , J = 8.0 Hz , 1H ) , 7.48 – 7.26 ( m , 2H ) , 7.09 ( d , J = 7.7 Hz , 2H ) , - 6.97 ( s , 2H ) , 6.54 ( s , 1H ) , 3.81 ( d , J = 12.6 Hz , 2H ) , 3.77 – 3.62 ( m , 2H ) , 3.29 – 2.99 ( m , 6H ) , - 2.73 ( d , J = 28.4 Hz , 2H ) , 2.66 ( d , J = 12.9 Hz , 4H ) , 2.15 ( d , J = 11.0 Hz , 1H ) , 2.11 – 1.97 ( m , 1H ) , 1.88 ( d , J = 12.8 Hz , 2H ) , 1.48 ( s , 8H ) , 1.38 ( d , J = 11.6 Hz , 2H ) , 1.00 ( t , J = 7.1 Hz , 3H ) .

LCMS : C46H56FN11O4S2 requires : 909.4 , found : m / z = 910.3 [ M + H ] * . [ 0001298 ] ( 3R ) -3- ( 4- [ 4 - ( { 4- [ 6 - ( { 4- [ 2 - tert - butyl - 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } - - fluorophenyl ) -1,3 - thiazol - 5 - yl ] pyrimidin - 2 - yl } amino ) pyridin - 3 - yl ] piperazin - 1- ylmethyl ) piperidin - 1 - yl ] phenyl } piperidine - 2,6 - dione ( 128 ) LCMS : C46H56FN11O4S2 requires : 909.4 , found : m / z = 910.2 [ M + H ] * . [ 0001299 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 7 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1 - oxo- 1,2 - dihydroisoquinolin - 6 - yl } piperidin - 4 - yl ) methyl ] -7 - azaspiro [ 3.5 ] nonan - 2- yl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 129 ) LCMS : C48H58FN9O5S2 requires : 923.4 , found : m / z = 924.2 [ M + H ] * . [ 0001300 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 7 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenoxy } cyclohexyl ] methyl } -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 130 ) LCMS : C46H58FN7O5S2 requires : 871.4 , found : m / z = 872.3 [ M + H ] * [ 0001301 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 7- { 2- [ 4- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 1 - yl ] acetyl } -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ] pyrimidin - 4 - yl } - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 131 ) = LCMS : C46H58FN9O5S2 requires : 899.4 , found : m / z = 900.3 [ M + H ] * . - 710 - 1100573566 5 AMERICAS [ 0001302 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 7- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3- dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -7 - azaspiro [ 3.5 ] nonan - 2- yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 132 ) LCMS : C47H55FN1007S2 requires : 954.4 , found : m / z = 955.4 [ M + H ] * . [ 0001303 ] N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 7 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -7 - azaspiro [ 3.5 ] nonan - 2 - yl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 133 ) LCMS : C45H57FN8O4S2 requires : 856.4 , found : m / z = 857.3 [ M + H ] * . [ 0001304 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1s , 4s ) -4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 134 ) LCMS : C46H61FN10O4S2 requires : 900.4 , found : m / z = 901.8 [ M + H ] * . [ 0001305 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 135 ) LCMS : C46H61FN10O4S2 requires : 900.4 , found : m / z = 901.4 [ M + H ] * . [ 0001306 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 1 ' - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin- - yl } piperidin - 4 - yl ) methyl ] - [ 1,4 ' - bipiperidin ] -4 - yl } amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } - - fluorophenyl ) propane - 1 - sulfonamide ( 136 ) LCMS : C46H61FN10O4S2 requires : 900.4 , found : m / z = 901.5 [ M + H ] * . [ 0001307 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4- [ 4- ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperazin - 1 - yl ] cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 137 ) LCMS : C46H59FN10O5S2 requires : 914.4 , found : m / z = 915.4 [ M + H ] * . -711- 1100573566 5 AMERICAS [ 0001308 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1s , 4s ) -4- [ 4- ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperazin - 1 - yl ] cyclohexyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 138 ) LCMS : C46H59FN10O5S2 requires : 914.4 , found : m / z = 915.3 [ M + H ] * . [ 0001309 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ ( 1r , 4r ) -4 - ( { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) methyl ) cyclohexyl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 139 ) LCMS : C48H64FN9O4S2 requires : 913.5 , found : m / z = 914.4 [ M + H ] * . [ 0001310 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2 - { [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidine - 4 - carbonyl ) piperidin - 4 - yl ] methyl } -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 140 ) LCMS : C49H62FN9O5S2 requires : 939.4 , found : m / z = 940.3 [ M + H ] * . [ 0001311 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -4 - fluoropiperidine - 4 - carbonyl } -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 141 ) LCMS : C49H61F2N9O5S2 requires : 957.4 , found : m / z = 958.2 [ M + H ] * . [ 0001312 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2 - ( { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) methyl ) -2 - azaspiro [ 3.3 ] heptan - 6- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 142 ) - = H¹ NMR ( 500 MHz , DMSO - do ) 8 10.79 ( s , 1H ) , 9.76 ( d , J = 34.2 Hz , 2H ) , 8.94 ( s , 1H ) , 8.( s , 1H ) , 7.63 – 7.49 ( m , 2H ) , 7.41 ( t , J = 7.0 Hz , 1H ) , 7.34 ( t , J = 7.8 Hz , 1H ) , 7.09 ( d , J = 8.Hz , 2H ) , 6.96 ( d , J = 8.2 Hz , 2H ) , 6.23 ( d , J = 90.8 Hz , 1H ) , 4.40 – 4.03 ( m , 3H ) , 3.57 ( d , J = 11.9 Hz , 2H ) , 3.23 ( s , 2H ) , 3.16 – 2.97 ( m , 6H ) , 2.89 ( d , J = 11.9 Hz , 2H ) , 2.82 – 2.57 ( m , 3H ) , 2.24 ( d , J = 20.9 Hz , 1H ) , 2.21 – 2.12 ( m , 1H ) , 2.08 ( s , 6H ) , 2.01 ( dq , J = 14.9 , 6.2 , 5.5 Hz , 2H ) , 1.85 ( t , J = 17.8 Hz , 6H ) , 1.69 ( p , J = 7.5 Hz , 2H ) , 1.45 ( s , 11H ) , 1.40 - 1.29 ( m , 2H ) , 0.91 ( t , J = 7.4 Hz , 3H ) .

