WO2026064520A1 - Covalent-induced drug conjugates targeting kras and comprising a tubulin inhibitor payload - Google Patents

Covalent-induced drug conjugates targeting kras and comprising a tubulin inhibitor payload

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WO2026064520A1
WO2026064520A1 PCT/US2025/046984 US2025046984W WO2026064520A1 WO 2026064520 A1 WO2026064520 A1 WO 2026064520A1 US 2025046984 W US2025046984 W US 2025046984W WO 2026064520 A1 WO2026064520 A1 WO 2026064520A1
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compound
optionally substituted
aliphatic
sulfur
nitrogen
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Alfredo C. Castro
Nicholas CALANDRA
Erik Meredith
Yue Pan
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Tesseract Medicines Us LLC
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Tesseract Medicines Us LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The present disclosure provides covalent-induced drug conjugates comprising a KRASG12C binding moiety and a tubulin inhibitor payload moiety, as well as compositions and methods of use thereof.

Description

COVALENT-INDUCED DRUG CONJUGATES TARGETING KRAS AND
COMPRISING A TUBULIN INHIBITOR PAYLOAD
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63/696,683, filed September 19, 2024; the contents of which is herein incorporated by reference.
BACKGROUND
[0002] In 2024, over 2 million new cancer diagnoses are expected in the US, and an estimated 1680 people are predicted to die from cancer each day in the US. Cancer Facts & Figures 2024, Atlanta: American Cancer Society; 2024. Current treatments for cancer largely rely on chemotherapy using cytotoxic agents. Patients taking these cytotoxic agents, however, often experience serious side effects related to off-target effects of the drugs on non-cancerous cells. Therapies that specifically target cancer cells while minimally affecting non-cancer cells are desirable.
SUMMARY
[0003] The present disclosure provides bifunctional compounds comprising a KRASG12C binding moiety and a tubulin inhibitor payload moiety. As described further herein, provided compounds act as covalent-induced drug conjugates, whereby a cytotoxic payload (e g., a tubulin inhibitor payload moiety) is specifically delivered to a cell expressing an oncogenic protein (e.g., KRASG12C). Upon binding to KRASG12C, the tubulin inhibitor payload moiety is released and thereby is allowed to engage with targets within the cell.
[0004] In some embodiments, the present disclosure provides compounds of Formula I: i or a pharmaceutically acceptable salt thereof, wherein L1, X, Rx, Ry, Rz, KBM, and TPM are as defined herein. BRIEF DESCRIPTION OF THE DRAWING
[0005] FIG. 1A is a schematic showing a proposed mechanism of payload release from a covalent-induced drug conjugate.
[0006] FIG. IB is a schematic showing a proposed mechanism of payload release from a covalent-induced drug conjugate comprising a self-immolative or degradable linker.
DETAILED DESCRIPTION
Compounds and Definitions
[0007] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, 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 by reference.
[0008] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, atropisomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.
[0009] Unless otherwise indicated, structures depicted herein 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 including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. [0010] In some embodiments, provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19(1977).
[0011] The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e g., Cue). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e g., C1.5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.
[0012] The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, Ci-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. The term “alkylene,” as used herein, alone or in combination, refers to a bivalent, saturated, optionally substituted straight or branched hydrocarbon, such as methylene (-CH2-).
[0013] The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. [0014] The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2- 10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
[0015] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
[0016] The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C5-C10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carboncarbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
[0017] The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 7t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 7- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
[0018] The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
[0019] As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 5- to 10-membered bicyclic heterocyclic moiety or a 10- to 16-membered polycyclic (i.e., comprising three or more rings) moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic or polycyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 6- to 11 -membered spirocyclic bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic or polycyclic heterocyclic ring can also be a bridged ring system (e g., 6- to 11-membered bridged bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
[0020] As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moi eties, as herein defined.
[0021] As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
[0022] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
[0023] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CH2)o 4R0; -(CH2)o-4OR°; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O 4CH(0RO)2; -(CH2)O^ISRC; -(CH2)o 4Ph, which may be substituted with R°; -(CH2)0 40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o 40(CH2)o 1 -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O 4N(RO)2; -(CH2)O 4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O
4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O 4N(RO)C(O)OR°;
N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)o 4C(O)R°; - C(S)R°; -(CH2)O 4C(O)ORO; -(CH2)O 4C(O)SR°; -(CH2)O 4C(O)OSiR°3; -(CH2)o 4OC(O)R°; - OC(0)(CH2)o 4SR0; -(CH2)O 4SC(O)RO; -(CH2)O 4C(O)NRO 2; -C(S)NRO 2; -C(S)SR°; - SC(S)SR°, -(CH2)0 4OC(O)NRO 2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)o 4SSR0; -(CH2)0 ^S(O)2R°; -(CH2)o^S(0)2OR0; -(CH2)o 4OS(O)2RO; - S(O)2NR°2; -(CH2)O 4S(O)R°; -N(R°)S(O)2NRO 2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO 2; - (CH2)O 4P(O)2R°; (CH2)O 4P(O)RO 2; (CH2)O 4P(O)(ORO)2; (CH2)O 4OP(O)RO 2; (CH2)O 4OP(O)(OR°)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or - (Ci^i straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0024] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o 2R*, -(haloR*), -(CH2)0 2OH, -(CH2)O 2OR*, -(CH2)O 2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)O 2C(O)OH, -(CH2)O 2C(O)OR*, -(CH2)O 2SR’, -(CH2)O -2SH, -(CH2)O 2NH2, - (CH2)0 2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR*. -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C i 4 aliphatic, - CH2Ph, -0(CH2)o-iPh, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
[0025] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R’2))2 3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0026] Suitable substituents on the aliphatic group of R include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0027] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R;, -NR‘: 2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf,
C(O)CH2C(O)Rt, -S(O)2RT, -S(O)2NRT 2, -C(S)NRT 2, -C(NH)NRt 2, or -N(RT)S(O)2RT; wherein each R is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-7-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R' , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0028] Suitable substituents on the aliphatic group of R: are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^t aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3-7- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0029] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
[0030] In some embodiments, the term appears adjacent to a point of atropisomerism. In such cases, it is understood to denote either an “Ra” or “Sa” atropisomer, but the particular isomer was not determined.
[0031] In some embodiments, a bond is denoted by In such cases, it is understood to denote either an “R” or “S” stereoisomer, but the particular isomer was not determined.
Covalent-Induced Drug Conjugates
[0032] In some embodiments, the present disclosure provides covalent-induced drug conjugates (CIDCs), as described further herein. Provided CIDCs are bifunctional compounds that deliver a cytotoxic payload specifically to cancer cells expressing an oncogenic protein. Such CIDCs comprise (i) a protein binding moiety, typically targeting an oncogenic protein capable of covalently interacting with the protein binding moiety, such as through a reactive cysteine residue; (ii) a payload moiety; and (iii) a linking moiety connecting the protein binding moiety to the payload moiety. Exemplary schemes are shown in FIG. lAand FIG. IB. First, the protein binding moiety (“R”) binds the oncogenic protein (“Target”), which bears a reactive cysteine residue. Then, the reactive cysteine residue covalently binds an a,|3-unsaturated carbonyl moiety (or other suitable Michael acceptor) of the CIDC, triggering cleavage of the linking moiety and release of the activated payload moiety (“Payload”).
[0033] CIDCs have the potential to reduce off-target side effects, because the cytotoxic payload is inactivated when it is part of the CIDC and is not released until the CIDC covalently binds an oncogenic target, meaning the payload is activated only upon delivery to a cancer cell expressing a particular oncogenic protein. Like antibody-drug conjugates (ADCs), the CIDC delivery mechanism allows for specific targeting of cancer cells; however, unlike ADCs, which target extracellular surface markers, CIDCs can also exploit intracellular proteins for precise payload delivery. Additionally, CIDCs are small molecules, in contrast to large-molecule ADCs, which makes CIDCs potentially amenable for oral administration.
[0034] The present disclosure, in particular, relates to CIDCs comprising a KRASG12C protein binding moiety and a tubulin inhibitor payload moiety.
Provided Compounds
[0035] In some embodiments, the present disclosure provides a compound of Formula I:
I or a pharmaceutically acceptable salt thereof, wherein:
KBM is a KRASG12C binding moiety;
Rx is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-6 aliphatic, C3.7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ry is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rz is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic;
X is a covalent bond, -O-, -N(RW)-, or -S-;
Rw is hydrogen or optionally substituted C1-6 aliphatic;
L1 is a covalent bond or a linking moiety; and
TPM is a tubulin inhibitor payload moiety.
[0036] In some embodiments, the present disclosure provides a compound of Formula I-a: or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, X, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.
[0037] In some embodiments, the present disclosure provides a compound of Formula I-b:
Lb or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:
La is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0038] In some embodiments, the present disclosure provides a compound of Formula I-c:
I-c or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:
La is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0039] In some embodiments, the present disclosure provides a compound of Formula I-d:
I-d or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:
Lh is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0040] In some embodiments, the present disclosure provides a compound of Formula I-e: or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein:
Lb is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0041] In some embodiments, the present disclosure provides a compound of Formula I-f: or a pharmaceutically acceptable salt thereof, wherein KBM, Rx, Ry, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; and wherein: Lb is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-,
-OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0042] In some embodiments, the present disclosure provides a compound of Formula I-g:
I-g or a pharmaceutically acceptable salt thereof, wherein KBM, L1, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination.
[0043] In some embodiments, the present disclosure provides a compound of Formula I-h:
I-h or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h, Rz is not hydrogen.
[0044] In some embodiments, the present disclosure provides a compound of Formula I-h- 1 :
I-h-1 or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-1, Rz is not hydrogen.
[0045] In some embodiments, the present disclosure provides a compound of Formula I-h-2:
I-h-2 or a pharmaceutically acceptable salt thereof, wherein KBM, L1, Rz, and TPM are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination. In some embodiments of Formula I-h-2, Rz is not hydrogen.
[0046] In some embodiments of any Formulae described herein, Rx is hydrogen, halogen, cyano, or optionally substituted Ci-6 aliphatic. In some embodiments, Rx is hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, Rx is hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Rx is an optionally substituted group selected from C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rx is an optionally substituted group selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rx is hydrogen. In some embodiments, Rx is halogen (e.g., fluoro). In some embodiments, Rx is cyano. In some embodiments, Rx is optionally substituted C1-6 aliphatic. In some embodiments, Rx is C1-6 aliphatic optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Rx is Ci-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Rx is C1-6 alkyl. In some embodiments, Rx is -CH3. In some embodiments, Rx is C1-6 aliphatic. In some embodiments, Rx is optionally substituted C1-6 alkyl. In some embodiments, Rx is C1-6 alkyl. In some embodiments, Rx is optionally substituted C3-7 cycloaliphatic. In some embodiments, Rx is C3-7 cycloaliphatic. In some embodiments, Rx is optionally substituted C3-7 cycloalkyl. In some embodiments, Rx is C3-7 cycloalkyl. In some embodiments, Rx is optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rx is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rx is optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rx is -CH2C(CH3)2N(H)CH3.
[0047] In some embodiments of any Formulae described herein, Ry is hydrogen, halogen, cyano, or optionally substituted C1-6 aliphatic. In some embodiments, Ry is hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, Ry is hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Ry is an optionally substituted group selected from C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ry is an optionally substituted group selected from 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ry is hydrogen. In some embodiments, Ry is halogen (e.g., fluoro). In some embodiments, Ry is cyano. In some embodiments, Ry is optionally substituted C1-6 aliphatic. In some embodiments, Ry is C1-6 aliphatic optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ry is Ci-6 alkyl optionally substituted with one or more halogen, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), or -NH2. In some embodiments, Ry is Ci-6 alkyl. In some embodiments, Ry is -CH3. In some embodiments, Ry is Ci-6 aliphatic. In some embodiments, Ry is optionally substituted Ci-6 alkyl. In some embodiments, Ry is Ci-6 alkyl. In some embodiments, Ry is optionally substituted C3-7 cycloaliphatic. In some embodiments, Ry is C3-7 cycloaliphatic. In some embodiments, Ry is optionally substituted C3-7 cycloalkyl. In some embodiments, Ry is C3-7 cycloalkyl. In some embodiments, Ry is optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ry is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ry is optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ry is -CH3, -CH2CH3, -CF3, -CH2N(CH3)2, - CH2CH2N(H)CH3, or -CH2C(CH3)2N(H)CH3.
[0048] In some embodiments of any Formulae described herein, each Rz is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, each Rz is independently hydrogen or Ci-6 aliphatic. In some embodiments, each Rz is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each Rz is independently hydrogen or C1-6 alkyl. In some embodiments, each Rz is hydrogen. In some embodiments, one Rz is hydrogen and the other Rz is optionally substituted C1-6 alkyl. In some embodiments, one Rz is hydrogen and the other Rz is C1-6 alkyl. In some embodiments, a Rz is hydrogen. In some embodiments, a Rz is halogen (e.g., fluoro). In some embodiments, a Rz is optionally substituted C1-6 aliphatic. In some embodiments, a Rz is C1-6 aliphatic optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), - NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rz is C1-6 aliphatic. In some embodiments, a Rz is optionally substituted C1-6 alkyl. In some embodiments, a Rz is Cue alkyl. In some embodiments, a Rz is C1-6 alkyl optionally substituted with one or more halogen atoms. In some embodiments, a Rz is C1-6 alkyl optionally substituted with one or more fluorine atoms. In some embodiments, a Rz is CF3. In some embodiments, a Rz is C1-6 alkyl optionally substituted with one or more -N(CI-6 alkyl)2, -NH(CI-6 alkyl), -NH2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Rz is C1-6 alkyl.
In some embodiments, a Rz is hydrogen, -CH3,
. In some embodiments, one Rz is hydrogen, and one Rz is optionally substituted
Ci-6 aliphatic.
[0049] In some embodiments of any Formulae described herein, X is -O- or -N(RW)-. In some embodiments, X is -O-. In some embodiments, X is -N(RW)-. In some embodiments, X is -N(H)- . In some embodiments, X is -N(CHs)-. In some embodiments, X is -S-. In some embodiments, X is a covalent bond. It will be appreciated that, in some embodiments, when X is a covalent bond, -i -TPM is a sufficient leaving group to result in release of the tubulin inhibitor payload upon binding of the compound to KRASG12C.
[0050] In some embodiments of any Formulae described herein, Rw is hydrogen. In some embodiments, Rw is optionally substituted Ci-6 aliphatic. In some embodiments, Rw is Ci-6 aliphatic. In some embodiments, Rw is optionally substituted Ci-6 alkyl. In some embodiments, Rw is Ci-6 alkyl (e.g., methyl).
[0051] In some embodiments of any Formulae described herein, L1 is a covalent bond. In some embodiments, L1 is a linking moiety.
[0052] In some embodiments of any Formulae described herein, L1 is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S- , -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-, wherein each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multi cyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0053] In some embodiments of any Formulae described herein, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Cno hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.
[0054] In some embodiments of any Formulae described herein, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2- , and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-io hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)- , -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-.
[0055] In some embodiments of any Formulae described herein, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O- , -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, - N(R)C(0)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, - SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-.
[0056] In some embodiments of any Formulae described herein, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2- , and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci- 6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N- , -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-.
[0057] In some embodiments of any Formulae described herein, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O- , -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, -OC(O)N(R)-, or - Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(0)N(R)-, -N(R)C(O)-, - N(R)C(0)0-, -0C(0)N(R)-, or -Cy-.
[0058] In some embodiments of any Formulae described herein, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-20 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units are optionally and independently replaced by -Cy-. In some embodiments, L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1-2 methylene units are optionally and independently replaced by -Cy-.
O
[0059] In some embodiments of any Formulae described herein, L1 is R , wherein La and R are as defined above for Formula I-b and described in classes and subclasses herein, both singly and in combination; and the L1 moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-b.
[0060] In some embodiments of any Formulae described herein, L1 is , wherein
La is as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; and the L1 moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-c.
[0061] In some embodiments of any Formulae described herein, L1 is , wherein
La is as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM. [0062] In some embodiments of any Formulae described herein, , wherein La and R are as defined above for Formula I-c and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.
[0063]
R v v [0064] In some embodiments of any Formulae described herein, L1 is O , wherein
Lb and R are as defined above for Formula I-d and described in classes and subclasses herein, both singly and in combination; and the L1 moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-d.
O
[0065] In some embodiments of any Formulae described herein, L1 is R wherein Lb and R are as defined above for Formula I-e and described in classes and subclasses herein, both singly and in combination; and the L1 moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-e.
[0066] In some embodiments of any Formulae described herein, L1 is O , wherein Lb and R are as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; and the L1 moiety is attached to the rest of the molecule in the same orientation as shown in Formula I-f.
[0067] In some embodiments of any Formulae described herein, L1 is , wherein
Lb is as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.
[0068] In some embodiments of any Formulae described herein, L1 is R wherein Lb is as defined above for Formula I-f and described in classes and subclasses herein, both singly and in combination; the bond labeled A is attached to X; and the bond labeled B is attached to
TPM.
[0069] In some embodiments of any Formulae described herein, L1 is 0
[0070] In some embodiments of any Formulae described herein, L1 is selected from: a covalent wherein R is as defined herein; each Lc is independently an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled ^4 is attached to X; and the bond labeled B is attached to TPM.
[0071] In some embodiments of any Formulae described herein, L1 is selected from:
wherein R is as defined herein; each Lc is independently an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.
[0072] In some embodiments of any Formulae described herein, L1 is selected from: optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain.
[0073] In some embodiments of any Formulae described herein, L1 is selected from: a covalent
wherein the bond labeled A is attached to X; and the bond labeled B is attached to TPM.
[0074] In some embodiments of any Formulae described herein, L1 is selected from: a covalent and the bond labeled B is attached to TPM.
[0075] In some embodiments of any Formulae described herein, L1 is selected from: a covalent , p y p y substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled A is attached to X; and the bond labeled B is attached to TPM.
[0076] In some embodiments of any Formulae described herein, L1 is selected from: a covalent
X; and the bond labeled B is attached to TPM.
[0077] In some embodiments of any Formulae described herein, La is a covalent bond.
[0078] In some embodiments of any Formulae described herein, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-
[0079] In some embodiments of any Formulae described herein, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, La is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.4 hydrocarbon chain, wherein 1 -2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-
[0080] In some embodiments of any Formulae described herein, Lb is a covalent bond.
[0081] In some embodiments of any Formulae described herein, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-
[0082] In some embodiments of any Formulae described herein, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O- N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O- , -0C(0)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-. In some embodiments, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, - SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-4 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-. In some embodiments, Lb is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.4 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, -N(R)C(O)O-, or -OC(O)N(R)-, and 1 methylene unit is optionally replaced by -Cy-
[0083] In some embodiments of any Formulae described herein, Lc is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain. In some embodiments, Lc is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.3 hydrocarbon chain. In some embodiments, Lc is optionally substituted C1-6 alkylene. In some embodiments, Le is optionally substituted C1-3 alkylene. In some embodiments, Lc is Ci-6 alkylene. In some embodiments, Lc is C1-3 alkylene. In some embodiments, Le is -CH2- . In some embodiments, Lc is -CH2CH2-. In some embodiments, Lc is -CH2CH2CH2-.
[0084] In some embodiments of any Formulae described herein, each R is independently hydrogen or an optionally substituted group selected from Ci-6 alkyl, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic and C3-7 monocyclic carbocyclyl. In some embodiments, each R is independently hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, each R is independently hydrogen or Ci-6 aliphatic optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, - N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, each R is independently hydrogen or optionally substituted C1-6 alkyl. In some embodiments, each R is independently hydrogen or Ci- 6 alkyl optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, each R is independently hydrogen or C1-6 alkyl. In some embodiments, each R is hydrogen. In some embodiments, a R is hydrogen. In some embodiments, a R is optionally substituted C1-6 aliphatic. In some embodiments, a R is C1-6 aliphatic optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, an R is -CH2CH2N(CH3)2. In some embodiments, a R is optionally substituted Ci-6 alkyl. In some embodiments, a R is Ci-6 alkyl optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), -NH2, -N(H)(CI-6 alkyl) or -N(CI-6 alkyl)2. In some embodiments, a R is Ci-6 alkyl (e g., methyl). In some embodiments, an R is isopropyl. In some embodiments, an R is methyl. In some embodiments, a R is optionally substituted phenyl. In some embodiments, a R is optionally substituted C3-7 monocyclic carbocyclyl. In some embodiments, a R is optionally substituted C3-7 cycloalkyl (e.g., cyclopropyl). In some embodiments, a R is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a R is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0085] In some embodiments of any Formulae described herein, each Cy is independently an optionally substituted, mono- or multi cyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, phenylene, a bicyclic C9-10 arylene, a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10- membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a monocyclic C3-7 carbocyclylene, phenylene, a monocyclic 3- to 7- membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring system selected from a bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene, a bicyclic C9-10 arylene, a bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0086] In some embodiments of any Formulae described herein, a Cy is an optionally substituted monocyclic C3-7 carbocyclylene. In some embodiments, a Cy is an optionally substituted bicyclic C4-11 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Cy is bivalent bicyclo[l. l. l]pentane. In some embodiments, a Cy is an optionally substituted phenylene. In some embodiments, a Cy is an optionally substituted bicyclic C9-10 arylene. In some embodiments, a Cy is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e g., a bivalent pyrrolidine). In some embodiments, a Cy is an optionally substituted bicyclic 5- to 11-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a Cy is an optionally substituted monocyclic 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is bivalent tetrazole. In some embodiments, a Cy is an optionally substituted bicyclic 9- to 10-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0087] In some embodiments of any Formulae described herein, -X-L1- forms a self- immolative or degradable linking moiety, such that upon binding of the compound to KRASG12C, the tubulin inhibitor payload is released from the compound. It will be appreciated therefore that, in some embodiments, when both X and L1 are a covalent bond, TPM is a sufficient leaving group to result in release of the tubulin inhibitor payload upon binding of the compound to KRASG12C. KRABP12C Binding Moiety
[0088] As described and defined herein, KBM is a KRASG12C binding moiety, i.e., a moiety capable of binding KRASG12C protein. Typically, a KBM is considered to be capable of binding a KRASG12C protein if it specifically (or preferentially) associates with the KRASG12C protein when contacted with KRASG12C protein in the presence of at least one other protein. In some embodiments, a KBM is considered to be capable of binding KRASG12C protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a KBM is considered capable of binding a KRASG12C protein if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less).
[0089] In some embodiments, the present disclosure provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and TPM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein:
Y is CR2 or N;
R1 is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;
R2 is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;
R3 is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R4 is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; R5 is hydrogen, -OR6, V°^^^Cy1 , -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R6 is optionally substituted Ci-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Cy1 and Cy2 are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L2 is a covalent bond or -N(R’)(CH2)m-;
L3 is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted Ci-6 aliphatic;
Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclyl ene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.
[0090] In some embodiments, the present disclosure provides a compound of Formula 11-a:
Il-a or a pharmaceutically acceptable salt thereof, wherein L1, R2, R3, R4, R\ Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein:
Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.
[0091] In some embodiments, the present disclosure provides a compound of Formula Il-b:
II-b or a pharmaceutically acceptable salt thereof, wherein Cy2, L1, R2, R3, R4, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein: each R7 is independently optionally substituted Ci-6 aliphatic, or two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and/or spirofused with the ring to which the R7 moieties are attached; and n is 0, 1, 2, 3, 4, 5, or 6.
[0092] In some embodiments, the present disclosure provides a compound of Formula II-c:
II-C or a pharmaceutically acceptable salt thereof, wherein L1, R3, R4, R5, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein: Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene.
[0093] In some embodiments, the present disclosure provides a compound of Formula Il-d: n-d or a pharmaceutically acceptable salt thereof, wherein Cy2, L1, R3, R4, Rx, Ry, Rz, X, and TPM are as defined in Formula II and described in classes and subclasses herein, both singly and in combination, and wherein: each R7 is independently optionally substituted Ci-6 aliphatic, or two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and/or spirofused with the ring to which the R7 moieties are attached; and n is 0, 1, 2, 3, 4, 5, or 6.