LCMS : C49H64FN9O4S2 requires : 925.5 , found : m / z = 926.3 [ M + H ] * . - 712 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001313 ] 5- ( 4 - { [ ( 3R ) -3 - { [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] methyl } pyrrolidin - 1- yl ] methyl } piperidin - 1 - yl ) -N - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 143 ) LCMS : C42H53FN10O5S2 requires : 860.4 , found : m / z = 861.2 [ M + H ] * . [ 0001314 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } -2 - methylpropyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 144 ) LCMS : C46H61FN8O4S2 requires : 872.4 , found : m / z = 873.3 [ M + H ] * . [ 0001315 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl ) methyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 145 ) LCMS : C43H55FN8O4S2 requires : 830.4 , found : m / z = 831.2 [ M + H ] * . [ 0001316 ] 5- { 4 - [ ( 4- { 1 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -2 - methylpropan - 2 - yl } piperidin - 1- yl ) methyl ] piperidin - 1 - yl } -N - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 146 ) LCMS : C46H61FN10O5S2 requires : 916.4 , found : m / z = 917.3 [ M + H ] * . [ 0001317 ] 5- { 4 - [ ( 4 - { [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] methyl } piperidin - 1 - yl ) methyl ] piperidin - 1 - yl } -N- [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 147 ) LCMS : C43H55FN10O5S2 requires : 874.4 , found : m / z = 875.2 [ M + H ] * . [ 0001318 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 2- [ 4- ( 3- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 4 - yl } propyl ) piperazin - 1 - yl ] acetyl } -2- azaspiro [ 3.3 ] heptan - 6 - yl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1- sulfonamide ( 148 ) LCMS : C48H57FN10O7S2 requires : 968.4 , found : m / z = 969.2 [ M + H ] * . -713 - 1100573566 5 AMERICAS [ 0001319 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 149 ) LCMS : C50H55FN10O7S2 requires : 990.4 , found : m / z = 991.2 [ M + H ] * . [ 0001320 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3 - oxo- 2,3 - dihydro - 1H - isoindol - 5 - yl } hexanoyl ) -2 - azaspiro [ 3.3 ] heptan - 6 - yl ] amino } pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 150 ) LCMS : C45H53FN8O6S2 requires : 884.4 , found : m / z = 885.2 [ M + H ] * . [ 0001321 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } hexanoyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 151 ) = LCMS : C50H57FN8O6S2 requires : 948.4 , found : m / z = 885.2 [ M + H ] + . [ 0001322 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3- dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -2- azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide ( 152 ) LCMS : C48H55FN10O7S2 requires : 966.4 , found : m / z = 967.2 [ M + H ] * . [ 0001323 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 153 ) LCMS : C53H59FN10O7S2 requires : 1030.4 , found : m / z = 1031.2 [ M + H ] * . [ 0001324 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3- dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] -2- -714 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT azaspiro [ 3.3 ] heptan - 6 - yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1- sulfonamide ( 154 ) LCMS : C48H55FN10O7S2 requires : 966.4 , found : m / z = 967.2 [ M + H ] * . [ 0001325 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3- dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidine - 4 - carbonyl ) piperidin - 4- yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 155 ) LCMS : C50H54FN9O7S2 requires : 975.4 , found : m / z = 976.2 [ M + H ] * . [ 0001326 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 156 ) LCMS : C47H54FN9O5S2 requires : 907.4 , found : m / z = 930.2 [ M + Na ] * . [ 0001327 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 2- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3- dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -2 - azaspiro [ 3.3 ] heptan - 6- yl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ) propane - 1 - sulfonamide ( 157 ) [ 0001328 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] - 1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] piperidin - 4- yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 158 ) LCMS : C56H65FN10O7S2 requires : 1072.4 , found : m / z = 537.1 [ M / 2 + H ] * . [ 0001329 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } azetidine - 3 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 159 ) LCMS : C45H50FN9O5S2 requires : 879.3 , found : m / z = 880.2 [ M + H ] + . [ 0001330 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 2- ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- methyl - 2 - oxo - 2,3 - dihydro - 1H - 1,3 - benzodiazol - 4 - yl } piperidine - 4 - carbonyl ) -2- -715 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT azaspiro [ 3.3 ] heptan - 6 - yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 160 ) LCMS : C45H53FN10O6S2 requires : 912.4 , found : m / z = 913.2 [ M + H ] * . [ 0001331 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- methyl - 2 - oxo - 2,3 - dihydro - 1H - 1,3 - benzodiazol - 4 - yl } piperidine - 4 - carbonyl ) piperidin - 4- yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 161 ) LCMS : C50H57FN10O6S2 requires : 976.4 , found : m / z = 977.3 [ M + H ] * . [ 0001332 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3S ) -1- { 1 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] - - methyl - 2 - oxo - 2,3 - dihydro - 1H - 1,3 - benzodiazol - 5 - yl } pyrrolidin - 3 - yl ] acetyl } piperidin - 4- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 162 ) LCMS : C50H57FN10O6S2 requires : 976.4 , found : m / z = 977.2 [ M + H ] * . [ 0001333 ] rac - N- ( 3- { 2 - tert - butyl - 5- [ 2 - ( { 4- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl ) amino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 163 ) [ 0001334 ] N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 3R ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidine - 3 - carbonyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 164 ) LCMS : C46H52FN9O5S2 requires : 893.2 , found : m / z = 894.2 [ M + H ] + . [ 0001335 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 165 ) LCMS : C48H55FN8O5S2 requires : 906.4 , found : m / z = 907.2 [ M + H ] + . -716- 1100573566 5 AMERICAS [ 0001336 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3S ) -1- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] phenylpyrrolidin - 3 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 166 ) = LCMS : C48H57FN8O5S2 requires : 906.4 , found : m / z = 907.3 [ M + H ] + . [ 0001337 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 167 ) LCMS : C48H57FN8O4S2 requires : 892.4 , found : m / z = 893.3 [ M + H ] * . [ 0001338 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1 - { [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) oxy ) cyclohexyl ] methyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 168 ) LCMS : C48H57FN8O5S2 requires : 908.4 , found : m / z = 909.3 [ M + H ] * . [ 0001339 ] rac - 5- [ 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidin - 1- yl ) methyl ] piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 169 ) LCMS : C48H57FN10O5S2 requires : 936.4 , found : m / z = 937.3 [ M + H ] * . [ 0001340 ] rac - 4- [ 4 - ( { 6 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1 - sulfonamido ) phenyl ] - 1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] -2 - azaspiro [ 3.3 ] heptan - 2 - yl ) methyl ) piperidin - 1 - yl ] - N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] benzamide ( 170 ) LCMS : C44H54FN9O5S2 requires : 871.4 , found : m / z = 872.3 [ M + H ] + . [ 0001341 ] rac - 4- { 4 - [ ( 4- { 4 - [ ( 4- { 2 - tert - butyl - 4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 5 - yl } pyrimidin - 2 - yl ) amino ] phenyl } piperidin - 1- yl ) methyl ] piperidin - 1 - yl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] benzamide ( 171 ) LCMS : C49H58FN9O5S2 requires : 935.4 , found : m / z = 936.3 [ M + H ] * . -717- 1100573566 5 AMERICAS [ 0001342 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 2- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } -2 - azaspiro [ 3.3 ] heptan - 6 - yl ) amino ] pyrimidin - 4 - yl } - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 172 ) LCMS : C42H52FN9O4S2 requires : 829.4 , found : m / z = 830.3 [ M + H ] * . [ 0001343 ] N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl ) pyrrolidin - 3 - yl ] ethyl } piperidin - 4 - yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 173 ) LCMS : C47H56FN9O4S2 requires : 893.4 , found : m / z = 894.4 [ M + H ] * . [ 0001344 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2- ( 4- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - ylpiperazin - 1 - yl ) acetyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 174 ) LCMS : C47H55FN10O5S2 requires : 922.4 , found : m / z = 923.4 [ M + H ] * . [ 0001345 ] rac - N- { 3- [ 2 - tert - butyl - 5- ( 2 - { [ 4- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4- yl ) phenyl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 175 ) LCMS : C53H65FN10O5S2 requires : 1004.5 , found : m / z = 1005.4 [ M + H ] [ 00001346 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1- [ 2 - ( { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3- dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) oxy ) acetyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4- yl } -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 176 ) LCMS : C46H47FN8O8S2 requires : 922.3 , found : m / z = 923.5 [ M + H ] * . [ 0001347 ] rac - N- [ 3- ( 2 - tert - butyl - 5- { 2 - [ ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 3 - ylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) amino ] pyrimidin - 4 - yl } -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 177 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.87 ( s , 1H ) , 9.67 ( s , 1H ) , 9.15 ( s , 2H ) , 8.34 ( d , J = 5.3 Hz , – 1H ) , 8.21 ( d , J = 2.7 Hz , 1H ) , 7.85 ( s , 1H ) , 7.67 – 7.52 ( m , 3H ) , 7.47 ( t , J = 7.0 Hz , 1H ) , 7. - 718 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT ( t , J = 7.9 Hz , 1H ) , 7.22 ( s , 1H ) , 7.15 ( d , J = 8.1 Hz , 2H ) , 6.43 ( d , J = 5.1 Hz , 1H ) , 3.93 – 3.( m , 3H ) , 3.68 – 3.55 ( m , 5H ) , 3.18 ( d , J = 4.7 Hz , 2H ) , 3.12 ( q , J = 7.4 Hz , 6H ) , 2.99 ( t , J = 7.Hz , 2H ) , 2.83 – 2.63 ( m , 4H ) , 2.31 ( qd , J = 12.7 , 4.3 Hz , 2H ) , 2.02 ( dq , J = 8.5 , 5.8 , 4.5 Hz , 2H ) , 1.67 ( h , J = 7.5 Hz , 2H ) , 1.48 ( s , 9H ) , 1.29 ( d , J = 6.8 Hz , 36H ) , 0.98 -0.82 ( m , 4H ) . [ 0001348 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4- yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 178 ) LCMS : C45H53FN8O6S2 requires : 884.4 , found : m / z = 885.2 [ M + H ] * . [ 0001349 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- { 2 - [ ( propan - 2- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 179 ) ' H NMR ( 500 MHz , DMSO - do ) 8 9.72 ( s , 1H ) , 8.11 ( d , J = 5.2 Hz , 1H ) , 7.53 ( t , J = 7.6 Hz , 1H ) , 7.37 ( d , J = 7.1 Hz , 1H ) , 7.31 ( t , J = 7.9 Hz , 1H ) , 7.13 ( d , J = 7.9 Hz , 1H ) , 7.05 ( s , 2H ) , 6.90 ( s , 2H ) , 6.11 ( s , 1H ) , 4.36 ( s , 2H ) , 3.67 ( s , 4H ) , 3.13 ( s , 1H ) , 3.07 - 3.00 ( m , 2H ) , 2.75 ( s , 3H ) , 2.48 ( s , 6H ) , 2.14 ( d , J = 13.9 Hz , 4H ) , 2.00 ( s , 2H ) , 1.70 ( d , J = 7.7 Hz , 1H ) , 1.68 ( s , 3H ) , 1.63 ( s , 3H ) , 1.46 ( s , 1H ) , 1.39 ( s , 1H ) , 1.27 ( s , 3H ) , 1.11 ( d , J = 6.6 Hz , 6H ) , 0.91 ( t , J = 7.Hz , 3H ) . LCMS : C48H60FN9O6S2 requires : 941.4 , found : m / z = 942.2 [ M + H ] * . [ 0001350 ] N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( 2 - { [ ( 2R ) -1 - hydroxypropan - 2- yl ] amino } pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 180 ) LCMS : C46H57FN10O7S2 requires : 944.4 , found : m / z = 945.3 [ M + H ] * . [ 0001351 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 181 ) LCMS : C44H52FN9O6S2 requires : 885.3 , found : m / z = 886.6 [ M + H ] * . [ 0001352 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) - 1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 182 ) LCMS : C45H53FN8O6S2 requires : 884.4 , found : m / z = 855.3 [ M + H ] * . -719- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001353 ] rac- ( 3S ) -3- { 6- [ 4- ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -5- { 2 - [ ( propan - 2 - yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 183 ) LCMS : C46H58FN11O6S2 requires : 943.4 , found : m / z = 944.2 [ M + H ] * . [ 0001354 ] rac - N- ( 3- { 2- [ 1- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] aminophenyl ) piperidin - 4 - yl ] acetyl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] -5- ( pyrimidin - 4- yl ) -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 184 ) LCMS : C45H54FN9O6S2 requires : 899.4 , found : m / z = 900.3 [ M + H ] + . [ 0001355 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 4- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] amino } phenyl ) piperidin - 4 - yl ] acetyl } piperidin - 4 - yl ) phenyl ] -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 185 ) LCMS : C45H50FN9O5S2 requires : 879.3 , found : m / z = 880.1 [ M + H ] * . [ 0001356 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 186 ) – 1H NMR ( 500 MHz , DMSO - do ) § 10.80 ( s , 1H ) , 9.79 ( s , 1H ) , 9.43 ( s , 1H ) , 8.11 ( d , J = 5.3 Hz , 1H ) , 7.92 ( d , J = 8.4 Hz , 2H ) , 7.59 ( t , J = 7.6 Hz , 1H ) , 7.48 ( t , J = 7.1 Hz , 1H ) , 7.38 ( t , J = 7.Hz , 1H ) , 7.16 ( d , J = 8.7 Hz , 2H ) , 7.10 ( d , J = 8.1 Hz , 2H ) , 6.95 ( d , J = 39.3 Hz , 4H ) , 6.13 ( d , J = 5.3 Hz , 1H ) , 4.04 ( d , J = 12.0 Hz , 3H ) , 3.83 – 3.58 ( m , 6H ) , 3.29 – 3.13 ( m , 6H ) , 3.13 – 3.04 ( m , 2H ) , 2.79 ( s , 2H ) , 2.66 ( tt , J = 12.1 , 5.2 Hz , 1H ) , 2.22 – 1.97 ( m , 2H ) , 1.88 ( d , J - - - = 12.6 Hz , 2H ) , 1.72 ( q , J = 7.6 Hz , 2H ) , 1.39 ( d , J = 12.7 Hz , 2H ) , 0.94 ( t , J = 7.4 Hz , 3H ) . LCMS : C43H48FN9O4S2 requires : 837.3 , found : m / z = 838.3 [ M + H ] * . [ 0001357 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 187 ) 1H NMR ( 500 MHz , DMSO - do ) § 10.87 ( s , 1H ) , 9.79 ( s , 1H ) , 9.44 ( s , 1H ) , 8.10 ( d , J = 5.2 Hz , 1H ) , 7.987.85 ( m , 3H ) , 7.59 ( t , J = 7.7 Hz , 1H ) , 7.48 ( t , J = 7.0 Hz , 1H ) , 7.38 ( t , J = 7.9 Hz , 1H ) , 7.16 ( d , J = 8.5 Hz , 2H ) , 6.85 ( s , 2H ) , 6.12 ( d , J = 5.2 Hz , 1H ) , 4.29 ( d , J = 12.8 Hz , 2H ) , 4.04 ( d , J = 12.3 Hz , 2H ) , 3.65 ( d , J = 11.2 Hz , 3H ) , 3.30 – 3.05 ( m , 7H ) , 2.98 ( s , 3H ) , 2.77 – 2.61 ( m , 2H ) , 2.37 ( s , 1H ) , 2.33 – 2.12 ( m , 2H ) , 2.04 – 1.93 ( m , 1H ) , 1.87 ( d , J = 12.7 Hz , 2H ) , - - - -720- 1100573566 5 AMERICAS = Attorney Docket No .: 121843.002NU - 3200 PCT 1.72 ( q , J = 7.6 Hz , 2H ) , 1.27 ( d , J = 13.4 Hz , 2H ) , 0.94 ( t , J = 7.4 Hz , 3H ) . LCMS : = C42H47FN10O4S2 requires : 838.3 , found : m / z = 839.1 [ M + H ] * . [ 0001358 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 4- [ 4- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperazin - 1 - yl ] phenyl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 188 ) LCMS : C42H45FN10O5S2 requires : 852.3 , found : m / z = 853.5 [ M + H ] * . [ 0001359 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- ( 4- [ 2- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperazin - 1 - yl ) phenyl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 189 ) LCMS : C43H47FN10O5S2 requires : 866.3 , found : m / z = 867.2 [ M + H ] * . rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 4- [ 4- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidine - 4 - carbonyl ) piperazin - 1 - yl ] phenyl } -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 190 ) LCMS : C43H46FN9O5S2 requires : 851.3 , found : m / z = 852.1 [ M + H ] * . [ 0001360 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 191 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.78 ( s , 1H ) , 8.08 ( d , J = 5.2 Hz , 1H ) , 7.85 ( s , 2H ) , 7.58 ( t , J = 7.8 Hz , 1H ) , 7.53 – 7.43 ( m , 1H ) , 7.37 ( t , J = 7.8 Hz , 1H ) , 7.05 ( d , J = 8.1 Hz , 4H ) , 6.91 ( d , J = 7.7 Hz , 2H ) , 6.78 ( s , 2H ) , 6.10 ( d , J = 5.2 Hz , 1H ) , 3.84 – 3.61 ( m , 4H ) , 3.- 3.03 ( m , 2H ) , 2.84 - 2.61 ( m , 1H ) , 2.33 – 1.96 ( m , 4H ) , 1.83 ( d , J = 12.4 Hz , 2H ) , 1.72 ( h , J = 7.5 Hz , 3H ) , 1.25 ( s , 2H ) , 0.94 ( t , J = 7.4 Hz , 3H ) . LCMS : C43H48FN9O4S2 requires : 837.3 , found : m / z = 838.4 [ M + H ] * . [ 0001361 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 1 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 192 ) . LCMS : C44H49FN8O4S2 requires : 836.3 , found : m / z = 837.3 [ M + H ] * . [ 0001362 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] pyridin - 2 - yl ) -4 - methylpiperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl } -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 193 ) -721- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 1H NMR ( 500 MHz , DMSO - εd ) § 10.87 ( s , 1H ) , 9.74 ( s , 1H ) , 8.09 ( d , J = 5.2 Hz , 1H ) , 7.90 ( s , 1H ) , 7.62 – 7.50 ( m , 1H ) , 7.45 – 7.37 ( m , 1H ) , 7.33 ( t , J = 7.9 Hz , 1H ) , 6.80 ( s , 2H ) , 6.( d , J = 5.2 Hz , 1H ) , 4.47 ( d , J = 12.6 Hz , 1H ) , 4.30 ( d , J = 12.8 Hz , 2H ) , 4.11 ( d , J = 13.4 Hz , 1H ) , 3.79 ( d , J = 41.1 Hz , 3H ) , 3.12 – 3.02 ( m , 2H ) , 2.95 ( d , J = 37.3 Hz , 1H ) , 2.82 – 2.62 ( m , 2H ) , 2.34 – 2.06 ( m , 6H ) , 2.02 – 1.93 ( m , 1H ) , 1.70 ( h , J = 6.9 , 6.2 Hz , 5H ) , 1.58 ( d , J = 11.Hz , 3H ) , 1.46 ( d , J = 12.2 Hz , 2H ) , 1.28 ( s , 3H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . LCMS : C44H53FN10O6S2 requires : 900.4 , found : m / z = 901.2 [ M + H ] * . [ 0001363 ] = rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] -4 - methylpiperidine - 4- carbonyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 194 ) = ' H NMR ( 500 MHz , DMSO - do ) 8 10.93 ( s , 1H ) , 9.75 ( s , 1H ) , 8.09 ( d , J = 5.3 Hz , 1H ) , 7.87 ( s , 1H ) , 7.55 ( t , J = 7.5 Hz , 1H ) , 7.40 ( t , J = 7.1 Hz , 1H ) , 7.33 ( t , J = 7.8 Hz , 1H ) , 6.87 ( s , 2H ) , 6.12 ( d , J = 5.3 Hz , 1H ) , 4.36 ( d , J = 13.0 Hz , 2H ) , 4.17 ( d , J = 13.2 Hz , 3H ) , 3.46 – 3.27 ( m , 2H ) , 3.222.95 ( m , 7H ) , 2.75 -2.62 ( m , 2H ) , 2.28 ( t , J = 6.3 Hz , 3H ) , 2.15 ( d , J = 12.3 Hz , 2H ) , 2.11 - 1.93 ( m , 3H ) , 1.81 ( d , J = 12.7 Hz , 2H ) , 1.75 – 1.54 ( m , 4H ) , 1.42 ( d , J = 12.8 Hz , 2H ) , 1.26 ( d , J = 12.5 Hz , 6H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . LCMS : C45H55FN1006S2 requires : 914.4 , found : m / z = 915.2 [ M + H ] * . = [ 0001364 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 1 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - 1,3 - benzodiazol - 4 - yl } piperidin - 4- yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 195 ) LCMS : C46H56FN11O6S2 requires : 941.4 , found : m / z = 942.2 [ M + H ] * . [ 0001365 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] phenylpiperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl } -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 196 ) = J : = H¹ NMR ( 500 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.74 ( s , 1H ) , 8.18 – 7.96 ( m , 1H ) , 7.55 ( t , 7.6 Hz , 1H ) , 7.41 ( t , J = 7.0 Hz , 1H ) , 7.33 ( t , J = 7.9 Hz , 1H ) , 7.06 ( s , 2H ) , 6.91 ( s , 2H ) , 6.( s , 2H ) , 6.10 ( d , J = 5.2 Hz , 1H ) , 4.37 ( s , 2H ) , 3.69 ( s , 3H ) , 3.20 – 2.95 ( m , 3H ) , 2.85 – 2.( m , 5H ) , 2.23 - 2.07 ( m , 4H ) , 2.02 ( dd , J = 13.3 , 5.3 Hz , 2H ) , 1.78 – 1.56 ( m , 7H ) , 1.43 ( d , J = 33.5 Hz , 1H ) , 1.28 ( s , 3H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . LCMS : C45H54FN9O6S2 requires : 899.4 , found : m / z = 900.3 [ M + H ] * . -722- 1100573566 5 AMERICAS [ 0001366 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) -4 - methylpiperidine - 4 - carbonyl ] piperidin - 4 - yl } -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 197 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.93 ( s , 1H ) , 9.75 ( s , 1H ) , 8.09 ( d , J = 5.3 Hz , 1H ) , 7.89 ( d , J = 2.2 Hz , 1H ) , 7.82 ( s , 1H ) , 7.56 ( t , J = 7.7 Hz , 1H ) , 7.41 ( t , J = 7.4 Hz , 1H ) , 7.34 ( t , J = 7.Hz , 1H ) , 6.89 ( s , 2H ) , 6.12 ( d , J = 5.3 Hz , 1H ) , 4.38 ( d , J = 12.8 Hz , 2H ) , 4.19 ( s , 3H ) , 3.90 ( d , J = 12.0 Hz , 2H ) , 3.76 ( s , 12H ) , 3.71 ( s , 1H ) , 3.21 – 3.11 ( m , 2H ) , 3.06 ( t , J = 7.7 Hz , 2H ) , 2.- 2.65 ( m , 1H ) , 2.28 ( d , J = 12.1 Hz , 1H ) , 2.16 ( d , J = 12.4 Hz , 2H ) , 2.05 - 1.96 ( m , 2H ) , 1.- 1.68 ( m , 3H ) , 1.65 - 1.60 ( m , 5H ) , 1.29 ( s , 3H ) , 0.93 ( t , J = 7.5 Hz , 3H ) . LCMS : C44H53FN10O6S2 requires : 900.4 , found : m / z = 901.2 [ M + H ] * . [ 0001367 ] rac - N- ( 3-5- [ 2- ( cyclopropylamino ) pyrimidin - 4 - yl ] -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4- yl } -1,3 - thiazol - 4 - yl } -2 - fluorophenyl ) propane - 1 - sulfonamide ( 198 ) [ 0001368 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 199 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( d , J = 8.1 Hz , 1H ) , 9.74 ( s , 1H ) , 9.16 ( s , 1H ) , 8.68 ( d , J = 5.5 Hz , 1H ) , 7.58 ( t , J = 7.7 Hz , 1H ) , 7.47 ( t , J = 6.9 Hz , 1H ) , 7.36 ( t , J = 7.9 Hz , 1H ) , 7.– – 7.04 ( m , 6H ) , 4.45 ( dd , J = 35.7 , 12.9 Hz , 2H ) , 4.14 ( d , J = 13.4 Hz , 1H ) , 4.03 ( d , J = 13.Hz , 1H ) , 3.88 – 3.63 ( m , 3H ) , 3.28 – 3.11 ( m , 1H ) , 3.06 ( dd , J = 9.1 , 6.2 Hz , 2H ) , 3.04 - 2.( m , 4H ) , 2.26 – 2.11 ( m , 1H ) , 2.06 – 1.95 ( m , 1H ) , 1.90 – 1.64 ( m , 10H ) , 1.46 – 1.28 ( m , 1H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . LCMS : C44H51FN8O6S2 requires : 870.3 , found : m / z = 871.2 [ M + H ] * . [ 0001369 ] _ N- [ 3- ( 2- { 1- [ 1- ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidine - 4- carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 200 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.82 ( s , 1H ) , 9.65 ( s , 1H ) , 8.58 ( d , J = 5.4 Hz , 2H ) , 7.51 ( t , J = 7.7 Hz , 1H ) , 7.43 ( t , J = 6.9 Hz , 1H ) , 7.32 ( d , J = 7.3 Hz , 3H ) , 7.17 ( s , 7H ) , 4.45 ( dd , J = 36.2 , 12.9 Hz , 2H ) , 4.14 ( d , J = 13.4 Hz , 1H ) , 4.03 ( d , J = 13.3 Hz , 1H ) , 3.80 ( s , 1H ) , 3.69 ( d , . - J = 11.8 Hz , 2H ) , 3.29 – 3.08 ( m , 1H ) , 3.06 – 2.84 ( m , 3H ) , 2.78 ( t , J = 12.1 Hz , 1H ) , 2.2.59 ( m , 2H ) , 2.27 – 2.11 ( m , 3H ) , 2.03 ( dt , J = 13.1 , 4.9 Hz , 1H ) , 1.91 – 1.46 ( m , 11H ) , 1.( s , 1H ) , 0.90 ( t , J = 7.4 Hz , 3H ) . LCMS : C45H52FN7O6S2 requires : 869.3 , found : m / z = 870.[ M + H ] * . - 723- 1100573566 5 AMERICAS [ 0001370 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 4- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] phenyl } -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 201 ) LCMS : C43H46FN9O5S2 requires : 851.3 , found : m / z = 852.4 [ M + H ] * . [ 0001371 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1 - ( { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ] - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 202 ) LCMS : C44H55FN10O5S2 requires : 886.4 , found : m / z = 887.2 [ M + H ] * . [ 0001372 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 203 ) LCMS : C44H53FN10O6S2 requires : 900.4 , found : m / z = 901.2 [ M + H ] * . [ 0001373 ] N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 204 ) LCMS : C45H56FN9O5S2 requires : 885.4 , found : m / z = 886.2 [ M + H ] * . [ 0001374 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4- yl ) ethyl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 205 ) LCMS : C45H55FN10O6S2 requires : 914.4 , found : m / z = 915.2 [ M + H ] * . [ 0001375 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- { 2 - [ ( propan - 2- yl ) amino ] pyrimidin - 4 - yl ) -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 206 ) LCMS : C46H57FN10O6S2 requires : 928.4 , found : m / z = 929.2 [ M + H ] * . [ 0001376 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 1- [ 2- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) acetyl ] piperidin - 4 - yl } phenyl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 207 ) LCMS : C44H48FN9O5S2 requires : 865.3 , found : m / z = 866.1 [ M + H ] * . - 724- 1100573566 5 AMERICAS [ 0001377 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 4- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } phenyl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 208 ) . LCMS : C43H48FN9O4S2 requires : 837.3 , found : m / z = 838.2 [ M + H ] * . [ 0001378 ] rac- ( 3S ) -3- { 6- [ 4- ( 4- { 4- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- ( 3- { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) -1,3 - thiazol - 2 - yl ] piperidine - 1- carbonyl } piperidine - 1 - carbonyl ) piperidin - 1 - yl ] pyridin - 3 - yl } piperidine - 2,6 - dione ( 209 ) LCMS : C43H52FN11O6S2 requires : 901.4 , found : m / z = 902.2 [ M + H ] * . [ 0001379 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol- - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 210 ) LCMS : C44H51FN8O6S2 requires : 870.3 , found : m / z = 871.2 [ M + H ] * . [ 0001380 ] rac - N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -5- ( pyridin - 4 - yl ) -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 211 ) LCMS : C44H53FN8O5S2 requires : 856.4 , found : m / z = 857.3 [ M + H ] * . [ 0001381 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl } -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 212 ) LCMS : C44H53FN10O6S2 requires : 900.4 , found : m / z = 901.2 [ M + H ] * . [ 0001382 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - { [ 1- ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidin - 4 - yl ] methyl } piperidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 213 ) LCMS : C43H53FN10O5S2 requires : 872.4 , found : m / z = 873.2 [ M + H ] * . [ 0001383 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1- ( 1- { 2- [ 1- ( 4 - { [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] amino } -2 - fluorophenyl ) -4 - hydroxypiperidin - 4 - yl ] acetyl } azetidin - 3- yl ) piperidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 214 ) LCMS : C42H50F2N10O6S2 requires : 892.3 , found : m / z = 893.2 [ M + H ] * . - 725 - 1100573566 5 AMERICAS [ 0001384 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1- [ 2- ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) acetyl ] azetidin - 3 - yl } piperidin - 4 - yl ) -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 215 ) LCMS : C42H50FN9O5S2 requires : 843.3 , found : m / z = 844.2 [ M + H ] * . [ 0001385 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] phenyl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 216 ) LCMS : C44H52FN9O6S2 requires : 885.3 , found : m / z = 886.4 [ M + H ] + . [ 0001386 ] rac - N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 217 ) LCMS : C44H55FN10O5S2 requires : 886.4 , found : m / z = 887.4 [ M + H ] * . [ 0001387 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } -4- methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 218 ) LCMS : C44H55FN10O5S2 requires : 886.4 , found : m / z = 887.2 [ M + H ] * . [ 0001388 ] rac - N- [ 3- ( 2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro- 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] piperidin - 4 - yl } -5- [ 2- ( methylamino ) pyrimidin - 4 - yl ] -1,3 - thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 219 ) LCMS : C44H49FN10O7S2 requires : 912.3 , found : m / z = 913.2 [ M + H ] * . [ 0001389 ] rac - N- [ 3- ( 2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 220 ) LCMS : C43H50FN9O6S2 requires : 871.3 , found : m / z = 872.2 [ M + H ] * . [ 0001390 ] rac - N- { 3- [ 2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -5- ( pyrimidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 221 ) LCMS : C43H52FN9O5S2 requires : 857.4 , found : m / z = 858.2 [ M + H ] * . - 726 - 1100573566 5 AMERICAS [ 0001391 ] Attorney Docket No .: 121843.002 N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1 - [ ( 1r , 4r ) -4 - ( { 6 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] -1,2,3,4 - tetrahydroisoquinolin - 2- NU - 3200 PCT ylmethyl ) cyclohexanecarbonyl ] piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 222 ) LCMS : C43H51FN8O5S2 requires : 842.3 , found : m / z = 843.6 [ M + H ] * . [ 0001392 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1 - ( { 1 - [ ( 1r , 4r ) -4- { 3 - [ ( 3RS ) -2,6- cyclohexanecarbonyl ] piperidin - 4 - yl ) methyl ) piperidin - 4 - yl ] - dioxopiperidin - 3 - yl ] phenoxy } 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 223 ) LCMS : C45H55FN8O6S2 requires : 886.4 , found : m / z = 887.3 [ M + H ] * . [ 0001393 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 1 - ( { 1 - [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] phenoxy } cyclohexanecarbonyl ] piperidin - 4 - yl } methyl ) piperidin - 4 - yl ] - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 224 ) LCMS : C45H55FN8O6S2 requires : 886.4 , found : m / z = 887.3 [ M + H ] + . [ 0001394 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1 - [ ( 1 - { [ ( 1r , 4r ) -4- { 4 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] phenoxy } cyclohexyl ] methyl } piperidin - 4 - yl ) methyl ] piperidin - 4 - yl } -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 225 ) LCMS : C45H57FN8O5S2 requires : 872.4 , found : m / z = 873.3 [ M + H ] * . [ 0001395 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1 - { [ 1- ( 2- { 6 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -1,2,3,4 - tetrahydroisoquinolin - 2 - yl ) acetyl ) piperidin - 4- yl ] methyl } piperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 226 ) LCMS : C43H52FN9O5S2 requires : 857.4 , found : m / z = 858.2 [ M + H ] * . [ 0001396 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } -4 - methylpiperidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 227 ) LCMS : C45H56FN9O5S2 requires : 885.4 , found : m / z = 886.2 [ M + H ] * . [ 0001397 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 4 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] phenyl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 228 ) LCMS : C44H54FN9O5S2 requires : 871.4 , found : m / z = 872.2 [ M + H ] * . -727- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001398 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- { 2- [ 4- ( 3- { 2 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 4 - yl } propyl ) piperazin - 1 - yl ] acetyl } - - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 229 ) . LCMS : C48H57FN10O7S2 requires : 968.4 , found : m / z = 969.2 [ M + H ] * . [ 0001399 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -2 - azaspiro [ 3.5 ] nonan - 7- yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 230 ) LCMS : C43H47FN10O7S2 requires : 898.3 , found : m / z = 899.1 [ M + H ] * . [ 0001400 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -3 - azaspiro [ 5.5 ] undecan- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 231 ) LCMS : C45H51FN10O7S2 requires : 926.3 , found : m / z = 927.2 [ M + H ] * . [ 0001401 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] -4 - methylpiperidin - 4- yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 232 ) . LCMS : C41H45FN10O7S2 requires : 872.3 , found : m / z = 873.1 [ M + H ] * . [ 0001402 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 4- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperazin - 1 - yl ) acetyl ] piperidin - 4 - yl } -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 233 ) LCMS : C40H43FN10O7S2 requires : 858.3 , found : m / z = 859.1 [ M + H ] * . [ 0001403 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] -3 - oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } hexanoyl ) -2 - azaspiro [ 3.5 ] nonan - 7 - yl ] -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 234 ) LCMS : C43H49FN8O6S2 requires : 856.3 , found : m / z = 857.1 [ M + H ] + . [ 0001404 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 6- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] -3 - oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } hexanoyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 235 ) LCMS : C45H53FN8O6S2 requires : 884.4 , found : m / z = 885.2 [ M + H ] * . - 728- 1100573566 5 AMERICAS [ 0001405 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -2- azaspiro [ 3.5 ] nonan - 7 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 236 ) . LCMS : C46H51FN10O7S2 requires : 937.3 , found : m / z = 939.2 [ M + H ] * . [ 0001406 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -3- azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 237 ) LCMS : C48H55FN10O7S2 requires : 966.4 , found : m / z = 967.2 [ M + H ] * . [ 0001407 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) acetyl ] -4- methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 238 ) LCMS : C44H49FN10O7S2 requires : 912.3 , found : m / z = 913.1 [ M + H ] * . [ 0001408 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7- yl ) acetyl ] piperidin - 4 - yl } -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 239 ) = = 1H NMR ( 500 MHz , DMSO - do ) § 11.08 ( s , 1H ) , 9.74 ( s , 1H ) , 9.55 ( s , 1H ) , 8.10 ( d , J = 5.2 Hz , 1H ) , 7.69 ( d , J = 8.2 Hz , 1H ) , 7.56 ( td , J = 7.8 , 1.9 Hz , 1H ) , 7.43 - 7.37 ( m , 1H ) , 7.34 ( t , J = 7.8 Hz , 1H ) , 6.94 – 6.74 ( m , 3H ) , 6.68 ( dd , J = 8.4 , 2.2 Hz , 1H ) , 6.12 ( d , J = 5.2 Hz , 1H ) , 5.( dd , J = 12.7 , 5.5 Hz , 1H ) , 4.51 – 4.25 ( m , 3H ) , 3.44 ( tt , J = 7.3 , 3.6 Hz , 3H ) , 3.28 ( t , J = 12.Hz , 1H ) , 3.17 – 3.00 ( m , 3H ) , 3.00 – 2.80 ( m , 2H ) , 2.67 – 2.56 ( m , 2H ) , 2.27 – 2.11 ( m , 4H ) , 2.11 – 1.97 ( m , 2H ) , 1.91 – 1.76 ( m , 1H ) , 1.80 – 1.57 ( m , 3H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . LCMS : C43H47FN10O7S2 requires : 898.3 , found : m / z = 900.0 [ M + H ] * . [ 0001409 ] - rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- { 1- [ 2- ( 2- { 2 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl ) -2,7 - diazaspiro [ 3.5 ] nonan - 7- yl ) acetyl ] piperidin - 4 - yl } propan - 2 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 240 ) LCMS : C46H53FN10O7S2 requires : 940.4 , found : m / z = 941.2 [ M + H ] * . [ 0001410 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] -2- azaspiro [ 3.5 ] nonan - 7 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 241 ) - 729 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS : C46H51FN10O7S2 requires : 938.3 , found : m / z = 939.0 [ M + H ] * . [ 0001411 ] NU - 3200 PCT rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3 - carbonyl ] piperidin- - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 242 ) LCMS : C43H47FN10O7S2 requires : 898.3 , found : m / z = 899.1 [ M + H ] * . [ 0001412 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 2- { 1- [ 1- ( 1- { 2 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidin - 4 - yl ) azetidine - 3- carbonyl ] piperidin - 4 - yl } propan - 2 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1- sulfonamide ( 243 ) LCMS : C46H53FN10O7S2 requires : 940.4 , found : m / z = 941.2 [ M + H ] * . [ 0001413 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 2- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidine - 4 - carbonyl ) -2 - azaspiro [ 3.5 ] nonan - 7- yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 244 ) LCMS : C43H46FN9O7S2 requires : 883.3 , found : m / z = 884.2 [ M + H ] + . [ 0001414 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidine - 4 - carbonyl ) -3 - azaspiro [ 5.5 ] undecan- - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 245 ) LCMS : C45H50FN9O7S2 requires : 911.3 , found : m / z = 912.2 [ M + H ] * . [ 0001415 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) -3 - azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 246 ) = LCMS : C42H50FN9O5S2 requires : 843.3 , found : m / z = 422.6 [ M / 2 ] + . [ 0001416 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 2- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -2- azaspiro [ 3.5 ] nonan - 7 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 247 ) LCMS : C49H57FN10O7S2 requires : 980.4 , found : m / z = 981.6 [ M + H ] * . [ 0001417 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -3- azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 248 ) - 730 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C51H61FN10O7S2 requires : 1008.4 , found : m / z = 1009.2 [ M + H ] * . [ 0001418 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] -4- methylpiperidin - 4 - yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 249 ) LCMS : C47H55FN10O7S2 requires : 954.4 , found : m / z = 955.2 [ M + H ] * . [ 0001419 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 2- ( 1 ' - { 2 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] -1,3 - dioxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } - [ 1,4 ' - bipiperidin ] -4 - yl ) acetyl ] piperidin - 4 - yl } - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 250 ) LCMS : C46H53FN10O7S2 requires : 940.4 , found : m / z = 941.2 [ M + H ] * . [ 0001420 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- [ 3- ( 1- { 1 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] -3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - 1,3 - benzodiazol - 4 - yl } piperidine - 4 - carbonyl ) -3- azaspiro [ 5.5 ] undecan - 9 - yl ] -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 251 ) LCMS : C45H53FN10O6S2 requires : 912.4 , found : m / z = 913.3 [ M + H ] * . [ 0001421 ] rac - 5- ( 4- { 9- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] -3 - azaspiro [ 5.5 ] undecane - 3 - carbonyl } piperidin - 1 - yl ) - N - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridine - 2 - carboxamide ( 252 ) LCMS : C43H51FN1006S2 requires : 886.3 , found : m / z = 887.2 [ M + H ] * . [ 0001422 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- { 2 - [ ( 3R ) -1- { 4 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] phenyl } pyrrolidin - 3 - yl ] acetyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol- - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 253 ) LCMS : C43H51FN8O5S2 requires : 842.3 , found : m / z = 843.2 [ M + H ] * . [ 0001423 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 1- [ 1- ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin- - yl ] pyridin - 2 - yl } piperidine - 4 - carbonyl ) piperidine - 4 - carbonyl ] piperidin - 4 - yl } -1,3 - thiazol - 4- yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 254 ) ' H NMR ( 500 MHz , DMSO - εd ) § 10.81 ( s , 1H ) , 9.74 ( s , 1H ) , 8.08 ( d , J = 5.2 Hz , 1H ) , 7.96 ( d , J = 2.4 Hz , 1H ) , 7.59 - 7.49 ( m , 1H ) , 7.46 – 7.36 ( m , 2H ) , 7.33 ( t , J = 7.9 Hz , 1H ) , 6.88 – 6.- ( m , 3H ) , 6.11 ( d , J = 5.2 Hz , 1H ) , 4.43 ( dd , J = 39.3 , 12.8 Hz , 2H ) , 4.28 ( d , J = 12.6 Hz , 2H ) , 4.08 ( dd , J = 36.0 , 13.4 Hz , 2H ) , 3.74 ( dd , J = 12.2 , 4.9 Hz , 1H ) , 3.29 – 3.19 ( m , 1H ) , 3.14 ( t , J = 12.6 Hz , 1H ) , 3.09 – 3.02 ( m , 2H ) , 3.02 – 2.83 ( m , 4H ) , 2.82 – 2.59 ( m , 3H ) , 2.37 ( d , J = 3.0 Hz , 1H ) , 2.27 – 2.07 ( m , 3H ) , 2.06 – 1.91 ( m , 1H ) , 1.70 ( td , J = 16.4 , 15.6 , 8.1 Hz , 7H ) , - = -731- 1100573566 5 AMERICAS 1.51 ( d , J = Attorney Docket No .: 121843.002NU - 3200 PCT 32.9 Hz , 1H ) , 1.35 ( s , 1H ) , 0.93 ( t , J = 7.4 Hz , 3H ) . LCMS : C43H51FN10O6Srequires : 886.3 , found : m / z = 887.2 [ M + H ] * . [ 0001424 ] 4 - ( { 4- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -4- [ 2 - fluoro - 3- ( propane - 1- sulfonamido ) phenyl ] -1,3 - thiazol - 2 - yl ] piperidin - 1 - yl ) methyl ) -N - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] benzamide ( 255 ) LCMS : C34H37FN8O5S2 requires : 720.2 , found : m / z = 721.2 [ M + H ] * . [ 0001425 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl } -1,3 - thiazol - 4 - yl ] -2- fluorophenylpropane - 1 - sulfonamide ( 256 ) . LCMS : C43H53FN8O4S2 requires : 828.4 , found : m / z = 829.3 [ M + H ] * . [ 0001426 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - { [ ( 1r , 4r ) -4 - ( { 5 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl ) oxy ) cyclohexyl ] methyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 257 ) LCMS : C43H53FN8O5S2 requires : 844.3 , found : m / z = 845.3 [ M + H ] * . [ 0001427 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3 - [ ( 1- { 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] -1 - oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl } piperidin - 4 - yl ) methyl ] -3 - azaspiro [ 5.5 ] undecan - 9- yl - 1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 258 ) LCMS : C45H54FN9O5S2 requires : 883.4 , found : m / z = 845.3 [ M + H ] * . [ 0001428 ] N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 3- { 2 - [ ( 3S ) -1- { 5 - [ ( 3RS ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } pyrrolidin - 3 - yl ] ethyl } -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3- thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 259 ) LCMS : C42H52FN9O4S2 requires : 829.4 , found : m / z = 830.3 [ M + H ] * . [ 0001429 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- { 3 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3 - azaspiro [ 5.5 ] undecan - 9 - yl ) -1,3 - thiazol - 4 - yl ] -2- fluorophenyl } propane - 1 - sulfonamide ( 260 ) LCMS : C42H52FN9O4S2 requires : 829.4 , found : m / z = 830.5 [ M + H ] + . [ 0001430 ] rac - N- { 3- [ 5- ( 2 - aminopyrimidin - 4 - yl ) -2- ( 1- { 1 - [ ( 1- { 5 - [ ( 3R ) -2,6- dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperidine - 4 - carbonyl } piperidin - 4- yl ) -1,3 - thiazol - 4 - yl ] -2 - fluorophenyl } propane - 1 - sulfonamide ( 261 ) -732- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS : C43H53FN10O5S2 requires : 872.4 , found : m / z = 873.7 [ M + H ] * .