[0094] In some embodiments of any Formulae described herein, KBM is: wherein L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
[0095] In some embodiments of any Formulae described herein, KBM is: wherein R2, R3, R4, R5, and Ring A are as defined herein for Formula Il-a and described in classes and subclasses herein, both singly and in combination.
[0096] In some embodiments of any Formulae described herein, KBM is: wherein Cy2, n, R2, R3, R4, and R7 are as defined herein for Formula Il-b and described in classes and subclasses herein, both singly and in combination.
[0097] In some embodiments of any Formulae described herein, KBM is: wherein R3, R4, R5, and Ring A are as defined herein for Formula II-c and described in classes and subclasses herein, both singly and in combination.
[0098] In some embodiments of any Formulae described herein, KBM is: wherein Cy2, n, R3, R4, and R7 are as defined herein for Formula Il-d and described in classes and subclasses herein, both singly and in combination.
[0099] In some embodiments of any Formulae described herein, Y is CR2. In some embodiments, Y is N.
[0100] In some embodiments of any Formulae described herein, R1 is hydrogen, halogen, - OR’, optionally substituted Ci-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, R1 is hydrogen. In some embodiments, R1 is halogen (e.g., fluoro or chloro). In some embodiments, R1 is -OR’ (e.g., -O(Ci-6 alkyl) or -O(Ci-6 haloalkyl)). In some embodiments, R1 is optionally substituted Ci-6 aliphatic. In some embodiments, R1 is Cue aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R1 is Ci-6 aliphatic. In some embodiments, R1 is optionally substituted Ci-6 alkyl. In some embodiments, R1 is Ci-6 alkyl optionally substituted with one or more halo (e.g., fluoro) (e.g., -CF3). In some embodiments, R1 is Ci-6 alkyl (e.g., -CH3). In some embodiments, R1 is optionally substituted C3-7 cycloaliphatic. In some embodiments, R1 is C3-7 cycloaliphatic. In some embodiments, R1 is optionally substituted C3-7 cycloalkyl. In some embodiments, R1 is C3-7 cycloalkyl (e.g., cyclopropyl).
[0101] In some embodiments of any Formulae described herein, R2 is hydrogen, halogen, - OR’, optionally substituted Ci-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, R2 is hydrogen. In some embodiments, R2 is halogen (e.g., fluoro or chloro). In some embodiments, R2 is chloro. In some embodiments, R2 is fluoro. In some embodiments, R2 is -OR’ (e.g., -O(Ci-6 alkyl) or-O(Ci-6 haloalkyl)). In some embodiments, R2 is optionally substituted Ci-6 aliphatic. In some embodiments, R2 is Ci-6 aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R2 is Ci-6 aliphatic. In some embodiments, R2 is optionally substituted Ci-6 alkyl. In some embodiments, R2 is Ci-6 alkyl optionally substituted with one or more halo (e.g., fluoro) (e.g., -CF3). In some embodiments, R2 is Ci-6 alkyl (e.g., -CH3). In some embodiments, R2 is optionally substituted C3-7 cycloaliphatic. In some embodiments, R2 is C3-7 cycloaliphatic. In some embodiments, R2 is optionally substituted C3-7 cycloalkyl. In some embodiments, R2 is C3-7 cycloalkyl (e.g., cyclopropyl).
[0102] In some embodiments of any Formulae described herein, R3 is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3). [0103] In some embodiments of any Formulae described herein, R3 is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is a substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted ring selected from naphthyl and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is a substituted ring selected from naphthyl and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0104] In some embodiments of any Formulae described herein, R3 is optionally substituted phenyl. In some embodiments, R3 is phenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is substituted phenyl. In some embodiments, R3 is phenyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3).
[0105] In some embodiments of any Formulae described herein, R3 is optionally substituted naphthyl. In some embodiments, R3 is naphthyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., - CF3). In some embodiments, R3 is substituted naphthyl. In some embodiments, R3 is naphthyl substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3).
[0106] In some embodiments of any Formulae described herein, R3 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is a substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or Ci-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is optionally substituted pyridyl. In some embodiments, R3 is pyridyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3).
[0107] In some embodiments of any Formulae described herein, R3 is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is a substituted 9- to 10- membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 9- to 10-membered bicyclic heteroaryl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is optionally substituted 9-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 9-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is optionally substituted 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), - NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is optionally substituted benzothiophenyl, optionally substituted benzothiazolyl, optionally substituted benzimidazolyl, or optionally substituted indazolyl. In some embodiments, R3 is benzothiophenyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, Ci-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3). In some embodiments, R3 is benzothiazolyl optionally substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2,
Ci-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3).
[0108] In some embodiments of any Formulae described herein, R3 is an optionally substituted ring selected from:
[0109] In some embodiments of any Formulae described herein, R3 is a ring selected from: wherein the ring is substituted with one or more halogen, -CN, -OH, -O(Ci-6 alkyl), -NH2, C1-6 aliphatic (e.g., -CH3 or -C=CH), or C1-6 haloaliphatic (e.g., -CF3).
[0110] In some embodiments of any Formulae described herein, R3 is selected from:
[0U1] In some embodiments of any Formulae described herein, R3 is selected from: some embodiments, some embodiments,
[0112] In some embodiments of any Formulae described herein, R4 is hydrogen, halogen, - OR’, optionally substituted Ci-6 alkyl, or optionally substituted C3-7 cycloalkyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is halogen (e.g., fluoro or chloro). In some embodiments, R4 is chloro. In some embodiments, R4 is fluoro. In some embodiments, R4 is -OR’ (e.g., -O(Ci-6 alkyl) or-O(Ci-6 haloalkyl)). In some embodiments, R4 is optionally substituted Ci-6 aliphatic. In some embodiments, R4 is Ci-6 aliphatic optionally substituted with one or more halo (e.g., fluoro). In some embodiments, R4 is Ci-6 aliphatic. In some embodiments, R4 is optionally substituted Ci-6 alkyl. In some embodiments, R4 is Ci-6 alkyl optionally substituted with one or more halo (e.g., fluoro) (e.g., -CF3). In some embodiments, R4 is C1-6 alkyl (e.g., -CH3). In some embodiments, R4 is optionally substituted C3-7 cycloaliphatic. In some embodiments, R4 is C3-7 cycloaliphatic. In some embodiments, R4 is optionally substituted C3-7 cycloalkyl. In some embodiments, R4 is C3-7 cycloalkyl (e.g., cyclopropyl). y°'^ / [0113] In some embodiments of any Formulae described herein, R5 is -OR6, Cy1
, -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is -OR6, , or -O(Ci-4 alkylene)Cy2. In some embodiments, R5 is y° / hydrogen. In some embodiments, R5 is -OR6. In some embodiments, R5 is Cy1 . In some embodiments, R5 is -O(Ci-4 alkylene)Cy2. In some embodiments, R5 is -OCFFCy2. In some embodiments, R5 is an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R' is an optionally substituted 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 is azetidinyl optionally substituted with -N(CI-6 alkyl^).
[0114] In some embodiments of any Formulae described herein, R? is selected from hydrogen, some embodiments, R5 is In some embodiments, R5 is embodiments, R is In some embodiments, R5 is embodiments, some embodiments, R5 is . In some embodiments, R5 is In some embodiments, some embodiments, R5 is In some embodiments, some embodiments, R5 is In some embodiments, R5 is In some embodiments, R5 is In some embodiments, R5 is
[0115] In some embodiments of any Formulae described herein, R6 is optionally substituted
Ci-6 alkyl or optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is optionally substituted Ci-6 aliphatic. In some embodiments, R6 is Ci-6 aliphatic optionally substituted with -N(CI-6 alkyl)2. In some embodiments, R6 is -CH2CH2N(CH.3)2. In some embodiments, R6 is optionally substituted Ci-6 alkyl. In some embodiments, R6 is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)2. In some embodiments, R6 is optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl. In some embodiments, R6 is monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl. In some embodiments, R6 is optionally substituted piperidinyl. In some embodiments, R6 is piperidinyl optionally substituted with Ci-6 alkyl. In some embodiments, R6 is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)? or 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl.
[0116] In some embodiments of any Formulae described herein, Cy1 is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0117] In some embodiments of any Formulae described herein, Cy1 is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or Ci-6 alkyl. In some embodiments, Cy1 is an optionally substituted monocyclic 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted monocyclic 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted monocyclic 5-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted pyrrolidine). In some embodiments, Cy1 is an optionally substituted monocyclic 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0118] In some embodiments of any Formulae described herein, Cy1 is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 6- to 8-membered bridged heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 5-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 6-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 7-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 9- membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy1 is an optionally substituted bicyclic 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0119] In some embodiments of any Formulae described herein, Cy1 is an optionally substituted ring selected from:
[0120] In some embodiments of any Formulae described herein, Cy1 is selected from: [0121] In some embodiments of any Formulae described herein, Cy2 is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0122] In some embodiments of any Formulae described herein, Cy2 is an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is a monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or Ci-6 alkyl. In some embodiments, Cy2 is an optionally substituted monocyclic 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted monocyclic 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted monocyclic 5-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted pyrrolidinyl). In some embodiments, Cy2 is an optionally substituted monocyclic 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted piperidinyl). In some embodiments, Cy2 is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0123] In some embodiments of any Formulae described herein, Cy2 is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is a bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halo or Ci-6 alkyl. In some embodiments, Cy2 is an optionally substituted bicyclic 6- to 8-membered fused heterocyclyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted bicyclic 5-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted bicyclic 6-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted bicyclic 7-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted bicyclic 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted hexahydro-lH-pyrrolizinyl). In some embodiments, Cy2 is an optionally substituted bicyclic 9-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy2 is an optionally substituted bicyclic 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0124] In some embodiments of any Formulae described herein, Cy2 is an optionally substituted ring selected from:
[0125] In some embodiments of any Formulae described herein, Cy2 is selected from: embodiments, Cy2 is In some embodiments, some embodiments, some embodiments, Cy2 is s , y .
[0126] In some embodiments of any Formulae described herein, Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring A is an optionally substituted monocyclic C3-7 carbocyclylene. In some embodiments, Ring A is an optionally substituted monocyclic C3-7 cycloalkylene. In some embodiments, Ring A is an optionally substituted bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene. In some embodiments, Ring A is an optionally substituted bicyclic C4-10 fused, bridged, or spirocyclic cycloalkylene.
[0127] In some embodiments of any Formulae described herein, Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0128] In some embodiments of any Formulae described herein, Ring A is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted monocyclic 4- to 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted monocyclic 3- to 7-membered heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 3-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 4-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e g., an optionally substituted bivalent azetidine ring). In some embodiments, Ring A is an optionally substituted 5-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent pyrrolidine ring). In some embodiments, Ring A is an optionally substituted 6-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., an optionally substituted bivalent piperazine ring, such as a piperazine substituted with one or more Ci-6 alkyl or -CH2CN). In some embodiments, Ring A is an optionally substituted 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0129] In some embodiments of any Formulae described herein, Ring A is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic 6- to 9-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having at least one nitrogen and optionally one additional heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 6-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 7-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a bivalent 2,6-diazaspiro[3.3]heptane ring). In some embodiments, Ring A is an optionally substituted 8-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a bivalent 3,8- diazabicyclo[3.2.1]octane ring). In some embodiments, Ring A is an optionally substituted 9- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0130] In some embodiments of any Formulae described herein, Ring A is optionally substituted 0A [0131] In some embodiments of any Formulae described herein, Ring wherein R7 and n are as defined herein for Formula Il-b and described in classes and subclasses herein, both singly and in combination.
[0132] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:
[0133] In some embodiments of any Formulae described herein, Ring A is an optionally substituted ring selected from:
[0134] In some embodiments of any Formulae described herein, Ring A is selected from:
[0135] In some embodiments of any Formulae described herein, Ring A is selected from: [0136] In some embodiments of any Formulae described herein, each R7 is independently optionally substituted Ci-6 alkyl, or two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and/or spirofused with the ring to which the R7 moieties are attached. In some embodiments, each R7 is independently optionally substituted Ci-6 aliphatic. In some embodiments, each R7 is independently optionally substituted Ci-6 alkyl. In some embodiments, a R7 is optionally substituted Ci-6 aliphatic. In some embodiments, a R7 is optionally substituted Ci-6 alkyl. In some embodiments, a R7 is Ci-6 alkyl optionally substituted with -CN. In some embodiments, a R7 is -CH3 or -CH2CN. In some embodiments, two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and/or spirofused with the ring to which the R7 moieties are attached. In some embodiments, two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is bridged with the ring to which the R7 moieties are attached.
[0137] In some embodiments of any Formulae described herein, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.
[0138] In some embodiments of any Formulae described herein, L2 is a covalent bond. In some embodiments, L2 is -N(R’)(CH2)m-. In some embodiments, L2 is -N(H)(CH2)m-. In some embodiments, L2 is -N(CH3)(CH2)m-. In some embodiments, L2 is -N(R’)-. In some embodiments, L2 is -N(R’)CH2-.
[0139] In some embodiments of any Formulae described herein, L3 is a covalent bond. In some embodiments, L3 is -(CH2)mN(R’)-. In some embodiments, L3 is -(CH2)mN(H)-. In some embodiments, L3 is -(CH2)mN(CH3)-. In some embodiments, L3 is -N(R’)-. In some embodiments, L3 is -CH2N(R’)-.
[0140] In some embodiments of any Formulae described herein, each R’ is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each R’ is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl. In some embodiments, a R’ is hydrogen. In some embodiments, a R’ is optionally substituted Ci-6 aliphatic. In some embodiments, a R’ is optionally substituted Ci-6 alkyl. In some embodiments, a R’ is Ci-6 alkyl. In some embodiments, a R’ is Ci-6 haloalkyl. [0141] In some embodiments of any Formulae described herein, each m is independently 0 or 1. In some embodiments, each m is independently 1 or 2. In some embodiments, an m is 0. In some embodiments, an m is 1. In some embodiments, an m is 2. embodiments, when L2 is -N(R’)(CH2)m-, then L3 is a covalent bond. In some embodiments, when L3 is -(CH2)mN(R’)-, then L2 is a covalent bond. In some embodiments, when Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene and a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, then L3 is -(CH2)mN(R’)-.
[0143] In some embodiments of any Formulae described herein, a moiety is selected from:
[0144] In some embodiments of any Formulae described herein, a moiety is selected from:
[0145] In some embodiments, KBM is a KRASG12C binding moiety (e.g., a moiety that binds and/or inhibits KRASG12C). The present disclosure encompasses the recognition that i) KRASG12C inhibitor compounds generally comprise an a,P-unsaturated carbonyl moiety (or other suitable Michael acceptor) at a suitable position to interact with a cysteine of KRASG12C, and ii) a KRASG12C binding moiety in the CIDCs described herein can be made by installing a linking moiety bound to a tubulin inhibitor payload moiety, as defined herein (e.g., such suitable position where an a, [3 -unsaturated carbonyl moiety is located on a KRASG12C inhibitor compound. In some embodiments, a KBM is a KRASG12C binding moiety (e.g., without an a,P-unsaturated carbonyl moiety) of a KRASG12C inhibitor selected from sotorasib, adagrasib, divarasib, opnurasib, garsorasib, MRTX-1257, BI-0474, ASP2453, BBO- 8520, AZD4625, LY3537982, ARS-1620, and AZD4747. In some embodiments, KBM is a KRASG12C binding moiety (e.g., without an a,0-unsaturated carbonyl moiety) of a KRASG12C inhibitor described in WO2018/119183; WO2018/217651; WO2019/051291; WO2020/259432;
WO2019/241157; WO2021/104431; W02020/156285; CN112225734; WO2021/027943;
CN112390796; W02021/037018; WO2021/043322; WO2021/063346; CN112574199;
CN112778302; CN112920183; WO2021/118877; CN113004269; WO2021/124222;
W02021/120890; WO2021/121371; WO2021/143693; WO2021/249563; WO2022/135591;
CN113754653; CN114380827; WO2022/111527; WO2022/135546; CN114685460;
CN114874234; W02023/045960; WO2023/066371; WO2023/072297; CN116120315;
CN116199703; CN116217592; WO2023/196959; WO2023/199180; WO2023/226902;
WO2013/155223; WO2014/143659; WO2014/152588; W02014/160200; WO2015/054572;
WO20 16/044772; WO2016/049524; WO2016/164675; WO2016/168540; W02017/058805; WO2017/015562; WO2017/058728; WO2017/058768; WO2017/058792; WO2017/058805;
W02017/058807; W02017/058902; WO2017/058915; WO2017/087528; W02017/100546;
W02017/201161; WO2018/064510; WO2018/068017; WO2018/119183; W02018/140512;
WO2018/140513; W02018/140514; WO2018/140598; WO2018/140599; WO2018/140600;
WO2018/143315; WO2018/206539; WO2018/218070; WO2018/218071; WO2019/099524;
W02019/110751; W02019/141250; W02019/150305; WO2019/155399; WO2019/213516;
WO2019/213526; WO2019/217307; WO2019/217691; WO2019/232419; W02020/050890;
W02020/035031; W02020/047192; W02020/081282; W02020/086739; W02020/106640;
W02020/113071; WO2021/055728; W02021/058018; WO2021/086833; WO2022/083569;
WO2022/087375; WO2022/087371; WO2022/093856; WO2022/109487; WO2022/109485;
WO2022/119748; WO2022/152233; WO2022/221528; WO2022/232318; WO2022/232320;
WO2022/269508; WO2022/269525; WO2023/225252; WO2023/133181; W02023/004102;
WO2023/283213; WO2023/284730; WO2023/287896; WO2023/284537; WO2023/283933;
W02023/001141; W02023/018809; W02023/018699; W02023/034290; W02023/030495;
W02023/030517; W02024/050640; W02023/039240; WO2023/049697; WO2023/046135;
WO2023/056421; WO2023/057985; WO2023/064857; W02023/081840; WO2023/086341;
WO2023/086383; WO2023/097227; WO2023/101928; WO2023/099623; WO2023/099612;
WO2023/099592; WO2023/105491; WO2023/114733; WO2023/125627; WO2023/133183;
W02023/141300; WO2023/150284; WO2023/154766; WO2023/152255; WO2023/159086;
WO2023/159087; WO2023/173014; WO2023/172737; WO2023/183755; WO2023/179703;
WO2023/183585; WO2023/205719; WO2023/212548; WO2023/212549; WO2023/215801;
WO2023/213269; WO2023/219941; WO2023/220421; WO2023/225302; W02023/230190;
WO2023/240263; WO2023/240189; WO2023/240188; WO2023/244604; WO2023/244599;
WO2023/244615; WO2023/244713; WO2023/246777; W02024/008610; W02024/008068;
W02024/009191; W02024/008179; W02024/008834; W02024/015262; W02024/015731;
W02024/030647; W02024/030633; W02024/036270; W02024/032703; W02024/032704;
W02024/032702; W02024/040109; W02024/040131; WO2024/041621; WO2024/041573;
WO2024/047135; WO2024/054926; WO2024/051721; WO2024/054647; WO2024/064353;
WO2024/076674; W02024/076670; WO2024/085661; WO2024/083168; WO2024/083246;
W02024/091409; WO2024/097559; W02024/103010; WO2024/107686; WO2024/112654;
WO2024/120419; WO2024/153116; WO2024/155706; WO2024/153119; WO2024/158778; WO2024/159471 ; WO2024/159470; WO2024/173842; WO2024/178304; WO2024/178313;
WO2024/179546; WO2024/192424; WO2024/197503; WO2024/206747; WO2024/206766;
WO2024/209339; WO2024/213979; WO2024/215754; WO2024/220532; WO2024/220645;
WO2024/218686; WO2024/227091; WO2024/229317; WO2024/229442; WO2024/229444;
WO2024/229447; WO2024/230734; WO2024/233776; WO2024/236452; WO2024/238343;
WO2024/238633; WO2024/235286; WO2024/243025; WO2024/241248; WO2024/246099;
WO2024/259169; WO2024/255795; W02025/006704; W02025/007000; W02025/006962;
W02025/006720; W02025/123007; WO2025/122619; WO2025/123318; WO2025/124415;
WO2025/137519; WO2025/151765; WO2025/151738; WO2025/151594; WO2025/153038;
WO2025/163494; WO2025/165972; WO2025/170938; WO2025/171055; WO2025/168072;
WO2025/179058; WO2025/184572; and WO2025/188668.
[0146] In some embodiments, KBM is a means for binding KRASG12C. In some embodiments, KBM is a means for targeting KRASG12C.
Tubulin Inhibitor Payload Moiety
[0147] As described and defined herein, TPM is a tubulin inhibitor payload moiety, i.e., a moiety capable of binding and/or inhibiting tubulin protein. Typically, a TPM is considered to be capable of binding a tubulin protein if it specifically (or preferentially) associates with the tubulin protein when contacted with tubulin protein in the presence of at least one other protein or DNA. In some embodiments, a TPM is considered to be capable of binding tubulin protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). In some embodiments, a TPM is considered capable of binding a tubulin protein if it binds to it with measurable affinity (e.g., a binding constant of less than about 10 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less). In some embodiments, a TPM is considered to be capable of inhibiting a tubulin protein if it inhibits it with measurable affinity (e.g., an IC50 of less than about 10 pM, less than about 1 pM, less than about 100 nM, less than about 10 nM, or less).
[0148] In some embodiments, the present disclosure provides a compound of Formula III:
Ill or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Ra is independently halogen, -OR33, -N(Raa)2, or optionally substituted Ci-6 aliphatic; each Rb is independently halogen, -OR33, -NQ 3^, or optionally substituted Ci-6 aliphatic;
Rc and Rd are each independently hydrogen, halogen, or optionally substituted Ci-6 aliphatic; each R33 is independently hydrogen or optionally substituted Ci-6 aliphatic; a is 0, 1, 2, 3, 4, or 5; and b is 0, 1, 2, 3, 4, or 5.
[0149] In some embodiments, the present disclosure provides a compound of Formula IILa:
Ill-a or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rx, Ry, Rz, X, a, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.
[0150] In some embodiments, the present disclosure provides a compound of Formula Ill-b : or a pharmaceutically acceptable salt thereof, wherein L1, Ra, Rb, Rc, Rd, Rx, Ry, Rz, X, b, and KBM are as defined in Formula III and described in classes and subclasses herein, both singly and in combination; and a is 0, 1, 2, 3, or 4.
[0151] In some embodiments of any Formulae described herein, TPM is: wherein Ra, Rb, Rc, Rd, a, and b are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.
[0152] In some embodiments of any Formulae described herein, TPM is: wherein Ra and a are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.
[0153] In some embodiments of any Formulae described herein, TPM is: wherein Ra, Rb, Re, Rd, a, and b are as defined in Formula Ill-b and described in classes and subclasses herein, both singly and in combination.
[0154] In some embodiments of any Formulae described herein, each Ra is independently halogen, -ORaa, -N(Raa)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Ra is independently -ORaa or -N(Raa)2. In some embodiments, each Ra is independently -ORaa (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Ra is -OH. In some embodiments, Ra is -OCH3. In some embodiments, a Ra is halogen. In some embodiments, a Ra is -ORaa(e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Ra is -N(Raa)2. In some embodiments, a Ra is -N(H)(Raa). In some embodiments, a Ra is optionally substituted Ci-6 aliphatic. In some embodiments, a Ra is Ci-6 aliphatic. In some embodiments, a Ra is optionally substituted Ci-6 alkyl. In some embodiments, a Ra is Ci-6 alkyl. In some embodiments, Ra is the point of attachment to the rest of the molecule.