NU - 3200 PCT [ 0001431 ] rac - 2 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -5- ( 3 - { [ 3- ( 4- { 4 - [ ( 1Z ) -1- ( hydroxyimino ) - 2,3 - dihydro - 1H - inden - 5 - yl ] -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ) phenyl ) azetidin - 1- yl ] methyl } azetidin - 1 - yl ) -2,3 - dihydro - 1H - isoindole - 1,3 - dione ( 262 ) [ 0001432 ] ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,4 - dioxotetrahydropyrimidin - 1 ( 2H ) - yl ) pyridin - 2 - yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ) -2 - fluorophenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ( 263 ) LCMS : C43H46CIF2N11O4S requires : 885.3 , found : m / z = 886.2 [ M + H ] * . [ 0001433 ] ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ( 264 ) LCMS : C44H47ClF2N10O4S requires : 884.3 , found : m / z = 885.2 [ M + H ] * . [ 0001434 ] rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) pyrrolidine - 1 - sulfonamide ( 265 ) - ' H NMR ( 500 MHz , DMSO ) 8 10.83 ( s , 1H ) , 9.94 ( s , 1H ) , 8.79 ( s , 1H ) , 8.64 – 8.53 ( m , 2H ) , 7.96 ( d , J = 2.5 Hz , 1H ) , 7.85 ( d , J = 8.8 Hz , 2H ) , 7.53 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.48 – 7.( m , 4H ) , 7.20 ( d , J = 8.7 Hz , 2H ) , 6.90 ( s , 1H ) , 4.31 ( d , J = 12.9 Hz , 2H ) , 3.91 ( d , J = 12.Hz , 2H ) , 3.76 ( dd , J = 12.1 , 4.8 Hz , 1H ) , 3.64 ( d , J = 11.5 Hz , 2H ) , 3.20 – 3.07 ( m , 8H ) , 2.- ( t , J = 12.6 Hz , 2H ) , 2.70 ( ddt , J = 17.4 , 12.4 , 5.6 Hz , 1H ) , 2.54 ( d , J = 4.2 Hz , 1H ) , 2.20 ( tt , J = 12.5 , 6.4 Hz , 2H ) , 2.03 – 1.94 ( m , 1H ) , 1.89 ( d , J = 12.6 Hz , 2H ) , 1.78 – 1.67 ( m , 4H ) , 1.( d , J = 11.7 Hz , 2H ) .

LCMS : C44H48CIFN10O4S requires : 866.3 , found : m / z = 867.3 [ M + H ] * . [ 0001435 ] rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ) pyrrolidine - 1 - sulfonamide ( 266 ) - = 1H NMR ( 500 MHz , DMSO ) 8 10.73 ( s , 1H ) , 9.86 ( s , 1H ) , 8.51 – 8.47 ( m , 2H ) , 8.37 ( d , J 2.0 Hz , 1H ) , 7.87 ( d , J = 2.5 Hz , 1H ) , 7.60 ( t , J = 9.0 Hz , 1H ) , 7.44 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.36 – 7.25 ( m , 4H ) , 6.98 ( d , J = 14.3 Hz , 1H ) , 6.88 ( d , J = 9.1 Hz , 1H ) , 6.73 ( d , J = 8.9 Hz , 1H ) , 4.20 ( d , J = 12.8 Hz , 2H ) , 3.66 ( dd , J = 12.1 , 4.9 Hz , 1H ) , 3.27 ( s , 10H ) , 3.11 - 3.04 ( m , -733- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 4H ) , 2.73 ( t , J = 12.4 Hz , 2H ) , 2.61 ( td , J = 12.2 , 6.2 Hz , 1H ) , 2.46 ( t , J = 4.1 Hz , 1H ) , 2.( td , J = 12.5 , 8.3 Hz , 1H ) , 1.90 ( dq , J = 13.4 , 4.7 Hz , 1H ) , 1.73 ( d , J = 12.9 Hz , 2H ) , 1.70 – 1.62 ( m , 4H ) , 1.05 ( d , J = 12.5 Hz , 2H ) . [ 0001436 ] rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) pyrrolidine - 1 - sulfonamide ( 267 ) LCMS : C44H48F2N10O4S requires : 850.4 , found : m / z = 851.3 [ M + H ] * . [ 0001437 ] N- ( 5 - chloro - 3- ( 1- ( 4 - ( ( R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ) pyrrolidine - 1 - sulfonamide ( 268 ) LCMS : C45H50CIFN10O4S requires : 880.3 , found : m / z = 881.2 [ M + H ] * . [ 0001438 ] ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) cyclopentanesulfonamide ( 269 ) – LCMS C46H48F4N8O4S requires : 884.4 , found : m / z = 885.2 [ M + H ] + . [ 0001439 ] rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin - 4- yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) cyclopentanesulfonamide ( 270 ) LCMS C45H48F3N9O4S requires : 867.4 , found : m / z = 868.2 [ M + H ] * . [ 0001440 ] rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5- ( 2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ) cyclopentanesulfonamide ( 271 ) = LCMS C45H48CIF2N9O4S requires : 883.3 found m / z = 884.6 [ M + H ] * . [ 0001441 ] ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2- fluorophenyl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ) cyclopentanesulfonamide ( 272 ) LCMS C46H48C1F3N8O4S requires : 900.3 , found m / z = 901.3 [ M + H ] * . [ 0001442 ] ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2- fluorophenyl ) piperidin - 4 - yl ) methyl ) -1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide ( 273 ) -734- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS C46H49C1F3N9O4S requires : 915.3 , found m / z = 916.5 [ M + H ] * .

NU - 3200 PCT [ 0001443 ] ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 1- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) -2 - fluorophenyl ) piperidin - 4- yl ) methyl ) -1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) pyrrolidine - 1 - sulfonamide ( 274 ) LCMS C46H49F4N9O4S requires : 899.4 , found : m / z = 900.7 [ M + H ] * . [ 0001444 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 275 ) LCMS : C45H50CIFN8O4S requires : 852.3 , found : m / z = 853.2 [ M + H ] * . [ 0001445 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ] propane - 1 - sulfonamide ( 276 ) LCMS : C44H49C1FN9O4S requires : 853.3 , found : m / z = 854.2 [ M + H ] * . [ 0001446 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 277 ) LCMS : C44H49CIFN9O4S requires : 853.3 , found : m / z = 854.2 [ M + H ] * . [ 0001447 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 38 ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 278 ) LCMS : C45H50CIFN8O4S requires : 852.3 , found : m / z = 853.3 [ M + H ] * . [ 0001448 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ] propane - 1 - sulfonamide ( 279 ) LCMS : C44H49CIFN9O4S requires : 853.3 , found : m / z = 854.3 [ M + H ] * . [ 0001449 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3S ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl } methyl ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] propane - 1 - sulfonamide ( 280 ) LCMS : C44H49CIFN9O4S requires : 853.3 , found : m / z = 854.3 [ M + H ] * . - 735 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001450 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 281 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.78 ( s , 1H ) , 9.94 ( s , 1H ) , 8.59 - 8.55 ( m , 2H ) , 8.45 ( s , 1H ) , 7.67 ( s , 1H ) , 7.52 ( dd , J = 6.5 , 2.7 Hz , 1H ) , 7.44 – 7.39 ( m , 2H ) , 7.36 ( dd , J = 5.7 , 2.7 Hz , 1H ) , 7.05 ( d , J = 8.2 Hz , 3H ) , 6.91 ( d , J = 8.3 Hz , 3H ) , 3.77 – 3.66 ( m , 4H ) , 3.24 ( s , 2H ) , 3.- 3.12 ( m , 4H ) , 2.24 ( s , 1H ) , 2.14 ( d , J = 11.1 Hz , 1H ) , 2.02 ( dd , J = 13.5 , 5.2 Hz , 1H ) , 1.( d , J = 12.7 Hz , 2H ) , 1.77 – 1.71 ( m , 4H ) , 1.25 ( s , 2H ) . [ 0001451 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 282 ) LCMS : C45H49C1FN9O4S requires : 865.3 , found : m / z = 866.2 [ M + H ] * . [ 0001452 ] N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin- - ylmethyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 283 ) LCMS : C44H48C1FN10O4S requires : 866.3 , found : m / z = 867.3 [ M + H ] * . [ 0001453 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } -4- fluoropiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 284 ) LCMS : C45H48CIF2N9O4S requires : 883.3 , found : m / z = 884.3 [ M + H ] * . [ 0001454 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 285 ) LCMS : C44H48C1FN10O4S requires : 866.3 , found : m / z = 867.4 [ M + H ] * . [ 0001455 ] N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide ( 286 ) LCMS : C44H48CIFN1004S requires : 866.3 , found : m / z = 867.2 [ M + H ] * . -736- 1100573566 5 AMERICAS [ 0001456 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin- - yl ) methyl ) piperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 287 ) LCMS : C43H47CIFN1104S requires : 867.3 , found : m / z = 868.2 [ M + H ] * . [ 0001457 ] rac - N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 288 ) LCMS : C43H47C1FN11O4S requires : 867.3 , found : m / z = 868.3 [ M + H ] * . [ 0001458 ] N- ( 3- ( 1- ( 4 - ( ( R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2 - yl ) piperidin- - yl ) methyl ) -3 - methylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ) pyrrolidine - 1 - sulfonamide ( 289 ) LCMS : C45H49F3N10O4S requires : 882.4 , found : m / z = 883.3 [ M + H ] * . [ 0001459 ] N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 290 ) LCMS : C43H47C1FN1104S requires : 867.3 , found : m / z = 868.3 [ M + H ] * . [ 0001460 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ( 291 ) LCMS : C45H48CIF2N9O4S requires : 883.3 , found : m / z = 884.2 [ M + H ] * . [ 0001461 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 292 ) LCMS : C44H47ClF2N10O4S requires : 884.3 , found : m / z = 885.3 [ M + H ] + . [ 0001462 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ( 293 ) LCMS : C44H47CIF2N1004S requires : 884.3 , found : m / z = 885.4 [ M + H ] * . -737- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001463 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 294 ) LCMS : C44H47CIF2N1004S requires : 884.3 , found : m / z = 885.2 [ M + H ] * . [ 0001464 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 295 ) = LCMS : C43H46C1F2N11O4S requires : 885.3 , found : m / z = 886.3 [ M + H ] + . [ 0001465 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ( 296 ) LCMS : C43H46ClF2N11O4S requires : 885.3 , found : m / z = 886.2 [ M + H ] * . [ 0001466 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 297 ) = LCMS : C43H46C1F2N11O4S requires : 885.3 , found : m / z = 886.4 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 2H ) , 10.07 ( s , 1H ) , 8.77 ( s , 2H ) , 8.61 - 8.56 ( m , 4H ) , 8.20 ( d , J = 2.Hz , 2H ) , 7.94 ( d , J = 2.5 Hz , 2H ) , 7.91 ( d , J = 9.0 Hz , 2H ) , 7.65 ( dd , J = 9.2 , 2.9 Hz , 2H ) , 7.( dd , J = 6.5 , 2.7 Hz , 2H ) , 7.48 – 7.43 ( m , 4H ) , 7.36 ( td , J = 7.8 , 6.7 , 2.7 Hz , 4H ) , 6.80 ( d , J 8.9 Hz , 2H ) , 5.34 ( s , 1H ) , 5.24 ( t , J = 3.5 Hz , 1H ) , 4.27 ( d , J = 12.7 Hz , 4H ) , 3.73 ( dd , J = 12.2 , 4.9 Hz , 2H ) , 3.48 – 3.34 ( m , 9H ) , 3.32 – 3.22 ( m , 15H ) , 2.80 ( t , J = 12.2 Hz , 4H ) , 2.68 ( ddd , J = 17.1 , 12.2 , 5.2 Hz , 3H ) , 2.57 ( s , 6H ) , 2.54 ( d , J = 4.1 Hz , 6H ) , 2.25 ( d , J = 6.6 Hz , 3H ) , 2.23 - 2.04 ( m , 6H ) , 1.98 ( ddt , J = 13.6 , 9.0 , 4.1 Hz , 3H ) , 1.80 ( d , J = 13.2 Hz , 5H ) , 1.10 ( dd , J = 19.0 , 7.4 Hz , 4H ) . [ 0001467 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 7- { 4 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } - - azaspiro [ 3.5 ] nonan - 2 - yl ) methyl ] piperazin - 1 - yl } pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 298 ) LCMS : C47H51C1F2N10O4S requires : 924.3 , found : m / z = 925.2 [ M + H ] * . = -738- 1100573566 5 AMERICAS [ 0001468 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenyl } pyrrolidine - 1 - sulfonamide ( 299 ) LCMS : C45H49F2N9O4S requires : 849.4 , found : m / z = 850.2 [ M + H ] * . [ 0001469 ] N- [ 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ] pyrrolidine - 1 - sulfonamide ( 300 ) LCMS : C44H48F2N10O4S requires : 850.4 , found : m / z = 851.3 [ M + H ] * . [ 0001470 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2 - yl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenylpyrrolidine - 1 - sulfonamide ( 301 ) LCMS : C44H48F2N10O4S requires : 850.4 , found : m / z = 851.4 [ M + H ] * . [ 0001471 ] ( 3R ) -N- ( 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 302 ) . LCMS : C44H47F3N10O4S requires : 868.3 , found : m / z = 869.3 [ M + H ] * . [ 0001472 ] ( 3R ) -N- [ 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin - 4- yl } methyl ) piperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2,5- difluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 303 ) LCMS : C43H46F3N11O4S requires : 869.3 , found : m / z = 870.3 [ M + H ] * . [ 0001473 ] ( 3R ) -N- ( 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ( 304 ) LCMS : C43H46F3N11O4S requires : 869.3 , found : m / z = 870.3 [ M + H ] * . [ 0001474 ] ( 3R ) -N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ( 305 ) LCMS : C43H46F3N11O4S requires : 869.3 , found : m / z = 870.4 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 2H ) , 10.08 ( s , 1H ) , 8.75 ( s , 2H ) , 8.61 – 8.56 ( m , 4H ) , 8.20 ( d , J = 2.Hz , 2H ) , 7.94 ( d , J = 2.5 Hz , 2H ) , 7.91 ( d , J = 9.0 Hz , 2H ) , 7.65 ( dd , J = 9.1 , 2.9 Hz , 2H ) , 7. - 739 - 1100573566 5 AMERICAS - – Attorney Docket No .: 121843.002NU - 3200 PCT 7.43 ( m , 4H ) , 7.40 – 7.28 ( m , 4H ) , 7.14 ( d , J = 10.1 Hz , 2H ) , 6.80 ( d , J = 8.9 Hz , 2H ) , 5.( s , 1H ) , 5.24 ( t , J = 3.6 Hz , 1H ) , 4.27 ( d , J = 12.7 Hz , 4H ) , 3.73 ( dd , J = 12.1 , 4.9 Hz , 2H ) , 3.- – 3.34 ( m , 8H ) , 3.32 – 3.23 ( m , 13H ) , 2.79 ( t , J = 12.3 Hz , 4H ) , 2.68 ( ddd , J = 17.6 , 12.4 , 5.Hz , 3H ) , 2.55 ( q , J = 7.7 , 6.2 Hz , 11H ) , 2.24 ( d , J = 6.7 Hz , 3H ) , 2.22 - 2.03 ( m , 6H ) , 1.( dt , J = 13.5 , 4.5 Hz , 3H ) , 1.80 ( d , J = 13.2 Hz , 5H ) , 1.10 ( td , J = 10.8 , 5.8 Hz , 4H ) . [ 0001475 ] ( 3R ) -3- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- yl } phenyl ) piperidine - 2,6 - dione ( 306 ) LCMS : C44H49C1FN9O4S requires : 853.3 , found : m / z = 854.3 [ M + H ] * . [ 0001476 ] 1- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- ylphenyl ) -1,3 - diazinane - 2,4 - dione ( 307 ) LCMS : C43H48C1FN10O4S requires : 854.3 , found : m / z = 855.2 [ M + H ] * [ 0001477 ] rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- yl } pyridin - 3 - yl ) piperidine - 2,6 - dione ( 308 ) LCMS : C43H48CIFN10O4S requires : 854.3 , found : m / z = 855.3 [ M + H ] * . [ 0001478 ] ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- ylpyridin - 3 - yl ) piperidine - 2,6 - dione ( 309 ) = LCMS : C43H48CIFN10O4S requires : 854.3 , found : m / z = 855.4 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 2H ) , 9.94 ( s , 1H ) , 8.75 ( s , 2H ) , 8.59 – 8.54 ( m , 4H ) , 7.95 ( d , J = 2.6 Hz , 2H ) , 7.79 ( d , J = 9.0 Hz , 4H ) , 7.49 — 7.34 ( m , 11H ) , 7.11 ( d , J = 8.8 Hz , 4H ) , 6.80 ( d , J = 8.Hz , 2H ) , 4.28 ( d , J = 12.8 Hz , 4H ) , 3.73 ( dd , J = 12.1 , 4.9 Hz , 3H ) , 3.24 ( s , 4H ) , 3.09 ( q , J = 7.1 Hz , 5H ) , 2.80 ( t , J = 12.3 Hz , 5H ) , 2.68 ( s , 8H ) , 2.53 ( s , 9H ) , 2.25 ( s , 1H ) , 2.17 ( td , J = 12.5 , 4.3 Hz , 3H ) , 2.00 ( s , 1H ) , 1.80 ( d , J = 13.1 Hz , 5H ) , 1.13 ( s , 2H ) , 1.12 – 1.02 ( m , 8H ) , 1.01 ( s , 2H ) . [ 0001479 ] ( 3R ) -3- ( 4- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1- yl ) methyl ] piperidin - 1 - yl ) phenyl ) piperidine - 2,6 - dione ( 310 ) - 740 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C43H48CIFN10O4S requires : 854.3 , found : m / z = 855.2 [ M + H ] * . [ 0001480 ] 1- ( 4- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1- yl ) methyl ] piperidin - 1 - yl } phenyl ) -1,3 - diazinane - 2,4 - dione ( 311 ) LCMS : C42H47C1FN11O4S requires : 855.3 , found : m / z = 856.3 [ M + H ] * . [ 0001481 ] rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1- yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) piperidine - 2,6 - dione ( 312 ) LCMS : C42H47CIFN11O4S requires : 855.3 , found : m / z = 856.2 [ M + H ] * . [ 0001482 ] 1- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1- yl ) methyl ] piperidin - 1 - yl ) pyridin - 3 - yl ) -1,3 - diazinane - 2,4 - dione ( 313 ) LCMS : C41H46CIFN12O4S requires : 856.3 , found : m / z = 857.4 [ M + H ] * . [ 0001483 ] ( 3R ) -3- ( 6- { 4 - [ ( 4- { 6- [ 4- ( 5 - chloro - 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2- fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] pyridin - 3 - yl } piperazin - 1- yl ) methyl ] piperidin - 1 - yl } pyridin - 3 - yl ) piperidine - 2,6 - dione ( 314 ) - LCMS : C42H47C1FN11O4S requires : 855.3 , found : m / z = 856.4 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 1H ) , 8.79 ( s , 1H ) , 8.61 – 8.56 ( m , 2H ) , 8.20 ( d , J = 2.9 Hz , 1H ) , 7.( d , J = 2.6 Hz , 1H ) , 7.91 ( d , J = 9.0 Hz , 1H ) , 7.64 ( dd , J = 9.2 , 2.8 Hz , 1H ) , 7.49 – 7.43 ( m , 3H ) , 7.37 ( dq , J = 5.7 , 2.5 Hz , 2H ) , 6.80 ( d , J = 8.9 Hz , 1H ) , 4.27 ( d , J = 12.7 Hz , 2H ) , 3.( dd , J = 12.1 , 4.9 Hz , 1H ) , 3.28 ( d , J = 5.9 Hz , 4H ) , 3.09 ( q , J = 7.1 Hz , 2H ) , 2.79 ( t , J = 11.Hz , 2H ) , 2.68 ( s , 4H ) , 2.55 ( d , J = 12.7 Hz , 4H ) , 2.24 ( d , J = 6.7 Hz , 2H ) , 2.17 ( td , J = 12.5 , 4.3 Hz , 1H ) , 1.98 ( dq , J = 8.3 , 4.4 Hz , 1H ) , 1.80 ( d , J = 13.1 Hz , 2H ) , 1.10 ( td , J = 10.7 , 5.Hz , 2H ) , 1.02 ( t , J = 7.1 Hz , 3H ) . [ 0001484 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 315 ) LCMS : C45H49CIF2N10O4S requires : 898.3 , found : m / z = 899.2 [ M + H ] * . -741- 1100573566 5 AMERICAS [ 0001485 ] Attorney Docket No .: 121843.002 N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- NU - 3200 PCT yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 316 ) LCMS : C46H51CIFN9O4S requires : 879.3 , found : m / z = 880.3 [ M + H ] * . [ 0001486 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 317 ) LCMS : C46H50C1F2N9O4S requires : 897.3 , found : m / z = 898.2 [ M + H ] * . [ 0001487 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 318 ) LCMS : C45H49C1F2N10O4S requires : 898.3 , found : m / z = 899.2 [ M + H ] * . [ 0001488 ] N- [ 5 - chloro - 3- ( 1- { 4 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 319 ) LCMS : C45H50CIFN1004S requires : 880.3 , found : m / z = 881.3 [ M + H ] * . [ 0001489 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 320 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.77 ( s , 1H ) , 10.08 ( s , 1H ) , 8.77 ( s , 1H ) , 8.61 - 8.56 ( m , 2H ) , 8.21 ( s , 1H ) , 7.91 ( d , J = 8.9 Hz , 1H ) , 7.65 ( s , 1H ) , 7.52 ( dd , J = 6.4 , 2.6 Hz , 1H ) , 7.48 – 7.43 ( m , 2H ) , 7.37 ( s , 1H ) , 7.04 ( d , J = 8.5 Hz , 2H ) , 6.90 ( d , J = 8.4 Hz , 2H ) , 5.34 ( s , 1H ) , 5.( s , 1H ) , 3.72 ( dd , J = 11.1 , 5.0 Hz , 1H ) , 3.68 ( s , 2H ) , 3.58 ( s , 2H ) , 3.46 ( s , 1H ) , 3.45 – 3.37 ( m , 1H ) , 3.40 – 3.35 ( m , 1H ) , 3.30 – 3.23 ( m , 1H ) , 2.99 ( s , 2H ) , 2.68 ( s , 3H ) , 2.16 – 2.10 ( m , 1H ) , 2.05 1.99 ( m , 1H ) , 1.91 ( d , J = 13.7 Hz , 1H ) , 1.73 ( s , 1H ) , 1.24 ( s , 3H ) , 1.10 ( s , 3H ) . - [ 0001490 ] – ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl } -3- ( pyridin - 4- yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 321 ) LCMS : C44H48C1F2N11O4S requires : 899.3 , found : m / z = 900.2 [ M + H ] * . - 742- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT [ 0001491 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 322 ) . LCMS : C44H48C1F2N1104S requires : 899.3 , found : m / z = 900.3 [ M + H ] * . [ 0001492 ] N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 323 ) LCMS : C44H49C1FN11O4S requires : 881.3 , found : m / z = 882.4 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - ²d ) 8 10.82 ( s , 1H ) , 9.94 ( s , 1H ) , 8.81 ( s , 1H ) , 8.59 ( d , J = 5.3 Hz , 2H ) , 8.31 ( s , 1H ) , 7.96 ( s , 2H ) , 7.75 ( s , 1H ) , 7.52 ( dd , J = 6.5 , 2.7 Hz , 1H ) , 7.48 – 7.43 ( m , 2H ) , 7.40 ( dd , J = 5.7 , 2.7 Hz , 1H ) , 6.84 ( s , 1H ) , 4.33 ( s , 2H ) , 4.02 ( s , 1H ) , 3.74 ( dd , J = 12.0 , 4.9 Hz , 1H ) , 3.58 ( s , OH ) , 3.48 ( s , 1H ) , 3.20 ( s , 2H ) , 3.18 – 3.12 ( m , 2H ) , 3.00 ( s , 2H ) , 2.84 ( s , 2H ) , 2.18 ( dd , J = 14.0 , 9.9 Hz , 1H ) , 2.01 – 1.94 ( m , 1H ) , 1.91 ( s , 1H ) , 1.77 – 1.71 ( m , 3H ) , 1.39 ( s , 2H ) , 1.25 ( s , 3H ) , 1.08 ( s , 1H ) . [ 0001493 ] _ N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 324 ) LCMS : C44H49C1FN1104S requires : 881.3 , found : m / z = 882.4 [ M + H ] * . [ 0001494 ] N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 325 ) LCMS : C44H49C1FN11O4S requires : 881.3 , found : m / z = 882.3 [ M + H ] * . [ 0001495 ] N- [ 5 - chloro - 3- ( 1- { 5 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -3 - methylpiperazin - 1 - yl ] pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 326 ) LCMS : C45H50CIFN10O4S requires : 880.3 , found : m / z = 881.3 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.77 ( s , 1H ) , 9.94 ( s , 1H ) , 8.78 ( s , 1H ) , 8.61 – 8.56 ( m , 2H ) , 8.20 ( s , 1H ) , 7.( d , J = 9.0 Hz , 1H ) , 7.65 ( d , J = 9.2 Hz , 1H ) , 7.52 ( dd , J = 6.5 , 2.7 Hz , 1H ) , 7.47 – 7.42 ( m , 2H ) , 7.41 - 7.37 ( m , 1H ) , 7.04 ( d , J = 8.6 Hz , 2H ) , 6.90 ( d , J = 8.5 Hz , 2H ) , 3.76 – 3.65 ( m , 3H ) , 3.58 ( s , 2H ) , 3.34 ( dd , J = 10.8 , 6.2 Hz , 5H ) , 3.18 – 3.12 ( m , 2H ) , 2.98 ( s , 2H ) , 2.69 ( d , J = - - = -743- . 1100573566 5 AMERICAS – Attorney Docket No .: 121843.002NU - 3200 PCT 13.1 Hz , 2H ) , 2.64 – 2.58 ( m , OH ) , 2.31 ( s , 1H ) , 2.08 ( s , 1H ) , 2.02 ( s , 2H ) , 1.91 ( d , J = 12.- Hz , 1H ) , 1.77 – 1.70 ( m , 4H ) , 1.26 ( d , J = 13.7 Hz , 1H ) , 1.20 ( s , 1H ) , 1.09 ( s , 2H ) . [ 0001496 ] ( RS ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( R ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) butane - 2 - sulfonamide ( 327 ) = LCMS : C44H49C1FN9O4S requires : 853.3 , found : m / z = 854.4 [ M + H ] * . [ 0001497 ] rac- ( 2R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] butane - 2 - sulfonamide ( 328 ) LCMS : C44H49CIFN9O4S requires : 853.3 , found : m / z = 854.3 [ M + H ] * . [ 0001498 ] rac- ( R ) -N- ( 5 - chloro - 3- ( 1- ( 4- ( 4 - ( ( 1- ( 5 - ( ( S ) -2,6 - dioxopiperidin - 3 - yl ) pyridin - 2- yl ) piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ) butane - 2 - sulfonamide ( 329 ) LCMS : C44H49CIFN9O4S requires : 853.3 , found : m / z = 854.3 [ M + H ] * . [ 0001499 ] ( 2RS ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylbutane - 2 - sulfonamide ( 330 ) LCMS : C45H50CIFN8O4S requires : 852.3 , found : m / z = 853.4 [ M + H ] * . [ 0001500 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide ( 331 ) LCMS : C43H45CIF2N10O4S requires : 870.3 , found : m / z = 871.2 [ M + H ] * . [ 0001501 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide ( 332 ) LCMS : C43H45CIF2N10O4S requires : 870.3 , found : m / z = 871.2 [ M + H ] * . [ 0001502 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl - 3 - fluoroazetidine - 1 - sulfonamide ( 333 ) -744- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS : C44H46ClF2N9O4S requires : 869.3 , found : m / z = 870.2 [ M + H ] * . [ 0001503 ] NU - 3200 PCT ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 334 ) LCMS : C44H46CIF3N10O4S requires : 902.3 , found : m / z = 903.2 [ M + H ] * . [ 0001504 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenyl - 3 - fluoropyrrolidine - 1 - sulfonamide ( 335 ) LCMS : C44H46CIF3N10O4S requires : 902.3 , found : m / z = 903.2 [ M + H ] * . [ 0001505 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 336 ) LCMS : C45H47ClF3N9O4S requires : 901.3 , found : m / z = 902.3 [ M + H ] * . [ 0001506 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenyl ) -3 - fluoroazetidine - 1 - sulfonamide ( 337 ) LCMS : C43H44ClF3N10O4S requires : 888.3 , found : m / z = 889.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - d6 ) 8 12.74 ( s , 1H ) , 10.81 ( s , 1H ) , 8.60 – 8.55 ( m , 2H ) , 8.46 ( d , J = 2.0 Hz , 1H ) , 8.( s , 1H ) , 7.95 ( d , J = 2.5 Hz , 1H ) , 7.68 ( t , J = 9.0 Hz , 1H ) , 7.50 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.- = - 7.40 ( m , 2H ) , 7.40 – 7.35 ( m , 2H ) , 7.07 ( d , J = 14.9 Hz , 1H ) , 6.95 ( d , J = 9.3 Hz , 1H ) , 6.( d , J = 8.8 Hz , 1H ) , 5.35 ( dd , J = 6.9 , 3.1 Hz , OH ) , 5.23 ( td , J = 6.1 , 3.1 Hz , OH ) , 4.28 ( d , J = 12.8 Hz , 2H ) , 4.06 ( ddd , J = 19.7 , 10.4 , 6.1 Hz , 2H ) , 3.89 ( ddd , J = 24.5 , 10.7 , 3.8 Hz , 2H ) , 3.73 ( dd , J = 12.1 , 4.9 Hz , 1H ) , 2.81 ( t , J = 12.4 Hz , 2H ) , 2.74 – 2.65 ( m , 1H ) , 2.24 – 2.13 ( m , 1H ) , 2.01 1.94 ( m , 1H ) , 1.88 ( s , 1H ) , 1.80 ( d , J = 12.9 Hz , 2H ) , 1.13 ( d , J = 12.2 Hz , 2H ) . [ 0001507 ] - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } -3 - fluoroazetidine - 1 - sulfonamide ( 338 ) LCMS : C44H45C1F3N9O4S requires : 887.3 , found : m / z = 888.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.77 ( s , 1H ) , 10.23 ( s , 1H ) , 8.60 – 8.55 ( m , 2H ) , 8.45 ( d , J = 2.0 Hz , 1H ) , 7.( t , J = 9.1 Hz , 1H ) , 7.50 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.45 – 7.40 ( m , 2H ) , 7.35 ( s , 1H ) , 7.09 – - -745- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT 7.02 ( m , 3H ) , 6.95 ( d , J = 9.1 Hz , 1H ) , 6.90 ( d , J = 8.8 Hz , 2H ) , 5.34 ( td , J = 6.1 , 3.1 Hz , 0H ) , 5.23 ( ddd , J = 9.9 , 6.0 , 3.9 Hz , 1H ) , 4.06 ( ddd , J = 19.5 , 10.0 , 6.0 Hz , 2H ) , 3.88 ( ddd , J = 24.5 , 10.5 , 3.8 Hz , 2H ) , 3.76 – 3.65 ( m , 3H ) , 3.35 ( s , 2H ) , 2.68 ( d , J = 12.2 Hz , 2H ) , 2.64 – 2.58 ( m , 1H ) , 2.50 – 2.42 ( m , 1H ) , 2.33 ( s , 2H ) , 2.19 – 2.06 ( m , 1H ) , 2.05 – 1.98 ( m , 1H ) , 1.82 ( d , J 12.7 Hz , 2H ) , 1.25 ( q , J = 11.4 Hz , 2H ) . [ 0001508 ] N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin- - yl ) methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide ( 339 ) = LCMS : C43H44CIF3N1004S requires : 888.3 , found : m / z = 889.1 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.26 ( s , 1H ) , 8.60 – 8.55 ( m , 2H ) , 8.45 ( d , J = 2.0 Hz , 1H ) , 7.67 ( t , J = 9.1 Hz , 1H ) , 7.50 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.45 – 7.40 ( m , 2H ) , 7.35 ( s , 1H ) , 7.17 – 7.12 ( m , 2H ) , 7.( d , J = 14.9 Hz , 1H ) , 6.97 - 6.91 ( m , 2H ) , 5.38 5.31 ( m , OH ) , 5.22 ( dd , J = 7.0 , 3.1 Hz , 1H ) , _ — 4.11 – 4.00 ( m , 2H ) , 3.88 ( ddd , J = 24.7 , 10.4 , 3.8 Hz , 2H ) , 3.73 – 3.67 ( m , 4H ) , 3.35 ( s , 1H ) , 2.69 ( h , J = 5.0 Hz , 4H ) , 2.59 ( s , 4H ) , 2.32 ( s , 3H ) , 1.83 ( d , J = 12.9 Hz , 2H ) , 1.76 ( s , 1H ) , 1.- 1.22 ( m , 2H ) . [ 0001509 ] N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenylpyrrolidine - 1 - sulfonamide ( 340 ) LCMS : C45H48F3N9O4S requires : 867.4 , found : m / z = 868.2 [ M + H ] + . [ 0001510 ] rac - N- { 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - 2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide ( 341 ) LCMS : C44H47F3N10O4S requires : 868.3 , found : m / z = 869.2 [ M + H ] * . [ 0001511 ] N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2,5- difluorophenyl } pyrrolidine - 1 - sulfonamide ( 342 ) LCMS : C43H47F2N11O4S requires : 851.4 , found : m / z = 852.3 [ M + H ] * . [ 0001512 ] rac - N- { 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - 2,5 - difluorophenyl } pyrrolidine - 1 - sulfonamide ( 343 ) -746 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT LCMS : C42H46F2N12O4S requires : 852.3 , found : m / z = 853.2 [ M + H ] * [ 0001513 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 344 ) ' H NMR ( 500 MHz , DMSO - do ) 8 10.73 ( s , 1H ) , 9.86 ( s , 1H ) , 8.65 ( s , 1H ) , 8.51 – 8.46 ( m , - 2H ) , 7.73 – 7.68 ( m , 2H ) , 7.46 – 7.41 ( m , 1H ) , 7.38 – 7.33 ( m , 2H ) , 7.04 ( s , 1H ) , 7.03 – 6.- ( m , 2H ) , 6.64 ( d , J = 10.0 Hz , 2H ) , 3.81 ( dd , J = 12.4 , 5.0 Hz , 1H ) , 3.65 ( d , J = 12.3 Hz , 2H ) , 3.15 ( s , 5H ) , 3.06 ( s , 5H ) , 2.63 ( t , J = 12.1 Hz , 3H ) , 2.16 ( d , J = 7.0 Hz , 2H ) , 2.07 ( dd , J = 13.0 , 4.2 Hz , 1H ) , 1.91 – 1.85 ( m , 1H ) , 1.73 ( d , J = 13.6 Hz , 2H ) , 1.69 – 1.63 ( m , 4H ) , 1.18 – 1.( m , 3H ) . [ 0001514 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] -1,4 - diazepan - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 345 ) - = LCMS : C45H49C1F2N10O4S requires : 898.3 , found : m / z = 899.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 1H ) , 9.93 ( s , 1H ) , 8.59 – 8.54 ( m , 2H ) , 8.40 ( d , J = 1.9 Hz , 1H ) , 8.14 ( s , 1H ) , 7.94 ( s , 1H ) , 7.63 ( s , 1H ) , 7.51 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.43 – 7.38 ( m , 2H ) , 7.35 ( dd , J = 5.7 , 2.7 Hz , 1H ) , 6.82 ( s , 3H ) , 6.74 ( s , 1H ) , 4.29 ( s , 2H ) , 3.73 ( d , J = 10.1 Hz , 1H ) , 3.53 ( s , 2H ) , 3.183.12 ( m , 5H ) , 2.80 ( s , 3H ) , 2.72 – 2.64 ( m , 1H ) , 2.18 ( d , J = 10.5 Hz , 2H ) , 2.01 – 1.94 ( m , 1H ) , 1.77 – 1.71 ( m , 4H ) . [ 0001515 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] -1,4 - diazepan - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 346 ) LCMS : C46H50CIF2N9O4S requires : 897.3 , found : m / z = 898.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.77 ( s , 1H ) , 9.93 ( s , 1H ) , 8.63 – 8.49 ( m , 2H ) , 8.39 ( d , J = 1.9 Hz , 1H ) , 8.14 ( s , OH ) , 7.59 ( s , 1H ) , 7.51 ( dd , J = 6.5 , 2.7 Hz , 1H ) , 7.42 – 7.39 ( m , 2H ) , 7.34 ( dd , J = 5.5 , 2.7 Hz , 1H ) , 7.00 ( d , J = 8.2 Hz , 2H ) , 6.87 ( d , J = 8.3 Hz , 2H ) , 6.78 ( s , 2H ) , 6.70 ( s , 1H ) , 3.77 – 3.( m , 6H ) , 3.53 ( s , 2H ) , 3.19 – 3.09 ( m , 4H ) , 2.69 – 2.56 ( m , 4H ) , 2.39 – 2.34 ( m , 1H ) , 2.18 – 2.05 ( m , 1H ) , 2.00 ( dd , J = 13.2 , 5.0 Hz , 1H ) , 1.89 ( s , 2H ) , 1.80 – 1.67 ( m , 4H ) , 1.21 ( d , J = 28.0 Hz , 2H ) . - – -747- 1100573566 5 AMERICAS [ 0001516 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2- fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 347 ) LCMS : C45H48C1F2N9O4S requires : 883.3 , found : m / z = 884.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.82 ( s , 1H ) , 9.94 ( s , 1H ) , 8.75 ( s , 1H ) , 8.57 ( d , J = 5.2 Hz , 2H ) , 7.80 ( s , 2H ) , 7.52 ( dd , J = 6.4 , 2.7 Hz , 1H ) , 7.46 — 7.36 ( m , 2H ) , 7.11 ( s , 1H ) , 6.99 ( d , J = 22.1 Hz , 3H ) , 3.80 ( d , J = 9.1 Hz , 1H ) , 3.23 ( s , 3H ) , 3.18 – 3.10 ( m , 1H ) , 2.74 – 2.59 ( m , 4H ) , 2.39 – 2.( m , 1H ) , 2.20 ( d , J = 8.7 Hz , 0H ) , 2.01 ( s , 1H ) , 1.85 ( s , 2H ) , 1.79 – 1.65 ( m , 3H ) , 1.30 ( m , 3H ) . [ 0001517 ] - - - rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3- fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 348 ) - LCMS : C45H48C1F2N9O4S requires : 883.3 , found : m / z = 884.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.81 ( s , 1H ) , 9.93 ( s , 1H ) , 8.74 ( s , 1H ) , 8.59 – 8.54 ( m , 2H ) , 7.79 ( d , J = 8.6 Hz , 2H ) , 7.52 ( dd , J = 6.5 , 2.7 Hz , 1H ) , 7.46 – 7.38 ( m , 3H ) , 7.14 – 7.04 ( m , 3H ) , 6.72 ( d , J = 10.Hz , 2H ) , 3.88 ( dd , J = 12.4 , 5.1 Hz , 1H ) , 3.73 ( d , J = 12.3 Hz , 2H ) , 3.37 ( s , 1H ) , 3.34 ( s , 3H ) , 3.36 – 3.27 ( m , 1H ) , 3.22 ( s , 3H ) , 3.18 – 3.12 ( m , 2H ) , 2.72 ( t , J = 12.4 Hz , 3H ) , 2.24 ( s , 2H ) , - - = 2.15 ( dd , J = 12.7 , 4.2 Hz , 1H ) , 1.99 – 1.93 ( m , 1H ) , 1.81 ( d , J = 13.0 Hz , 2H ) , 1.77 – 1.71 ( m , 4H ) , 1.22 ( s , 3H ) . [ 0001518 ] N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 349 ) LCMS : C46H50F3N9O4S requires : 881.4 , found : m / z = 882.3 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - oɖ ) 8 10.78 ( s , 1H ) , 9.91 ( s , 1H ) , 8.76 ( s , 1H ) , 8.58 – 8.53 ( m , 2H ) , 7.81 ( s , 2H ) , 7.( d , J = 6.7 Hz , 1H ) , 7.51 ( d , J = 5.9 Hz , 1H ) , 7.43 – 7.38 ( m , 2H ) , 7.10 ( s , 1H ) , 7.05 ( d , J = 8.Hz , 2H ) , 6.90 ( d , J = 8.2 Hz , 2H ) , 3.73 ( dd , J = 11.0 , 4.9 Hz , 1H ) , 3.25 – 3.19 ( m , 5H ) , 3.19 – 3.13 ( m , 5H ) , 2.66 ( s , 2H ) , 2.48 ( s , 2H ) , 2.24 ( s , 1H ) , 2.13 ( d , J = 9.4 Hz , 1H ) , 2.05 – 1.98 ( m , 1H ) , 1.83 ( d , J = 12.7 Hz , 2H ) , 1.77 – 1.70 ( m , 4H ) , 1.25 ( s , 3H ) . [ 0001519 ] rac - N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 350 ) -748 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT – LCMS : C45H49F3N10O4S requires : 882.4 , found : m / z = 883.3 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.82 ( s , 1H ) , 9.91 ( s , 1H ) , 9.26 ( s , 1H ) , 8.79 ( s , 1H ) , 8.58 - 8.53 ( m , 2H ) , 8.( s , 1H ) , 7.96 ( d , J = 2.5 Hz , 1H ) , 7.85 ( s , 2H ) , 7.72 ( dd , J = 7.0 , 2.1 Hz , 1H ) , 7.54 – 7.48 ( m , 1H ) , 7.44 7.36 ( m , 3H ) , 7.18 ( s , 2H ) , 7.11 ( s , OH ) , 6.84 ( d , J = 9.0 Hz , 1H ) , 4.30 ( d , J = 12.Hz , 2H ) , 3.93 ( s , 1H ) , 3.74 ( dd , J = 12.1 , 4.9 Hz , 1H ) , 3.65 ( s , 1H ) , 3.21 ( s , 5H ) , 3.19 – 3.( m , 4H ) , 2.84 ( s , 2H ) , 2.69 ( td , J = 12.2 , 6.2 Hz , 1H ) , 2.54 ( d , J = 3.8 Hz , OH ) , 2.19 ( qd , J = 12.7 , 4.4 Hz , 1H ) , 2.01 – 1.94 ( m , 1H ) , 1.82 ( d , J = 12.7 Hz , 2H ) , 1.78 – 1.69 ( m , 4H ) , 1.20 ( s , 3H ) . [ 0001520 ] N- { 5 - chloro - 3- [ 1- ( 6- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 351 ) LCMS : C44H48C1FN10O4S requires : 866.3 , found : m / z = 867.2 [ M + H ] * . [ 0001521 ] rac - N- { 5 - chloro - 3- [ 1- ( 6- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 3 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 352 ) LCMS : C43H47C1FN11O4S requires : 867.3 , found : m / z = 868.3 [ M + H ] * . [ 0001522 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 353 ) LCMS : C45H47C1F3N9O4S requires : 901.3 , found : m / z = 902.2 [ M + H ] * . [ 0001523 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) -2,5 - difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 354 ) LCMS : C44H46CIF3N10O4S requires : 902.3 , found : m / z = 903.2 [ M + H ] + . [ 0001524 ] N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 355 ) LCMS : C43H47C1FN11O4S requires : 867.3 , found : m / z = 868.2 [ M + H ] + . -749- 1100573566 5 AMERICAS [ 0001525 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5- ( difluoromethyl ) -3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 356 ) LCMS : C45H48F4N10O4S requires : 900.4 , found : m / z = 901.2 [ M + H ] * . [ 0001526 ] rac - N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] pyridin - 2 - yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 357 ) LCMS : C45H48F4N10O4S requires : 900.4 , found : m / z = 901.3 [ M + H ] * . [ 0001527 ] N- [ 5 - chloro - 3- ( 1- { 5- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin- - yl ) methyl ) piperazin - 1 - yl ] pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 358 ) LCMS : C42H46CIFN12O4S requires : 868.3 , found : m / z = 869.3 [ M + H ] * . [ 0001528 ] rac - N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenylpyrrolidine - 1 - sulfonamide ( 359 ) LCMS : C42H46CIFN12O4S requires : 868.3 , found : m / z = 869.2 [ M + H ] * . [ 0001529 ] N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } pyrimidin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol- - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 360 ) LCMS : C43H47CIFN11O4S requires : 867.3 , found : m / z = 868.2 [ M + H ] * . [ 0001530 ] N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) phenyl ] piperidin- - yl ) methyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 361 ) LCMS : C44H47C1F2N10O4S requires : 884.3 , found : m / z = 885.3 [ M + H ] * . [ 0001531 ] N- [ 5- ( difluoromethyl ) -3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 362 ) LCMS : C46H49F4N9O4S requires : 899.4 , found : m / z = 900.3 [ M + H ] * . - 750 - 1100573566 5 AMERICAS [ 0001532 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 363 ) LCMS : C44H47C1F2N1004S requires : 884.3 , found : m / z = 885.2 [ M + H ] * . [ 0001533 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 364 ) LCMS : C45H48ClF2N9O4S requires : 883.3 , found : m / z = 884.2 [ M + H ] * . [ 0001534 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 4- ( 2,4 - dioxo - 1,3 - diazinan - 1- yl ) phenyl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ) -2 - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 365 ) LCMS : C44H46ClF3N10O4S requires : 902.3 , found : m / z = 903.2 [ M + H ] * . [ 0001535 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3RS ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] - - fluorophenyl } -3 - fluoropyrrolidine - 1 - sulfonamide ( 366 ) LCMS : C44H46CIF3N10O4S requires : 902.3 , found : m / z = 903.2 [ M + H ] * . [ 0001536 ] ( 3R ) -N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } -3 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H- pyrazol - 4 - yl ] -2 - fluorophenyl ) -3 - fluoropyrrolidine - 1 - sulfonamide ( 367 ) LCMS : C45H47CIF3N9O4S requires : 901.3 , found : m / z = 902.3 [ M + H ] * . [ 0001537 ] N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - ylmethyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide ( 368 ) LCMS : C42H44C1F2N11O4S requires : 871.3 , found : m / z = 872.3 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.34 ( s , 1H ) , 8.76 ( s , 1H ) , 8.60 – 8.53 ( m , 2H ) , 8.14 ( s , 1H ) , 8.05 ( d , J = 2.8 Hz , 1H ) , 7.79 ( d , J = 8.6 Hz , 2H ) , 7.54 – 7.36 ( m , 4H ) , 7.12 ( s , 2H ) , 6.86 ( d , J = 9.1 Hz , 1H ) , 4.( d , J = 12.7 Hz , 2H ) , 4.07 ( s , 2H ) , 3.89 ( dd , J = 24.4 , 10.0 Hz , 2H ) , 3.70 ( t , J = 6.7 Hz , 2H ) , 2.82 ( d , J = 12.5 Hz , 1H ) , 2.71 ( t , J = 6.7 Hz , 2H ) , 2.64 ( q , J = 1.9 Hz , 1H ) , 2.37 ( p , J = 1.Hz , 1H ) , 1.81 ( d , J = 12.9 Hz , 2H ) , 1.14 ( s , 2H ) . -751- 1100573566 5 AMERICAS [ 0001538 ] Attorney Docket No .: 121843.002NU - 3200 PCT N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - yl } methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ] -3 - fluoroazetidine - 1 - sulfonamide ( 369 ) LCMS : C42H43 ClF3N11O4S requires : 889.3 , found : m / z = 890.2 [ M + H ] * . ' H NMR ( 500 MHz , - - = DMSO - do ) 8 10.34 ( s , 1H ) , 8.62 - 8.54 ( m , 2H ) , 8.45 ( s , 1H ) , 8.14 ( s , 1H ) , 8.05 ( d , J = 2.9 Hz , 1H ) , 7.67 ( t , J = 9.1 Hz , 1H ) , 7.56 – 7.45 ( m , 2H ) , 7.45 – 7.40 ( m , 2H ) , 7.36 ( s , 1H ) , 7.( d , J = 14.9 Hz , 1H ) , 6.95 ( d , J = 9.1 Hz , 1H ) , 6.85 ( d , J = 9.0 Hz , 1H ) , 5.34 ( s , 1H ) , 4.29 ( d , J = 12.8 Hz , 2H ) , 4.05 ( d , J = 19.6 Hz , 2H ) , 3.95 – 3.80 ( m , 2H ) , 3.70 ( t , J = 6.7 Hz , 2H ) , 2.( t , J = 12.3 Hz , 2H ) , 2.70 ( t , J = 6.7 Hz , 2H ) , 2.66 – 2.62 ( m , 1H ) , 2.39 – 2.35 ( m , 1H ) , 1.( d , J = 13.0 Hz , 2H ) , 1.13 ( d , J = 12.9 Hz , 2H ) . [ 0001539 ] = N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ] pyrrolidine - 1 - sulfonamide ( 370 ) LCMS : C43H46CIF2N11O4S requires : 885.3 , found : m / z = 886.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - do ) 8 10.34 ( s , 1H ) , 9.94 ( s , 1H ) , 8.60 - 8.54 ( m , 2H ) , 8.44 ( d , J = 2.0 Hz , 1H ) , 8.( d , J = 2.8 Hz , 1H ) , 7.68 ( d , J = 9.4 Hz , 1H ) , 7.54 – 7.45 ( m , 2H ) , 7.45 – 7.39 ( m , 2H ) , 7.( dd , J = 5.6 , 2.7 Hz , 1H ) , 7.05 ( s , 1H ) , 6.94 ( s , 1H ) , 6.85 ( d , J = 9.1 Hz , 1H ) , 4.29 ( d , J = 12.Hz , 2H ) , 3.70 ( t , J = 6.7 Hz , 2H ) , 3.15 ( td , J = 5.5 , 3.3 Hz , 4H ) , 2.83 ( t , J = 12.4 Hz , 2H ) , 2.( t , J = 6.7 Hz , 2H ) , 2.22 ( s , 2H ) , 1.81 ( d , J = 13.0 Hz , 2H ) , 1.78 – 1.70 ( m , 4H ) , 1.13 ( s , 2H ) . [ 0001540 ] ( 3R ) -N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) - - fluorophenyl ] -3 - fluoropyrrolidine - 1 - sulfonamide ( 371 ) LCMS : C43H45C1F3N11O4S requires : 903.3 , found : m / z = 904.2 [ M + H ] * . ' H NMR ( 500 MHz , DMSO - ²d ) § 10.34 ( s , 1H ) , 10.08 ( s , 1H ) , 8.61 – 8.51 ( m , 2H ) , 8.43 ( d , J = 1.9 Hz , 1H ) , 8.( d , J = 2.8 Hz , 1H ) , 7.68 ( s , 1H ) , 7.57 - 7.45 ( m , 2H ) , 7.45 - 7.37 ( m , 2H ) , 7.34 ( dd , J = 5.7 , 2.6 Hz , 1H ) , 7.06 ( s , 1H ) , 6.95 ( s , 1H ) , 6.86 ( d , J = 9.1 Hz , 1H ) , 4.29 ( d , J = 12.8 Hz , 2H ) , 3.- ( t , J = 6.8 Hz , 2H ) , 3.44 – 3.35 ( m , 2H ) , 2.84 ( t , J = 12.4 Hz , 2H ) , 2.71 ( t , J = 6.7 Hz , 2H ) , 2.- – 1.89 ( m , 2H ) , 1.81 ( d , J = 13.0 Hz , 2H ) , 1.14 ( s , 2H ) . [ 0001541 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylcyclopentanesulfonamide ( 372 ) - 752 - 1100573566 5 AMERICAS Attorney Docket No .: 121843.002 LCMS : C45H49C1FN9O4S requires : 865.3 , found : m / z = 866.2 [ M + H ] * .