[0155] In some embodiments of any Formulae described herein, each Rb is independently halogen, -ORaa, -N(Raa)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rb is independently -ORaa or -N(Raa)2. In some embodiments, each Rb is independently -ORaa (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRb is halogen. In some embodiments, a Rb is -ORaa (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rb is -N R^. In some embodiments, a Rb is -N(H)(Raa). In some embodiments, a Rb is optionally substituted C1-6 aliphatic. In some embodiments, a Rb is C1-6 aliphatic. In some embodiments, a Rb is optionally substituted Ci-6 alkyl. In some embodiments, a Rb is C1-6 alkyl.
[0156] In some embodiments of any Formulae described herein, a moiety is
[0157] In some embodiments of any Formulae described herein, Rc is hydrogen, halogen, or optionally substituted Ci-6 alkyl. In some embodiments, Re is hydrogen. In some embodiments, Rc is halogen. In some embodiments, Rc is optionally substituted C1-6 aliphatic. In some embodiments, Re is Ci-6 aliphatic. In some embodiments, Rc is optionally substituted Ci-6 alkyl. In some embodiments, Rc is Ci-6 alkyl.
[0158] In some embodiments of any Formulae described herein, Rd is hydrogen, halogen, or optionally substituted Ci-6 alkyl. In some embodiments, Rd is hydrogen. In some embodiments, Rd is halogen. In some embodiments, Rd is optionally substituted Ci-6 aliphatic. In some embodiments, Rd is Ci-6 aliphatic. In some embodiments, Rd is optionally substituted Ci-6 alkyl. In some embodiments, Rd is Ci-6 alkyl.
[0159] In some embodiments of any Formulae described herein, each Raa is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Raa is hydrogen. In some embodiments, each Raa is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Raa is independently Ci-6 aliphatic. In some embodiments, each Raa is independently optionally substituted Ci-6 alkyl. In some embodiments, each Raa is independently Ci-6 alkyl. In some embodiments, a Raa is hydrogen. In some embodiments, a Raa is optionally substituted Ci-6 aliphatic. In some embodiments, a R33 is Ci-6 aliphatic. In some embodiments, a Raa is optionally substituted Ci-6 alkyl. In some embodiments, a Raa is Ci-6 alkyl (e g., methyl). [0160] In some embodiments of any Formulae described herein, a is 0, 1, 2, or 3. In some embodiments, a is 0, 1, or 2. In some embodiments, a is 1, 2, or 3. In some embodiments, a is 0 or 1. In some embodiments, a is 1 or 2. In some embodiments, a is 2 or 3. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4. In some embodiments, a is 5.
[0161] In some embodiments of any Formulae described herein, b is 0, 1, 2, or 3. In some embodiments, b is 0, 1, or 2. In some embodiments, b is 1, 2, or 3. In some embodiments, b is 0 or 1. In some embodiments, b is 1 or 2. In some embodiments, b is 2 or 3. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4. In some embodiments, b is 5.
[0162] In some embodiments, the present disclosure provides a compound of Formula IV:
IV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Re is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic, or two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1 is independently halogen or optionally substituted Ci-6 aliphatic, each Rg is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic; each Rbb is independently hydrogen or optionally substituted Ci-6 aliphatic; e is 0, 1, 2, 3, 4, or 5; f is 0, 1, 2, or 3; and g is 0, 1, 2, 3, 4, or 5.
[0163] In some embodiments, the present disclosure provides a compound of Formula IV-a: or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, Ring Z, e, f, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.
[0164] In some embodiments, the present disclosure provides a compound of Formula IV-b:
IV-b or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, e, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and f is 0 or 1.
[0165] In some embodiments, the present disclosure provides a compound of Formula IV-c:
or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, e, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and f is 0 or 1.
[0166] In some embodiments, the present disclosure provides a compound of Formula IV-d:
IV-d or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rx, Ry, Rz, X, e, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.
[0167] In some embodiments, the present disclosure provides a compound of Formula IV-e:
IV-e or a pharmaceutically acceptable salt thereof, wherein L1, Re, R1, Rx, Ry, Rz, X, Ring Z, f, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, or 3.
[0168] In some embodiments, the present disclosure provides a compound of Formula IV-f:
IV-f or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rg, Rx, Ry, Rz, X, Ring Z, f, g, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, 3, or 4.
[0169] In some embodiments, the present disclosure provides a compound of Formula IV-g: or a pharmaceutically acceptable salt thereof, wherein L1, Re, Rf, Rx, Ry, Rz, X, Ring Z, f, and KBM are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination; and e is 0, 1, 2, or 3.
[0170] In some embodiments of any Formulae described herein, TPM is: wherein Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.
[0171] In some embodiments of any Formulae described herein, TPM is: wherein Re, Rf, Ring Z, e, and f are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.
[0172] In some embodiments of any Formulae described herein, TPM is: wherein Re, Rf, e, and f are as defined in Formula IV-b and described in classes and subclasses herein, both singly and in combination.
[0173] In some embodiments of any Formulae described herein, TPM is: wherein Re, Rf, e, and f are as defined in Formula IV-c and described in classes and subclasses herein, both singly and in combination.
[0174] In some embodiments of any Formulae described herein, TPM is: wherein Re and e are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination.
[0175] In some embodiments of any Formulae described herein, TPM is: wherein Re, R1, e, and f are as defined in Formula IV-e and described in classes and subclasses herein, both singly and in combination.
[0176] In some embodiments of any Formulae described herein, TPM is: wherein Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV-f and described in classes and subclasses herein, both singly and in combination.
[0177] In some embodiments of any Formulae described herein, TPM is: wherein Re, Rf, Ring Z, e, and f are as defined in Formula IV-g and described in classes and subclasses herein, both singly and in combination.
[0178] In some embodiments of any Formulae described herein, Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a oxazole, isoxazole, or triazole. In some embodiments, Ring Z is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0179] In some embodiments of any Formulae described herein, Ring Z is selected from: wherein each ring is substituted with /instances of Rf.
[0180] In some embodiments of any Formulae described herein, Ring Z substituted with f instances of Rf is selected from:
[0181] In some embodiments of any Formulae described herein, each Re is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic. In some embodiments, each Re is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Re is independently -ORbb or -N(Rbb)2. In some embodiments, each Re is independently -ORbb (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Re is -OCH3. In some embodiments, a Re is halogen. In some embodiments, a Re is -ORbb (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Re is -N(Rbb)2. In some embodiments, a Re is -N(H)(Rbb). In some embodiments, a Re is optionally substituted C1-6 aliphatic. In some embodiments, a Re is Ci- 6 aliphatic. In some embodiments, a Re is optionally substituted Ci-6 alkyl. In some embodiments, a Re is Ci-6 alkyl. In some embodiments, each Re is independently -ORbb (e.g., -O(Ci-6 alkyl), e.g., -OCH3), or two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Re is independently -ORbb (e.g., -O(Ci-6 alkyl), e.g., -OCH3), or two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Re are taken together with the atoms to which they are attached to form an optionally substituted imidazole ring. In some embodiments, two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Re is the point of attachment to the rest of the molecule. In some embodiments, the ring formed by taking two Re together is the point of attachment to the rest of the molecule.
[0182] In some embodiments of any Formulae described herein, each Rf is independently halogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rf is independently halogen. In some embodiments, each R1 is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rf is independently Ci-6 aliphatic. In some embodiments, each Rf is independently optionally substituted Ci-6 alkyl. In some embodiments, each Rf is independently Ci-6 alkyl. In some embodiments, a R* is halogen. In some embodiments, a R1 is optionally substituted Ci-6 aliphatic. In some embodiments, a Rf is Ci-6 aliphatic. In some embodiments, a Rf is optionally substituted Ci-6 alkyl. In some embodiments, aR1 is Ci-6 alkyl.
[0183] In some embodiments of any Formulae described herein, each Rg is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rg is independently -ORbb or -N(Rbb)2. In some embodiments, each Rg is independently -ORbb (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRg is halogen. In some embodiments, a Rg is -ORbb (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rs is -N(Rbb)2. In some embodiments, a Rg is -N(H)(Rbb). In some embodiments, a Rg is optionally substituted C1-6 aliphatic. In some embodiments, a Rg is C1-6 aliphatic. In some embodiments, a Rg is optionally substituted C1-6 alkyl. In some embodiments, a R8 is C1-6 alkyl.
[0184] In some embodiments of any Formulae described herein, a moiety [0185] In some embodiments of any Formulae described herein, each Rbb is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rbb is hydrogen. In some embodiments, each Rbb is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rbb is independently Ci-6 aliphatic. In some embodiments, each Rbb is independently optionally substituted Ci-6 alkyl. In some embodiments, each Rbb is independently Ci-6 alkyl. In some embodiments, a Rbb is hydrogen. In some embodiments, a Rbb is optionally substituted Ci-6 aliphatic. In some embodiments, a Rbb is Ci-6 aliphatic. In some embodiments, a Rbb is optionally substituted Ci-6 alkyl. In some embodiments, a Rbb is Ci-6 alkyl (e.g., methyl).
[0186] In some embodiments of any Formulae described herein, e is 0, 1, 2, 3, or 4. In some embodiments, e is 0, 1, 2, or 3. In some embodiments, e is 0, 1, or 2. In some embodiments, e is 1, 2, or 3. In some embodiments, e is 0 or 1. In some embodiments, e is 1 or 2. In some embodiments, e is 2 or 3. In some embodiments, e is 0. In some embodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, e is 4. In some embodiments, e is 5.
[0187] In some embodiments of any Formulae described herein, f is 0, 1, or 2. In some embodiments, f is 0 or 1. In some embodiments, f is 1 or 2. In some embodiments, f is 2 or 3. In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3.
[0188] In some embodiments of any Formulae described herein, g is 0, 1, 2, or 3. In some embodiments, g is 0, 1, or 2. In some embodiments, g is 1, 2, or 3. In some embodiments, g is 0 or 1. In some embodiments, g is 1 or 2. In some embodiments, g is 2 or 3. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5.
[0189] In some embodiments, the present disclosure provides a compound of Formula V:
V or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Z’ is NH, O, or S; each Rh is independently halogen, -ORCC, -N(R“)2, or optionally substituted Ci-6 aliphatic;
R1 is hydrogen, halogen, optionally substituted Ci-6 aliphatic, or optionally substituted phenyl; each Rk is independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rcc is independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.
[0190] In some embodiments, the present disclosure provides a compound of Formula V-a:
V-a or a pharmaceutically acceptable salt thereof, wherein L1, Rh, R>, Rx, Ry, Rz, X, h, and KBM are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0191] In some embodiments, the present disclosure provides a compound of Formula V-b:
V-b or a pharmaceutically acceptable salt thereof, wherein L1, Rh, R', Rk, Rx, Ry, Rz, X, h, k, and KBM are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0192] In some embodiments of any Formulae described herein, TPM is: wherein Rh, Rj, Rk, Z1, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0193] In some embodiments of any Formulae described herein, TPM is: wherein Rh, R>, and h are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0194] In some embodiments of any Formulae described herein, TPM is: wherein Rh, Rj, Rk, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0195] In some embodiments, the present disclosure provides a compound of Formula V’: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination; and wherein: each Rh is independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rk is independently halogen, -ORce, -N(Rec)2, or optionally substituted Ci-6 aliphatic; each Rcc is independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.
[0196] In some embodiments, the present disclosure provides a compound of Formula V’-a:
V’-a or a pharmaceutically acceptable salt thereof, wherein L1, Rh, Rx, Ry, Rz, X, h, and KBM are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.
[0197] In some embodiments of any Formulae described herein, TPM is: wherein Rh and h are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.
[0198] In some embodiments of any Formulae described herein, TPM is: wherein Rk, Rh, k, and h are as defined in Formula V’ and described in classes and subclasses herein, both singly and in combination.
[0199] In some embodiments of any Formulae described herein, Z1 is NH. In some embodiments, Z1 is O. In some embodiments, Z1 is S. In some embodiments, Z1 is the point of attachment to the rest of the molecule.
[0200] In some embodiments of any Formulae described herein, each Rh is independently halogen, -ORce, -N(Rec)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rh is independently -ORCC or -N(RCC)2. In some embodiments, each Rh is independently -ORCC (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rh is -OCH3. In some embodiments, a Rh is halogen. In some embodiments, a Rh is -ORec (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rh is -N(RCC)2. In some embodiments, a Rh is -N(H)(R“). In some embodiments, a Rh is optionally substituted C1-6 aliphatic. In some embodiments, a Rh is C1-6 aliphatic. In some embodiments, a Rh is optionally substituted C1-6 alkyl. In some embodiments, Rh is methyl. In some embodiments, a Rh is C1-6 alkyl. In some embodiments, Rh is the point of attachment to the rest of the molecule.
[0201] In some embodiments of any Formulae described herein, Rj is hydrogen, halogen, optionally substituted C1-6 alkyl, or optionally substituted phenyl. In some embodiments, R> is optionally substituted C1-6 aliphatic or optionally substituted phenyl. In some embodiments, ' is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, R1 is hydrogen. In some embodiments, R) is halogen. In some embodiments, R> is optionally substituted C1-6 aliphatic. In some embodiments, R' is C1-6 aliphatic. In some embodiments, R' is optionally substituted C1-6 alkyl. In some embodiments, R' is C1-6 alkyl (e.g., methyl). In some embodiments, R' is methyl. In some embodiments, R' is optionally substituted phenyl (e.g., phenyl optionally substituted with one or more halogen, -OH, -O(Ci-6 alkyl), or C1-6 alkyl). In some embodiments, R1 is phenyl. [0202] In some embodiments of any Formulae described herein, each Rk is independently halogen, -ORce, -N(Rec)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rk is independently -ORCC or -N(Rec)2. In some embodiments, each Rk is independently -ORCC (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rk is -OCH3. In some embodiments, a Rk is halogen. In some embodiments, a Rk is -ORec (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rk is -N(RCC)2. In some embodiments, a Rk is -N(H)(RCC). In some embodiments, a Rk is optionally substituted C1-6 aliphatic. In some embodiments, a Rk is C1-6 aliphatic. In some embodiments, a Rk is optionally substituted C1-6 alkyl. In some embodiments, a Rk is Ci-6 alkyl. [0203] In some embodiments of any Formulae described herein, a moiety if J“(Rk)k is
[0204] In some embodiments of any Formulae described herein, each Rcc is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rccis hydrogen. In some embodiments, each Rcc is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rcc is independently Ci-6 aliphatic. In some embodiments, each Rcc is independently optionally substituted Ci-6 alkyl. In some embodiments, each Rcc is independently Ci-6 alkyl. In some embodiments, a Rcc is hydrogen. In some embodiments, a Rce is optionally substituted Ci-6 aliphatic. In some embodiments, a Rcc is Ci-6 aliphatic. In some embodiments, a Rec is optionally substituted Ci-6 alkyl. In some embodiments, a Rcc is Ci-6 alkyl (e.g., methyl).
[0205] In some embodiments of any Formulae described herein, h is 0, 1, 2, or 3. In some embodiments, h is 0, 1, or 2. In some embodiments, h is 0 or 1 . In some embodiments, h is 1 or 2.
In some embodiments, h is 2 or 3. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4.
[0206] In some embodiments of any Formulae described herein, k is 0, 1, 2, or 3. In some embodiments, k is 0, 1, or 2. In some embodiments, k is 1, 2, or 3. In some embodiments, k is 0 or 1. In some embodiments, k is 1 or 2. In some embodiments, k is 2 or 3. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. [0207] In some embodiments, the present disclosure provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Z2 is CH or N;
Ring Y is phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Q is -CH2- or -C(O)-;
W is -CH2-, -CHOH-, -C(O)-, -NH-, or -O-;
Rm is hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rn is independently halogen or optionally substituted Ci-6 aliphatic; each Rp is independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rdd is independently hydrogen or optionally substituted Ci-6 aliphatic; n4 is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.
[0208] In some embodiments, the present disclosure provides a compound of Formula Vl-a:
VLa or a pharmaceutically acceptable salt thereof, wherein L1, Rm, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0209] In some embodiments, the present disclosure provides a compound of Formula Vl-b:
VI-b or a pharmaceutically acceptable salt thereof, wherein L1, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0210] In some embodiments, the present disclosure provides a compound of Formula VI-c:
VI-c or a pharmaceutically acceptable salt thereof, wherein L1, Rm, Rn, Rp, Rx, Ry, Rz, X, n4, p, and KBM are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0211] In some embodiments of any Formulae described herein, TPM is: wherein Rm, Rn, Rp, Q, W, Z2, Ring Y, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination. [0212] In some embodiments of any Formulae described herein, TPM is: wherein Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0213] In some embodiments of any Formulae described herein, TPM is: wherein Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0214] In some embodiments of any Formulae described herein, TPM is: wherein Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0215] In some embodiments of any Formulae described herein, Z2 is CH. In some embodiments, Z2 is N.
[0216] In some embodiments of any Formulae described herein, Ring Y is phenyl or a 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is phenyl. In some embodiments, Ring Y is a 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a furan, thiophene, pyrrole, or isoxazole). In some embodiments, Ring Y is a 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a pyridine). In some embodiments, Ring Y is a 3- to 7-membered carbocyclic ring. In some embodiments, Ring Y is a 5- to 6- membered carbocyclic ring. In some embodiments, Ring Y is a 5-membered carbocyclic ring. In some embodiments, Ring Y is a 6-membered carbocyclic ring. In some embodiments, Ring Y is a C3-7 cycloalkyl ring. In some embodiments, Ring Y is a C5-6 cycloalkyl ring. In some embodiments, Ring Y is a C5 cycloalkyl ring. In some embodiments, Ring Y is a C& cycloalkyl ring. In some embodiments, Ring Y is a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0217] In some embodiments of any Formulae described herein, Q is -CH2-. In some embodiments, Q is -C(O)-.
[0218] In some embodiments of any Formulae described herein, W is -CH2-. In some embodiments, W is -CHOH-. In some embodiments, W is -C(O)-. In some embodiments, W is - NH-. In some embodiments, W is -O-. In some embodiments, W is the point of attachment to the rest of the molecule.
[0219] In some embodiments of any Formulae described herein, Q is -C(O)- and W is -NH-. In some embodiments, Q is -CH2- and W is -CH2. In some embodiments, Q is -CH2- and W is - C(O)-. In some embodiments, Q is -CH2- and W is -CHOH-. In some embodiments, Q is -CH2- and W is -O-.
[0220] In some embodiments of any Formulae described herein, Rm is hydrogen, halogen, - ORdd, -N(Rdd)2, or optionally substituted C1-6 alkyl. In some embodiments, Rm is halogen, -N(Rdd)2, or optionally substituted C1-6 aliphatic. In some embodiments, Rm is halogen, -N(Rdd)2, or C1-6 alkyl. In some embodiments, Rm is hydrogen. In some embodiments, Rm is halogen. In some embodiments, Rm is -ORdd (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rm is - N(Rdd)2. In some embodiments, Rm is -N(H)(Rdd) (e.g., -NH(CI-6 alkyl), e.g., -N(H)CH3). In some embodiments, Rm is -N(H)CH3. In some embodiments, Rm is optionally substituted Ci-6 aliphatic. In some embodiments, Rm is Ci-6 aliphatic. In some embodiments, Rm is optionally substituted Ci- 6 alkyl. In some embodiments, Rm is Ci-6 alkyl. In some embodiments, Rm is the point of attachment to the rest of the molecule.
[0221] In some embodiments of any Formulae described herein, each Rn is independently halogen or optionally substituted Ci-6 alkyl. In some embodiments, a Rn is halogen. In some embodiments, a Rn is optionally substituted Ci-6 aliphatic. In some embodiments, a Rn is Ci-6 aliphatic. In some embodiments, a R11 is optionally substituted Ci-6 alkyl. In some embodiments, a Rn is Ci-6 alkyl.
[0222] In some embodiments of any Formulae described herein, each Rp is independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rp is independently -ORdd or -N(Rdd)2. In some embodiments, each Rp is independently -ORdd (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, Rp is -OCH3. In some embodiments, a Rp is halogen. In some embodiments, a Rp is -ORdd (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rp is -N(Rdd)2. In some embodiments, a Rp is -N(H)(Rdd). In some embodiments, a Rp is optionally substituted Ci-6 aliphatic. In some embodiments, a Rp is Ci-6 aliphatic. In some embodiments, a Rp is optionally substituted Ci-6 alkyl. In some embodiments, a Rp is Ci-6 alkyl.
[0223] In some embodiments of any Formulae described herein, each Rdd is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rdd is hydrogen. In some embodiments, each Rdd is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rdd is independently Ci-6 aliphatic. In some embodiments, each Rdd is independently optionally substituted Ci-6 alkyl. In some embodiments, each Rdd is independently Ci-6 alkyl. In some embodiments, a Rdd is hydrogen. In some embodiments, a Rdd is optionally substituted Ci-6 aliphatic. In some embodiments, a Rdd is Ci-6 aliphatic. In some embodiments, a Rdd is optionally substituted Ci-6 alkyl. In some embodiments, a Rdd is Ci-6 alkyl (e.g., methyl).
[0224] In some embodiments of any Formulae described herein, n4 is 0, 1, 2, or 3. In some embodiments, n4 is 0, 1, or 2. In some embodiments, n4 is 1, 2, or 3. In some embodiments, n4 is 0 or 1. In some embodiments, n4 is 1 or 2. In some embodiments, n4 is 2 or 3. In some embodiments, n4 is 0. In some embodiments, n4 is 1. In some embodiments, n4 is 2. In some embodiments, n4 is 3. In some embodiments, n4 is 4. In some embodiments, n4 is 5. [0225] In some embodiments of any Formulae described herein, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.
[0226] In some embodiments, the present disclosure provides a compound of Formula VII:
VII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rq is independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci-6 aliphatic; each Rr is independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci.6 aliphatic; each Rs is independently halogen or optionally substituted Ci-6 aliphatic;
Rl is -N(Ree)(Ci-4 alkylene)CN; each Ree is independently hydrogen or optionally substituted Ci-6 aliphatic; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, or 4; and s is 0, 1, or 2.
[0227] In some embodiments, the present disclosure provides a compound of Formula Vll-a: \TI-a or a pharmaceutically acceptable salt thereof, wherein L1, Rq, Rr, Rl, Rx, Ry, Rz, X, q, r, and KBM are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.
[0228] In some embodiments, the present disclosure provides a compound of Formula Vll-b:
VILb or a pharmaceutically acceptable salt thereof, wherein L1, Rq, Rr, Rs, R Rx, Ry, Rz, X, q, r, s, and KBM are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination; and q is 0, 1, 2, 3, or 4.
[0229] In some embodiments of any Formulae described herein, TPM is: wherein Rq, Rr, Rs, Rl, Ring X, q, r, and s are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.
[0230] In some embodiments of any Formulae described herein, TPM is: wherein Rq, Rr, R q, and r are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.
[0231] In some embodiments of any Formulae described herein, TPM is:
wherein Rq, Rr, Rs, R\ q, r, and s are as defined in Formula VH-b and described in classes and subclasses herein, both singly and in combination.
[0232] In some embodiments of any Formulae described herein, Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring X is an oxadiazole (e.g., a 1,2,5-oxadiazole). In some embodiments,
Ring X is
[0233] In some embodiments of any Formulae described herein, each Rq is independently halogen, -ORCC, -N(Rec)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rq is independently -ORee or -N(Ree)2. In some embodiments, each Rq is independently -ORee (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRq is halogen. In some embodiments, a Rq is -ORee (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rq is -N(Ree)2. In some embodiments, a Rq is -N(H)(Ree). In some embodiments, a Rq is optionally substituted C1-6 aliphatic. In some embodiments, a Rq is C1-6 aliphatic. In some embodiments, a Rq is optionally substituted C1-6 alkyl. In some embodiments, a Rq is C1-6 alkyl. In some embodiments, a Rq is the point of attachment to the rest of the molecule.