NU - 3200 PCT [ 0001542 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 5 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } cyclopentanesulfonamide ( 373 ) LCMS : C45H49C1FN9O4S requires : 865.3 , found : m / z = 866.3 [ M + H ] * . [ 0001543 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3- yl ] phenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenyl } cyclopentanesulfonamide ( 374 ) LCMS : C46H50CIFN8O4S requires : 864.3 , found : m / z = 865.2 [ M + H ] * . [ 0001544 ] ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- yl } pyridin - 3 - yl ) piperidine - 2,6 - dione ( 375 ) LCMS : C43H48F2N10O4S requires : 838.4 , found : m / z = 839.3 [ M + H ] * . [ 0001545 ] rac- ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenylpiperazin - 1 - yl ) methyl ] piperidin - 1- yl } pyridin - 3 - yl ) piperidine - 2,6 - dione ( 376 ) – LCMS : C43H48F2N10O4S requires : 838.4 , found : m / z = 839.3 [ M + H ] * . [ 0001546 ] ( 3R ) -3- ( 4- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2,5- difluorophenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] phenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- yl } phenyl ) piperidine - 2,6 - dione ( 377 ) LCMS : C44H49F2N9O4S requires : 837.4 , found : m / z = 838.3 [ M + H ] * . [ 0001547 ] N- [ 3- ( 1- { 4 - [ ( 3R ) -4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] phenyl } piperidin - 4- yl ) methyl ] -3 - methylpiperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] propane - 1 - sulfonamide ( 378 ) LCMS : C45H51FN8O4S requires : 818.4 , found : m / z = 819.3 [ M + H ] * . [ 0001548 ] ( 3R ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethylmethyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] -3 - fluorophenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- ylpyridin - 3 - yl ) piperidine - 2,6 - dione ( 379 ) LCMS : C43H48F2N10O4S requires : 838.4 , found : m / z = 839.3 [ M + H ] * . - 753- 1100573566 5 AMERICAS [ 0001549 ] Attorney Docket No .: 121843.002NU - 3200 PCT ( 3S ) -3- ( 6- { 4 - [ ( 4- { 4- [ 4- ( 3 - { [ ethyl ( methyl ) sulfamoyl ] amino } -2 - fluorophenyl ) - 3- ( pyridin - 4 - yl ) -1H - pyrazol - 1 - yl ] -2 - fluorophenyl } piperazin - 1 - yl ) methyl ] piperidin - 1- yl } pyridin - 3 - yl ) piperidine - 2,6 - dione ( 380 ) . LCMS : C43H48F2N10O4S requires : 838.4 , found : m / z = 839.2 [ M + H ] * . [ 0001550 ] rac- ( R ) -N- ( 3- ( 1- ( 4- ( 4 - ( ( 4- ( 4- ( 2,6 - dioxopiperidin - 3 - yl ) phenyl ) piperazin - 1- yl ) methyl ) piperidin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) propane- - sulfonamide ( 381 ) LCMS : C44H49FN8O4S requires : 804.4 , found : m / z = 805.2 [ M + H ] * . [ 0001551 ] N- ( 5 - chloro - 3- ( 1- ( 4 - ( ( 3R , 5R ) -4 - ( ( 1- ( 5 - ( ( RS ) -2,6 - dioxopiperidin - 3 - yl ) pyridin- - yl ) piperidin - 4 - yl ) methyl ) -3,5 - dimethylpiperazin - 1 - yl ) -2 - fluorophenyl ) -3- ( pyridin - 4 - yl ) - 1H - pyrazol - 4 - yl ) -2 - fluorophenyl ) pyrrolidine - 1 - sulfonamide ( 382 ) LCMS : C46H51ClF2N10O4S requires : 912.3 , found : m / z = 913.2 [ M + H ] * . [ 0001552 ] N- { 5 - chloro - 3- [ 1- ( 5- { 4 - [ ( 1- { 5 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] pyridin - 2- yl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) pyridin - 2 - yl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ] -2- fluorophenylpyrrolidine - 1 - sulfonamide ( 383 ) LCMS : C43H47C1FN1104S requires : 867.3 , found : m / z = 868.2 [ M + H ] * . [ 0001553 ] N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3S ) -2,6 - dioxopiperidin - 3 - yl ] -3- fluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 384 ) LCMS : C45H48C1F2N9O4S requires : 883.3 , found : m / z = 884.2 [ M + H ] * . [ 0001554 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2,3- difluorophenyl } piperidin - 4 - yl ) methyl ] piperazin - 1 - yl } phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 385 ) = LCMS : C45H47C1F3N9O4S requires : 901.3 , found : m / z = 902.2 [ M + H ] + . [ 0001555 ] rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -2,5- difluorophenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 386 ) LCMS : C45H47C1F3N9O4S requires : 901.3 , found : m / z = 902.2 [ M + H ] * . - 754 - 1100573566 5 AMERICAS [ 0001556 ] Attorney Docket No .: 121843.002NU - 3200 PCT rac - N- { 5 - chloro - 3- [ 1- ( 4- { 4 - [ ( 1- { 4 - [ ( 3R ) -2,6 - dioxopiperidin - 3 - yl ] -3,5- difluorophenylpiperidin - 4 - yl ) methyl ] piperazin - 1 - yl ) phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4- yl ] -2 - fluorophenyl } pyrrolidine - 1 - sulfonamide ( 387 ) LCMS : C45H47ClF3N9O4S requires : 901.3 , found : m / z = 902.2 [ M + H ] * . [ 0001557 ] N- [ 5 - chloro - 3- ( 1- { 4- [ 4 - ( { 1- [ 5- ( 2,4 - dioxo - 1,3 - diazinan - 1 - yl ) pyridin - 2- yl ] piperidin - 4 - yl ) methyl ) piperazin - 1 - yl ] phenyl ) -3- ( pyridin - 4 - yl ) -1H - pyrazol - 4 - yl ) -2- fluorophenyl ] cyclopentanesulfonamide ( 388 ) LCMS : C44H48C1FN10O4S requires : 866.3 , found : m / z = 867.2 [ M + H ] * . [ 0001558 ] Cell Line Generation for HiBiT Evaluation [ 0001559 ] An A375 cell line expressing a homozygous V600E mutation was purchased from ATCC ( Manassas , VA , USA ) . An A375 clone 1F10 cell line with an endogenous C- terminal HiBiT fusion tag on BRAF V600E allele was generated internally using CRISPR- Cas9 technology and cultured in DMEM , high glucose supplemented with 10 % FBS and 1X GlutaMAX . A HCT - 116 BRAF - / - cell line overexpressing the C - terminal HiBiT - tagged G466V , G469A , and D594G mutants were generated by lentiviral transduction , externally at Biosettia Inc ( San Diego , CA , USA ) . The stably transfected cells were cultured in RPMI media supplemented with 10 % FBS , 1X GlutaMAX , and 0.25 gµ / ml puromycin . DMEM medium , RPMI 1640 medium , GlutaMAX , fetal bovine serum ( FBS ) , and puromycin were purchased from Gibco ( Grand Island , NY , USA ) . HCT - 116 BRAF - / - cells were purchased from Horizon Discovery ( Waterbeach , UK ) . [ 0001560 ] BRAF HiBiT Degradation Assay Protocol [ 0001561 ] The C - terminal HiBiT tagged BRAF A375 cells ( monoclonal cell line , cell clone 1F10 ) were seeded at a density of 10,000 cells / well in 30 Lµ media ( DMEM , high glucose supplemented with 10 % FBS and 1X GlutaMAX ) in white opaque 384 - well plates ( Corning # 3570 ) from column 1 to column 23. The wildtype A375 cells were seeded in column at the same cell density in 30 Lµ media . Cells were incubated at 37 ° C with 5 % CO2 for h . [ 0001562 ] The C - terminal HiBiT tagged mutant BRAF G466V , G469A , and D594G overexpressed in HCT - 116 BRAF - / - cells ( monoclonal cell line , cell clones 8 , 34 , and 63 , respectively ) were seeded at the density of 3,000 cells / well in 30 Lμ media ( RPMI supplemented with 10 % FBS and 1X GlutaMAX ) in white opaque 384 - well plates ( Corning - 755- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT # 3570 ) from column 1 to column 23. Wildtype HCT - 116 BRAF cells were seeded in column at the same cell density in 30 Lμ media . Cells were incubated at 37 ° C with 5 % ₂OC for h . [ 0001563 ] Intermediate compound dilution series ( 5 - point , ranging from 5 mM to 0.5 Mµ , - fold dilutions in DMSO ) were prepared in a source plate ( Beckman Coulter cat . no . 001- 16128 ) . Final compound dilution series ( 11 - point , ranging from 1 Mμ to 0.01 nM , half - log dilutions in DMSO ) were stamped into the assay plate ( Corning # 3570 , column 1-11 and 12- ) using the Echo Acoustic Liquid Handler ( Beckman Coulter ) . Each compound was plated in duplicate , and the total volume of compound DMSO solution was 60 nL / well ( 0.2 % final DMSO concentration ) . DMSO was included in wells A23 - L23 and A24 - L24 . The DMSO- treated HiBiT - tagged samples served as Negative Control ( NC ) and the DMSO - treated wildtype samples served as Background Control ( BC ) for the HiBiT assay . [ 0001564 ] HiBiT signal was measured by a Nano - Glo HiBiT Lytic assay ( Promega cat . no . N3050 ) . HiBiT lytic detection reagent ( Nano - Glo HiBiT Lytic Buffer with 1:50 Nano - Glo HiBiT Lytic Substrate and 1 : 100 LgBiT Protein , 40 Lµ ) was added using Bravo . The mixture was incubated at room temperature , in the dark , and with gentle shaking for 10 min . Luminesce units ( LU ) were read on an EnVision plate reader 2105 ( Perkin Elmer ) . [ 0001565 ] [ 0001566 ] HiBiT Data Analysis Percent protein remaining and viability remaining per sample were calculated as follows : % Protein remaining = [ ave sample LU - average BC LU Laverage NC LU average BC LU - x1 [ 0001567 ] % Protein remaining values were plotted as a function of compound concentration . XC50 ( DC50 ) values were determined by fitting curves using the following equation : = Y = LowerBound + ( UpperBound - LowerBound ) / ( 1+ ( ( XC50 / x ) ^ Hill ) [ 0001568 ] For the HiBiT degradation assay , the key parameters reported include : The dose of compound that produces 50 % degradation ( DC 50 at 50 % ) : DC 50 at 50 % : the Fitted X value ( Conc . ) at Y = 50 ( response ) -756- 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT Observed Dmax ( Obs . Dmax ) is the percentage protein degraded at maximal compound effect relative to DMSO - treated control : Obs . Dmax = 100 – minimum Y value ( response ) - 757- 1100573566 5 AMERICAS [ 0001569 ] Hibit Assay Results Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Number Dmax DC50 Dmax DC50 Dmax DC50 Dmax DC( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) A B A C B B B B B B A C B D B B B B A B C D B B B D B C A B C D B D B D A B B D B C B D A B B D B D B D A C A B B D B B B D B C B C Attorney Docket No .: 121843.002NU - 3200 PCT -758- 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) A B B C A B C D B B B D A B B C A B B A B C A B B D B B B B A B B D B B B B A B A B B D B B B D A B C D B C B D A B C D B B B D 224 A B C D B B B D A B C D B B B D Attorney Docket No .: 121843.002NU - 3200 PCT - 759 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) B C A A B C A B B B A A B B B A B B A B B B A A B A A A B B B B B A A B A A A B B A B A B B A B A A C A A B BB B D B D C D B D B B A A C B C D B D Attorney Docket No .: 121843.002NU - 3200 PCT - 760 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) A A A A B B B D B D A A B B B C B B A A C D C D B D A A B B B B B A A A C D C D C D A B B D A A B B A A B D B A B C A A B D A A B B A A C D C D B D A A B D B D B D A B A A B D B C B C Attorney Docket No .: 121843.002NU - 3200 PCT - 761- 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) A A C D C D C D A A A A A B A A B B B A B A A A B D B D B D A B B D B C B D A B B D A A B B A B A A B A B D B D A A B A B B B D A A A B Attorney Docket No .: 121843.002NU - 3200 PCT -762 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) A A B D B D B D A A B A C D C D B D A B B C B C B D A B C D B D B D B C C D C D B D B B B B C D B D B D B C B B A B C D C D C D B B C D C D C D B B C D C D B D Attorney Docket No .: 121843.002NU - 3200 PCT - 763 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) A B B A A A C D B D B D A B B B A A C C C C C C A C C D C D B D B B C D B D B D BAB C B B D B B B D B A B B D B D B D B B Attorney Docket No .: 121843.002NU - 3200 PCT - 764 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) B C B D C D C D C D B B A A B D B A B A B B A B B D B D B D A B C D B D B D B B B B 100 A A C D C D B C 101 A B 102 B B 103 B B Attorney Docket No .: 121843.002NU - 3200 PCT - 765 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 104 B C 105 B D 106 B C 107 B B 108 A A C D C D B D 109 A A C D C D C D 110 B A C D C D C D 111 B A C C C C B C 112 B A C D C D B D 113 A B 114 A B C D C D B D 115 B C 116 A B C D B D C D Attorney Docket No .: 121843.002NU - 3200 PCT - 766 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 117 A A C D C D B D 118 A A C D C D B D 119 A A C D C D B D 120 B C 121 B C 122 B 123 B B C D C D C D 124 B C 125 A B 126 A B BB D C D C D B A B B A 127 A B B B B B B A 128 A C C D B C B D 129 B C C D C D C D Attorney Docket No .: 121843.002NU - 3200 PCT - 767 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 130 B D 131 A B C D B D C D 132 B B 133 B B 134 A B B C B B B B 135 B C 136 B C 137 B C 138 A A B A B A B B 139 B B 140 A B 141 A B C D C D C D 142 B C Attorney Docket No .: 121843.002NU - 3200 PCT - 768 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 143 B C 144 B C 145 B D 146 B C B D B A B D 147 B C C D C D C D 148 B D 150 B C 151 B B 152 B B C D C D B D 153 B C 154 A C 155 B C 156 A B Attorney Docket No .: 121843.002NU - 3200 PCT - 769 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 157 B C 158 B C 159 A A C D C D B D 160 B 161 B B 162 B B 163 B C C D C D C D 164 A A C D B D B D 111BBB B C D C D C D B C B B B D B D B D 168 A B 169 B C Attorney Docket No .: 121843.002NU - 3200 PCT - 770 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 170 B C C D C D C D 171 B C C D C D C D 172 B C 173 A B C D B D B D 174 A B C D C D C D 175 B B 176 B B 177 A B C D C D C D 178 A A 179 A A C D B D B A 180 A A B B B A B A 181 A A B D A A A A 182 A A Attorney Docket No .: 121843.002NU - 3200 PCT - 771 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 183 A A B D B A B A 184 A A 185 B B 186 A B C D B D B D 187 A A B B B B B A 188 A A 189 A A 190 B B 191 A A B D B B 192 A B C D B D BB D D 193 A A B D B B B A 194 A A C D B D B D 195 A A B A B A B A Attorney Docket No .: 121843.002NU - 3200 PCT -772- 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 196 A A 197 A A B B B A B A 198 A A B D B D B A 199 A A 200 A B 201 B B 202 A A 203 A A B D A A B A 204 A A B D B D B D 205 A A B D B D B D 206 A A B D B B B A 207 A B B D B D B D 208 A B B D B D B D Attorney Docket No .: 121843.002NU - 3200 PCT - 773 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 209 A A B B A A A A 210 A A B C B A B A 211 A C C D B D B D 212 A A B B B A B A 213 A A 214 B B 215 A B C D C D C D 216 A A 217 A B C D B D B D 218 A C 219 A A B D B A B D 220 A A B D B B B A 221 A B B D B D B D Attorney Docket No .: 121843.002NU - 3200 PCT 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 222 B D 223 B C 224 A A C D B D B D 225 A B C D B D B D 226 B C 227 A A B D B D B D 228 A A 229 B D 222BBB A A C 233 B B 234 A A C D B B B A Attorney Docket No .: 121843.002NU - 3200 PCT 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 235 A A B D B D B D 236 A A 237 A A 238 A A B D B B B A 239 A A 240 B D 241 A A 242 A A 2243 B C C D C D 244 A A C D B B BB D A 245 A A B D B D B A 246 A B C D C D B D 247 A B C D B D B D Attorney Docket No .: 121843.002NU - 3200 PCT - 776 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 248 A A 249 B C 250 A C C D B D B D 251 A A B D B A B A 252 A B C D C D C D 253 B B 254 A A B B A A B A 255 C D 2222260 BABBB C B C D C D C D B A C D B D C D B C D C D C D B C D C D C D Attorney Docket No .: 121843.002NU - 3200 PCT - 777 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 261 A A B D B C B D 262 A A C D C D C D 263 A A B A A A B A 264 A A A A A A A A 265 A A A A A A A A 266 A A A B A A B A 267 A A A B A A A A 268 A A A A A A A A 275 A A B 276 A A A 277 A A B BAB A A A A BB A A A A B C 278 A A B D A A B C 279 A A B B A A B A Attorney Docket No .: 121843.002NU - 3200 PCT - 778 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 280 A B C D B D C D 281 A A B B A A B A 282 A A B A A A B A 283 A A B D A A B A 284 A B A B A A A A 285 A A A A A A B A 286 A A B B A A A A 287 A A B B B A B A 288 A A A A A A A A 289 A A A B A A A A 290 A A A A A A A A 291 A A A A A A A A 292 A A B C B A B A Attorney Docket No .: 121843.002NU - 3200 PCT - 779 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 293 A A A A A A A A 294 A A A A A A A A 295 A A B C B A B A 296 A A A A A A A A 297 A A A A A A A A 298 B C C D C D C D 299 A A B B A A B A 300 A B B C A A B A 3A A A 302 A A B BB A A B A A A A A 303 A A B C B B B A 304 A A A B A A A A 305 A A A A A A A A Attorney Docket No .: 121843.002NU - 3200 PCT - 780 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 306 A A B B A A B A 307 A A B C A A B B 308 A A A B A A A A 309 A A A B A A B A 310 A A B B A B A A 311 A B B D B C B B 312 A A B A A A A A 313 A B B C A B B A 314 A A B 315 A A B BB B A B A A B A A B A 316 A A A B A A B A 317 A A A A A A B A 318 A A A A A A A A Attorney Docket No .: 121843.002NU - 3200 PCT - 781 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 319 A A B C A A B A 320 A A A A A A A A 321 A A A A A A A A 322 A A B C B A B A 323 A A A A A A A A 324 A A B C B A B A 325 A A A B A A A A 326 A A B B A A A A 327 A A A B A A A A 328 A A B C A B B A 329 A A A B A A A A 330 A A B B A A B A 331 A A A A A A B A Attorney Docket No .: 121843.002NU - 3200 PCT -782 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 332 A A A A A A B A 333 A A B A A A B A 334 A A A B A A A A 335 A A A B A A A A 336 A A A B A A A A 337 A A B B A A B A 338 A A B A A A B A 339 A A C D B A B B 340 A A 341 A A 342 A A 343 A A 344 A A A A A A A A Attorney Docket No .: 121843.002NU - 3200 PCT - 783 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 345 A A C D B D C D 346 A A C D B D C D 347 A A B B A A A A 348 A A B B A A B A 349 A A A A A A A A 350 A A A A A A A A 351 A A B B A A B A 352 A A A A A A B A 353 A A A A A A A A 354 A A B B A A B A 355 A A B B A A B A 356 A B C D B B B D 357 A A A B A A B A Attorney Docket No .: 121843.002NU - 3200 PCT 784 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 358 A A B D B B B A 359 A A A A A A A A 360 A A B A A A A A 361 A A B D A A B A 362 A A B B A A B A 363 A A A A A A A A 364 A B A B A A A A 365 A A B D B A B A 366 A A A A A A A A 367 A A A A A A A A 368 A A B B B A B A 369 A A B A B B B A 370 A A B D B A B A Attorney Docket No .: 121843.002NU - 3200 PCT - 785 - 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 371 A A B A B A B A 372 A A A B A B A A 373 A A A B A A A A 374 A A B B A B B B 375 A A A B A A A A 376 A A B B A A A A 377 A B B A A B B B 378 A B B D B B B D 379 A C B D B C B C 380 A C B D B C B B 381 A B B B B B B A 382 A A A B A A A A 383 A A A B A A A A Attorney Docket No .: 121843.002NU - 3200 PCT - 786- 1100573566 5 AMERICAS Class 1 Class 2 Class A375 A375 G469A G469A G466V G466V D594G D594G Cmpd Dmax DC50 Dmax DC50 Dmax DC50 Dmax DCNumber ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) ( % ) ( nM ) 384 A B B D B B B D 385 A B B C A A B A 386 A B B C A B B B 387 A B B B A A B A 388 A A B B A A B A DC50 ( nM ) : D > 500 ; 50 < C < 500 ; 10 < B < 50 ; A < Dmax ( % ) : C < 30 ; 30 < B < 70 , A > Attorney Docket No .: 121843.002NU - 3200 PCT 1100573566 5 AMERICAS Attorney Docket No .: 121843.002NU - 3200 PCT OTHER EMBODIMENTS [ 0001570 ] It is to be understood that the foregoing description is intended to illustrate and not limit the scope of this disclosure , which is defined by the scope of the appended claims . Other aspects , advantages , and modifications are within the scope of the following claims . - 788 - 1100573566 5 AMERICAS

Claims (88)

Attorney Docket No. : 121843.00271NU-3200 PCT WHAT IS CLAIMED IS:

1. A compound of Formula (I) wherein R1is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; Rlais halogen;RU,is hydrogen, haloalkyl, or halogen; R2is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; X1is carbon or nitrogen; X2is carbon or nitrogen; X3is sulfur, nitrogen, oxygen, or carbon;the bonds among X1, X2,and X3comprise single and double bonds, and the ring containing X1, X2,and X3is aromatic; X4is carbon or nitrogen; X5is hydrogen or -NR3R4; R3is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl; R4is hydrogen, alkyl, cycloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBMwherein Ar1is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen; Z1is a bond or -CH2-; nis zero or one; Z2is absent, -C(O)-, -0-, Cmo alkylene, Cmo alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-Cmo alkylene, heterocycloalkylene, or -C(Me)(Me)-; Cy1is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen; - 789 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT Z3 is absent, Cmo alkylene, or -C(O)-;Lisa linker according to -4?-£2-£3-£4- or -L4-L3-L2-L1-, wherein-L1- is absent, -N(R10)-, -C(Rn)2-, -C(O)-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-;each -L2-, -L3-, and -L4- is independently, absent, -N(R10)-, -C(R2(״-, -C(O)-, -0-, -(CH2CH2-0)1-8-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-;each R10 is independently, hydrogen or methyl;each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl;each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl, hydroxyl, or halogen;each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring;each -Q3- is a three- to six-membered cycloalkylene;UBM is a ubiquitin ligase binding moiety;wherein at least one of R2 or R4 is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; or a stereoisomer and/or pharmaceutical salt thereof.