[0234] In some embodiments of any Formulae described herein, each Rr is independently halogen, -ORee, -N(Ree)2, or optionally substituted C1-6 alkyl. In some embodiments, each Rr is independently -ORee or -N(Ree)2. In some embodiments, each Rr is independently -ORee (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rr is halogen. In some embodiments, a Rr is -ORee (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rr is -N(Ree)2. In some embodiments, a Rr is -N(H)(Ree). In some embodiments, a Rr is optionally substituted C1-6 aliphatic. In some embodiments, a Rr is C1-6 aliphatic. In some embodiments, a Rr is optionally substituted C1-6 alkyl. In some embodiments, a Rr is Ci-6 alkyl. [0235] In some embodiments of any Formulae described herein, each Rs is independently halogen or optionally substituted Ci-6 alkyl. In some embodiments, a Rs is halogen. In some embodiments, a Rs is optionally substituted Ci-6 aliphatic. In some embodiments, a Rs is Ci-6 aliphatic. In some embodiments, a Rs is optionally substituted Ci-6 alkyl. In some embodiments, a Rs is Ci-6 alkyl.
[0236] In some embodiments of any Formulae described herein, Rl is -N(H)(CI-4 alkylene)CN. In some embodiments, R‘ is -N(Ree)(Ci-2 alkylene)CN. In some embodiments, Rl is -N(H)(CI-2 alkylene)CN. In some embodiments, R‘ is -N(Ree)CH2CH2CN. In some embodiments, Rl is - N(H)CH2CH2CN.
[0237] In some embodiments of any Formulae described herein, each Ree is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Reeis hydrogen. In some embodiments, each Ree is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Ree is independently Ci-6 aliphatic. In some embodiments, each Ree is independently optionally substituted Ci-6 alkyl. In some embodiments, each Ree is independently Ci-6 alkyl. In some embodiments, a Ree is hydrogen. In some embodiments, a Ree is optionally substituted Ci-6 aliphatic. In some embodiments, a Ree is Ci-6 aliphatic. In some embodiments, a Ree is optionally substituted Ci-6 alkyl. In some embodiments, a Ree is Ci-6 alkyl (e.g., methyl).
[0238] In some embodiments of any Formulae described herein, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.
[0239] In some embodiments of any Formulae described herein, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 2 or 3. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.
[0240] In some embodiments of any Formulae described herein, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.
[0241] In some embodiments, the present disclosure provides a compound of Formula VIII:
VIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, X, and KBM are as defined in Formula I and described in classes and subclasses herein, both singly and in combination, and wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
M is a covalent bond or Ci-4 alkylene; each Ru is independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 aliphatic; each Rv is independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 aliphatic; each Rff is independently hydrogen or optionally substituted Ci-6 aliphatic;
Rsg is hydrogen or optionally substituted Ci-6 aliphatic; u is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, 3, or 4.
[0242] In some embodiments, the present disclosure provides a compound of Formula Vlll-a:
VUI-a or a pharmaceutically acceptable salt thereof, wherein L1, Ru, Rv, Rx, Ry, Rz, Rff, X, u, v, and KBM are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0243] In some embodiments, the present disclosure provides a compound of Formula Vlll-b: vni-b or a pharmaceutically acceptable salt thereof, wherein L1, M, Ru, Rv, Rx, Ry, Rz, Rfl, Rgg, X, u, v, and KBM are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0244] In some embodiments, the present disclosure provides a compound of Formula VIII-c:
VIII-c or a pharmaceutically acceptable salt thereof, wherein L1, Ru, Rv, Rx, Ry, Rz, Rff, X, u, v, and KBM are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0245] In some embodiments of any Formulae described herein, TPM is: wherein M, Ru, Rv, Rfl, Rgg, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0246] In some embodiments of any Formulae described herein, TPM is:
wherein Ru, Rv, Rft, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0247] In some embodiments of any Formulae described herein, TPM is: wherein M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0248] In some embodiments of any Formulae described herein, TPM is: wherein Ru, Rv, Rff, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0249] In some embodiments of any Formulae described herein, M is a covalent bond. In some embodiments, M is Ci-4 alkylene. In some embodiments, M is C1-2 alkylene. In some embodiments, M is -CH2-.
[0250] In some embodiments, a moiety [0251] In some embodiments of any Formulae described herein, each Ru is independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Ru is independently -ORff or -N(Rff)2. In some embodiments, each Ru is independently -ORff (e.g., - O(Ci-6 alkyl) or -OH). In some embodiments, a Ru is halogen. In some embodiments, a Ru is -ORff (e.g., -O(Ci-6 alkyl) or -OH). In some embodiments, a Ru is -N(Rff)2. In some embodiments, a Ru is -N(H)(Rff). In some embodiments, a Ru is optionally substituted Ci-6 aliphatic. In some embodiments, a Ru is Ci-6 aliphatic. In some embodiments, a Ru is optionally substituted Ci-6 alkyl. In some embodiments, a Ru is Ci-6 alkyl. In some embodiments, a Ru is the point of attachment to the rest of the molecule.
[0252] In some embodiments of any Formulae described herein, each Rv is independently halogen, -ORff, -N(Rft)2, or optionally substituted Ci-6 alkyl. In some embodiments, each Rv is independently -ORfl or -N(Rff)2. In some embodiments, each Rv is independently -ORfl (e.g., - O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, aRv is halogen. In some embodiments, a Rv is -ORff (e.g., -O(Ci-6 alkyl), e.g., -OCH3). In some embodiments, a Rv is -N(Rff)2. In some embodiments, a Rv is -N(H)(Rff). In some embodiments, a Rv is optionally substituted Ci-6 aliphatic. In some embodiments, a Rv is Ci-6 aliphatic. In some embodiments, a Rv is optionally substituted Ci-6 alkyl. In some embodiments, a Rv is Ci-6 alkyl.
[0253] In some embodiments of any Formulae described herein, each Rff is independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, each Rff is hydrogen. In some embodiments, each Rff is independently optionally substituted Ci-6 aliphatic. In some embodiments, each Rff is independently Ci-6 aliphatic. In some embodiments, each Rff is independently optionally substituted Ci-6 alkyl. In some embodiments, each Rffis independently Ci-6 alkyl. In some embodiments, a Rfl is hydrogen. In some embodiments, a Rfl is optionally substituted Ci-6 aliphatic. In some embodiments, a Rff is Ci-6 aliphatic. In some embodiments, a Rffis optionally substituted Ci-6 alkyl. In some embodiments, a Rffis Ci-6 alkyl (e.g., methyl).
[0254] In some embodiments of any Formulae described herein, Rgg is hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, Rgg is hydrogen. In some embodiments, Rgg is optionally substituted Ci-6 aliphatic. In some embodiments, Rgg is Ci-6 aliphatic. In some embodiments, Rgg is optionally substituted Ci-6 alkyl. In some embodiments, Rgg is Ci-6 alkyl.
[0255] In some embodiments of any Formulae described herein, u is 0, 1, 2, or 3. In some embodiments, u is 0, 1, or 2. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 0 or 1 . In some embodiments, u is 1 or 2. In some embodiments, u is 2 or 3. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5.
[0256] In some embodiments of any Formulae described herein, v is 0, 1, 2, or 3. In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0 or 1. In some embodiments, v is 1 or 2. In some embodiments, v is 2 or 3. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4.
[0257] In some embodiments, TPM is a tubulin inhibitor payload moiety (e g., a moiety that binds and/or inhibits tubulin). In some embodiments, TPM is a tubulin inhibitor payload moiety targeting the colchicine binding site. The present invention encompasses the recognition that a tubulin inhibitor payload moiety in the CIDCs described herein can be made by installing a linking moiety bound to a KRASG1C binding moiety, as defined herein any suitable position on a tubulin inhibitor compound. In some embodiments, TPM is a tubulin inhibitor (e.g., a radical of such inhibitor compound) selected from ABT-751, avanbulin, BNC105P, cabazitaxel, colchicine, combretastatin A-4, combretastatin A-l, docetaxel, dolastatin 10, EAPB0203, EAPB02303, EAPB0503, epothilone A, eribulin, fosbretabulin, ixabepilone, KX2-361, lisavanbulin, monomethyl auristatin E, A-acetylcolchicinol, ombrabulin, Oxi4503, paclitaxel, plinabulin, tesetaxel, sabizabulin, verubulin, vinblastine, and vincristine. In some embodiments, TPM is a tubulin inhibitor (e.g., a radical of such inhibitor compound) described in Hawesh, M. Biomolecules 2022, 12, 1843; Weng, H., et al., Future Med. Chem. 2023, 15(1), 73- 95; Beale, T. M., et al., ACS Med. Chem. Lett. 2012, 3, 177-181; Liou, J.-P., et al., J. Med. Chem. 2004, 47, 2897-2905; Patinote, C., et al., Eur. J. Med. Chem. 2021, 212, 113031; Pochampally, S., et al., ACS Pharmacol. Transl. Sci. 2023, 6, 526-45; Prota, A. E., et al., J. Mol. Biol. 2014, 426, 1848-60; Sun, C.-M., et al., Bioorg. Med. Chem. Lett. 2007, 17, 1078-81; Zhou, J. et al., Eur. J. Med. Chem. 2013, 68, 222-32; WO1996/030355; WO1998/045301; WO 1999/002514; W02002/056872; US2003/0195244; W02004/054498; W02005/054199; US2005/0065595; WO20 12/027481; or WO2012/106522. [0258] In some embodiments, TPM is a means for binding tubulin. In some embodiments, TPM is a means for inhibiting tubulin. In some embodiments, TPM is a means for inhibiting tubulin at the colchicine binding site.
Exemplary Compounds of the Disclosure
[0259] In some embodiments, the present disclosure provides a compound of Formula IX: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula III and described in classes and subclasses herein, both singly and in combination.
[0260] In some embodiments, the present disclosure provides a compound of Formula IX-a:
IX-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R?, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ra, Rh, Rc, Rd, a, and b are as defined in Formula Ill-b and described in classes and subclasses herein, both singly and in combination.
[0261] In some embodiments, the present disclosure provides a compound of Formula IX-al :
IX-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Ra, Rb, Rc, Rd, a, and b are as defined in Formula Ill-b and described in classes and subclasses herein, both singly and in combination. [0262] In some embodiments, the present disclosure provides a compound of Formula X: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R?, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, R1, Rg, Ring Z, e, f, and g are as defined in Formula IV and described in classes and subclasses herein, both singly and in combination. [0263] In some embodiments, the present disclosure provides a compound of Formula X-a: X-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV-f and described in classes and subclasses herein, both singly and in combination. [0264] In some embodiments, the present disclosure provides a compound of Formula X-al :
X-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Rg, Ring Z, e, f, and g are as defined in Formula IV-f and described in classes and subclasses herein, both singly and in combination.
[0265] In some embodiments, the present disclosure provides a compound of Formula X-b: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Re, R1, Ring Z, e, and f are as defined in Formula IV-g and described in classes and subclasses herein, both singly and in combination.
[0266] In some embodiments, the present disclosure provides a compound of Formula X-bl :
X-bl or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Re, Rf, Ring Z, e, and f are as defined in Formula IV-g and described in classes and subclasses herein, both singly and in combination. [0267] In some embodiments, the present disclosure provides a compound of Formula XI: or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R3, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rh, Rj, Rk, Z1, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0268] In some embodiments, the present disclosure provides a compound of Formula Xl-a:
Xl-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rh, R', Rk, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0269] In some embodiments, the present disclosure provides a compound of Formula XI-al :
XI-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rh, R>, Rk, h, and k are as defined in Formula V and described in classes and subclasses herein, both singly and in combination.
[0270] In some embodiments, the present disclosure provides a compound of Formula XII:
XII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Q, Rm, R11, Rp, W, Z2, Ring Y, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0271] In some embodiments, the present disclosure provides a compound of Formula Xll-a:
XII-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0272] In some embodiments, the present disclosure provides a compound of Formula Xll-al :
Xll-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0273] In some embodiments, the present disclosure provides a compound of Formula Xll-b:
XILb or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R\ Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0274] In some embodiments, the present disclosure provides a compound of Formula Xll-bl :
Xll-bl or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rm, Rn, Rp, n4, and p are as defined in Formula VI and described in classes and subclasses herein, both singly and in combination.
[0275] In some embodiments, the present disclosure provides a compound of Formula XIII:
XIII or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R', Ring X, q, r, and s are as defined in Formula VII and described in classes and subclasses herein, both singly and in combination.
[0276] In some embodiments, the present disclosure provides a compound of Formula XIILa:
Xlll-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R3, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Vll-b and described in classes and subclasses herein, both singly and in combination.
[0277] In some embodiments, the present disclosure provides a compound of Formula XIII- al :
XIILal or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Rq, Rr, Rs, R‘, Ring X, q, r, and s are as defined in Formula Vll-b and described in classes and subclasses herein, both singly and in combination.
[0278] In some embodiments, the present disclosure provides a compound of Formula XIV:
XIV or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rsg, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0279] In some embodiments, the present disclosure provides a compound of Formula XlV-a:
XlV-a or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R5, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rgg, u, and v are as defined in Formula Vlll-b and described in classes and subclasses herein, both singly and in combination. [0280] In some embodiments, the present disclosure provides a compound of Formula XIV- al :
XlV-al or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and M, Ru, Rv, Rff, Rss, u, and v are as defined in Formula Vlll-b and described in classes and subclasses herein, both singly and in combination.
[0281] In some embodiments, the present disclosure provides a compound of Formula XlV-b:
XlV-b or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; L2, L3, R1, R3, R4, R?, Y, and Ring A are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rfl, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0282] In some embodiments, the present disclosure provides a compound of Formula XIV- bl :
XIV-bl or a pharmaceutically acceptable salt thereof, wherein L1, Rx, Ry, Rz, and X are as defined herein for Formula I and described in classes and subclasses herein, both singly and in combination; Y R3, R4, R7, n, and Cy2 are as defined herein for Formula II and Formula Il-b and described in classes and subclasses herein, both singly and in combination; and Ru, Rv, Rff, u, and v are as defined in Formula VIII and described in classes and subclasses herein, both singly and in combination.
[0283] In some embodiments, the present disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
Table 1. Exemplary Compounds of the Disclosure
Preparing Provided Compounds
[0284] Provided compounds generally can be prepared using the processes described in the ensuing schemes and examples. [0285] In some embodiments, provided compounds (e.g., compounds wherein KBM comprises an amine, either a cyclic amine as in A.l or a primary amine as in A.2) are prepared according to the following Schemes:
A.2 B.1 C.2 wherein KBM, TPM, L',RX, Ry, Rz, and X are as defined in Formulae herein. Accordingly, in some embodiments, a compound C.l or C.2 is prepared by a process comprising contacting intermediate A.l or A.2 with intermediate B.l in the presence of a suitable coupling agent and optionally in the presence of a suitable base. In some embodiments, B.l is first converted to an acyl chloride before coupling with the amine of intermediate A.1 or A.2.
[0286] In some embodiments, provided compounds (e.g., compounds wherein X is not a covalent bond and L1 comprises a carbonyl moiety) are prepared according to the following Scheme:
A.3 B.2 C.3 wherein KBM, TPM, L RX, Ry, Rz, and X are as defined in Formulae herein. Accordingly, in some embodiments, a compound C.3 is prepared by a process comprising contacting intermediate A.3 with intermediate B.2 in the presence of a suitable coupling agent and optionally in the presence of a suitable base.
[0287] In some embodiments, provided compounds (e.g., compounds wherein X is not a covalent bond) are prepared according to the following Scheme:
A.4 B.3 C.4 wherein KBM, TPM, L1, Rx, Ry, Rz, and X are as defined in Formulae herein; and LG1 is a suitable leaving group (e.g., Br or OMs). Accordingly, in some embodiments, a compound C.4 is prepared by a process comprising contacting intermediate A.4 with intermediate B.3 in the presence of a suitable base.
[0288] In some embodiments, provided compounds (e g., compounds wherein L1 is bound to X via a carbonyl-containing moiety, such as an amide, urea, or carbamate) are prepared according to the following Schemes:
A.5 B.5 C.6 wherein KBM, TPM, Cy, L1, Rx, Ry, Rz, and X are as defined in Formulae herein; and LG2 is a suitable leaving group. Accordingly, in some embodiments, a compound C.5 or C.6 is prepared by a process comprising contacting intermediate A.5 with intermediate B.4 or B.5 in the presence of a suitable coupling agent and optionally in the presence of a suitable base.
Compositions
[0289] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.
[0290] In some embodiments, provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-h-1, 1-h-2, II, Il-a, Il-b, II-c, ILd, III, Ill-a, IILb, IV, IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, V, V-a, V-b, V’, V’- a, VI, VI-a, Vl-b, VLc, VII, VILa, VILb, VIII, Vlll-a, VIILb, VIILc, IX, IX-a, IX-al, X, X-a, X- al, X-b, X-bl, XI, Xl-a, XLal, XII, Xll-a, XILal, XILb, Xll-bl, XIII, XIILa, XIILal, XIV, XIV- a, XlV-al, XlV-b, and XlV-bl).
[0291] In some embodiments, a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-h-1, 1-h-2, II, ILa, Il-b, II-c, ILd, III, Ill-a, Ill-b, IV, IV-a, IV-b, IV-c, IV- d, IV-e, IV-f, IV-g, V, V-a, V-b, V’, V’-a, VI, VI-a, Vl-b, VI-c, VII, Vll-a, VILb, VIII, Vlll-a, VIII- b, VIILc, IX, IX-a, IX-al, X, X-a, X-al, X-b, X-bl, XI, XLa, Xl-al, XII, Xll-a, Xll-al, XILb, Xll-bl, XIII, XIILa, XIILal, XIV, XlV-a, XlV-al, XlV-b, and XlV-bl) and further comprises a pharmaceutically acceptable carrier.
[0292] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.
[0293] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.
[0294] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
[0295] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and/or decreasing incidence and/or intensity of) a disease or disorder, for example as described herein.
[0296] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition.
Uses
[0297] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
[0298] In some embodiments, provided compounds are useful as covalent-induced drug conjugates, e.g., CIDCs targeting cells expressing mutant KRAS (e.g., KRASG12C).
[0299] In some embodiments, the present disclosure provides methods of inhibiting tubulin, comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C) in the presence of tubulin. In some embodiments, contacting occurs in a cell. In some embodiments, contacting occurs in a subject (e.g., a human subject).
[0300] In some embodiments, the present disclosure provides methods of releasing a tubulin inhibitor payload (e.g., a tubulin inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C). In some embodiments, contacting occurs in a subject (e.g., a human subject).
[0301] In some embodiments, the present disclosure provides methods of delivering a tubulin inhibitor payload (e.g., a tubulin inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting a provided compound with a KRAS protein (e.g., KRASG12C). In some embodiments, contacting occurs in a subject (e.g., a human subject). [0302] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with KRAS (e.g., mutant KRAS, e.g., KRASG12C).
[0303] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with KRAS (e.g., mutant KRAS, e.g., KRASG12C), comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, provided methods are for treating cancer. In some embodiments, a cancer is characterized by a solid tumor. In some embodiments, a cancer is characterized by a hematologic tumor. In some embodiments, a cancer is selected from hematopoietic cancers, including leukemias, lymphomas (e.g., Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastrointestinal cancers and nervous system cancers, benign lesions such as papillomas, and the like. In some embodiments, provided methods are for treating a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.) In some embodiments, provided methods are for treating a disease, disorder, or condition selected from acute myeloid leukemia (AML), neuroblastoma, non-small cell lung cancer (NCSLC), small cell lung cancer (SCLC), colorectal cancer, melanoma, and prostate cancer. In some embodiments, a cancer is non-small cell lung cancer or colorectal cancer. In some embodiments, a cancer is non- small cell lung cancer. In some embodiments, a cancer is colorectal cancer.
[0304] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
[0305] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
EXAMPLES
[0306] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
Preparation of Intermediates
Preparation of Intermediate B (Int-B)
[0307] Step 1: To a solution of B.7 (2.0 g, 7.8 mmol, 1.0 equiv.) in DMF was added NaH (560 mg, 7.8 mmol, 1.0 equiv.) at 0 °C under N2, and the mixture was stirred at 0 °C for 1 hr. Then, PMBCI (6.5 g, 23.4 mmol, 3.0 equiv.) was added at 0 °C. The mixture was stirred at rt for additional 3 hrs. LCMS showed the reaction was completed. The mixture was poured into water, extracted with ethyl acetate (EA) twice. The combined organic layer was washed with brine, dried over Na2SCU and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography to afford B.8 (2.8 g, 5.7 mmol, yield: 72.1%) as a white solid. LCMS(ESI) [M+l]+ = 495.2. [0308] Step 2: To a solution of B.l (25.0 g, 75.7 mmol, 1 .0 equiv.) and DIEA (24.4 g, 189.2 mmol, 2.5 equiv.) in THF (130.0 mL) was added B.l (22.7 g, 113.5 mmol, 1.5 equiv.) at 0 °C. The mixture was warmed to room temperature and stirred for 1 hr. LCMS showed the reaction was completed. The mixture was cooled to 0 °C, poured into water (100 mL), and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. The residue was triturated with petroleum ether (PE):DCM = 10: 1 and filtered. The filter cake was further triturated with PE: EA(20: l, 50 mLx 2) and filtered to afford B.3 (36.5 g, 73.8 mmol, yield: 97.5%) as white solid. LCMS (ESI) [M+l]+ = 493.0.
[0309] Step 3: To a solution of B.3 (34.0 g, 68.7 mmol, 1.0 equiv.) in DMA (200.0 mL) was added CsF (49.9 g, 859.9 mmol, 12.5 equiv.). The reaction mixture was heated to 110 °C and stirred overnight. LCMS showed the reaction was completed. The mixture was cooled down and poured into water (500 ml), and extracted with EtOAc (200 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with DCM:PE=1 : 10 (300 ml) and filtered to give a crude product, which was further triturated with DCM:PE=l :10 (50 ml x 3) to afford B.4 (32.0 g, 67.0 mmol, 97.3%) as a white solid. LCMS (ESI) [M+l]+ = 497.2.
[0310] Step 4: To a mixture of B.4 (10.0 g, 20.9 mmol, 1.0 equiv.) and B.5 (3.6 g, 31.3 mmol, 1.5 equiv.) in THF (100.0 mL) was added t-BuONa (3.0 g, 31.3 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed the reaction was completed. Then the reaction mixture was poured into water and extracted with EtOAc twice. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a crude product, which was purified by flash chromatography eluting with DCM:MeOH =100:5 to afford B.6 (6.0 g, 10.4 mmol, yield: 50.0%) as a yellow solid. LCMS(ESI) [M+l]+ = 574.2.
[0311] Step 5: To a solution of B.6 (1.1 g, 1.9 mmol, 1.0 equiv.) in THF (10.0 mL) was added dropwise i-PrMgCl.LiCl (1.3 mL, 2 M solution in THF, 2.5 mmol, 1.3 equiv.) at -70 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 30 min. To the mixture was added zinc chloride (1.0 mL, 2 M solution in THF, 2.5 mmol, 1.3 equiv.) at -10 °C, and the resulting reaction mixture was stirred for additional 1 h to give a solution A. To a solution of B.8 (950 mg, 1.9 mmol, 1.0 equiv.) and Pd(PPh3)2Ch (280.7 mg, 0.4 mmol, 0.2 equiv.) in dioxane (9 mL) was added solution A under N2 atmosphere, and the mixture was stirred at 50 °C overnight. LCMS showed the reaction was completed. The mixture was poured into water (20 ml) and extracted with EtOAc (20 ml x 2). The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography eluted with DCM:MeOH=10: l to afford B.8 (1.3 g, 1.4 mmol, yield: 74.5%) as a yellow solid. LCMS(ESI) [M+l]+ = 909.4.
[0312] To a mixture of B.9 (1.3 g, 1.4 mmol, 1.0 equiv.) in DCM (10.0 mL) was added TFA (3.0 mL). The mixture was stirred at r.t. for 2 h. LCMS showed the reaction was completed. The solvent was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography to afford Int-B (800.0 mg, 1.0 mmol, 69.1%) as a yellow solid. LCMS(ESI) [M+l]+ = 808.6.