2. The compound of claim 1, having the following Formula (I) whereinR1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl;Rla is halogen;Rlb is hydrogen or halogen; - 790 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT R2is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; X1is carbon or nitrogen; X2is carbon or nitrogen; X3is sulfur, nitrogen, oxygen, or carbon;the bonds among X1, X2,and X3comprise single and double bonds, and the ring containing X1, X2,and X3is aromatic; X4is carbon or nitrogen;X5 is hydrogen or -NR3R4; R3is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl; R4is hydrogen, alkyl, cycloalkyl, or -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBMwherein Ar1is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen; Z1is a bond or -CH2-; n is zero or one; Z2is absent, -C(O)-, -0-, Cmo alkylene, Cmo alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-CM0 alkylene, heterocycloalkylene, or -C(Me)(Me)-; Cy1is absent or heterocycloalkylene, unsubstituted or substituted with alkyl; Z3is absent, Cmo alkylene, or -C(O)-;Lisa linker according to -L4-L2-L3-L4-or -L4-L3-L2-L1-,wherein -L1-is absent, -N(R10)-, -C(Rn)2-, -C(O)-, -C1-8 alkylene-,- C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-;each -L2-, -L3-,and -L4-is independently, absent, -N(R10)-,- C(R11)2-, -C(O)-, -0-, -(CH2CH2-0)1-8-, -C1-8 alkylene-, -C2-8 alkynylene-,- C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-;each R10 is independently, hydrogen or methyl;each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl;each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl, hydroxyl, or halogen;each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered -791 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring;each -Q3- is a three- to six-membered cycloalkylene; UBMis a ubiquitin ligase binding moiety;wherein at least one of R2or R4is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM;or a stereoisomer and/or pharmaceutical salt thereof.

3. The compound of claim 2, wherein X1is nitrogen; X2is carbon, X3is sulfur; and X4is carbon or nitrogen.

4. The compound of claim 3, whereinR1 is alkyl;Rla is fluoro; R2is [Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; nis zero; Z2is absent; and Cy1is an unsubstituted heterocycloalkylene.

5. The compound of claim 4, wherein Z3 is -C(O)-.

6. The compound of claim 5, wherein L1 is Q1.

7. The compound of claim 6, wherein L2 is -C(O)-.

8. The compound of claim 7, wherein L3 is Q1;and L4is absent.

9. The compound of any one of claims 4-8, wherein R1 is -CH2CH2CH3.

10. The compound of claim 2, wherein X1is carbon or nitrogen; X2is nitrogen, and X3is carbon or nitrogen.

11. The compound of claim 10, wherein X1is carbon; X2is nitrogen, and X3is nitrogen.

12. The compound of claim 11, whereinR1 is alkyl;Rla is fluoro; R2is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; Ar1is Z1is a bond; nis one; Z2and Z3are absent; and - 792 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT Cy1is an unsubstituted heterocycloalkylene.

13. The compound of claim 12, wherein X4 is carbon and X5 is hydrogen.

14. The compound of claim 13, wherein L1 is -C(R11)2-.

15. The compound of claim 14, wherein is R11 hydrogen.

16. The compound of claim 15, wherein L2is Q1;and L3and L4are absent.

17. The compound of any one of claims 11-16, wherein R1 is -CH2CH2CH3.

18. The compound of claim 2, wherein X1 is nitrogen; X2 is carbon, X3 is sulfur; and X4 isnitrogen.

19. The compound of claim 18, whereinR1 is alkyl;Rla is fluoro;R2 is alkyl; nis zero;Z2 is absent; and Cy1is an unsubstituted heterocycloalkylene.

20. The compound of claim 19, wherein Z3 is absent, -CH2- or -C(O)-.

21. The compound of claim 20, wherein L1 is Q1,-C(R11)2-, or -CHCHCHCHCH-, or Q3

22. The compound of claim 21, wherein L2 is absent, Q1, Q2,-C(R11)2-, -C(O)-, or -0-.

23. The compound of claim 22, wherein L3is absent, Q1,or -CH2CH2CH2-; and L4 isabsent.

24. The compound of any one of claims 19-23, wherein R1 is -CH2CH2CH3.

25. The compound of claim 2, wherein UBMbinds an E3 ubiquitin ligase.

26. The compound of claim 2, wherein UBMbinds SCFB-TRCP, VHL, MDM2, IAP, or CRBN.

27. The compound of claim 2, wherein UBMbinds VHL.

28. The compound of claim 27, wherein UBMbinds VHL and has the following chemical formula L Z4 r9 5 X6n״r NH R8 wherein - 793 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT L designates attachment to L; Z4is a bond, -CH2-, -C(O)-, -C(O)N(R12)-,or -N(R12)-,wherein R12is hydrogen or methyl; X6is C-H or nitrogen; R8is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R13),or -S(O)2(R13);wherein R13is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted;R9 is hydrogen, unsubstituted or substituted C1-8 alkyl, or -AA1-AA2-R14 wherein each AAand AA2 is an amino acid residue, and R14 is hydrogen or methyl.

29. The compound of claim 27, wherein UBMbinds VHL and has the following chemical formula R15 L designates attachment to L; Z5is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, -N(R12)-,or -0-,wherein R12is hydrogen or methyl;A is phenyl or C4-heteroaryl; X7is -CH2, -NR12,oxygen, or sulfur, wherein R12is hydrogen or methyl; pis zero or one;R15 is unsubstituted or substituted C1-8 alkyl, -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl.

30. The compound of claim 27, wherein UBMbinds VHL and has the following chemical formula ) — ־־־^ z6-w —R16 wherein L designates attachment to L; -794-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT Z6is a bond, -CH2, ־C(O)-, -C(O)N(R12)-, or N(R12), wherein R12 is hydrogen or methyl; R18 wherein, X9 ؛ designates attachment to X8, wherein ؛ designates attachment to X9, and wherein, |z6؛ designates attachment to Z6; X8 is carbon or nitrogen;X9 is C-H or -CH2-; R16is hydrogen, -OH, halogen, -NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -C6-10 aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; R17is -C(O)N(H)-C6-10 aralkyl, -C(O)CH(Cbutyl)-N(H)-C3-6 cycloalkyl, -C(O)-CH(t-butyl)-N(H)C(O)-C3-C6 cycloalkyl , or -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue and R14 is hydrogen or methyl; and R18is halogen or S—/

31. The compound of claim 2, wherein UBMbinds CRBN.32. The compound of claim 31, wherein UBMbinds CRBN and has the following chemicalformula - 795 -11005735665AMERICAS

32. Attorney Docket No. : 121843.00271NU-3200 PCT r or r wherein X6absent or NR3; X7absent or -C(O)-; and X8is arylene or heteroarylene.

33. The compound of claim 32, wherein UBMbinds CRBN and is selected from the group X9is absent or halogen; and mis one, two, three, or four. - 796 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT

34. A compound of Formula (II) wherein R1is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; Rlais halogen; Rlbis hydrogen or halogen; R2is -[Ar1-Z1]n-Z2-Cy1-Z3-L-UBMwherein Ar1is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen; Z1is a bond or -CH2-; nis zero or one; Z2is absent, -C(O)-, -0-, Cmo alkylene, Cmo alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cycloalkylene-C1-10 alkylene, heterocycloalkylene, or -C(Me)(Me)-; Cy1is absent or heterocycloalkylene, unsubstituted or substituted with alkyl; Z3is absent, Cmo alkylene, or -C(O)-;Lisa linker according to ^1-L2^3^4-or -L4-L3-L2-L1-,wherein-L1- is absent, -N(R10)-, -C(Rn)2-, -C(O)-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, or -Q2-;each -L2-, -L3-, and -L4- is independently, absent, -N(R10)-, -C(R2(״-, -C(O)-, -0-, -(CH2CH2-0)1-8-, -C1-8 alkylene-, -C2-8 alkynylene-, -C6-10 aryl-, -C4-10 heteroaryl-, -Q1-, -Q2-, or -Q3-;each R10 is independently, hydrogen or methyl;each R11 is, independently, hydrogen, methyl, aryl, or heteroaryl;each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with methyl, hydroxyl, or halogen; - 797 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring;each -Q3- is a three- to six-membered cycloalkylene; UBMis a ubiquitin ligase binding moiety;X1 is nitrogen or oxygen;X3 is sulfur when X1 is nitrogen; oxygen when X1 is nitrogen; or nitrogen when X1 is oxygen;the bonds among X1 and X3 comprise single and double bonds, and the ring containing X1 and X3 is aromatic;X4 is carbon or nitrogen;X5 is hydrogen or -NR3R4; R3is hydrogen or alkyl where alkyl is unsubstituted or substituted with hydroxyl; R4is hydrogen, alkyl, or cycloalkyl; or a stereoisomer and/or pharmaceutical salt thereof.

35. The compound of claim 34, wherein X1 is nitrogen; X3 is oxygen; and X4 is carbon or nitrogen.

36. The compound of claim 34, wherein X1 is oxygen; X3 is nitrogen; and X4 is carbon or nitrogen.

37. The compound of claim 34, wherein X1 is nitrogen; X3 is sulfur; and X4 is carbon or nitrogen.

38. The compound of claim 37, wherein R1is alkyl; Rlais fluoro; R2is [Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; nis zero;Z2 is absent; and Cy1is an unsubstituted heterocycloalkylene.

39. The compound of claim 38, wherein Z3 is -C(O)-.

40. The compound of claim 39, wherein L1 is Q1.

41. The compound of claim 40, wherein L2 is -C(O)-. - 798 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT

42. The compound of claim 41, wherein L3is Q1and L4is absent.

43. The compound of any one of claims 38-42, wherein R1 is -CH2CH2CH3.

44. The compound of claim 34, wherein UBMbinds an E3 ubiquitin ligase.

45. The compound of claim 34, wherein UBMbinds SCFB-TRCP, VHL, MDM2, IAP, orCRBN.

46. The compound of claim 45, wherein UBMbinds VHL.

47. The compound of claim 46, wherein UBMbinds VHL and has the following chemicalformula L R8 wherein ' designates attachment to L; Z4is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, or -N(R12)-, wherein R12 is hydrogen or methyl; X6is C-H or nitrogen;R8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R13), or -S(O)2(R13); wherein R13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted;R9 is hydrogen, unsubstituted or substituted C1-8 alkyl, or -AA1-AA2-R14 wherein each AAand AA2 is an amino acid residue, and R14 is hydrogen or methyl.

48. The compound of claim 46, wherein UBM binds VHL and has the following chemical formula p wherein designates attachment to L; - 799 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT Z5is a bond, -CH2-, -C(O)-, -C(O)N(R12)-, -N(R12)-, or -0-, wherein R12 is hydrogen or methyl;A is phenyl or C4-heteroaryl;X7 is -CH2, -NR12, oxygen, or sulfur, wherein R12 is hydrogen or methyl; pis zero or one;R15 is unsubstituted or substituted C1-8 alkyl, -AA1-AA2-R14, wherein each AA1 and AA2 is an amino acid residue, and R14 is hydrogen or methyl.

49. The compound of claim 46, wherein UBMbinds VHL and has the following chemical formula :9 R17 ׳-؛ z6_w —R16 wherein R18 wherein, ؛ designates attachment to X8, wherein ؛ designates attachment to X9, and wherein, |z6designates attachment to Z6;X8 is carbon or nitrogen;X9 is C-H or -CH2-;R16 is hydrogen, -OH, halogen, -NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -C6-10 aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;R17 is -C(O)N(H)-C6-10 aralkyl, -C(O)CH(Cbutyl)-N(H)-C3-6 cycloalkyl, -C(O)-CH(Cbutyl)-N(H)C(O)-C3-C6 cycloalkyl, - 800 -11005735665AMERICAS 5 designates attachment to L; Z6is a bond, -CH2, ־C(O)-, -C(O)N(R12)-, or N(R12), wherein R12 is hydrogen or methyl; Attorney Docket No. : 121843.00271NU-3200 PCT amino acid residue and R14 is hydrogen or methyl; and R18is halogen or

50. The compound of claim 34, wherein UBMbinds CRBN.51. The compound of claim 50, wherein UBMbinds CRBN and has the following chemicalformula ז or ז wherein X6is absent or NR3; X7is absent or -C(O)-; and X8is arylene or heteroarylene.52. The compound of claim 51, wherein UBMbinds CRBN and is selected from the group consisting of - 801 -11005735665AMERICAS

51. Attorney Docket No. : 121843.00271NU-3200 PCT

52. X9is absent or halogen; and mis one, two, three, or four.

53. The compound of claim 2 Formula (I)or claim 34 Formula (II),wherein Lcomprises at least one -Q1-; at least one -Q2-; at least one -Q3-; at least one -C(R11)2-;or at least one C1-8 alkylene-.54. The compound of claim 53, wherein L is selected from the group consisting ofa. -Q1-; b. -QLC^-Q1-;c. -C(R11)2-Q1-; d. -Q1-C(R11)2-Q1-; e. -C(R2(״- O-;f -Q3-O-; g. -C(R11)2-Q1-Q1-; h -Q1-Q1-;i. -C(R2(״-Q2-; j. -C1-8 alkylene-;k. -C(R11)2-Q1-C1-8alkylene-;1. -Q3-C(R11)2-; m. -C(R2(״-; - 802 - 11005735665AMERICAS

54. Attorney Docket No. : 121843.00271NU-3200 PCT n. -Q2-; 0. -Q1-C(O)-C(R11)2-; p. -Q1-C(O)-Q3-O-; q. -Q1-C(O)-C(R11)2-Q1-; r. -Q1-C(R11)2-Q3-O-;and S. -Q1-C(R2(״-.

55. The compound of claim 54, wherein -Q1- is wherein R19is hydrogen, hydroxyl, halogen, or unsubstituted alkyl, n1is one or two, n2is one or two, and n3is one or two.ww

56. The compound of claim 55, wherein -Q1- is selected from the group consisting of wherein R19 is hydrogen, hydroxyl, fluoro, or methyl.ww n N57. The compound of claim 54, wherein -Q2-is , wherein n4is one or two, n5 is one or two, and n6is one or two. - 803 -11005735665AMERICAS

57. Attorney Docket No. : 121843.00271NU-3200 PCTJVW

58. N 58. The compound of claim 57, wherein -Q2- is selected from the group consisting of nA/Wn^)n»

59. The compound of claim 54, wherein -Q3- is , wherein n7is one or two, and n8is one or two.

60. The compound of claim 59, wherein -Q3- is selected from the group consisting of

61. The compound of claim 54, wherein each R11 is, independently, hydrogen or methyl.62. The compound of claim 61, wherein both R11 are hydrogen; one R11 is hydrogen and oneR11 is methyl; or both R11 are methyl.63. The compound of claim 54, wherein -C1-8 alkylene- is selected from the group consisting of -CH2-, -CH CH- -CH CH CH2- -CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, and-CH2CH2CH2CH2CH2CH2CH2CH2-.64. The compound of claim 54, wherein the linker L is selected from - 804-11005735665AMERICAS

62. Attorney Docket No. : 121843.00271NU-3200 PCT

63. Z3 Z3 z3 z3 z3 - 805 -11005735665AMERICAS

64. Attorney Docket No. : 121843.00271NU-3200 PCT 23 UBMindicates attachment to Z3,and indicates attachment to UBM.

65. The compound of any one of claims 2-9, 31-33, or 53-64 selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-di oxopiperi din-3-yl)pyri din-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- - 806 - 11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, and (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide.

66. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of(A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-di oxopiperi din-3-yl)-1,3- dioxoisoindolin-4-yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)- 2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(5-(2-aminopyrimidin-4-yl)-2-( 1 -((1 S,4r)-4-((6- ((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(177)-yl)methyl)cyclohexane-l- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l- (l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(T-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-TV-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(177)-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2- (l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(T-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- - 807-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT yl)-2-(2-( 1 -(1 -(1 -(2-(2,6-di oxopiperi din-3 -yl)-1,3 -di oxoisoindolin-5-yl)piperi din-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((U?,4r)-4-(3-((A)-2,6-di oxopiperi din-3-yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3-azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(4-((2,6-di oxopiperi din-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (4-(2,6-di oxopiperi din-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thi azol -4- yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2- (l-(4-((2,6-di oxopiperi din-3-yl)amino)phenyl)piperidin-4-yl)acetyl)piperi din-4- yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(l-(5-(2,6-di oxopiperi din-3-yl)pyri din-2-yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((lS,4r)-4-((5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-l- yl)-A-(2,6-dioxopiperidin-3-yl)picolinamide, A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((5)-l- (5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)- 2-(l-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, -808-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(l-(l-((l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(l'-(2-(2,6-di oxopiperi din-3-yl)-l,3-di oxoisoindolin-5- yl)-[l,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2- (l-((l-(((lS,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(2-(2,6-di oxopiperi din-3-yl)-1,3-di oxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-A-(3-(2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2,6-di oxopiperi din-3-yl)-1,3-di oxoisoindolin-5- yl)piperazin-l-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamidef, (A)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(4-((l-(4-(2,6-di oxopiperi din-3-yl)phenyl)piperi din-4-yl)methyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(l-(5-(2,6-dioxopiperidin-3-yl)pyri din-2- -809-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(l-(5- (2,6-di oxopiperi din-3-yl)pyri din-2-yl)piperidin-4-yl)acetyl)piperazin-l-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(T- (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2,6-di oxopiperi din-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((lA,4r)-4-(4-((A)-2,6-di oxopiperi din-3-yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-di oxopiperi din-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, A-(3-(2-(l-(l- (l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(((A)-l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac-(3 A)-3 - { 6- [4-(4- { 4- [5 -(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2,6-dione, rac-(3A)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl } -1,3 -thiazol-2-yl]piperidine- 1 -carbonyl }piperidine-1 -carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2,6-dione, (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((l-(2-(2,6-dioxopiperidin-3-yl)-l- -810-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (A)-A-(3-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 2,7-di azaspiro [3.5 ]nonan-7 -yl)acetyl)piperidin-4-yl)-5 -(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-di oxopiperi din-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3-azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((A)-l-(4-((5)-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-((l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- - 811 - 11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-l/7-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (/?)-N-(3-(2-(l-(I-((I-(4-(2,6-di oxopiperi di n-3-yl )phenyl )pi peri di n-4-yl )methyl )pi peri di ne-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(l-(l-(2-(2,6-di oxopiperi din-3-yl)-1,3-di oxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane- 1 -sulfonamide, (5)-A-(3 -(5-(2-aminopyrimidin-4-yl)-2-(l -(1 -((1 -(1 -(2,6-di oxopiperi din-3-yl)-3-methyl-2-oxo-2, 3-dihydro-l/7-benzo[d]imidazol-4-yl)piperi din- 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(l-(2-(2-(2-(2,6-di oxopiperi din-3-yl)-l,3-dioxoisoindolin-5-yl)-2, 7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, and (A)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3-(propyl sulfonami do)phenyl )thi azol-2-yl )pi peri di n-l-yl )methyl )-N-(2,6-di oxopiperi din-3- yl)benzamide.

67. The compound of any one of claims 2, 18-24, 31-33, or 53-64 selected from the group consisting of (A)-4-(4-((6-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thi azol-5- yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)methyl)piperidin-l-yl)-7V-(2,6- di oxopiperi din-3-yl)benzamide, A-(3-(2-(tert-butyl)-5-(2-((2-(2-((5)-l-(5-((5)-2,6-di oxopiperi din-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-2-azaspiro[3. 3 ]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(T-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'- bipiperidin]-4-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(terZ-butyl)-5-(2-((2-(l-(l-(2,6- -812-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT di oxopiperi din-3-yl)-3-m ethyl-2-oxo-2,3-dihydro-l/7-benzo[<7]imidazol-4-yl)piperidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((2-(l-(l-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(2-(tert-butyl)-5-(2-((2-(2-(2-(2-(2,6-di oxopiperi din-3 -yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-TV-(3-(2-(A77-butyl)-5-(2-((2-((l-((l-(4-(2,6-di oxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((2-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)propyl)piperazin-l-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (/?)-N-(3-(2-(/c77-butyl)-5-(2-((2-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-4-fluoropiperidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((2-((l-(l-(4-(2,6-di oxopiperi din-3-yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2- (tert-butyl)-5-(2-((r-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)- [ 1,4'-bipiperidin]-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 - sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((7-(2-(4-(4-((2,6-di oxopiperi din-3-yl)amino)phenyl)piperidin-l-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(/c/7-butyl)-5-(2-((7- (((lS,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)-7- azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(2-(tert-butyl)-5-(2-((7-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin- 4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((7- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, and (R)-N-(3- - 813 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT (2-(Zert-butyl)-5-(2-((7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin- l-yl)acetyl)-7-azaspiro[3.5]nonan-2-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl )prop ane-1 - sulfonami de.

68. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of(5)-A-(3-(2-(ZerZ-butyl)-5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (A)-7V-(3-(2-(Zert-butyl)-5-(2-((4-(l-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(ZerZ-butyl)-5-(2-((4-(l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, 7V-(3-(2-(Zert-butyl)-5-(2-((4-(l-(2-((5)-l-(5-((5)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-4-(4-((4-(4-((4-(2-(A77-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l-yl)methyl)piperi din-l-yl)-A-(2,6-di oxopiperi din-3-yl)benzamide, (A)-5-(4-((4-(4-((4-(2-(tert- butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-7V-(2,6-dioxopiperidin-3- yl)picolinamide, 7V-(3-(2-(terZ-butyl)-5-(2-((4-(l-(((lS,4r)-4-((5-((5)-2,6-dioxopiperidin-3- yl)pyridin-2-yl)oxy)cyclohexyl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(Zert-butyl)-5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, A-(3-(2-(tert-butyl)-5-(2-((4-(l-(2- ((5)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3- (2-(/c/׳Z-butyl )-5-(2-((4-(l-(2-((/?)-l-(4-(CS')-2,6-di oxopiperi di n-3-yl )phenyl )pyrrol i din-3- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, 7V-(3-(2-(Zert-butyl)-5-(2-((4-(l-((A)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thi azol-4- - 814-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(tert-butyl)-5-(2-((4-(l-(l-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(A77-butyl)-5-(2-((4-(l-(2-(r-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- [l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, CV)-N-(3-(2-(/c/7-butyl)-5-(2-((4-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3- (2-(tert-butyl)-5-(2-((4-(l-(2-((5)-l-(l-((A)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-l/7-benzo[<7]imidazol-5-yl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(l-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- l/7-benzo[<7]imidazol-4-yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l- (l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)azetidine-3-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N- (3-(2-(tert-butyl)-5-(2-((4-(l-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-(2-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7- yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l-(6-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)hexanoyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(2-(tert-butyl)-5-(2-((4-(l-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-5- (4-((4-(((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)methyl)piperidin- 1 -yl)methyl)piperidin- 1 -yl)-A-(2,6-di oxopiperi din-3 - yl)picolinamide, (5)-5-(4-((4-(l-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-methylpropan-2- yl)piperi din-l-yl)methyl)piperi din-l-yl)-A-(2,6-di oxopiperi din-3-yl)picolinamide, (R)-N-(3- (2-(tert-butyl)-5-(2-(((l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- - 815 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT 1-sulfonamide, (A)-TV-(3-(2-(ZerZ-butyl)-5-(2-((2-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2-methylpropyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 5-(4-(((A)-3-(((4-(2-(tert-butyl)-4-(2- fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)methyl)pyrrolidin-l- yl)methyl)piperi din-l-yl)-TV-((5)-2,6-di oxopiperi din-3-yl)picolinamide, TV-(3-(2-(Ze/7-butyl)- 5-(2-(((lr,4r)-4-((4-((l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)methyl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, A-(3-(2-(tert-butyl)-5-(2-(((15,45)-4-(4-(l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, TV- (3-(2-(Zc77-butyl)-5-(2-(((lz4,׳z4)-4-(׳-(l-(5-((،S')-2,6-dioxopiperidin-3-yl)pyri din-2- yl)piperidine-4-carbonyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, TV-(3-(2-(ZerZ-butyl)-5-(2-(((lr,4r)-4-(4-((l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, TV- (3-(2-(ZerZ-butyl)-5-(2-(((15,45)-4-(4-((l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)cyclohexyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (3A)-3-{4-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl} amino)pyri din-3 -yl]piperazin-1 -yl }methyl)piperidin- 1 -yl]phenyl }piperidine-2, 6-dione, (31S')-3-[4-[4-([4-[6-([4-[2-Zc77-butyl-4-(3-[ [ethyl (methyl )sulfamoyl ]amino} -2- fluorophenyl)-!,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l- yl}methyl)piperidin-l-yl]phenyl }piperidine-2,6-dione, rac-(35)-3-{6-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl} amino)pyri din-3 -yl]piperazin-1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperidine-2,6- dione, rac-(3S)-3-(2-{[(lr,4r)-4-{4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}cyclohexyl]methyl}-l,2,3,4- tetrahydroisoquinolin-6-yl)piperidine-2,6-dione, rac-(3S)-3-(2-{[(lr,4r)-4-{4-[6-({4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}cyclohexyl]methyl}-l,2,3,4- tetrahydroisoquinolin-7-yl)piperidine-2,6-dione, (A)-TV-(3-(2-(ZerZ-butyl)-5-(2-((2-(2-(4-(4- ((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)-l,2,3,4-tetrahydroisoquinolin- -816-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT 6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-5-(4-(6- ((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2- yl)amino)-l, 2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-l-yl)-A-(2,6-di oxopiperidin-3- yl)picolinamide, A-(3-(2-(tert-butyl)-5-(2-((2-((A)-l-(5-((،2,6-(؟-dioxopiperidin-3-yl)pyridin- 2-yl)pyrrolidine-3-carbonyl)-l,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(/e77-butyl)-5-(2-((2-(2- (4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)acetyl)-l,2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(l/7)-yl)acetyl)piperidin-4-yl)methyl)-l/7-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, A-(3-(2-(tert- butyl)-5-(2-((l-((l-((lS,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-l- carbonyl)piperidin-4-yl)methyl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-((l-((lS,4r)-4-((5-((5)-2,6- di oxopiperi din-3-yl)pyridin-2-yl)oxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)- 1/7- pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (A)- A-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- l-yl)acetyl)piperidin-4-yl)methyl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (7?)-5-(4-(4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/7-pyrazol-l- yl)methyl)piperi dine-l-carbonyl)piperi din-l-yl)-A-(2,6-di oxopiperi din-3-yl)picolinamide, TV- (3-(2-(terZ-butyl)-5-(2-((l-((l-((/?)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine- 3-carbonyl)piperidin-4-yl)methyl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((l-((l-(2-(4-(4-(2,6- di oxopiperi din-3-yl)pyridin-2-yl)piperazin-l-yl)acetyl)piperidin-4-yl)methyl)-l/7-pyrazol -4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(tert- butyl)-5-(2-((l-((l-(2-((5)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)methyl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, TV-(3-(2-(Zert-butyl)-5-(2-((l-((l-(2-((/?)-l-(4-((5)-2,6- di oxopiperi din-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)m ethyl)-l/7-pyrazol-4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(tert- butyl)-5 -(2-(( 1 -(1 -((1 S,4r)-4-(4-((5)-2,6-di oxopiperi din-3 -yl)phenoxy)cy clohexane- 1 - carbonyl)piperidin-4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- - 817-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((l-(l-((lS,4r)-4-((5-((5)-2,6- di oxopiperi din-3-yl)pyridin-2-yl)oxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)-l/7-pyrazol -4- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(2- (tert-butyl)-5-(2-((l-(l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l- yl)acetyl)piperidin-4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-5-(4-(4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/7-pyrazol-l-yl)piperidine- l-carbonyl)piperi din-l-yl)-A-(2,6-di oxopiperi din-3-yl)picolinamide, A-(3-(2-(tert-butyl)-5-(2-((l-(l-((A)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, A-(3-(2-(te^butyl)-5-(2-((l-(l-(2-((5)-l-(4-((5)-2,6- dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-TV-(3-(2- (tert-butyl)-5-(2-((3-(l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(U7)-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((3-(l-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thi azol-4- yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(2-(tert-butyl)-5 -(2-((3 -(1 -((R)-1 -(5 -((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(A77-butyl)-5-(2-((3-((l-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(177)- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)-A-(3 -(2-(tert-butyl)-5 -(2-((3 -((1 -(1 -(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3 -(2-(terZ-butyl)-5 -(2-((3 -((1 -(1 -(3 -(2,6-di oxopiperi din-3 -yl)phenyl)piperidine-4- carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((3-((l-((lS,4r)-4-(4-((5)-2,6- di oxopiperi din-3-yl)phen oxy)cy cl ohexane-l-carbonyl)piperi din-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, TV- (3-(2-(terZ-butyl)-5-(2-((3-((l-((lS,4r)-4-((5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)cyclohexane-l-carbonyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-(2-(4-(4- -818-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT ((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-5-(4-(4-(3-((4-(2-(terZ-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thi azol-5- yl)pyrimidin-2-yl)amino)phenoxy)piperidine-l-carbonyl)piperidin-l-yl)-7V-(2,6-dioxopiperidin-3-yl)picolinamide, A-(3-(2-(te^butyl)-5-(2-((3-((l-((7?)-l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidine-3-carbonyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-(2-(4-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin- l-yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((5)-l-(4-((5)-2,6- dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, TV- (3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((A)-l-(4-((5)-2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3- yl)acetyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-TV-(3-(2-(A77-butyl)-5-(2-((4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((4-(l- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(tert-butyl)-5-(2-((4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperi din-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)-3- fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (2S,4A)-l-((5)-2-(5-(4-(4-((4-(2-(terZ-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)piperidin-l-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-7V-((5)-l-(4-(4-methylthi azol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((2-((l-(2-(2,6- di oxopiperi din-3-yl)-l-oxo-1,2-dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)-l, 2,3,4- tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(terZ-butyl)-5-(2-((l-((l-(((lS,4r)-4-(4-((5)-2,6-dioxopiperidin-3- yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)methyl)-l/7-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)-N-(3-(2-(torCbutyl)-5-(2-(( 1 -((1 - -819-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)methyl)-l/Z-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-5-(4-((4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/7-pyrazol-l-yl )methyl )pi peri din-1-yl )methyl )pi peri din-l-yl)-N-(2,6-di oxopiperi di n-3-yl )pi col inamide, TV- (3-(2-(terZ-butyl)-5-(2-((l-((l-(2-((A)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)methyl)-l//-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-TV-(3-(2-(terf-butyl)-5-(2-((l-(l- ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4- yl)methyl)piperidin-4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-5-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/7-pyrazol-l-yl)piperidin-l- yl)methyl)piperi din-l-yl)-TV-(2,6-di oxopiperi din-3-yl)picolinamide, N-(3-(2-(/c/7-butyl)-5-(2- ((l-(l-(2-((A)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin- 4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, N-(3-(2-(/c77-butyl)-5-(2-((l-(l-(2-(CS')-l-(5-(CV)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)-l/7-pyrazol-4-yl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-TV-(3-(2-(terf-butyl)-5-(2-((3-(l- ((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- -sulfonamide, N-(3 -(2-(/c77-butyl )-5 -(2-((3-(1 -(2-((A)-1 -(5 -((5)-2,6-di oxopiperi din-3 -yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4- yl)-2-fluorophenyl)propane- 1 -sulfonamide, N-(3-(2-(/c77-buty 1 )-5-(2-((3-(1 -(2-((5)-1 -(5-((5)- 2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(/c77-butyl)-5-(2-((3-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin- 4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3-(2-(/c77-butyl)-5-(2-((3-((l-(((LS',4/')-4-(4-(CS')-2,6- dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydroisoquinolin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(terf-butyl)-5-(2-((3-((l-(2- -820-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT ((A)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, TV- (3-(2-(terZ-butyl)-5-(2-((3-((l-(2-((5)-l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)pyrrolidin-3-yl)ethyl)piperidin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((3-((l-((l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperidin-4- yl)oxy)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-5-(4-((4-(4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-l/7-pyrazol-l-yl)piperidin-l-yl)methyl)piperidin-l-yl)-7V-(2,6- dioxopiperidin-3-yl)picolinamide, (A)-5-(4-((4-((4-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5-yl)pyrimidin-2-yl)amino)-l/7-pyrazol-l- yl)methyl)piperi din-l-yl)methyl)piperi din-l-yl)-7V-(2,6-di oxopiperi din-3-yl)picolinamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-((4-(l-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2-((4-(l-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-((5-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- 7V-(3-(5-(2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l- yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-7V-(3-(5-(2-((5-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)pyri din-2-yl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(tert-butyl)-5-(2-((4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(tert-butyl)-5-(2-((4-(4-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, rac-(3A)-3-[6-(4-{4-[6-({4-[2-tert-butyl-4-(3- - 821 - 11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)pyridin-3-yl]piperidine-2,6- dione, (5)-7V-(3-(5-(2-((4-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(te/7-butyl)-5-(2-((4-(4-((A)-l-(5-((A)-2,6- di oxopiperi din-3 -yl)pyridin-2-yl)pyrrolidine-3 -carbonyl)piperazin- 1 -yl)-3 -fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- A-(3-(5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(te/7-butyl)-5-(2-((4-(4-((A)-l-(5-((A)-2,6- di oxopiperi din-3 -yl)pyridin-2-yl)pyrrolidine-3 -carbonyl)piperazin- 1 -yl)-3 -fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac- (35)-3-[6-(3-{4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)- l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carbonyl}azetidin-l-yl)pyridin-3-yl]piperidine-2,6-dione, (5)-A-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(l-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-l-yl)- 3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin- 2(177)-yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(2-(tert-butyl)-5-(2-((4-(4-((lS,4r)-4-((5-((5)-2,6- di oxopiperi din-3-yl)pyridin-2-yl)oxy)cy cl ohexane-l-carbonyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (R)- A-(3-(2-(tert-butyl)-5-(2-((4-(4-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(tert-butyl)-5-(2-((4-(4-((l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-N- (3-(2-(tert-butyl)-5-(2-((4-(4-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(tert-butyl)-5-(2-((4-(4-((l-(5-(2,6- dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)-3-fluorophenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)- N-(3 -(5-(2-((4-( 1 -(2-( 1 -(4-((2,6-di oxopiperi din-3 -yl)amino)phenyl)piperi din-4- -822-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT yl)acetyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, rac-(35)-3-{6-[4-({4-[6-({4-[4-(3-{[ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5-yl]pyrimidin-2- yl} amino)pyri din-3 -yl]piperazin-1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperi dine-2,6- dione, rac-(35)-3-[6-(4-{4-[6-({4-[2-terZ-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-!,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carbonyl}-4- m ethylpiperi din-l-yl)pyri din-3-yl]piperi dine-2,6-dione, (3A)-3-{4-[4-({4-[6-({4-[4-(3- {[ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5-yl]pyrimidin-2- yl} amino)pyri din-3 -yl]piperazin-1 -yl }methyl)piperidin- 1 -yl]phenyl }piperidine-2, 6-dione, rac-(35)-3-[6-(4-{4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2- methyl-l,3-thiazol-5-yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazine-l-carbonyl }piperi din- l-yl)pyridin-3-yl]piperi dine-2,6-dione, rac-(3A)-3-{6-[4-(2-{4-[6-({4-[4-(3-{[ethyl (methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}-2-oxoethyl)piperidin-l-yl]pyridin-3-yl }piperidine-2,6- dione, (5)-TV-(3-(2-(A77-butyl)-5-(2-((4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine- 4-carbonyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, CV)-N-(3-(2-(/c/7-butyl)-5-(2-((4-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidin-4-yl)phenyl)amino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, rac-(35)-3-[4-(4-[4-[6-([4-[2-tert- butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazine-l-carbonyl}piperidin-l-yl)phenyl]piperidine-2,6-dione, (A)-A-(3-(2-(tert-butyl)-5-(2-((4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, rac-(35)-3-[6-[4-({4-[6-([4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-2-methyl- 1,3 -thiazol-5-yl]pyrimidin-2-yl } amino)pyri din-3 -yl]piperazin-1 - yl}methyl)-4-methylpiperidin-l-yl]pyridin-3-yl}piperidine-2,6-dione, rac-(35)-3-{4-[4-({4-[6-({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thi azol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-4-fluoropiperidin-l- yl]phenyl}piperidine-2,6-dione, (5)-7V-(3-(5-(2-((4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin- 2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-l-yl)phenyl)amino)pyrimidin-4-yl)-2- methylthiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-((4-(4-((l-(4-(2,6- dioxopiperidin-3-yl)phenyl)-4-fluoropiperidin-4-yl)methyl)piperazin-l- yl)phenyl)amino)pyrimidin-4-yl)-2-methylthiazol-4-yl)-2-fluorophenyl)propane-l- - 823 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT sulfonamide, rac-(3A)-3-{6-[6-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)-2-azaspiro[3.3]heptan-2-yl]pyridin-3- yl}piperidine-2,6-dione, (3A)-3-{6-[4-({4-[6-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-5-yl]pyrimidin-2- yl} amino)pyri din-3 -yl]piperazin-1 -yl }methyl)piperidin- 1 -yl]pyri din-3 -yl }piperi dine-2,6- dione, rac-(3A)-3-[2-(2-{4-[4-({4-[2-tert-butyl-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2- fluorophenyl)-!,3-thiazol-5-yl]pyrimidin-2-yl}amino)-2-fluorophenyl]piperazin-l-yl}-2- oxoethyl)-!, 2,3,4-tetrahydroisoquinolin-6-yl]piperidine-2,6-dione, and (3A)-3-{6-[4-({4-[6- ({4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-2-methyl-l,3-thi azol-5- yl]pyrimidin-2-yl}amino)pyridin-3-yl]piperazin-l-yl}methyl)piperidin-l-yl]pyridin-3- yl }piperi dine-2,6-dione.

69. The compound of any one of claims 2, 10-17, 31-33, or 53-64 selected from the group consisting of (5)-A-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (A)-A-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, and (5)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluoropheny !)prop ane-1 - sulfonami de.

70. The compound of any one of claims 2, 31-33, or 53-64 selected from the group consisting of (A)-7V-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4- carbonyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(l-(4-((l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)phenyl)-3-(pyridin-4-yl)-U/- pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- - 824-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (7?)-A-(3-(l-(4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)- 3-(pyridin-4-yl)-l/Z-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-A-(3-(1 -(1 -(1 - (l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(l- (4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N- (3-(l-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin- 4-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)- A-(3-(l-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-di oxopiperi din-3-yl)-2-fluorophenyl)piperi din-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (5)-A-(3-(l-(6-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)pyri din-3-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(l-(4-(4-(2-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)-A-(3 -(1 -(1 -(1 -((1 -(5 -(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)- 3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-A-(3-(l-(4-(4- ((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-A-(3-(l-(6-(4- ((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)pyridin-3- yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(l-(4- (l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-A-(3 -(1 -(4-( 1 -((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)- l//-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (S)-A-(3 -(1 -(4-( 1 -((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-A-(3-(l-(4-(4- ((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3- (pyridin-4-yl)- 1H-pyrazol -4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)-7V-(3-(1 -(1 -(1 -(1 - (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4- - 825 - 11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT carbonyl)piperidin-4-yl)-3-(pyridin-4-yl)-l/Z-pyrazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3 -(1 -(4-(l -((1 -(4-(2,6-di oxopiperi din-3 -yl)-3 -fluorophenyl)piperi din-4-yl)methyl)piperidin-4-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane-1-sulfonamide, and (A)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl )prop ane-1 - sulfonami de.

71. The compound of any one of claims 34, 37-45, or 50-54 selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-di oxopiperi din-3-yl)pyri din-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, and (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5- (pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide.

72. The compound of any one of claims 34, 37, 44, 45, or 50-64 selected from the group consisting of (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4-yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((lS,4r)- 4-((6-((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(177)-yl)methyl)cyclohexane-l- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l- (l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- -826-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(T-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(2-(6- (2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(177)-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3- azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2- (l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(r2,6)-2) ־-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetyl)piperidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-( 1 -(1 -(1 -(2-(2,6-di oxopiperi din-3 -yl)-1,3 -dioxoisoindolin-5-yl)piperidin-4- yl)azetidine-3-carbonyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((U?,4r)-4-(3-((A)-2,6-di oxopiperi din-3-yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3-azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(4-((2,6-di oxopiperi din-3-yl)amino)-2-fluorophenyl)- 4-hydroxypiperidin-4-yl)acetyl)azetidin-3-yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (4-(2,6-di oxopiperi din-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thi azol -4- - 827-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(2- (l-(4-((2,6-di oxopiperi din-3-yl)amino)phenyl)piperidin-4-yl)acetyl)piperi din-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-(l-(5-(2,6-di oxopiperi din-3-yl)pyri din-2-yl)piperidine-4- carbonyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, N-(3- (5-(2-aminopyrimidin-4-yl)-2-(3-(((lS,4r)-4-((5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)oxy)cyclohexyl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(4- (2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-5-(4-(9-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carbonyl)piperidin-l- yl)-A-(2,6-dioxopiperidin-3-yl)picolinamide, A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((5)-l- (5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)- 2-(l-(l-(2-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetyl)azetidin-3- yl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-7V-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(2-(l-(l-((l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2- (methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(2-(2-(l'-(2-(2,6-di oxopiperi din-3-yl)-l,3-dioxoisoindolin-5- yl)-[l,4'-bipiperidin]-4-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyridin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2- (l-((l-(((lS,4r)-4-(4-((5)-2,6-dioxopiperidin-3-yl)phenoxy)cyclohexyl)methyl)piperidin-4- -828-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(2-(2,6-di oxopiperi din-3-yl)-1,3-di oxoisoindolin-5- yl)piperidine-4-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-A-(3-(2-(l-(l-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4- yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin- 4-yl)ethyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(4-(2-(2,6-di oxopiperi din-3-yl)-1,3-di oxoisoindolin-5- yl)piperazin-l-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(4-(4-((l-(4-(2,6-di oxopiperi din-3-yl)phenyl)piperi din-4-yl)methyl)piperazin-l-yl)phenyl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (S)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-(l-(5-(2,6-dioxopiperidin-3-yl)pyri din-2- yl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-(2-(l-(5- (2,6-di oxopiperi din-3-yl)pyri din-2-yl)piperidin-4-yl)acetyl)piperazin-l-yl)phenyl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(T- (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-[l,4'-bipiperidin]-4-yl)acetyl)-3- azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperidine-4-carbonyl)-4-methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N- (3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(2-(2,6-di oxopiperi din-3-yl)-l,3-di oxoisoindolin-5- yl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- -829-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT 1-sulfonamide, A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((l-((lA,4r)-4-(4-((A)-2,6-di oxopiperi din-3-yl)phenoxy)cy cl ohexane-l-carbonyl)piperidin-4-yl)methyl)piperi din-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(6-(2-(2,6-di oxopiperi din-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, A-(3-(2-(l-(l- (l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(((A)-l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)thi azol-4- yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(4-(4-((l- (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)thiazol- 4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, rac-(35)-3 - { 6- [4-(4- { 4- [5 -(2-aminopyrimidin- 4-yl)-4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-l,3-thiazol-2-yl]piperidine-l- carbonyl}piperidine-l-carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2,6-dione, rac-(35)-3- {6-[4-(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-5-{2-[(propan-2- yl)amino]pyrimidin-4-yl } -1,3 -thiazol-2-yl]piperidine- 1 -carbonyl }piperidine-1 - carbonyl)piperidin-l-yl]pyridin-3-yl}piperidine-2,6-dione, (5)-7V-(3-(5-(2-aminopyrimidin-4- yl)-2-(l-(l-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-(l-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-((l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-4- methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-7V-(3-(5-(2- aminopyrimidin-4-yl)-2-(3-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidine-4-carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide, (A)-A-(3-(2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- 2,7-di azaspiro [3.5 ]nonan-7 -yl)acetyl)piperidin-4-yl)-5 -(2-(methylamino)pyrimidin-4- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(3-(6-(2-(2,6-di oxopiperi din-3-yl)-3-oxoisoindolin-5-yl)hexanoyl)-3-azaspiro[5. 5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3-(5- (2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- -830-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (R)-N-(3- (5-(2-aminopyrimidin-4-yl)-2-(l-(l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin- 4-yl)acetyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (5)-A-(3-(2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidin-4-yl)-5-(2-(isopropylamino)pyrimidin-4-yl)thiazol- 4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(5-(2-(cyclopropylamino)pyrimidin-4- yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (5)-A-(3-(2-(l- (l-(l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbonyl)-4-methylpiperidine-4- carbonyl)piperidin-4-yl)-5-(pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-((A)-l-(4-((5)-2,6-dioxopiperidin-3- yl)phenyl)pyrrolidin-3-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(2-(2-(2-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-2- azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(l-((l-(2-(l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(l-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-l/7-benzo[d]imidazol-4-yl)piperidine-4- carbonyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(2-( l-(l-((l-(4-(2,6-di oxopiperi din-3-yl)phenyl)piperidin-4-yl)methyl)piperidine-4- carbonyl)piperidin-4-yl)-5-(2-(methylamino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-3-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2- aminopyrimidin-4-yl)-2-(2-(l-(l-(2-(2,6-di oxopiperi din-3-yl)-1,3-di oxoisoindolin-5- yl)piperidin-4-yl)azetidine-3-carbonyl)-2-azaspiro[3.5]nonan-7-yl)thiazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, (5)-A-(3 -(5-(2-aminopyrimidin-4-yl)-2-(l -(1 -((1 -(1 -(2,6-di oxopiperi din-3-yl)-3-methyl-2-oxo-2, 3-dihydro-l/7-benzo[<7]imidazol-4-yl)piperi din- - 831 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT 4-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l- sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetyl)-3-azaspiro[5.5]undecan-9- yl)thiazol-4-yl)-2-fluorophenyl)propane-l-sulfonamide, (A)-A-(3-(5-(2-aminopyrimidin-4- yl)-2-(2-(l-(2-(2-(2-(2,6-di oxopiperi din-3-yl)-l,3-dioxoisoindolin-5-yl)-2, 7- diazaspiro[3.5]nonan-7-yl)acetyl)piperidin-4-yl)propan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide, and (A)-4-((4-(5-(2-aminopyrimidin-4-yl)-4-(2-fluoro- 3-(propyl sulfonami do)phenyl )thi azol-2-yl )pi peri di n-l-yl )methyl )-N-(2,6-di oxopiperi din-3- yl)benzamide.