Preparation of Intermediate D (Int-D)
D.2
[0313] Step 1: At room temperature, D.l (24.0 g, 95.07 mmol, 1.0 equiv.) and DIEA (29.5 g, 228.2 mmol, 2.4 equiv.) were dissolved in DCM (280.0 mL) and cooled in a water bath. D.2 (21.2 g, 99.82 mmol, 1.5 equiv.) was added, then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 200 mL DCM, and washed with 100 mL of water and 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (PE/EA=90/10 to 75 /25) to give D.3 (40.0 g, 93.40 mmol, 98.2%) as a yellow solid.
[0314] Step 2: To a solution of D.3 (20.0 g, 46.7 mmol, 1.0 equiv.) in dioxane (200.0 mL) were added D.4 (11.2 g, 70.1 mmol, 1.5 equiv.) and DIEA (12.1g, 93.4 mmol). The reaction solution was stirred at 80 °C for 12 hours and cooled to room temperature. 100 mL of water was added to the reaction mixture, and the resulting solution was extracted with ethyl acetate, the organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain D.5 (11.3 g, 20.54 mmol, yield: 44.0%). LCMS (ESI) [M+H]+=551.5.
[0315] Step 3: To a mixture of D.5 (3.0 g, 5.4 mmol, 1.0 equiv.), D.6 (3.4 g, 6.5 mmol, 1.2 equiv.) and tripotassium phosphate (3.5 g, 16.3 mmol, 3.0 equiv.) in THF (24.0 mL) and H2O (6.0 mL) was added CataCXium A Pd G3 (0.4 g, 0.5 mmol, 0.1 equiv.) under N2. The mixture was stirred at 80 °C for 2 hours under N2. After completion, the mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column to afford D.7 (3.8 g, 4.2 mmol, yield: 77.5%) as a yellow solid. LCMS(ESI)[M+1]+ -901.46.
[0316] Step 4: To a solution of D.7 (3.8 g, 4.2 mmol, 1.0 equiv.) in DMF (20.0 mL) was added CsF (6.4 g, 42.2 mmol, 10.0 equiv.). The reaction mixture was stirred at rt under N2 for 2 hours. LCMS showed reaction was completed. The reaction was purified by prep-HPLC to afford D.8 (3.0 g, 4.0 mmol, yield : 95.5%) as a brown solid. LCMS(ESI)[M+1]+ =745.32.
[0317] Step 5: To a stirred mixture of D.8 (3.0 g, 4.03 mmol, 1.0 equiv.) in DCM (20.0 mL) were added TMSOTf (2.0 mL) and HMDS (4.0 mL). The resulting mixture was stirred under N2 at 0 °C for 1 hr. LCMS showed reaction was completed. After completion, the mixture was quenched with NaHCOs(aq) and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated to afford Int-D (2.5 g, 3.9 mmol, yield: 96.3%) as a brown solid. LCMS(ESI)[M+1]+ =645.27. Preparation of Intermediate N (Int-N)
[0318] Step 1: To a solution of N.I (10.0 g, 39.6 mmol, 1.0 equiv.) in THF (100.0 mL) was added N.2 (9.4 g, 41.6 mmol, 1.2 equiv.). The mixture was cooled to 0 °C, and DIEA (15.4 g, 118.8 mmol, 3.0 equiv.) was added to the mixture. The resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford N.3 (17.0 g, 38.5 mmol, yield: 97.3%) as a yellow solid. LCMS (ESI) [M+l]+ = 442.0. [0319] Step 2: To a solution of N.3 (8.2 g, 18.6 mmol, 1.0 equiv.) in dioxane (90.0 mL) were added N.4 (3.9 g, 24.2 mmol, 1.3 equiv.) and DIEA (4.8 g, 37.2 mmol, 2.0 equiv.) at 0 °C. The mixture was stirred at 80 °C for 48 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated under vacuum. The residue was purified by flash silica chromatography to give N.5 (8.1 g, 14.4 mmol, yield: 77.3%) as a yellow solid. LCMS (ESI) [M+l]+= 563.9.
[0320] Step 3: To a solution of N.5 (8.1 g, 14.4 mmol, 1.0 equiv.) in THF (80.0 mL) and H2O (16.0 mL) were added N.6 (8.8 g, 17.2 mmol, 1.2 equiv.), CataCXium A Pd G3 (1.1 g, 1.4 mmol, 0.1 equiv.), and K3PO4 (9.1 g, 43.1 mmol, 3.0 equiv.). The mixture was stirred at 80 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was poured into water, and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford N.7 (10.4 g, 11.4 mmol, yield: 79.2%) as a yellow solid. LCMS (ESI) [M+l]+ = 914.5.
[0321] Step 4: To a solution of N.7 (5.0 g, 5.5 mmol, 1.0 equiv.) in DMF (10.0 mL) was added CsF (8.3 g, 54.7 mmol, 10.0 equiv.), and the mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was poured into water, and extracted with EA. The organic layer was separated and washed with brine, dried over Na2SC>4, and concentrated under vacuum. The residue was purified using silica gel column chromatography to afford N.8 (4.0 g, 5.3 mmol, yield: 96.5%) as a yellow solid. LCMS (ESI) [M+l]+ = 758.6.
[0322] Step 5: To a solution of N.8 (1.0 g, 1.3 mmol, 1.0 equiv.) in DCM (2.0 mL) were added TMSOTf (0.6 mL) and HMDS (1.2 mL) and the mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was poured into saturated sodium bicarbonate aqueous and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated to give Int-N (800.0 mg, 1.2 mmol, yield: 92.2%) as a brown solid. LCMS (ESI) [M+l]+ = 658.5. Preparation of Intermediate R (Int-R)
lnt-R-1 and lnt-R-2
[0323] Step 1: To a solution of R.1 (40 g, 399.3 mmol, 1.0 equiv.) in 1-butanol (3200 mL) was added CbzCl (68.8 g, 403.3 mmol, 1.1 equiv.) over 90 min at 0-10 °C. The reaction mixture was stirred at 0-10 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was partitioned between 25% aqueous NaOH (250 mL) and toluene (300 mL). The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give R.2 (70.0 g, 298.7 mmol, 74.8%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) 5 7.35 (d, J= 2.0 Hz, 5H), 5.07 (s, 2H), 3.81 (d, J= 12.6 Hz, 2H), 2.82 (d, J= 11.7 Hz, 2H), 2.59 - 2.46 (m, 3H), 2.40 (d, J= 28.2 Hz, 1H), 0.94 (d, J= 6.2 Hz, 3H).
[0324] Step 2: To a solution of R.3 (56.4 g, 170.7 mmol, 1.0 equiv.) and TEA (71.0 mL, 512.1 mmol, 3.0 equiv.) in THF (500 mL) was added R.2 (40.0 g, 170.7 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at RT for 1.5 h. The reaction was monitored by LCMS. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated with PE:DCM (10: 1) and filtered. The filter cake was further triturated with PE:EA (20: 1) and filtered to afford R.4 (70.0 g, 132.5 mmol, 77.6%) as a white solid. LCMS (ESI) [M+l]+ = 529.2.
[0325] Step 3: To a solution of R.4 (70.0 g, 132.5 mmol, 1.0 equiv.) in DMA (300 mL) was added potassium fluoride (153.9 g, 2650.4 mmol, 20.0 equiv.) at 25 °C under N2. The mixture was stirred at 120 °C for 16 hours. TLC indicated the reaction was complete. The reaction was quenched with water and extracted with EA three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give R.5 (65.0 g, 97.8 mmol, 74.3%) as a yellow oil. LCMS (ESI) [M+l]+ = 511.3. [0326] Step 4: To a solution of R.5 (65.0 g, 127.0 mmol, 1.0 equiv.) and R.6 (20.2 g, 127.0 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (10 mL) at -10 °C was added t-BuONa (12.2 g, 127.0 mmol, 1.0 equiv.) at -10 °C. The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction mixture was poured into a saturated aqueous NH4CI solution and extracted with EA three times. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 20-30% EtOAc in petroleum ether to afford R.7 (40.0 g, 55.3 mmol, 43.5%) as a colorless oil. LCMS (ESI) [M+l]+ = 652.3.
[0327] Step 5: To a mixture of R.7 (15.0 g, 23.0 mmol, 1.0 equiv.), R.8 (15.5 g, 34.5 mmol, 1.5 equiv.), K3PO4 (14.6 g, 69.1 mmol, 3.0 equiv.) in dioxane (200 mL) and toluene (200 mL) were added potassium fluoride (4.0 g 69.1 mmol, 3.0 equiv.) and Pd(DPEphos)Ch (3.3 g, 4.6 mmol, 0.2 equiv.). The reaction mixture was heated to 90 °C under nitrogen and stirred for 16 hours. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc, then the combined extracts were dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography, eluting with a gradient of 0 to 10% MeOH in DCM to afford R.9 (10.0 g, 11.6 mmol, 50.3%) as a yellow solid. LCMS (ESI) [M+l]+= 862.6. Step 6: To a solution of R.9 (15.0 g, 23.1 mmol, 1.0 equiv.) in methanol (100 mL) was added Pd/C (5.0 g, 11.60 mmol). The mixture was stirred at 25 °C for 16 h under a H2 atmosphere (25 psi). LCMS showed the reaction was complete. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with a gradient of 0 to 10% MeOH in DCM to give Int-R (10 g) which was further purified by SFC to give a first eluting rotamer Int-R-1 (3.9 g, 6.3 mmol, 30.9%) and a second eluting rotamer Int-R-2 (4.0 g, 6.3 mmol, 31.7%) as a yellow solid. Int-R-1: LCMS (ESI) [M+l] + = 728.5. Int-R-2: LCMS (ESI) [M+l]+ = 728.5. SFC separation was performed according to the following method: Column: CHIRALPAK IE (IE00CE-BS027); Column size: 0.46 cm I.D. x 25 cm L; Injection: 3 pL; Mobile phase: MeOH/DEA= 100/0.1 (V/V); Flow rate: 1.0 mL/min; Wavelength: UV 254 nm; Temperature: 35 °C; HPLC equipment: Shimadzu LC- 20AD CP-HPLC-05. Int-R-1 Retention time: 4.526 min; Int-R-2 Retention time: 6.015 min. Preparation of Intermediate S (Int-S)
[0328] Step 1: To a solution of S.l (32.0 g, 96.9 mmol, 1.0 equiv.) in THF (250.0 mL) was added DIEA (31.3 g, 242.2 mmol, 2.5 equiv.), the mixture was cooled to 0 °C, then S.2 (25.0 g, 96.9 mmol, 1.0 equiv.) was added, and the resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was cooled to 0 °C, poured into water and extracted with EA three times. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to afford S.3 (55.0 g, 95.4 mmol, 98.5%) as a yellow solid. LCMS(ESI)[M+1] + = 551.3. [0329] Step 2: To a solution of S.3 (55.0 g, 99.4 mmol, 1 .0 equiv.) in DMA (500.0 mL) was added potassium fluoride (69.3 g, 1193.0 mmol, 12.0 equiv.), and the mixture was stirred at 120 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was cooled down, poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 28% ethyl acetate in petroleum ether to afford S.4 (52.0 g, 96.9 mmol, 97.4%) as a yellow solid. LCMS(ESI)[M+1] + = 536.2.
[0330] Step 3: To a solution of S.4 (50.0 g, 85.7 mmol, 1.0 equiv.) and S.5 (13.6 g, 85.7 mmol, 1.0 equiv.) in 2-MeTHF (500.0 mL) was added t-BuONa (12.3 g, 128.5 mmol, 1.5 equiv.) at -10 °C, and the mixture was stirred at -10 °C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was poured into NH4CI aqueous and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 70% ethyl acetate in petroleum ether to afford S.6 (38.5 g, 57.0 mmol, 66.5%) as yellow oil. LCMS(ESI)[M+1] = 675.3.
[0331] Step 4: To a solution of S.6 (10.0 g, 14.8 mmol, 1.0 equiv.) in toluene (150.0 mL) and 1,4-dioxane (150.0 mL) was added S.7 (9.0 g, 22.2 mmol, 1.5 equiv.), Pd(DPEphos)C12 (2.1 g, 2.9 mmol, 0.2 equiv.), K3PO4 (9.4 g, 44.4 mmol, 3.0 equiv.) and potassium fluoride (2.6 g, 44.4 mmol, 3.0 equiv.). The mixture was stirred at 90 °C for 16 h. LCMS showed the reaction was complete. The reaction mixture was filtered, the filtrate was poured into water, and extracted with EA three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 6% methanol in DCM to give a crude product which was further purified by reversed phase CombiFlash® (40% MeOH in H2O (0.1% HCOOH)) to afford S.8 (6.1 g, 6.9 mmol, 46.5%) as a yellow solid. LCMS(ESI)[M+1]+ = 887.4.
[0332] Step 5: To a solution of S.8 (16.0 g, 13.4 mmol) in MeOH (120.0 mL) and THF (20.0 mL) was added Pd/C (8.0 g), and the suspension was stirred at room temperature for 6 hours under H2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was filtered through celite and filtrate was concentrated in vacuum. The residue was purified using silica gel column chromatography eluting with 10% methanol in DCM to give 11 g of Int-S as a mixture of atropisomers which was further purified by SFC separation to afford a first eluting isomer Int-S- 1 (3.7 g, 4.9 mmol, 36.2%) as a yellow solid and a second eluting isomer Int-S-2 (3.9 g, 5.2 mmol, 38.9%) as a yellow solid. Int-S-1 : LCMS(ESI)[M+1]+ = 753.2; Int-S-2: LCMS(ESI)[M+1]+ = 753.2. SFC was performed using the following conditions: Column: CHIRALPAK IA (IA00CE- VD015); Column size: 0.46 cm I.D. x 25 cm L; Injection: 0.5 pl; Mobile phase: EtOH/TFA/DEA= 100/0.1/0.03 (V/V/V); Flow rate: 1.0 ml/min; Wave length: UV 254 nm; Temperature: 35 °C; HPLC equipment: Shimadzu LC-20AT CP-HPLC-09. Int-S-1, retention time: 8.352 min; Int-S-2, retention time: 18.661 min.
Preparation of Intermediate L-5 rt, 48 hrs 0°C L-5
[0333] Step 1: To a solution of /c/7-butyl acrylate (56.6 mL, 390.1 mmol, 1.0 equiv.) in dioxane/IbO (250.0 mL) was added DABCO (131.2 g, 1.1 mol, 3.0 equiv.) and formaldehyde (95.1 mL, 1.1 mol, 3.0 equiv.). The reaction was stirred at rt for 48 hrs. TLC showed the reaction was completed. The mixture was extracted with EA, washed with water and brine. The organic layer was dried by Na2SC>4, purified by silica gel chromatography (20% EA in PE) to give L-4 (22.0 g, 139.0 mmol, yield: 35.6%) as a yellow oil. ’H NMR (400 MHz, MeOD) 5 6.13 (dd, J = 3.1, 1.5 Hz, 1H), 5.79 (q, J= 1.8 Hz, 1H), 4.84 (s, 1H), 4.21 (t, J= 1.5 Hz, 2H), 1.49 (s, 9H).
[0334] Step 2: To a solution of L-4 (10.0 g, 63.3 mmol, 1.0 equiv.) in Et20 (100.0 mL) was added PB (11.9 g, 44.4 mmol, 0.7 equiv.) at -10 °C, the reaction was stirred at 0 °C for 5 hrs. TLC showed the reaction was completed. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography to give L-5 (9.2 g, 41.8 mmol, yield: 66.1%) as a yellow oil. ' H NMR (400 MHz, CDCh) 8 6.23 (d, J = 0.9 Hz, 1H), 5.86 (d, J= 0.8 Hz, 1H), 4.15 (d, J = 0.7 Hz, 2H), 1.52 (s, 9H).
Preparation of Intermediate L-6 80 C, 16 h
[0335] Step 1: To a solution of acetaldehyde (51.0 mL, 908.0 mmol, 1.0 equiv.) in H2O (45.0 mL) and dioxane (45.0 mL) were added tert-butyl acrylate (174.5 g, 1.3 mol, 1.5 equiv.) and DABCO (101.8 g, 908.0 mmol, 1.0 equiv.) at rt under N2. The reaction mixture was stirred at rt for 48 h under N2. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE/EA=10/l) to afford L-1 (50.0 g, 290.3 mmol, yield: 31.9%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) 5 5.96 (dd, J= 2.0, 1.0 Hz, 1H), 5.76 (dd, J = 3.4, 1.6 Hz, 1H), 4.95 (d, J= 4.8 Hz, 1H), 4.42 (dd, J = 6.2, 5.1 Hz, 1H), 1.44 (s, 9H), 1.17 (d, J= 6.4 Hz, 3H).
[0336] Step 2: To a solution of NBS (15.5 g, 87.0 mmol, 1.5 equiv.) in DCM (100.0 mL) was added dimethylsulfane (7.3 mL, 98.7 mmol, 1.7 equiv.) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h under N2. Then L-1 (10.0 g, 58.0 mmol, 1.0 equiv.) was added in the solution at 0 °C. The reaction mixture was stirred at rt for 16 h under N2. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product L-2 (13.0 g, 55.2 mmol, yield: 95.2%) as a yellow oil which was used to next step.
[0337] Step 3: To a solution of Na2HPC>4 (12.0 g, 85.0 mmol, 2.0 equiv.) and NaH2PO4 (12.2 g, 85.0 mmol, 2.0 equiv.) in DMPU (80.0 mL) and H2O (40.0 mL) was added L-2 (10.0 g, 42.5 mmol, 1.0 equiv.) at rt under N2. The reaction mixture was stirred at 100 °C overnight under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE/EA=10/l) to afford L-6 (3.0 g, 17.420 mmol, yield: 40.9%) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 6.72 (q, J= 7.2 Hz, 1H), 4.55 (t,J= 5.5 Hz, 1H), 4.10 (d, J= 5.5 Hz, 2H), 1.82 (d, J= 7.2 Hz, 3H), 1.43 (s, 9H). Preparation of Intermediate L-7 , L-7
[0338] To a solution of L-1 (50.0 g, 290.3 mmol, 1.0 equiv.), DMAP (14.1 g, 116.1 mmol, 0.4 equiv.) and pyridine (23.4 mL, 290.3 mmol, 1.0 equiv.) in DCM (500.0 mL) was added methyl chloromethanoate (33.6 mL, 435.4 mmol, 1.5 equiv.) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. The reaction mixture was washed with a Nal ICCh solution, the organic layer was dried over anhydrous ISfeSCh, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0~10% EtOAc in petroleum ether to afford L-7 (30.0 g, 130.2 mmol, yield: 44.8%) as a colorless oil. ’H NMR (400 MHz, CDC13) 8 6.22 (s, 1H), 5.78 (s, 1H), 5.56 (q, J = 6.4 Hz, 1H), 3.79 (s, 1H), 1.50 (s, 9H), 1.44 (d, J = 6.5 Hz, 3H).
Preparation of Intermediate L-8
1 ? 1/ Triphosgene
H° l! " TEA Pentane, rt, 16h * L-1
[0339] To a solution of ISfeCCh (24.6 g, 232.3 mmol, 2.0 equiv.) and triphosgene (25.2 g, 84.8 mmol, 0.7 equiv.) in pentane (200 mL) was added TEA (1.6 mL, 11.6 mmol, 0.1 equiv.) at 0°C. The mixture was stirred for 30 min under N2. Then L-1 (20.0 g, 116.1 mmol, 1.0 equiv.) was added and the reaction was stirred at rt for 16 h. TLC showed a new spot. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography to give L-8 (11.5 g, 49.0 mmol, yield: 42.2%) as a yellow oil. 1H NMR (400 MHz, CDCh) 86.25 (s, 1H), 5.75 (s, 1H), 5.68 (q, .7= 6.5 Hz, 1H), 1.44 Cd, 2.2 Hz, 12H).
Preparation of Provided Compounds Example 1: Preparation of Compound 1
[0340] Step 1: To a solution of compound 1.1 (600.0 mg, 1.7 mmol, 1.0 equiv.) in DMF (10.0 mL) were added K2CO3 (709.9 mg, 5.1 mmol, 3.0 equiv.) and compound 1.2 (402.6 mg, 1.7 mmol, 1.0 equiv.). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous NasSCL and concentrated to dryness. The mixture was purified by prep-HPLC to give compound 1.3 (50.0 mg, 0.1 mmol, yield: 5.9%) as a yellow solid. LCMS(ESI)[M+1]+ = 505.3. [0341] Step 2: To a solution of compound 1.3 (50.0 mg, 0.1 mmol, 1 .0 equiv.) in DCM (10.0 mL) and TFA (3.0 mL). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated to give compound 1.4 (35.0 mg, 0.1 mmol, yield: 87.3%) as a white solid.
[0342] Step 3: To a solution of 1.3 (35.0 mg, 0.1 mmol, 1.0 equiv.) in DMF (5.0 mL) were added 1.5 (59.4 mg, 0.1 mmol, 1.0 equiv.), DIEA (45.9 mg, 0.3 mmol, 3.0 equiv.), and I 3P (58.0 mg, 0.2 mmol, 1.2 equiv.). The reaction was stirred at 0 °C for 1 hour. The mixture poured into water (60.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 1 : 2) to give 1.6 (20.0 mg, 50.0 pmol, yield: 19.6%) as a yellow solid. LCMS(ESI)[M+1]+ = 1031.3.
[0343] Step 4: To a solution of compound 1.6 (20.0 mg, 50.0 pmol, 1.0 equiv.) in DCM (2.0 mL) was added HCl/MeOH (2.0 mL). The resulting mixture was stirred at 0 °C for 1 h under N2 atmosphere. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC to give Compound 1 (3.0 mg, 3.0 pmol, yield: 5.6%) as a white solid. Prep-HPLC was performed using a E-Prep LC 012 LH-40 with the following conditions: Column: XBring Prep Phenyl 19*250mm; Temperature: 25 °C; Inject number: 1; Wave length: 254nm/220nm; phase A: H2O (0.1%TFA); phase B: CH3CN; Gradient(%B/time): 15% B 0.01 min; 15% B 4.00 min; 80% B 25.00 min; 95% B 28.00 min; 95% B 34.00. LCMS(ESI)[M+1]+ = 987.3. ’H NMR (400 MHz, DMSO-de) 8 10.76 (s, 1H), 10.21 (s, 1H), 9.59 (s, 1H), 9.14 (s, 1H), 8.06 - 7.93 (m, 1H), 7.71 (s, 1H), 7.50 (m, J= 22.9, 13.8 Hz, 2H), 7.43 - 7.29 (m, 3H), 7.16 (t, J= 27.9 Hz, 3H), 6.96 (d, J = 12.9 Hz, 2H), 5.68 - 5.53 (m, 2H), 5.27 (s, 1H), 4.66 (dd, J = 66.8, 49.3 Hz, 7H), 3.88 (s, 3H), 3.31 (s, 2H), 3.12 (s, 4H), 2.36 - 2.00 (m, 6H), 1.87 (d, J= 60.8 Hz, 5H), 1.54 (s, 3H), 1.24 (s, 1H).
Example 2: Preparation of Compound 2 2.7 .
[0344] Step 1: To a solution of compound 2.1 (10.0 g, 50.2 mmol, 1.0 equiv.) in DMF (100 mL) was added ammonium carbonate (24.1 g, 251.2 mmol, 5.0 equiv.). The reaction was stirred at 80 °C for 16 h. LCMS showed the reaction was completed. The mixture was poured into water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EA = 3 : 1) to give compound 2.2 (5.0 g, 27.8 mmol, yield: 55.4%) as a white solid. LCMS(ESI) [M+l]+ = 180.2.