73. The compound of claim 1, wherein X1 is carbon; X2 is nitrogen, X3 is nitrogen; X4 is carbon; and X5 is hydrogen.74. The compound of claim 73, wherein R1is alkyl, dialkylamino, cycloalkyl, or heterocycloalkyl each unsubstituted or substituted with one or more halogen; Rlais halogen; Rlbis hydrogen, haloalkyl or halogen; R2is [Ar1-Z1]n-Z2-Cy1-Z3-L-UBM; Ar1is arylene or heteroarylene, each unsubstituted or substituted with one or more halogen; Z1is a bond; nis one; Z2is absent; Cy1is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen; Z3is absent or Cmo alkylene;Lisa linker according to ^1-L2^3^4-or -L4-L3-L2-L1-,wherein-L1- is -Q1- or -Q2-;each -L2-, -L3-, and -L4- is independently, absent, -C1-8 alkylene-, or -Q1-;each -Q1- is a three- to seven-membered heterocycloalkylene comprising at least one nitrogen and is unsubstituted or substituted with one or more methyl or halogen; - 832 - 11005735665AMERICAS

74. Attorney Docket No. : 121843.00271NU-3200 PCT each -Q2- is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; and UBMis a ubiquitin ligase binding moiety; ora stereoisomer and/or pharmaceutical salt thereof.

75. The compound of claim 73 or 74, wherein R1 is selected from the group consisting of propyl, ethylmethylamino, sec-butyl

76. The compound of any one of claims 73-75, wherein Rlais chloro or fluoro; and Rlbis hydrogen, chloro, fluoro, or haloalkyl.

77. The compound of any one of claims 73-76, wherein Ar1is arylene or heteroarylene unsubstituted or substituted with one or two halogen.

78. The compound of any one of claims 73-77, wherein UBMbinds an E3 ubiquitin ligase.

79. The compound of claim 78, wherein UBMbinds SCFB-TRCP, VHL, MDM2, IAP, orCRBN.

80. The compound of claim 79, wherein UBMbinds CRBN.

81. The compound of claim 80, wherein UBMbinds CRBN and has the following chemical formula ז wherein X6absent or NR3; X7absent or -C(O)-; and X8is arylene or heteroarylene. - 833 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT

82. The compound of claim 81, wherein UBMbinds CRBN and is selected from the group X9is absent or halogen; and mis one, two, three, or four.

83. The compound of any one of claims 1 or 73-82, wherein the compound is selected from the group consisting of (A)-A-(5-chloro-3-(l-(4-(4-((l-(5-(2,4-dioxotetrahydropyrimidin- l(277)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; (A)-A-(5-chloro-3-(l-(4-(4- ((l-(5-((A)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3 -(pyridin-4-yl)-1 TZ-pyrazol -4-yl )-2-fl uorophenyl )-3 -fluoropyrrolidine- 1 - sulfonamide; rac-(A)-A-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l-sulfonamide; rac-(A)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6- - 834-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l-yl)-2-fluorophenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l-sulfonamide; rac-(A)-7V-(3-(l- (4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-l- yl)phenyl)-3-(pyridin-4-yl)-l/Z-pyrazol-4-yl)-2,5-difluorophenyl)pyrrolidine-l-sulfonamide; A-(5-chloro-3-(l-(4-((A)-4-((l-(5-((A5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)-3-methylpiperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/Z-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine-l-sulfonamide; (A)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)- 2-fluorophenyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2,5-difluorophenyl)cyclopentanesulfonamide;rac-(A)-7V-(3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2,5- difluorophenyl)cyclopentanesulfonamide;rac-(A)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)cyclopentanesulfonamide;(A)-A-(5-chloro-3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4- yl)methyl)piperazin-l-yl)-3-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)cyclopentanesulfonamide;(A)-A-(5-chloro-3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4- yl)methyl)-l,4-diazepan-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)pyrrolidine- 1 -sulfonamide;(A)-A-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-l,4- diazepan-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2,5- difluorophenyl)pyrrolidine-l-sulfonamide; A-[5-chloro-3-(l-{4-[(3A)-4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; A-[5-chloro-3-(l-{4- [(3A)-4-[(l-{5-[(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]propane-l- sulfonamide; 7V-[5-chloro-3-(l-{4-[(3A)-4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l//- pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[(35)-4-[(l-{4- [(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; A-[5- - 835 - 11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT chloro-3-(l-{4-[(35)-4-[(l-{5-[(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/Z-pyrazol-4-yl)-2- fluorophenyl]propane-l-sulfonamide; TV-[5-chloro-3-(l-{4-[(35)-4-({l-[4-(2,4-dioxo-l,3- diazinan-1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]phenyl} -3 -(pyri din-4- yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; TV-{5-chloro-3-[l-(4-{4-[(l-{4- [(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)- 3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; N-{5-chloro-3- [l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l- yl }phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-1-sulfonamide; TV- [5-chl oro-3-(l-{4-[4-({l-[4-(2,4-di oxo-1,3-diazinan-l-yl)phenyl]piperi din-4- yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l-sulfonamide; rac-TV-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]phenyl}-4-fluoropiperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine- 1-sulfonamide; TV-{ 5-chl oro-3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin- l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; TV-{5-chloro-3-[l-(5-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2- fluorophenyl }pyrrolidine-1-sulfonamide; TV-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-1 -yl)phenyl]piperidin-4-yl }methylpiperazin- 1 -yl]pyri din-2-yl} -3 -(pyridin-4-yl)- l/f-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; rac-TV-{5-chloro-3-[l-(5-{4-[(l- {5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin- 2-yl)-3-(pyridin-4-yl)- l/7-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine-1 -sulfonamide; TV-(3-(l- (4-((A)-4-((l-(5-((A5)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)-3- methylpiperazin- 1 -yl)-2-fluorophenyl)-3 -(pyridin-4-yl)-1 H-py razol-4-yl)-2, 5 - difluorophenyl)pyrrolidine- 1 -sulfonamide; TV- { 5 -chi oro-3 - [ 1 -(5 - { 4- [(1 - { 5 -[(3 A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; (3A)-TV-{5- chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1-sulfonamide; (3A)-TV-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan-1 -yl)phenyl]piperidin-4-yl }methylpiperazin- 1 -yl]phenyl} -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine- 1 -sulfonamide; (3A)-TV-{ 5-chioro-3 -[ 1 -(4- -836-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT {4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl }phenyl)-3 -(pyridin-4-yl)- l/Z-pyrazol-4-yl]-2-fluorophenyl } -3 -fluoropyrrolidine- 1 - sulfonamide; (3A)-7V-{5-chloro-3-[l-(5-{4-[(l-{4-[(3A)-2,6-dioxopiperi din-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (3A)-A-[5-chloro-3-(l-{5-[4-({l-[4- (2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]pyridin-2-yl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (3R)-N- {5-chloro-3-[l-(5-{4-[(l-{5-[(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1-sulfonamide; (3A)-A-{5-chloro-3-[l-(5-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (3R)-N- {5-chloro-3-[l-(5-{4-[(7-{4-[(3A5)-2,6-dioxopiperidin-3-yl]phenyl}-7-azaspiro[3.5]nonan-2- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}-3- fluoropyrrolidine- 1-sulfonamide; 7V-{3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]- 2,5-difluorophenyl}pyrrolidine-l-sulfonamide; 7V-[3-(l-{4-[4-({l-[4-(2,4-dioxo-l,3-diazinan- l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)- 2,5-difluorophenyl]pyrrolidine-l-sulfonamide; A-{3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4- yl)-l/7-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidine-l-sulfonamide; (3A)-7V-{3-[l-(5-{4-[(l- {4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)- 3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2,5-difluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (3A)-A-[3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4- yl}methyl)piperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2,5- difluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (3A)-A-{3-[l-(5-{4-[(l-{5-[(3R5)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2-yl)-3- (pyridin-4-yl)-l/7-pyrazol-4-yl]-2,5-difluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; (3A)-A-{3-[l-(5-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}pyridin-2-yl)-3-(pyridin-4-yl)-l//-pyrazol-4-yl]-2,5- difluorophenyl} -3-fluoropyrrolidine- 1-sulfonamide; (3A)-3-(4-{4-[(4-{4-[4-(5-chloro-3- {[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-l//-pyrazol-l- yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)piperidine-2,6-dione; l-(4-{4-[(4-{4- - 837-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT [4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-177- pyrazol-l-yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)-l,3-diazinane-2,4-dione; rac-(3A)-3-(6-{4-[(4-{4-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)-I //-pyrazol -1 -yl]phenyl }piperazin-1 -yl)methyl]piperidin- 1 -yl }pyri din-3 - yl)piperidine-2,6-dione; (3A)-3-(6-{4-[(4-{4-[4-(5-chl oro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-l//-pyrazol-l- yl]phenyl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2,6-dione; (3A)-3-(4- {4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)- l/T-pyrazol- 1 -yl]pyri din-3 -yl }piperazin-1 -yl)methyl]piperidin- 1 -yl }phenyl)piperidine-2,6- dione; l-(4-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3- (pyridin-4-yl)-l//-pyrazol-l-yl]pyridin-3-yl}piperazin-l-yl)methyl]piperidin-l-yl}phenyl)- l,3-diazinane-2,4-dione; rac-(3A)-3-(6-{4-[(4-{6-[4-(5-chl oro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-l-yl]pyridin- 3-yl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2,6-dione; l-(6-{4-[(4-{6- [4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-l//- pyrazol-l-yl]pyridin-3-yl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)-l,3-diazinane- 2,4-dione; (3A)-3-(6-{4-[(4-{6-[4-(5-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3 -(pyridin-4-yl)-1 //-pyrazol -1 -yl]pyri din-3 -yl }piperazin-1 - yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine-2,6-dione; (3A)-7V-[5-chloro-3-(l-{4-[(3A)- 4-({ 1 -[4-(2,4-dioxo- 1,3 -diazinan-1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 - yl]phenyl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine- 1- sulfonamide; 7V-[5-chloro-3-(l-{4-[(3A)-4-[(l-{4-[(3A)-2,6-di oxopiperi din-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l//- pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; (3A)-A-[5-chloro-3-(l-{4-[(3A)-4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]phenyl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine- 1- sulfonamide; (3A)-7V-[5-chloro-3-(l-{4-[(3A)-4-[(l-{5-[(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl} piperi din-4-yl)methyl]-3 -methylpiperazin- 1 -yl]phenyl} -3 -(pyridin-4-yl)- 1H- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; A-[5-chloro-3-(l-{4-[(3A)- 4-({ 1 -[4-(2,4-dioxo- 1,3 -diazinan-1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 - yl]phenyl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; (3A)-A-[5-chloro-3-(l-{5-[(3A)-4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]-3 -methylpiperazin- 1 -yl]pyri din-2-yl} -3 -(pyridin-4-yl)- l/7-pyrazol-4-yl)-2- -838-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (3A)-7V-[5-chloro-3-(l-{5-[(3A)-4-[(l-{5- [(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3-methylpiperazin-l- yl]pyridin-2-yl} -3 -(pyridin-4-yl)- l/Z-pyrazol-4-yl)-2-fluorophenyl]-3 -fluoropyrrolidine- 1 - sulfonamide; (3A)-A-[5-chloro-3 -(1 - { 5-[(3A)-4-({ 1 -[4-(2,4-dioxo- 1,3 -diazinan-1 -yl)phenyl]piperidin-4-yl}methyl)-3-methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7- pyrazol-4-yl)-2-fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; A-[5-chloro-3-(l-{5-[(3A)- 4-[(l-{5-[(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]pyridin-2-yl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine- 1 -sulfonamide; N-[5-chl oro-3 -(1 -{5-[(3A)-4-({ 1 -[4-(2,4-dioxo- 1,3- diazinan-1 -yl)phenyl]piperidin-4-yl }methyl)-3 -methylpiperazin- 1 -yl]pyridin-2-yl} -3 - (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; N-[5-chloro-3-(1- {5-[(3A)-4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]-3- methylpiperazin-l-yl]pyri din-2-yl}-3-(pyridin-4-yl)-17/-pyrazol-4-yl)-2- fluorophenyl]pyrrolidine-l-sulfonamide; A-[5-chloro-3-(l-{5-[(3A)-4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]pyridin-2-yl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; (RS)-N-(5-chloro- 3-(l-(4-(4-((l-(5-((A)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin- -yl)phenyl)-3 -(pyridin-4-yl)-17/-py razol -4-yl )-2-fl uorophenyl )butane-2-sulfonami de; rac-(2A)-A-[5-chl oro-3 -(1 - {4-[4-({ 1 -[4-(2,4-dioxo- 1,3 -diazinan-1 -yl)phenyl]piperi din-4- yl}methyl)piperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]butane- 2-sulfonamide; rac-(A)-A-(5-chloro-3-(l-(4-(4-((l-(5-((5)-2,6-dioxopiperidin-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2- fluorophenyl)butane-2-sulfonamide; (2A5)-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)- l/7-pyrazol-4-yl]-2-fluorophenyl}butane-2-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{5- [(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}-3-fluoroazetidine-l-sulfonamide; rac-A-{5- chloro-3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperi din-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}-3- fluoroazetidine- 1-sulfonamide; A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl } -3 -fluoroazetidine- 1 -sulfonamide; (3 R)-N- { 5 -chi oro-3 -[ 1 -(4- { 4- [(1 - { 5 - [(3 A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)- -839-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT 3-(pyridin-4-yl)-17/-pyrazol-4-yl]-2-fluorophenyl }-3-fluoropyrrolidine-l-sulfonamide; (3 A)- A-{5-chloro-3-[l-(4-{4-[(l-{5-[(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl }piperidin-4- yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2-fluorophenyl} -3-fluoropyrrolidine- 1-sulfonamide; (3A)-A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)- 2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3- (pyridin-4-yl)-l^-pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; rac-A- {5-chloro-3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2-fluorophenyl} -3-fluoroazetidine- 1-sulfonamide; A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2-fluorophenyl}-3-fluoroazetidine-l-sulfonamide; A-[5- chi oro-3-(l-{4-[4-({l-[4-(2,4-di 0x0-1,3-diazinan-l-yl)phenyl]piperi din-4-yl }methyl)piperazin- 1 -yl]-2-fluorophenyl } -3 -(pyridin-4-yl)-1 A-pyrazol -4-yl )-2- fluorophenyl]-3-fluoroazetidine- 1-sulfonamide; A-{3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2,5-difluorophenyl}pyrrolidine-l-sulfonamide; rac-A-{3-[l- (4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl} -2-fluorophenyl)-3 -(pyridin-4-yl)- 1 A-pyrazol-4-yl]-2, 5-difluorophenyl }pyrrolidine- 1 - sulfonamide; A-{3-[l-(5-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2,5- difluorophenyl } pyrrolidine- 1 -sulfonamide; rac-A- { 3 - [ 1 -(5 - { 4- [(1 - { 5 - [(3 A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3- (pyridin-4-yl)-l A-pyrazol-4-yl]-2,5-difluorophenyl Jpyrrolidine-1-sulfonamide; A-{5-chloro- 3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine-1-sulfonamide; rac-A-{5-chloro-3-[l-(4-{4-[(l-{5-[(3A)-2,6- di oxopiperi din-3 -yl]pyridin-2-yl }piperi din-4-yl)methyl]- 1,4-diazepan-1 -yl} -2-fluorophenyl)- 3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; A-{5-chloro-3- [l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]-l,4-diazepan-l- yl} -2-fluorophenyl)-3 -(pyridin-4-yl)- lA-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine- 1 - sulfonamide; rac-A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]-2-fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-lA-pyrazol-4- yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; rac-A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- -840-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; A-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl]pyrrolidine-l-sulfonamide; rac-A-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(3A)- 2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-l-sulfonamide; N-{5-chloro-3 -[1- (6-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l- yljpyri din-3-yl)-3-(pyri din-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine-1- sulfonamide; rac-A-{5-chloro-3-[l-(6-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-3-yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2- fluorophenyl }pyrrolidine-1-sulfonamide; A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3- (pyridin-4-yl)-177-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; rac-A-{5-chloro- 3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl]piperazin-l-yl}-2,5-difluorophenyl)-3-(pyridin-4-yl)-lA-pyrazol-4-yl]-2- fluorophenyl }pyrrolidine-1-sulfonamide; A-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3- diazinan-1 -yl)pyri din-2 -yl]piperi din-4-yl }methyl)piperazin- 1 -yl]phenyl} -3 -(pyridin-4-yl)- lA-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; A-[5-(difluoromethyl)-3-(l-{4- [4-({l-[4-(2,4-dioxo-l,3-diazinan-l-yl)phenyl]piperidin-4-yl}methyl)piperazin-l-yl]-2- fluorophenyl }-3-(pyridin-4-yl)- I//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide; rac-A-[5-(difluoromethyl)-3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2- yl}piperidin-4-yl)methyl]piperazin-l-yl}-2-fluorophenyl)-3-(pyridin-4-yl)-177-pyrazol-4-yl]- 2-fluorophenyl]pyrrolidine-l-sulfonamide; A-[5-chloro-3-(l-{5-[4-({l-[4-(2,4-dioxo-l,3-diazinan-1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]pyrimidin-2-yl } -3 -(pyridin-4-yl)- lA-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; rac-A-{5-chloro-3-[l-(5-{4-[(l- {5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l- yl}pyrimidin-2-yl)-3-(pyridin-4-yl)- I//-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine-1- sulfonamide; A-{5-chloro-3-[l-(5-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin- 4-yl)methyl]piperazin-l-yl}pyrimidin-2-yl)-3-(pyridin-4-yl)-17/-pyrazol-4-yl]-2- fluorophenyl }pyrrolidine-1-sulfonamide; A-[5-chloro-3-(l-{4-[4-({l-[4-(2,4-dioxo-1, 3-diazinan-1 -yl)phenyl]piperidin-4-yl }methyl)piperazin- 1 -yl]-3 -fluorophenyl } -3 -(pyri din-4- yl)-17/-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; A-[5-(difluoromethyl)-3-[l- - 841 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT (4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-2- fluorophenyl)-3-(pyridin-4-yl)-l/Z-pyrazol-4-yl]-2-fluorophenyl]pyrrolidine-l-sulfonamide; rac-A-{5-chloro-3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4- yl)methyl ]piperazin-1 -yl} -3 -fluorophenyl)-3 -(pyridin-4-yl)-1 77-pyrazol -4-yl ]-2- fluorophenyl }pyrrolidine-1-sulfonamide; A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}-3-fluorophenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; (3A)-A-[5- chi oro-3-(l-{4-[4-({l-[4-(2,4-di 0x0-1,3-diazinan-l-yl)phenyl]piperi din-4- yl} methyl)piperazin- 1 -yl] -3 -fluorophenyl } -3 -(py ridin-4-yl)-17/-py razol -4-y 1 )-2- fluorophenyl]-3-fluoropyrrolidine-l-sulfonamide; (3A)-7V-{5-chloro-3-[l-(4-{4-[(l-{5- [(3A5)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}-3- fluorophenyl)-3 -(pyridin-4-yl)- 17/-py razol -4-yl ]-2-fl uorophenyl } -3 -fluoropyrrolidine- 1 - sulfonamide; (3A)-N-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperi din-3-yl]phenyl }piperi din-4-yl)methyl]piperazin- 1 -yl} -3 -fluorophenyl)-3 -(pyridin-4-yl)- 1H- pyrazol-4-yl]-2-fluorophenyl}-3-fluoropyrrolidine-l-sulfonamide; 7V-[5-chloro-3-(l-{4-[4- ({1 -[5-(2,4-dioxo- 1,3 -diazinan-1 -yl)pyri din-2-yl]piperi din-4-yl }methyl)piperazin- 1 - yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]-3-fluoroazetidine-l- sulfonamide; 7V-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-177-pyrazol-4-yl)- 2-fluorophenyl] -3-fluoroazetidine- 1-sulfonamide; A-[5-chloro-3-(l-{4-[4-({l-[5-(2,4-dioxo- l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin-l-yl]-2-fluorophenyl}-3- (pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]pyrrolidine-l-sulfonamide; (3A)-7V-[5-chloro- 3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- l-yl]-2-fluorophenyl}-3-(pyridin-4-yl)-l//-pyrazol-4-yl)-2-fluorophenyl]-3- fluoropyrrolidine- 1-sulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(3A)-2,6-dioxopiperidin-3- yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4- yl]-2-fluorophenyl}cyclopentanesulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{5-[(3A)-2,6- dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4- yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide; 7V-{5-chloro-3-[l-(4-{4-[(l- {4-[(3A)-2,6-dioxopiperidin-3-yl]phenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}cyclopentanesulfonamide; (3A)-3-(6-{4-[(4- {4-[4-(3-{ [ethyl (methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin-4-yl)-l/7-pyrazol- -yl]phenyl }piperazin-1 -yl)methyl]piperidin- 1 -yl }pyri din-3 -yl)piperidine-2,6-dione; rac- -842-11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT (3A)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)-3-(pyridin- 4-yl)- H-pyrazol- 1 -yl]phenyl }piperazin-1 -yl)methyl]piperidin- 1 -yl }pyri din-3 -yl)piperidine- 2,6-dione; (3A)-3-(4-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2,5-difluorophenyl)- -(pyridin-4-yl)-1 //-pyrazol -1 -yl]phenyl }piperazin-1 -yl)methyl]piperidin- 1 - yl}phenyl)piperidine-2,6-dione; A-[3-(l-{4-[(3A)-4-[(l-{4-[(3A)-2,6-dioxopiperidin-3- yl]phenyl}piperidin-4-yl)methyl]-3-methylpiperazin-l-yl]phenyl}-3-(pyridin-4-yl)-l//- pyrazol-4-yl)-2-fluorophenyl]propane-l-sulfonamide; (3A)-3-(6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-l//-pyrazol-l-yl]-3- fluorophenyl }piperazin-1 -yl)methyl]piperidin- 1 -yl }pyridin-3 -yl)piperidine-2,6-dione; (35)-3 - (6-{4-[(4-{4-[4-(3-{[ethyl(methyl)sulfamoyl]amino}-2-fluorophenyl)-3-(pyridin-4-yl)-l/7- pyrazol-l-yl]-2-fluorophenyl}piperazin-l-yl)methyl]piperidin-l-yl}pyridin-3-yl)piperidine- 2,6-dione; rac-(A)-N-(3-(l-(4-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-l-yl)methyl)piperidin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1-sulfonamide; A-(5-chloro-3-(l-(4-((3A,5A)-4-((l-(5-((A5)-2,6-dioxopiperidin-3-yl)pyridin- 2-yl)piperidin-4-yl)methyl)-3,5-dimethylpiperazin-l-yl)-2-fluorophenyl)-3-(pyridin-4-yl)- l/7-pyrazol-4-yl)-2-fluorophenyl)pyrrolidine-l-sulfonamide; A-{5-chloro-3-[l-(5-{4-[(l-{5- [(35)-2,6-dioxopiperidin-3-yl]pyridin-2-yl}piperidin-4-yl)methyl]piperazin-l-yl}pyridin-2- yl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; A-{5- chloro-3-[l-(4-{4-[(l-{4-[(35)-2,6-dioxopiperidin-3-yl]-3-fluorophenyl}piperidin-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine-1-sulfonamide; rac-A-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]-2,3-difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; rac-N-5 ؛-chloro- 3-[l-(4-{4-[(l-{4-[(3A)-2,6-dioxopiperidin-3-yl]-2,5-difluorophenyl}piperi din-4- yl)methyl]piperazin-l-yl}phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl]-2-fluorophenyl }pyrrolidine-1-sulfonamide; rac-7V-{5-chloro-3-[l-(4-{4-[(l-{4-[(3A)-2,6- dioxopiperidin-3-yl]-3,5-difluorophenyl}piperidin-4-yl)methyl]piperazin-l-yl}phenyl)-3- (pyridin-4-yl)-l//-pyrazol-4-yl]-2-fluorophenyl}pyrrolidine-l-sulfonamide; and 7V-[5-chloro- 3-(l-{4-[4-({l-[5-(2,4-dioxo-l,3-diazinan-l-yl)pyridin-2-yl]piperidin-4-yl}methyl)piperazin- l-yl]phenyl}-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl]cyclopentanesulfonamide.

84. A pharmaceutical composition comprising the compound of any one of the previous claims and a pharmaceutically acceptable carrier, excipient, and/or diluent. - 843 -11005735665AMERICAS Attorney Docket No. : 121843.00271NU-3200 PCT

85. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or composition of any one of the previous claims.

86. The method of claim 85, wherein the disease or disorder is cancer.

87. The compound or composition of any one of the previous claims for use in therapy.

88. The compound or composition of any one of the previous claims for use in the treatment of cancer. - 844-11005735665AMERICAS