[0345] Step 2: To a solution of compound 2.2 (5.0 g, 27.8 mmol, 1.0 equiv.) in THF (50.0 mL) and H2O (50.0 mL) was added compound 2.3 (16.5 g, 83.5 mmol, 3.0 equiv.). The reaction was stirred at 75 °C for 16 h. LCMS showed the reaction was completed. The mixture poured into water (150 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 3 : 1) to give compound 2.4 (3.5 g, 17.2 mmol, yield: 61.7%) as a yellow solid. LCMS(ESI) [M+l]+ = 204.0.
[0346] Step 3: To a solution of compound 2.4 (3.5 g, 17.2 mmol, 1.0 equiv.) in DMF (40 mL) were added methanamine (1.5 g, 34.4 mmol, 2.0 equiv.) and DIEA (6.7 g, 51.5 mmol, 3.0 equiv.). The reaction was stirred at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture poured into water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 3 : 1) to give compound 2.5 (2.0 g, 10.1 mmol, yield: 58.7%) as a white solid. LCMS(ESI)[M+1]+ = 199.1. [0347] Step 4: To a solution of compound 2.5 (2.0 g, 10.1 mmol, 1.0 equiv.) in CHCh (20 mL) was added NBS (2.2 g, 12.1 mmol, 1.2 equiv.) at 0 °C. The reaction was stirred at 60 °C for 2 hrs. LCMS showed the reaction was completed. The mixture was concentrated and purified by column chromatography on silica gel to give compound 2.6 (2.0 g, yield: 80.0%) as a yellow solid. LCMS(ESI) [M+l] 1 = 278.9.
[0348] Step 5: To a solution of compound 2.7 (10.0 g, 90.8 mmol, 1.0 equiv.) in acetone (200.0 mL) were added chloro(methoxy)methane (7.3 g, 90.8 mmol, 1.0 equiv.) and K2CO3 (37.6 g, 272.5 mmol, 3.0 equiv.). The reaction was stirred at 25 °C for 24 hours. The mixture poured into water (1000 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were purified by column chromatography on silica gel (PE : EtOAc = 5 : 1) to give compound 2.8 (5.0 g, 25.2 mmol, yield: 27.8%) as yellow oil.
[0349] Step 6: To a solution of compound 2.8 (5.0 g, 32.5 mmol, 1.0 equiv.) in DMF (100.0 mL) was added NBS (5.8 g, 32.5 mmol, 1.0 equiv.). The reaction was stirred at 0 °C for 30 minutes. The mixture poured into water (1000 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 3 : 1) to give compound 2.9 (2.5 g, 232.5 mmol, yield: 41.7%) as a yellow solid. LCMS(ESI) [M+l] + = 231.2.
[0350] Step 7: To a solution of compound 2.9 (2.5 g, 10.7 mmol, 1.0 equiv.) in dioxane (50.0 mL) were added compound 2.10 (3.3 g, 12.8 mmol, 1.2 equiv.), KO Ac (3.2 g, 32.2 mmol, 3.0 equiv.) and Pd(dppf)C12 (0.8 g, 1.1 mmol, 0.1 equiv.). The reaction was stirred at 85 °C for 1 hour. The mixture poured into water (100.0 mL) and extracted with EtOAc (30.0 mLx 3). The combined organic phases were purified by column chromatography on silica gel (PE : EtOAc = 5 : 1) to give compound 2.11 (2.0 g, 7.1 mmol, yield: 66.6%) as a yellow solid.
[0351] Step 8: To a solution of compound 2.6 (2.0 g, 7.2 mmol, 1.0 equiv.) in dioxane (20 mL) and H2O (5.0 mL) were added compound 2.11 (2.0 g, 7.2 mmol, 1.0 equiv.), K2CO3 (3.0 g, 21.6 mmol, 3.0 equiv.) and Pd(dppf)Ch (0.5 g, 0.7 mmol, 0.1 equiv ). The mixture was degassed for three times under N2 atmosphere and stirred at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give compound 2.12 (600.0 mg, 1.7 mmol, yield: 23.7%) as a yellow solid. LCMS(ESI) [M+l]+ = 351.2.
[0352] Step 9: To a solution of compound 2.12 (600.0 mg, 1.7 mmol, 1.0 equiv.) in DMF (10.0 mL) were added K2CO3 (709.9 mg, 5.1 mmol, 3.0 equiv.) and compound 2.13 (402.6 mg, 1.7 mmol, 1.0 equiv.). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 1 : 1) to give compound 2.14 (500.0 mg, 1.0 mmol, yield: 57.9%) as a yellow solid. LCMS(ESI) [M+l]+ = 505.3.
[0353] Step 10: To a solution of compound 2.14 (500.0 mg, 1.0 mmol, 1.0 equiv.) in DCM (10.0 mL) and TFA (3.0 mL). The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated to give compound 2.15 (350.0 mg, 0.9 mmol, yield: 87.3%) as a white solid. LCMS(ESI) [M+l]+ = 405.2.
[0354] Step 11: To a solution of compound 2.15 (100.0 mg, 0.3 mmol, 1.0 equiv.) in DMF (5.0 mL) were added compound 2.16 (159.4 mg, 0.3 mmol, 1.0 equiv.), DIEA(95.9 mg, 0.7 mmol, 2.5 equiv.) and T3P (118.0 mg, 0.4 mmol, 1.2 equiv.). The reaction was stirred at 0 °C for 1 hour. The mixture poured into water (60.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE : EtOAc = 1 : 2) to give compound 2.17 (50.0 mg, 0.1 mmol, yield: 19.6%) as a yellow solid. LCMS(ESI) [M+l]+ = 1031.3. [0355] Step 12: To a solution of compound 2.17 (50.0 mg, 0.1 mmol, 1 .0 equiv.) in DCM (2.0 mL) was added HCl/MeOH (2.0 mL). The resulting mixture was stirred at 0 °C for 1 h under N2 atmosphere. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC to give Compound 2 (3.0 mg, 3.0 pmol, yield: 0.3%) as a white solid. Prep-HPLC was performed using a E-Prep LC 012 LH-40 with the following conditions: Column: XBring Prep Phenyl 19*250mm; Temperature: 25 °C; Inject number: 1; Wave length: 254nm/220nm; phase A: H2O (0.1%TFA); phase B: CH3CN; Gradient(%B/time): 15% B 0.01 min; 15% B 4.00 min; 80% B 25.00 min; 95% B 28.00 min; 95% B 34.00. LCMS(ESI) [M/2]+ = 494.3. ’H NMR (400 MHz, DMSO-d6) 6 11.52 (s, 1H), 10.22 (s, 1H), 9.76 (s, 1H), 9.10 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.98 (dd, J= 9.2, 6.0 Hz, 1H), 7.67 (s, 1H), 7.50 - 7.36 (m, 4H), 7.25 (dt, J= 6.1, 3.1 Hz, 3H), 7.03 - 6.97 (m, 2H), 6.20 (q, J = 6.8 Hz, 1H), 5.58 (d, J = 53.7 Hz, 1H), 4.91 (s, 2H), 4.78 - 4.44 (m, 6H), 3.97 (s, 1H), 3.78 (dd, J= 26.1, 17.2 Hz, 6H), 3.31 (d, J= 3.4 Hz, 6H), 2.66 - 2.53 (m, 1H), 2.32 (d, J= 9.3 Hz, 1H), 2.17 (dd, J= 18.4, 9.2 Hz, 2H), 2.06 (d, J = 10.2 Hz, 1H), 1.93 (d, J = 7.0 Hz, 4H), 1.79 (s, 2H).
Example 3: Preparation of Compound 3
Compound 3
[0356] Step 7: To a solution of [(2S)-l-methylpyrrolidin-2-yl]methanol (229 mg, 1.991 mmol) in THF (5 mL) was added NaH (60% dispersion in oil) (191 mg, 7.960 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2 atmosphere. Then, tert-butyl (2S)-4-(7-bromo-6- chloro-2,8-difluoro-quinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (1.0 g, 1.991 mmol) in THF (5 mL) was added the mixture The reaction mixture was stirred at 25 °C for 1 hour under N2 atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dry over Na2SO4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=10:l) to give tert-butyl (2S)-4-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l-carboxylate (600 mg, 1.00 mmol, 50.45% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 599.3. [0357] Step 2'. To a solution of tert-butyl (2S)-4-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-l - methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l -carboxylate (310 mg, 0.518 mmol) in dioxane (10 mL) were added K2CO3 (215 mg, 1.561 mmol), tert-butyl N-[3- cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (377 mg, 0.933 mmol), and di chloropalladium; [1 -(2-diphenylphosphanyl-l-naphthyl)-2-naphthyl]- diphenyl-phosphane (83 mg, 0.104 mmol). The reaction mixture was stirred at 105 °C for 16 hours under N2 atmosphere. Then, the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=10: 1) to give tert-butyl (2S)-4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4- yl]-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-2- (cyanomethyl)piperazine-l -carboxylate (300 mg, 0.370 mmol, 71.49% yield) as a dark red oil. LCMS (ESI) m/z: [M+H]+ 810.1.
[0358] Step 3: To a solution of tert-butyl (2S)-4-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7- fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l -carboxylate (200 mg, 0.247 mmol) in DCM (4 mL) was added TFA (1.5 g, 13.071 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Cis reverse column chromatography (ACN:H2O=2: 1) to give 2-amino-4-[6- chloro-4-[(3S)-3-(cyanomethyl)piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (120 mg, 0.197 mmol, 79.72% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 610.1.
[0359] Step 4: To a solution of 2-(hydroxymethyl)prop-2-enoic acid (50 mg, 0.492 mmol) in DCM (5 mL) were added DIEA (106 mg, 0.821 mmol), T4P (177 mg, 0.493 mmol), and 2-amino- 4-[6-chloro-4-[(3S)-3-(cyanomethyl)piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (100 mg, 0.164 mmol). The reaction mixture was stirred at 25 °C for 15 minutes under air atmosphere. Then the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=8: l) to give 2-amino-4-[6-chloro-4-[(3S)-3- (cyanomethyl)-4-[2-(hydroxymethyl)prop-2-enoyl]piperazin-l-yl]-8-fluoro-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (15 mg, 0.021 mmol, 13.18% yield) as white solid. LCMS (ESI) m/z: [M+H]+ 694.2.
[0360] Step 5: To a solution of 2-amino-4-[6-chloro-4-[(3S)-3-(cyanomethyl)-4-[2- (hydroxymethyl)prop-2-enoyl]piperazin-l-yl]-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile (70 mg, 0.101 mmol) in DCM (5 mL) were added DIEA (39 mg, 0.303 mmol) and methanesulfonic anhydride (53 mg, 0.303 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=8: l) to give 2-[(2S)-4-[7-(2-amino-3-cyano-7-fluoro- benzothiophen-4-yl)-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]quinazolin-4- yl]-2-(cyanomethyl)piperazine-l-carbonyl]allyl methanesulfonate (20 mg, 0.026 mmol, 25.68% yield) as white solid. LCMS (ESI) m/z: [M+H]+ 771.4.
[0361] Step 6: To a solution of 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol (7 mg, 0.021mmol) in DMF (2 mL) was added CS2CO3 (0.019 mg, 0.058 mmol). The reaction mixture was stirred at 25 °C for 10 minutes under air atmosphere. Then, 2-[(2S)-4-[7-(2-amino-3- cyano-7-fluoro-benzothiophen-4-yl)-6-chloro-8-fluoro-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-4-yl]-2-(cyanomethyl)piperazine-l-carbonyl]allyl methanesulfonate (15 mg, 0.019 mmol) was added. The mixture was stirred at 35 °C for 2 h. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=7:l) to give 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)-4-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((S)-l-methylpyrrolidin- 2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1.6 mg, 0.001 mmol, 8.30% yield) as white solid. 'H NMR (400 MHz, DMSO-d6) 8 8.12 (s, 3H), 7.29 - 7.21 (m, 1H), 7.16 (td, J = 9.0, 3.1 Hz, 1H), 6.90 (d, J = 6.0 Hz, 3H), 6.60 - 6.44 (m, 4H), 5.70 - 5.24 (m, 2H), 4.88 (d, J = 64.5 Hz, 1H), 4.56 (s, 2H), 4.38 (s, 1H), 4.21 (d, J = 10.7 Hz, 3H), 3.73 (s, 3H), 3.63 (d, J = 9.3 Hz, 9H), 2.94 (d, J = 8.6 Hz, 2H), 2.63 - 2.56 (m, 1H), 2.36 (s, 3H), 2.20 - 2.15 (m, 1H), 1.95 (dd, J = 11.0, 6.9 Hz, 1H), 1.72 - 1.60 (m, 3H). LCMS (ESI) m/z: [M+H]+ 991.5. Example 4: Preparation of Compound 4
Boc
[0362] Step 1 To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (4.5 g, 13.620 mmol) in dioxane (15 mL) were added tert-butyl (S)-2-(cyanomethyl)piperazine-l-carboxylate (3.4 g, 14.980 mmol) and DIPEA (5.3 g, 40.860 mmol). The reaction solution was stirred at rt for 0.5 hr. The reaction mixture was purified by flash chromatography (eluting with DCM:EtOAc=100:0 to 85: 15) to give tert-butyl (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin- 4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (9.5 g, 12.810 mmol, 94.03% yield, 70% purity) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 520.2.
[0363] Step 2: To a solution of tert-butyl (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4- yl)-2-(cyanomethyl)piperazine-l -carboxylate (8.0 g, 15.410 mmol) in DMA (160 m ) was added KF (35.8 g, 616.340 mmol), and the reaction solution was stirred at 120 °C for 18 h under N2. The reaction was quenched with NaCl aq. and extracted with DCM, the organic layer was concentrated under reduce pressure, and the residue was purified by flash chromatography (eluting with DCM:EtOAc=100:0 to 70:30) to give tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin- 4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (5.4 g, 10.740 mmol, 69.71% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 504.1.
[0364] Step 3 To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (238 mg, 1.490 mmol) in THF (3 m ) was added NaH (60% dispersion in oil) (159 mg, 3.980 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under N2 atmosphere. Then, tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (500 mg, 0.995 mmol) in THF (5 mL) was added the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 10 minutes under N2 atmosphere. The mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM:MeOH=15: l) to give tert-butyl (S)-4- (7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (500 mg, 0.779 mmol, 78.32% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 643.3.
[0365] Step 4 A solution of tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine- 1-carboxylate (500 mg, 0.779 mmol) in dioxane (8 mL) were added tert-butyl (3-cyano-4-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (340 mg, 0.841 mmol), dichloropalladium; [l-(2-diphenylphosphanyl-l-naphthyl)-2-naphthyl]-diphenyl- phosphane (75 mg, 0.093 mmol), and K2CO3 (194 mg, 1.400 mmol). The reaction was stirred at 105 °C for 16 h under N2. The reaction mixture was concentrated to provide a residue, which was purified by filtering with (DCM:MeOH=15: l) to give tert-butyl (2S)-4-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2- (cyanomethyl)piperazine-l -carboxylate (480 mg, 0.562 mmol, 72.37% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 853.3.
[0366] Step 5: To a solution of tert-butyl (2S)-4-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano- 7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate (480 mg, 0.562 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to provide a residue, which was purified by Cis column to give
2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-
3-carbonitrile (250 mg, 0.383 mmol, 68.05% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 653.3.
[0367] Step 6: To a solution of 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)piperazin-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7- fluorobenzo[b]thiophene-3-carbonitrile (250 mg, 0.383 mmol) in DCM (5 mL) were added 2- (hydroxymethyl)prop-2-enoic acid (117 mg, 1.148 mmol), DIPEA(198 mg, 1.531 mmol), and T4P (276 mg, 0.766 mmol). The mixture was stirred at 25 °C for 10 minutes. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (DCM:MeOH=10:l) to give 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)-4-(2-
(hydroxymethyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (200 mg, 0.271 mmol, 70.88% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 737.3.
[0368] Step 7 A solution of 2-amino-4-(6-chloro-4-((S)-3-(cyanomethyl)-4-(2- (hydroxymethyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (200 mg, 0.271 mmol) in DCM (4 mL) were added DIPEA (140 mg, 1.084 mmol) and methyl sulfonyl methanesulfonate (142 mg, 0.814 mmol). The reaction was stirred at 25 °C for 16 h. The reaction mixture was concentrated to provide a residue which was purified by filtering with (DCM:MeOH=10:l) to give 2-((2S)-4-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-2-(cyanomethyl)piperazine-l-carbonyl)allyl methanesulfonate (100 mg, 0.123 mmol, 45.21% yield) as white solid. LCMS (ESI) m/z: [M+H]+ 815.4.
[0369] Step 8: To a solution of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (39 mg, 0.123 mmol) in DMF (3 mL) was added CS2CO3 (120 mg, 0.368 mmol). The mixture was stirred at 25 °C for 1 h. Then, 2-((2S)-4-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2- (cyanomethyl)piperazine-l-carbonyl)allyl methanesulfonate (100 mg, 0.123 mmol) in DMF (1 mL) was added to the mixture. The mixture was stirred at 35 °C for 2 h. The mixture was concentrated to provide a residue which was purified by Prep-TLC (DCM:MeOH=10: 1) to give crude product. The crude product was purified by Prep-HPLC to give 2-amino-4-(6-chloro-4-((S)- 3-(cyanomethyl)-4-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene- 3-carbonitrile (4.8 mg, 0.005 mmol, 3.69% yield) as a white solid. (400 MHz, DMSO- d6) 8 8.13 (s, 2H), 8.01 (s, 1H), 7.29 - 7.21 (m, 1H), 7.20 - 7.11 (m, 1H), 6.95 - 6.85 (m, 3H), 6.61 - 6.44 (m, 4H), 5.67 - 5.18 (m, 3H), 5.05 - 4.72 (m, 1H), 4.55 (d, J = 16.0 Hz, 2H), 4.44 - 4.16 (m, 2H), 4.16 - 3.99 (m, 3H), 3.74 (s, 4H), 3.63 (d, J = 8.0 Hz, 11H), 3.15 - 2.95 (m, 5H), 2.86 - 2.77 (m, 1H), 2.18 - 1.97 (m, 3H), 1.88 - 1.71 (m, 3H). LCMS (ESI) m/z: [M+H]+ 1035.6.
Example 5: Preparation of Compound 5
Compound 5
[0370] Step . To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.1 g, 4.221 mmol) in DCM (16 mL) was added DIEA (1.8 mL, 10.541 mmol) at -40 °C. The mixture was stirred at -40 °C for 15 min. Then tert-butyl (S)-2-(cyanomethyl)piperazine-l -carboxylate (950 mg, 4.221 mmol) (dissolved in DCM (4 mL) was added and stirred at -40 °C for 1 h. The reaction mixture was diluted with DCM (40 mL) quenched with water (40 mL), washed with brine (40 mL), and dried over anhydrous Na2SO4. The combined organic layers were concentrated under reduced pressure to give tert-butyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)piperazine-l-carboxylate (1.8 g, 96%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 441.1.
[0371] Step 2: To a mixture of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methanol (649 mg, 4.081 mmol) in THF (8 mL) was added NaH (326 mg, 8.162 mmol, 60% purity) at 0 °C. The mixture was stirred at rt for 15 min to give mixture A. To a mixture of tertbutyl (S)-2-(cyanomethyl)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-l- carboxylate (1.8 g, 4.081 mmol) in THF (40 mL) was added mixture A at 0 °C. The mixture was stirred at rt for 1.5 h. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 mL), washed with brine (50 mL), and dried over anhydrous Na2SO4. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (DCM) to give tert-butyl (S)-4-(7-chloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 2-(cyanomethyl)piperazine-l -carboxylate (1.7 g, 73%) as a yellow solid. LCMS (ESI) m/z: [M+Na]+ 564.3. [0372] Step 3: To a solution of tert-butyl (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-
(cyanomethyl)piperazine-l -carboxylate (900 mg, 1.601 mmol) in MeOH (10 mL) was added HC1 (4 M, 15 mL). The mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjust to pH 8 with NaHCCh, then was concentrated under reduced pressure to give another residue. The residue was dissolved with DCM and filtered. The filtrate was concentrated in vacuo to afford 2-((S)-4-(7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazin-2-yl)acetonitrile (700 mg, 94%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 464.3. [0373] Step 4: To a mixture of 2-((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (700 mg, 1.512 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)naphthalen-l -yl)ethynyl)triisopropylsilane (1.0 g, 1.963 mmol) in dioxane (20 mL) and water (8 mL) were added CS2CO3 (1.5 g, 4.531 mmol) and Pd(dppf)Ch.CH2C12 (185 mg, 0.226 mmol) . The mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (5% MeOH in DCM(0.5% TEA)) to give 2-((S)-4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (300 mg, 24%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 814.2.
[0374] Step 5: To a solution of 2-((S)-4-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (250 mg, 0.307 mmol) in THF (4 mL) was added TBAF (1 M, 0.921 mmol, 0.9 mL). The mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (6% MeOH in DCM) to give 2-((S)-4- (7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2- yl)acetonitrile (200 mg, 99%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 658.4.
[0375] Step 6: To a solution of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-
(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (150 mg, 0.228 mmol) and 2-(hydroxymethyl)acrylic acid (70 mg, 0.684 mmol) in DCM (5 mL) were added DIEA (118 mg, 0.912 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide (164 mg, 0.456 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was quenched with water, extracted with ethyl acetate (3 x 15 mL), washed with brine (30 mL), dried over anhydrous Na2SO4. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (8% MeOH in DCM) to give 2-((S)-4-(7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2- (hydroxymethyl)acryloyl)piperazin-2-yl)acetonitrile (110 mg, 65%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 742.5.
[0376] Step 7: To a solution of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-
(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-(hydroxymethyl)acryloyl)piperazin-2- yl)acetonitrile (90 mg, 0.121 mmol) in DCM (4 mL) were added TEA (37 mg, 0.364 mmol), pyridine (29 mg, 0.364 mmol) and DMAP (15 mg, 0.121 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure to give 2-((S)-2- (cyanomethyl)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R,7aS)-2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperazine-l-carbonyl)allyl methanesulfonate (90 mg, crude) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 820.5.
[0377] Step 8: To a mixture of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (52 mg, 0. 165 mmol) in ACN (3 mL) was added CS2CO3 (107 mg, 0.329 mmol). The mixture was stirred at rt for 30 min. Then 2-((S)-2-(cyanomethyl)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- I-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperazine-l-carbonyl)allyl methanesulfonate (90 mg, 0.110 mmol) was added and stirred at 60 °C for 1 h. The mixture was fdtered and the fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (MeOH/DCM=l/15) to give 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-
(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l- (2-((2-methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-2- yl)acetonitrile (60 mg, 52%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 1040.6.
[0378] Step 9: To a solution of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-
(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-2-yl)acetonitrile (60 mg, 0.058 mmol) in formic acid (3 mL) was stirred at rt for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 2-((S)-4-(7-(8-ethynyl- 7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)acryloyl)piperazin-2-yl)acetonitrile (18.1 mg) as a light yellow solid. ‘HNMR (400 MHz, DMSO-d6) 5 10.20 (s, 1H), 9.12 (s, 1H), 7.99 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.20 (t, J = 3.2 Hz, 1H), 6.96 - 6.86 (m, 3H), 6.61 - 6.43 (m, 4H), 5.74 - 5.19 (m, 3H), 5.00 - 4.75 (m, 1H), 4.66 - 4.34 (m, 4H), 4.30 - 3.89 (m, 4H), 3.86 - 3.67 (m, 5H), 3.63 (s, 10H), 3.20 - 2.98 (m, 5H), 2.90 - 2.79 (m, 1H), 2.16 - 2.11 (m, 1H), 2.08 - 1.98 (m, 2H), 1.88 - 1.74 (m, 3H). LCMS (ESI) m/z: [M+H] 1 996.6.
Example 6: Preparation of Compound 6
[0379] Step 1 To a solution of 5-bromo-2-iodo-phenol (3.0 g, 10.040 mmol) in THF (40 mL) at 0 °C was added NaH (60% dispersion in oil) (802 mg, 20.070 mmol). The mixture was stirred at 0 °C for 15 min, and bromo(methoxy)methane (1.6 g, 13.050 mmol) was added dropwise at 0 °C. The mixture was stirred for 30 min at 0 °C, quenched with water (10 mL), and extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (30 mL) three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 98:2) to give 4-bromo-l-iodo-2- (methoxymethoxy)benzene (3.4 g, 9.910 mmol, 98.78% yield). *HNMR (400 MHz, Chloroform- d) 8 7.54 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 5.16 (s, 2H), 3.45 (s, 3H).
[0380] Step 2: To a solution of 4-bromo-l-iodo-2-(meth oxymethoxy )benzene (3.5 g, 10.210 mmol), 2-trimethylsilylethanol (6.0 g, 51.030 mmol), Cui (388 mg, 2.040 mmol), 1,10- phenanthroline (735 mg, 4.080 mmol), and CS2CO3 (10.0 g, 30.620 mmol) in toluene (30 mL). The reaction was submitted to microwave irradiation for 60 minutes at 120 °C. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 98:2) to give 2-[4-bromo-2-(methoxymethoxy)phenoxy]ethyl- trimethyl -silane (1.2 g, 3.600 mmol, 35.28% yield). 'H NMR (400 MHz, Chloroform-d) 8 7.21 - 7.16 (m, 1H), 7.00 (dd, J = 8.6, 2.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.11 (s, 2H), 4.06 - 3.95 (m, 2H), 3.43 (s, 3H), 1.14 - 1.04 (m, 2H).
[0381] Step 3: To a solution of 2-[4-bromo-2-(methoxymethoxy)phenoxy]ethyl-trimethyl- silane (1.6 g, 4.80 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.8 g, 7.200 mmol), cyclopentyl(diphenyl)phosphane;dichloropalladium; iron (526 mg, 0.720 mmol) and KOAc (2.8 g, 28.080 mmol) in dioxane (20 mb). The resulting mixture was refluxed for 12 h. The solid was removed through a Celite® pad and washed with EtOAc (3 mb x 3). The filtrate and washings were combined and evaporated to give a yellow oil, which was chromatographed on SiCh (15 g, n-hexane/acetone = 5/1) to give (2-(2- (methoxymethoxy)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)ethyl)trimethylsilane (900 mg, 2.370 mmol, 49.29% yield). ’H NMR (400 MHz, Chloroform-d) 8 7.42 (d, J = 1.6 Hz, 1H), 7.40 - 7.35 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.15 (s, 2H), 3.45 (s, 3H), 1.24 (s, 13H), 1.20 - 1.09 (m, 5H), 0.01 (s, 9H).
[0382] Step 4: To a solution of 2-imidazol-l-ylaniline (1.0 g, 6.280 mmol) and CDI (1.1 g, 6.910 mmol) in 1,2-di chlorobenzene (16 mb). The reaction was irradiated in the microwave at 180 °C for 30 min. The reaction solution was cooled to 0 °C and filtrated. The filter cake was washed with toluene, PE and water and then dried over in vacuum to provide 5H-imidazo[l,2- a]quinoxalin-4-one (1.0 g, 5.400 mmol, 85.96% yield). LCMS (ESI) m/z: [M+H]+ 186.24.
[0383] Step 5: To a solution of 5H-imidazo[l,2-a]quinoxalin-4-one (300 mg, 1.620 mmol) in POC13 (5 mb). The reaction was stirred in 110 °C for 16 h. The reaction solution was concentrated under vacuum , washed with DCM, and filtrated. The filtrate was concentrated under reduced pressure to give 4-chloroimidazo[l,2-a]quinoxaline (300 mg, 1.470 mol, 90.94% yield). LCMS (ESI) m/z: [M+H]+ 204.22.
[0384] Step 6: To a solution of 4-chloroimidazo[l,2-a]quinoxaline (400 mg, 1.960 mmol) and methylamine (1.2 g, 39.290 mmol) in EtOH (5 mb). The reaction was submitted to microwave irradiation for 30 minutes at 100 °C. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc =70:30) to give N- methylimidazo[l,2-a]quinoxalin-4-amine (200 mg, 1.010 mmol, 51.36% yield). LCMS (ESI) m/z: [M+H]+ 199.31. [0385] Step 7: To a solution of N-methylimidazo[l,2-a]quinoxalin-4-amine (180 mg, 0.908 mmol) and NBS (129 mg, 0.726 mmol) in chloroform (5 mL) . The reaction was stirred at reflux for 40 min. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate, washed twice with a saturated aqueous NH4CI solution, saturated aqueous NaHCO.i solution, distilled water, brine, then dried over Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 70:30) to give l-bromo-N-methyl-imidazo[l,2-a]quinoxalin-4-amine (100 mg, 0.360 mmol, 39.74% yield). LCMS (ESI) m/z: [M+H]+ 277.21.
[0386] Step 8: To a solution of 2-[2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy]ethyl-trimethyl-silane (82 mg, 0.217 mmol), 1-bromo-N-methyl- imidazo[l,2-a]quinoxalin-4-amine (50 mg, 0.180 mmol), Na2CC>3 (38 mg, 0.360 mmol), and palladium;triphenylphosphine (21 mg, 0.018 mmol) in H2O (2 mL) and DME (2 mL). The reaction was irradiated in a microwave at 120 °C for 1 h. The reaction solution was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 60:40) to give l-(3-(methoxymethoxy)-4-(2-
(trimethylsilyl)ethoxy)phenyl)-N-methylimidazo[l,2-a]quinoxalin-4-amine (30 mg, 0.066 mmol, 36.90% yield). LCMS (ESI) m/z: [M+H]+451.56.
[0387] Step 9: To a solution of l-(3-(methoxymethoxy)-4-(2-(trimethylsilyl)ethoxy)phenyl)- N-methylimidazo[l,2-a]quinoxalin-4-amine (30 mg, 0.066 mmol) in THF was added TBAF (1.0 M in THF) (26 mg, 0.099 mmol). The reaction was stirred in 25 °C for 2 h. The resulting mixture was quenched with water and extracted with EtOAc (30 mL * 3). The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PE: EtOAc = 50:50) to obtain 2-(methoxymethoxy)-4-(4-(methylamino)imidazo[ 1,2- a]quinoxalin-l-yl)phenol (20 mg, 0.057 mmol, 85.74% yield). LCMS (ESI) m/z: [M+H]+ 351.49. [0388] Step 10: To a solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl methanesulfonate (6.13) (45 mg, 0.056 mmol) in ACN (5 mL) was added CS2CO3 (73 mg, 0.223 mmol). Compound 6.13 was prepared from Int-D in the same manner as 5.12 was prepared from 5.9. The mixture was stirred at 25 °C for 10 minutes. Then 2-(methoxymethoxy)-4-(4-(methylamino)imidazo[ 1,2- a]quinoxalin-l-yl)phenol (20 mg, 0.056 mmol) in ACN (2 mL) was added to the mixture. The mixture was stirred at 60 °C for 3 h. The reaction solution was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH=90: 10) to give l-(3-(7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2-((2-(methoxymethoxy)-4-(4-(methylamino)imidazo[l,2- a]quinoxalin-l-yl)phenoxy)methyl)prop-2-en-l-one (45 mg, 0.042 mmol, 76.04% yield). LCMS (ESI) m/z: [M+H] + 1061.6.
[0389] Step 11: To a solution of l-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-
1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2-(methoxymethoxy)-4-(4- (methylamino)imidazo[l,2-a]quinoxalin-l-yl)phenoxy)methyl)prop-2-en-l-one (45 mg, 0.042 mmol) in formic acid (5 mL). The reaction was stirred in 25 °C for 3 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give the residue which was further purified by Prep-HPLC to give l-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-
2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2-hydroxy-4-(4-(methylamino)imidazo[l,2-a]quinoxalin- l-yl)phenoxy)methyl)prop-2-en-l-one (13 mg, 0.013 mmol, 30.69% yield). 'H NMR (400 MHz, DMSO-de) 8 9.61 (s, 1H), 9.06 (s, 1H), 7.98 (dd, J= 9.2, 6.0 Hz, 1H), 7.75 - 7.66 (m, 1H), 7.59 (dd, J = 8.1, 1.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.35 - 7.26 (m, 2H), 7.22 - 7.15 (m, 2H), 7.02 - 6.93 (m, 3H), 5.85 (s, 1H), 5.64 (s, 1H), 5.39 - 5.17 (m, 1H), 4.89 (s, 2H), 4.84 - 4.41 (m, 4H), 4.13 (d, J = 10.4 Hz, 1H), 4.07 - 3.88 (m, 3H), 3.67 (s, 2H), 3.11 - 3.03 (m, 5H), 3.01 (s, 1H), 2.88 - 2.78 (m, 1H), 2.18 - 2.08 (m, 1H), 2.07 - 1.94 (m, 3H), 1.90 - 1.73 (m, 6H). LCMS (ESI) m/z: [M+H]+ 973.6.
Example 7: Preparation of Compound 7
[0390] Step 1 To a solution of 7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-l,3-dihydroquinoxalin-2-one (750 mg, 2.310 mmol) and tert-butyl 2-bromoacetate (674 mg, 3.460 mmol) in DMF (15 mb) was added K2CO3 (955 mg, 6.920 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The mixture was concentrated and purified by silica gel chromatography (eluting with 1/7 MeOH/DCM) to afford tert-butyl 2-[7-methoxy-4- [2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l- yl]acetate (370 mg, 0.841 mmol, 36.52% yield). LCMS (ESI) m/z: [M+H]+ 440.3.
[0391] Step 2: To a solution of tert-butyl 2-[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]acetate (370 mg, 0.841 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise. The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum and purified on a Biotage Isolera One (Cl 8 column, eluting with 5% to 95% ACN/H2O) to afford 2-[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]acetic acid (150 mg, 0.391 mmol, 46.47% yield). LCMS (ESI) m/z: [M+H]+ 384.2.
[0392] Step 3 A mixture of 2-[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]acetic acid (150 mg, 0.391 mmol), tert butyl 2-(hydroxyrnethyl)prop-2-enoate (185 mg, 1.170 mmol), DPPA (194 mg, 0.704 mmol), and TEA (79 mg, 0.782 mmol) in toluene (6 mL) was heated at 85 °C for 3 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was purified by silica gel chromatography (eluting with 3/97 MeOH/DCM) to afford tert-butyl 2-[[7-methoxy-4-[2-(methylamino)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l- yl]methylcarbamoyloxymethyl]prop-2-enoate (90 mg, 0.167 mmol, 42.71% yield). LCMS (ESI) m/z: [M+H]+ 539.4.
[0393] Step 4 A solution of tert-butyl 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoate (90 mg, 0.167 mmol) in formic acid (3 mL) was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum and purified on a Biotage Isolera One (C 18 column, eluting with 5% to 95% ACN/H2O) to afford 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoic acid (35 mg, 0.072 mmol, 43.41% yield). LCMS (ESI) m/z: [M+H] 1 483.3.
[0394] Step 5 To a solution of 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoic acid (35 mg, 0.072 mmol) in DCM (3 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en- 1-amine (39 mg, 0.290 mmol). The resulting mixture was stirred at rt for 1 hour. The reaction was quenched with MeOH. The mixture was concentrated and used directly in the next step. LCMS (ESI) m/z: [M+ Na]+ 497.4.
[0395] Step 6: To a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-l-yl]-2-[[(2S)- l-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (53 mg, 0.093 mmol) in DCM were added 2-chlorocarbonylallyl N-[[7-methoxy-4-[2- (methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l- yl]methyl]carbamate (36 mg, 0.072mmol) and 2,6-lutidine (23 mg, 0.215 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 5 min. The crude product was purified by silica gel chromatography (eluting with 1/8 MeOH/DCM) and prep-HPLC to afford 2-((3S)-4-(7-(6-amino- 4-methyl-3-(tri fluoromethyl )pyri din-2 -yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-l-carbonyl)allyl ((7 -methoxy -4-(2-
(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxo-3,4-dihydroquinoxalin- l(2H)-yl)methyl)carbamate (3 mg, 0.003 mmol, 4.45% yield). 1 H NMR (400 MHz, DMSO-de) 5 8.11 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 6.93 - 6.74 (m, 3H), 6.61 (m, 2H), 6.50 (s, 1H), 5.49 (s, 1H), 5.28 (m, 3H), 4.67 (s, 3H), 4.46 (s, 2H), 4.38 (m, 1H), 4.17 (m, 2H), 3.95 (m, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 2.94 (m, 1H), 2.77 (m, 3H), 2.60 - 2.52 (m, 4H), 2.36 (m, 6H), 2.17 (m, 1H), 1.96 (m, 3H), 1.67 (m, 5H), 1.24 (m, 3H). LCMS (ESI) m/z: [M+H]+ 1032.6.
Example 8: Preparation of Compound 8
Corapotffid 8
[0396] Step I To a solution of l-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-(hydroxymethyl)prop-2-en-l-one (100 mg, 0.137 mmol) in DCM (3 mL) were added TEA (42 mg, 0.411 mmol), pyridine (33 mg, 0.412 mmol), DMAP (17 mg, 0.137 mmol), and methanesulfonyl chloride (62.87 mg, 0.548 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under air atmosphere. Then the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over NajSCL, filtered and concentrated to provide a residue which was used for next step. LCMS (ESI) m/z: [M+H]‘ 807.5.
[0397] Step 2'. To a solution of 2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5-yl]phenol (22 mg, 0.062 mmol) in ACN (1 m ) was added CS2CO3 (50 mg, 0.154 mmol). The reaction mixture was stirred at 25 °C for 15 minutes under air atmosphere. Then 2-[3-[7-[8-ethynyl-7- fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carbonyl]allyl methanesulfonate (50 mg, 0.062 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours under N2 atmosphere. Then the mixture was filtered and concentrated to provide a residue which was purified by silica gel column chromatography (DCM: MeOH=10: 1) to give l-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2R,8S)-2- fhioro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octan-8-yl]-2-[[2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5- yl]phenoxy]methyl]prop-2-en-l-one (40 mg, 0.037 mmol, 60.38% yield) as white solid. LCMS (ESI) m/z: [M+H]+ 209.1.
[0398] Step 3 To l-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[[2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5- yl]phenoxy]methyl]prop-2-en-l-one (40 mg, 0.037 mmol) was added formic acid (1.2 g, 26.491 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep-HPLC to give l-[3- [7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]-2-[[2-methoxy-5-[l-(3,4,5-trimethoxyphenyl)tetrazol-5-yl]phenoxy]methyl]prop-2-en-l-one (15 mg, 0.014 mmol, 39.37% yield) as white solid. 'H NMR (400 MHz, DMSO-d6) 8 10.17 (s, 1H), 9.05 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 7.01 (s, 2H), 5.66 (s, 1H), 5.54 (s, 1H), 5.39 - 5.18 (m, 1H), 4.80 - 4.37 (m, 6H), 4.09 (dd, J = 37.8, 10.4 Hz, 2H), 3.93 (s, 1H), 3.83 (d, J = 26.4 Hz, 1H), 3.75 (d, J = 1.7 Hz, 12H), 3.67 (s, 1H), 3.08 (dd, J = 24.2, 13.6 Hz, 3H), 2.83 (dd, J = 15.3, 8.0 Hz, 1H), 2.14 (d, J = 5.2 Hz, 1H), 2.09 - 1.99 (m, 2H), 1.82 (dd, J =
22.3, 12.6 Hz, 7H). LCMS (ESI) m/z: [M+Hf 1025.6.
Example 9: Preparation of Compound 9
[0399] Step 1: To a solution of (6-methoxy-2-methyl-lH-indol-3-yl)-(3,4,5- trimethoxyphenyl)methanone (880 mg, 2.480 mmol) in DMF (10 mL) were added tert-butyl 2- bromoacetate (628 mg, 3.220 mmol) and K2CO3 (684 mg, 4.950 mmol). The mixture was stirred at 60 °C for 2 h. The mixture was quenched by sat. aq. citric acid (150 mL), and extracted with DCM (containing 10% methanol, 150 mLx4). The combined organic layers were dried by Na2SO4, filtered and concentrated under reduce pressure to give residue. The residue was purification by flash silica gel (80 g, EtOAc /PE=0~50%) to give tert-butyl 2-[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]acetate (800 mg, 1.700 mmol, 68.81% yield). LCMS (ESI) m/z: [M+H-56]+ 470.3.
[0400] Step 2: To a solution of tert-butyl 2-[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]acetate (800 mg, 1.700 mmol) in DCM and TFA. The reaction was stirred in 25 °C for 1 h. The mixture was concentrated and purified by reversed-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 80% in 30 min) and the fractions containing the product were combined and lyophilized to give 2-[6-methoxy-2- methyl-3-(3,4,5-trimethoxybenzoyl)indol-l-yl]acetic acid (350 mg, 0.846 mmol, 49.69% yield). LCMS (ESI) m/z: [M+H-56]+ 414.2.
[0401] Step 3 To a stirred solution of 2-[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]acetic acid (100 mg, 0.242 mmol), tert-butyl 2- (hydroxymethyl)prop-2-enoate (115 mg, 0.726 mmol), TEA (49 mg, 0.484 mmol), and DPPA(120 mg, 0.435 mmol) in toluene (5 mL) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 85 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography (DCM:MeOH= 98:2) to give tert-butyl 2-[[6-methoxy-2- methyl-3-(3,4,5-trimethoxybenzoyl)indol-l-yl]methylcarbamoyloxymethyl]prop-2-enoate (120 mg, 0.211 mmol, 87.25% yield). LCMS (ESI) m/z: [M+H]+ 569.4.
[0402] Step 4.' To a solution of tert-butyl 2-[[6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)indol-l-yl]methylcarbamoyloxymethyl]prop-2-enoate (60 mg, 0.106 mmol) in formic acid (5 mL). The reaction was stirred in 25 °C for 3 h. The mixture was purified by reversed-phase column (Mobile phase: A: 0.5% Formic acid in water, B Acetonitrile; B from 5% to 80% in 30 min) and the fractions containing the product were combined and lyophilized to give 2-[[6-m ethoxy -2-methyL3-(3, 4, 5-trimethoxybenzoyl)indol-l- yl]methylcarbamoyloxymethyl]prop-2-enoic acid (30 mg, 0.058 mmol, 55.47% yield). LCMS (ESI) m/z: [M+H]+ 513.3.
[0403] Step 5: To a solution of 2-[[6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)indol-l- yl]methylcarbamoyloxymethyl]prop-2-enoic acid (60 mg, 0.117 mmol) in DCM (3 mL) was added a solution of l-chloro-N,N,2-trimethylpropenylamine (31 mg, 0.234 mmol) in DCM (2 mL) at 0 °C slowly. The reaction was stirred in 25 °C for 1 hour under N2. The mixture was used to next step without further work-up.
[0404] Step 6: To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (73 mg, 0.113 mmol) and 2,6-dimethylpyridine (12 mg, 0.113 mmol) in DCM (4.99 mL) was added 2-chlorocarbonylallyl N-[[6-methoxy-2-methyl- 3-(3,4,5-trimethoxybenzoyl)indol-l-yl]methyl]carbamate (60 mg, 0.113 mmol). The reaction was stirred in 25 °C for 1 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l -yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl ((6-methoxy-2-methyl-3-(3,4,5- trimethoxybenzoyl)-lH-indol-l-yl)methyl)carbamate (40 mg, 0.035 mmol, 31.07% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 1139.6.
[0405] Step 7: To a solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl ((6-methoxy-2-methyl-3- (3,4,5-trimethoxybenzoyl)-lH-indol-l-yl)methyl)carbamate (40 mg, 0.035 mmol) in formic acid (5 mL). Th reaction was stirred in 25 °C for 3 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give the residue, which was further purified by Prep- HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carbonyl)allyl ((6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)- lH-indol-l-yl)methyl)carbamate (9 mg, 0.008 mmol, 23.67% yield) as a white solid. !H NMR (400 MHz, DMSO-d6) 8 10.25 (s, 1H), 9.01 (s, 1H), 8.69 - 8.55 (m, 1H), 8.01 - 7.88 (m, 1H), 7.46 (d, J = 12.0 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.34 (s, 1H), 7.29 - 7.19 (m, 2H), 6.92 (s, 2H), 6.72 (d, J= 8.7 Hz, 1H), 5.62 (s, 1H), 5.57 - 5.38 (m, 3H), 5.27 (d, J= 54.3 Hz, 1H), 4.92 - 4.16 (m, 6H), 4.11 (d, .7 = 8.0 Hz, 1H), 4.O1 (d, J= 12.0 Hz, 1H), 3.91 (s, 1H), 3.80 (s, 3H), 3.74 (d, 7= 4.3 Hz, 9H), 3.62 (s, 2H), 3.14 - 3.06 (m, 3H), 3.05 - 2.98 (m, 2H), 2.89 - 2.78 (m, 1H), 2.16 - 1.94 (m, 4H), 1.89 - 1.72 (m, 3H), 1.62 (s, 4H). LCMS (ESI) m/z: [M+H] + 1095.6.
Example 10: Preparation of Compound 10
[0406] Step 7: To a mixture of l-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(hydroxymethyl)prop-2-en-l-one (100 mg, 0.137 mmol), TEA (42 mg, 0.411 mmol), pyridine (32 mg, 0.411 mmol), and DMAP (16 mg, 0.137 mmol) in DCM (5 mL) under N2 was added methanesulfonyl chloride (62 mg, 0.548 mmol), and the mixture was stirred at 25 °C for 1 h. Then the mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl methanesulfonate (95 mg, 0.117 mmol, 85.81% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 807.27.
[0407] Step 2'. To a solution of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (55 mg, 0.176 mmol) in ACN (5 mL) was added CS2CO3 (153 mg, 0.470 mmol). The mixture was stirred at 25 °C for 10 minutes. Then 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl methanesulfonate (95 mg, 0.117 mmol) in ACN (2 mL) was added above the mixture. The mixture was stirred at 60 °C for 3 h. The residue was purified by silica gel column chromatography (2% MeOH in DCM). The residue was further purified by prep-HPLC to give l-(3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2- methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (35 mg, 0.034 mmol, 28.94% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 1027.41.
[0408] Step 3: To l-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- Iluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (35 mg, 0.034 mmol) was added FA (2 mL). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep-HPLC to give l-(3-(7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen- l -yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-l H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-((2- methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (8.8 mg, 0.009 mmol, 26.27% yield) as a white solid. (400 MHz, DMSO-d6) 5 10.29 (s, 1H), 9.05 (s, 1H), 8.04 - 7.92 (m, 1H), 7.52 - 7.34 (m, 2H), 7.19 (s, 1H), 6.96 - 6.83 (m, 3H), 6.62 - 6.42 (m, 4H), 5.62 (s, 1H), 5.51 (s, 1H), 5.40 - 5.18 (m, 1H), 4.80 - 4.35 (m, 6H), 4.19 - 4.10 (m, 1H), 4.09 - 4.00 (m, 1H), 3.97 - 3.78 (m, 2H), 3.68 (s, 3H), 3.64 (s, 3H), 3.63 - 3.59 (m, 6H), 3.48 - 3.41 (m, 1H), 3.15 - 3.06 (m, 2H), 3.02 (s, 1H), 2.88 - 2.80 (m, 1H), 2.17 - 2.10 (m, 1H), 2.09 - 1.98 (m, 2H), 1.96 - 1.73 (m, 7H). LCMS (ESI) m/z: [M+H]+ 983.6.
Example 11: Preparation of Compound 11
[0409] Step 1 To an ice-cooled, stirred solution of 4-(lH-benzimidazol-2-yl)-l,2,5-oxadiazol- 3-amine (3.0 g, 14.910 mmol) in pyridine (20 mL) was added sodium methoxide (1.5 g, 26.840 mmol) and subsequently prop-2-enenitrile (1.1 g, 19.390 mmol). The reaction mixture is stirred at room temperature overnight. The residue was suspended in 100 mL of water and extracted with 4x100 mL of ethyl acetate. The combined organic layers were washed with 2 x 500 mL of brine, dried over Na2SO4, concentrated under vacuum and purified by silica gel column chromatography (PE:EtOAc=3:l) to give 3-((4-(lH-benzo[d]imidazol-2-yl)-l,2,5-oxadiazol-3- yl)amino)propanenitrile (2.5 g, 9.83 mmol, 65.94% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 255.09. [0410] Step 2 To a solution of 3-((4-(lH-benzo[d]imidazol-2-yl)-l ,2,5-oxadiazol-3- yl)amino)propanenitrile (2.5 g, 9.830 mmol) in DMF (50 mL) were added K2CO3 (2.72 g, 19.670 mmol) and 2-bromo-l-(4-nitrophenyl)ethanone (2.9 g, 11.800 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water and extracted with EtOAc, dried over Na2SO4, concentrated under vacuum and purified by silica gel column chromatography (PE/EA=3 : 1) to 3- ((4-(l-(2-(4-nitrophenyl)-2-oxoethyl)-lH-benzo[d]imidazol-2-yl)-l,2,5-oxadiazol-3- yl)amino)propanenitrile (3.0 g, 7.19 mmol, 73.10% yield) as a yellow solid. LCMS (ESI) m/z: [M+H] + 418.12.
[0411] Step 3: To a solution of 3-((4-(l-(2-(4-nitrophenyl)-2-oxoethyl)-lH-benzo[d]imidazol- 2-yl)-l,2,5-oxadiazol-3-yl)amino)propanenitrile (2.5 g, 5.990 mmol) in DCM (20 mL) was added zinc (3.9 g, 59.900 mmol) and AcOH (2 mL) at 25 °C. The reaction mixture was stirred at rt for 5 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM/MeOH = 100:0 to 5:95) to afford 3-((4-(l- (2-(4-aminophenyl)-2-oxoethyl)-lH-benzo[d]imidazol-2-yl)-l,2,5-oxadiazol-3- yl)amino)propanenitrile (1.5 g, 3.870 mmol, 64.64% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 388.14.
[0412] Step 4: A mixture of 3-((4-(l-(2-(4-aminophenyl)-2-oxoethyl)-lH-benzo[d]imidazol- 2-yl)-l,2,5-oxadiazol-3-yl)amino)propanenitrile (310 mg, 0.800 mmol), tert-butyl 2- (hydroxymethyl)prop-2-enoate (379 mg, 2.40 mmol) and triphosgene (308 mg, 1.040 mmol) in DCM (5 mL) was stirred at 0 °C for 5 min. Then, triphosgene (308.70 mg, 1.04 mmol) in DCM (5 mL) was added slowly at 0 °C. The mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1/2 EtOAc/PE) to afford tert-butyl 2-((((4- (2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l- yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylate (220 mg, 0.384 mmol, 48.10% yield). LCMS (ESI) m/z: [M+H]+ 572.22.
[0413] Step 5: To a solution of tert-butyl 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5- oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylate (310 mg, 0.542 mmol) was added DCM (3 mL) and TFA (1 mL), and the reaction was stirred at 25 °C for 30 min. After completion of the reaction (as monitored by LC-MS), the mixture was concentrated under vacuum afford crude 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5- oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylic acid (220 mg, 0.426 mmol, 78.69% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 516.16.
[0414] Step 6: To a solution of 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)- lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylic acid (100 mg, 0.194 mmol) in DCM (6 mL) was added a solution of l-chloro-N,N,2-trimethylprop-l-en-l -amine (155 mg, 1.160 mmol) in DCM (6 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min and then quenched with MeOH. The reaction mixture used in the next step without further purification. LCMS (ESI) m/z: [M+H]+ 534.12.
[0415] Step 7: To a solution of 2-(chlorocarbonyl)allyl (4-(2-(2-(4-((2-cyanoethyl)amino)- l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (100 mg, 0.187 mmol) in DCM (3 mL) were added 2,6-lutidine (60 mg, 0.561 mmol) and 6-(6-chloro-8-fluoro-4- ((S)-2-methylpiperazin-l-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4- methyl-5-(trifluoromethyl)pyridin-2-amine (106 mg, 0.187 mmol) at 0 °C. The reaction was stirred at 25 °C for 0.5 h. The residue was purified by silica gel column chromatography (2% MeOH in DCM) to give a residue. The residue was purified by prep-HPLC to give 2-((3S)-4-(7- (6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3 -methylpiperazine- l-carbonyl)allyl (4-(2-(2- (4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l- yl)acetyl)phenyl)carbamate (2.2 mg, 0.002 mmol, 1.10% yield) as a white solid. ' H NMR (400 MHz, DMSO-d6) 8 10.40 (s, 1H), 8.18 - 8.12 (m, 2H), 7.95 (dd, J = 6.7, 2.3 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.53 - 7.43 (m, 3H), 6.90 (s, 2H), 6.56 (s, 1H), 6.38 (s, 2H), 5.72 (s, 1H), 5.50 (s, 1H), 5.04 - 4.89 (m, 2H), 4.79 (s, 1H), 4.49 - 4.07 (m, 5H), 3.78 - 3.71 (m, 3H), 3.22 - 3.13 (m, 1H), 3.03 - 2.96 (m, 3H), 2.66 - 2.61 (m, 1H), 2.45 - 2.42 (m, 3H), 2.41 - 2.39 (m, 3H), 2.25 - 2.18 (m, 1H), 2.04 - 1.95 (m, 1H), 1.77 - 1.65 (m, 3H), 1.43 - 1.35 (m, 3H). LCMS (ESI) m/z: [M+H]+ 1065.6.
Example 12: Preparation of Compound 12
[0416] Step 1 To a solution of 2-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methylcarbamoyloxymethyl]prop-2- enoic acid (20 mg, 0.041 mmol) in DCM (3 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en- 1 -amine (22 mg, 0.166 mmol). The resulting mixture was stirred at 25 °C for 1 hour. The mixture was concentrated and used directly in the next step. LCMS (ESI) m/z: [M+ Na]+ 497.4.
[0417] Step 2: To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-[8-ethynyl-7-fluoro-3- (methoxy methoxy)- 1 -naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidine (38 mg, 0.059 mmol) in DCM (5 mL) was added 2- chlorocarbonylallyl N-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methyl]carbamate (20 mg, 0.039 mmol) and 2,6-lutidine (13 mg, 0.119 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 5 min. The crude product was purified by silica gel chromatography (eluting with 1/8 MeOH/DCM) to afford 2-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-
3,8-diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[[7-methoxy-4-[2-(methylamino)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl]-2-oxo-3H-quinoxalin-l-yl]methyl]carbamate (19 mg, 0.017 mmol, 42.91% yield). LCMS (ESI) m/z: [M+H]+ 1109.6.
[0418] Step 3: A solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl ((7-methoxy-4-(2-
(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxo-3,4-dihydroquinoxalin- l(2H)-yl)methyl)carbamate (19 mg, 0.017mmol) in formic acid (3 mL) was stirred at 25 °C for 3 hours. The mixture was concentrated under vacuum and purified by prep-HPLC to afford 2-(3-(7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carbonyl)allyl ((7-methoxy-4-(2-(methylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2- oxo-3, 4-dihydroquinoxalin-l(2H)-yl)methyl)carbamate (5 mg, 0.005 mmol, 27.40% yield). !H NMR (400 MHz, DMSO-d6) 8 10.24 (s, 1H), 9.05 (s, 1H), 8.14 (m, 1H), 7.98 (m, 1H), 7.47 (m, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.61 (m, 2H), 5.54 (d, J = 32.1 Hz, 2H), 5.28 (m, 3H), 4.58 (d, J = 97.6 Hz, 8H), 4.17 - 4.00 (m, 2H), 3.92 (s, 1H), 3.78 (s, 3H), 3.69 (s, 2H), 3.13 - 3.06 (m, 2H), 3.02 (s, 1H), 2.84 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.58 (m, 2H), 2.13 (d, J = 4.5 Hz, 1H), 2.03 (m, 4H), 1.89 - 1.63 (m, 9H). LCMS (ESI) m/z: [M+H]+ 1065.7.
Example 13: Preparation of Compound 13
[0419] Step 1 To a solution of 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol (300 mg, 0.948 mmol) in DMF (6 mL) were added bis(4-nitrophenyl) carbonate (720 mg, 2.380 mmol) and DIEA (368 mg, 2.840 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. Then the mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL><3) and the combined organic layers were washed with brine, dried over Na2SC>4. The obtained crude product was subjected to silica gel column chromatography (PE/EtOAc=3:l) to give [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl](4- nitrophenyl) carbonate (400 mg, 0.830 mmol, 87.61% yield) as a yellow oil. LCMS (ESI) m/z: [M+H]+ 482.3.
[0420] Step 2: To a solution of [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] (4-nitrophenyl) carbonate (500 mg, 1.040 mmol) in DCM (5 mL) were added tert-butyl (2S)-2- (methylaminomethyl)pyrrolidine-l -carboxylate (289 mg, 1.350 mmol) and DIEA (403 mg, 3.120 mmol, 0.542 ml) at 25 °C. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (PE/EtOAc =3: 1) to give tert-butyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (500 mg, 0.898 mmol, 86.49% yield) as a transparent oil. LCMS (ESI) m/z: [M+H]+ 556.6.
[0421] Step 3: To a suspension of tert-butyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (500 mg, 0.898 mmol) in DCM (3 mb) was added TFA (1.49 g, 13.070 mmol, 1 m ). The reaction mixture was stirred at 25 °C for 1 h. The crude product was purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give [2-methoxy-5-[(Z)-2- (3,4,5-trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (278 mg, 0.609 mmol, 67.79% yield) as white solid. LCMS (ESI) m/z: [M+H]+ 457.3.
[0422] Step 4'. To a suspension of tert-butyl 2-(hydroxymethyl)prop-2-enoate (322 mg, 2.040 mmol) in DCM (5 mb) was added TEA (137 mg, 1.360 mmol, 0.189 mb). The reaction mixture was stirred at 25 °C for 1 h, and then [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (310 mg, 0.679 mmol) was added. The reaction mixture was stirred at 25 °C for 72 h. The crude product was purified by reversed-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product was combined and lyophilized to give 2-tert- butoxycarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (150 mg, 0.234 mmol, 34.48% yield) as a white oil. LCMS (ESI) m/z: [M+H]+ 641.5.
[0423] Step 5: A suspension of 2-tert-butoxycarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2- (3,4,5-trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carboxylate (150 mg, 0.234 mmol) in formic acid (2 mb) was stirred at 50 °C for 16 h. The crude product was purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give 2-[[(2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carbonyl]oxymethyl]prop-2-enoic acid (80 mg, 0.137 mmol, 58.45% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 585.4.
[0424] Step 6: To a solution of 2-[[(2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carbonyl]oxymethyl]prop-2-enoic acid (45 mg, 0.077 mmol) in DCM (3 mL) was added 1- chloro-N,N,2-trimethyl-prop-l-en-l -amine (21 mg, 0.154 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was used directly in the next step.
[0425] Step 7: To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l -naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahy dropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidine (80 mg, 0.124 mmol) and 2,6-lutidine (27 mg, 0.249 mmol) in DCM (5 mL) was added 2-chlorocarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (50 mg, 0.083 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: 1) to give the residue which was further purified by Prep-HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)- 3, 4, 5-trimethoxystyryl)phenoxy)carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (40 mg, 0.033 mmol, 39.83% yield) as a yellow solid . LCMS (ESI) m/z: [M+H]+ 1211.7.
[0426] Step 8 : A solution of 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)- 3, 4, 5-trimethoxystyryl)phenoxy)carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (40 mg, 0.033 mmol) in formic acid (4 mL) was stirred at 25 °C for 3 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10: l) to give a residue which was further purified by Prep-HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)-3,4,5- trimethoxystyryl)phenoxy)carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (17 mg, 0.015 mmol, 45.66% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 10.32 (s, OH), 9.06 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (dd, J = 13.5, 7.4 Hz, 2H), 6.56 (d, J = 5.5 Hz, 2H), 6.53 - 6.40 (m, 2H), 5.70 - 5.44 (m, 2H), 5.39 - 5.18 (m, 1H), 4.86 - 4.31 (m, 6H), 4.18 - 3.99 (m, 3H), 3.93 (s, 1H), 3.73 (d, J = 2.8 Hz, 6H), 3.62 (dd, J = 7.4, 1.9 Hz, 10H), 3.15 - 3.04 (m, 3H), 3.01 (s, 3H), 2.89-2.82 (m, 3H), 2.14 (d, J = 4.6 Hz, 1H), 2.10 - 1.93 (m, 3H), 1.86-1.75 (m, 12H). LCMS (ESI) m/z: [M+H] + 1167.7.
Example 14: Preparation of Compound 14
Compound 14
[0427] Step 1 To a solution of l-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2- yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazin-l-yl)-2-(hydroxymethyl)prop-2-en-l-one (50 mg, 0.077 mmol) in DCM (3 mL) was added PBn (20.76 mg, 0.077 mmol) in DCM (0.5mL) at 0 °C. The mixture was stirred at 25 °C for 10 minutes. The mixture was diluted with NaHCO? saturated aqueous solution and extracted with DCM, dried over Na2SC>4, and concentrated under vacuum to give crude l-((3S)-4-(7-(6- amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-l -yl)-2-(bromomethyl)prop-2-en-l -one (45 mg, 0.063 mmol, 82.08% yield) as a yellow solid. LCMS (ESI) m/z: [M+H]+ 714.3.
[0428] Step 2'. To a solution of (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (20 mg, 0.063 mmol) in ACN (3 mL) was added K2CO3 (26 mg, 0.189 mmol). The mixture was stirred at 25 °C for 10 minutes. Then l-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro- 8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-l-yl)-2- (brom omethyl)prop-2-en-l -one (45 mg, 0.063 mmol) in ACN (1 mL) was added to the mixture. The mixture was stirred at 60 °C for 3 h. The mixture was concentrated to provide a residue which was purified by Pre-TLC (DCM:MeOH=10: l) to give a crude product. The crude product was purified by Prep-HPLC to give l-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)- 6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin- l-yl)-2-((2-methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)methyl)prop-2-en-l-one (8 mg, 0.009 mmol, 14.04% yield) as a white solid. *HNMR (400 MHz, DMSO-d6) 8 7.78 (s, 1H), 7.00 - 6.78 (m, 5H), 6.62 - 6.42 (m, 5H), 5.55 (s, 1H), 5.33 (s, 1H), 4.81 - 4.44 (m, 3H), 4.39 (ddd, J = 11.7, 7.6, 4.5 Hz, 1H), 4.28 (d, J = 13.5 Hz, 1H), 4.17 (dt, J = 10.8, 7.1 Hz, 1H), 4.01 (s, 1H), 3.74 (d, J = 3.2 Hz, 3H), 3.64 (s, 3H), 3.62 (s, 6H), 3.29 - 3.08 (m, 4H), 2.95 (t, J = 6.6 Hz, 1H), 2.61 (s, 1H), 2.37 (d, J = 10.4 Hz, 6H), 2.18 (q, J = 8.5 Hz, 1H), 1.94 (q, J = 9.0 Hz, 1H), 1.67 (dtd, J = 15.4, 11.7, 10.0, 4.9 Hz, 3H), 1.31 - 1.20 (m, 3H). LCMS (ESI) m/z: [M+H]+ 950.6.
Example 15: Preparation of Compound 15
[0429] Step 1 To a solution of 2-((((4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)- lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamoyl)oxy)methyl)acrylic acid (100 mg, 0.194 mmol) in DCM (3 mb) was added a solution of l-chloro-N,N,2-trimethylprop-l-en-l -amine (78 mg, 0.582 mmol) in DCM (3mL) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min and quenched with MeOH. The reaction mixture used in the next step without further purification. LCMS (ESI) m/z: [M+H]+ 516.16.
[0430] Step 2: To a solution of 2-(chlorocarbonyl)allyl (4-(2-(2-(4-((2-cyanoethyl)amino)- l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (20 mg, 0.037 mmol) in DCM were added 2,6-lutidine (12 mg, 0.112 mmol) and 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (24 mg, 0.037 mmol) at 0 °C. The reaction was stirred at 25 °C for 0.5 h. The residue was purified by silica gel column chromatography (2% MeOH in DCM) to give a residue. The residue was purified by prep- HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (4-(2-(2-(4-((2-cyanoethyl)amino)-l,2,5- oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (10 mg, 0.008 mmol, 23.33% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 1141.42.
[0431] Step 3 To 2-(3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (4-(2-(2-(4-((2- cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate
(120 mg, 0.052 mmol) was added formic acid (2 mb). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep-HPLC to give 2-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)allyl (4-(2-(2-(4-((2- cyanoethyl)amino)-l,2,5-oxadiazol-3-yl)-lH-benzo[d]imidazol-l-yl)acetyl)phenyl)carbamate (5 mg, 0.004 mmol, 8.67% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6)5 10.34 (s, 1H), 9.08 (s, 1H), 8.14 - 8.00 (m, 2H), 7.97 - 7.86 (m, 2H), 7.84 - 7.77 (m, 1H), 7.74 - 7.65 (m, 2H), 7.49 - 7.34 (m, 5H), 7.21 - 7.11 (m, 1H), 6.28 (s, 2H), 5.83 - 5.56 (m, 2H), 5.38 - 5.18 (m, 1H), 4.91 (s, 6H), 4.15 - 3.99 (m, 2H), 3.94 (s, 1H), 3.84 - 3.64 (m, 4H), 3.15 - 2.91 (m, 6H), 2.86 - 2.76 (m, 1H), 2.13 - 1.71 (m, 10H). LCMS (ESI) m/z: [M+H]+ 1098.6.
Example 16: Preparation of Compound 16
[0432] Step 1 To a solution of 2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]aniline (300 mg, 0.841 mmol) in DCM (8 mL) was added triphosgene (149 mg, 0.505 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. Then TEA (255 mg, 2.531 mmol) was added. The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. The mixture was concentrated to provide a residue directly used for next step. LCMS (ESI) m/z: [M+H]+ 383.2.
[0433] Step 2'. To a solution of 4-(3-isocyanato-4-methoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)isoxazole (300 mg, 0.784 mmol) in DCM (5 mL) were added tert-butyl 2- (hydroxymethyl)prop-2-enoate (186 mg, 1.180 mmol) and TEA (158 mg, 1.570 mmol). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE:EtOAc=3: l) to give tert-butyl 2-[[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2-enoate (80 mg, 0.148 mmol, 18.86% yield) as a colorless oil. LCMS (ESI) m/z: [M+H]+ 541.3.
[0434] Step 3'. To a solution of tert-butyl 2-[[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2-enoate (80 mg, 0.148 mmol) in DCM (2 mL) was added TFA (1.5 g, 13.071 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Cis reverse column chromatography (ACN: H O=3: 1) to give 2- [[2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2- enoic acid (50 mg, 0.103 mmol, 69.74% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 485.3. [0435] Step 4: To a solution of 2-[[2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4- yl]phenyl]carbamoyloxymethyl]prop-2-enoic acid (10 mg, 0.021 mmol) in DCM (1 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en-l -amine (14 mg, 0.103 mmol). The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. Then the mixture was concentrated to provide a residue which was directly used for next step. LCMS (ESI) m/z: [M+H]+ 521.5.
[0436] Step 5 To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l -naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2, 3,5,6, 7-hexahy dropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidine (64 mg, 0.099 mmol) in DCM (2 mL) were added lutidine (32 mg, 0.298 mmol) and 2-chlorocarbonylallyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (50 mg, 0.099 mmol). The reaction mixture was stirred at 25 °C for 15 mins under air atmosphere. Then the mixture was purified by silica gel column chromatography (DCM: MeOH=10: l) to give 2-[3-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-l-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[2- methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (40 mg, 0.036 mmol, 36.21% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 1111.6.
[0437] Step 6: To 2-[3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-l-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (30 mg, 0.027 mmol) was added formic acid (2.4 g, 53.010 mmol, 2 ml). The reaction mixture was stirred at 25 °C for 3 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Prep- HPLC to give 2-[3-[7-(8-ethynyl-7-fluoro-3-hydroxy-l-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carbonyl]allyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (20 mg, 0.018 mmol, 69.42% yield) as a white solid. ' H NMR (400 MHz, DMSO-d6) 8 9.05 (s, 1H), 8.79 (s, 2H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 6.88 (s, 2H), 5.66 (s, 1H), 5.54 (s, 1H), 5.38 - 5.18 (m, 1H), 4.83 - 4.37 (m, 6H), 4.12 (d, J = 10.3 Hz, 1H), 4.03 (d, J = 10.5 Hz, 1H), 3.91 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.67 (s, 6H), 3.51 (s, 3H), 3.11 - 3.06 (m, 2H), 3.01 (s, 1H), 2.83 (dd, J = 15.4, 8.1 Hz, 1H), 2.09 (dd, J = 32.7, 3.9 Hz, 2H), 2.01 (dd, J = 7.6, 4.2 Hz, 1H), 1.88 - 1.69 (m, 7H). LCMS (ESI) m/z: [M+H]+ 1067.6.
Example 17: Preparation of Compound 17 Compound 17
[0438] Step 1. To a solution of 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol (300 mg, 0.948 mmol) in DMF (6 mL) were added bis(4-nitrophenyl) carbonate (720 mg, 2.380 mmol) and DIEA (368 mg, 2.840 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. Then the mixture was diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL><3) and the combined organic layers were washed with brine, dried over Na2SO4, and the obtained crude product was subjected to silica gel column chromatography (PE/EtO Ac=3 : 1 ) to give [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl](4- nitrophenyl) carbonate (400 mg, 0.830 mmol, 87.61% yield) as a yellow oil. LCMS (ESI) m/z: [M+H]+ 482.3.
[0439] Step 2 To a solution of [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] (4-nitrophenyl) carbonate (530 mg, 1 .100 mmol) in DCM (3 mL) were added tert-butyl N-methyl- N-[2-(methylamino)ethyl]carbamate (269 mg, 1.430 mmol) and DIEA (426 mg, 3.300 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (PE: EtOAc=2:l) to give [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-[2-[tert- butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (500 mg, 0.942 mmol, 85.60% yield) as a yellow oil. LCMS (ESI) m/z: [M+H-100]+ 431.3.
[0440] Step 3: To a suspension of [2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenyl] N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl- carbamate (500 mg, 0.94 mmol) in DCM (3 mL) was added TFA (1.5 g, 13.070 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The crude product was purified by reversed-phase column (Mobile phase: A: water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give [2-methoxy-5-[(Z)-2-(3, 4,5- trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[2-(methylamino)ethyl]carbamate (265 mg, 0.616 mmol, 65.33% yield) as a white solid. LCMS (ESI) m/z: [M+H] 1 431.3.
[0441] Step 4'. To a solution of tert-butyl 2-(hydroxymethyl)prop-2-enoate (374 mg, 2.370 mmol) in DCM (10 mL) were added TEA (159 mg, 1.580 mmol) and triphosgene (351.55 mg, 1.18 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then [2- methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[2-
(methylamino)ethyl]carbamate (340 mg, 0.789 mmol) was added. The mixture was stirred at 25 °C for 4 days. The crude product was purified by reverse-phase column (Mobile phase: A: water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give tert-butyl 2-[[2-[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]ethyl-methyl- carbamoyl]oxymethyl]prop-2-enoate (250 mg, 0.406 mmol, 51.50% yield) as a white solid. LCMS (ESI) m/z: [M+H-56]+ 559.4.
[0442] Step 5: To a solution of tert-butyl 2-[[2-[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]ethyl-methyl- carbamoyl]oxymethyl]prop-2-enoate (200 mg, 0.325 mmol) in formic acid (5 mL). The reaction was stirred at 50 °C for 12 h. The mixture was concentrated and purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 30 min) and the fractions containing the product were combined and lyophilized to give 2-[[2-[[2-methoxy-5- [(Z)-2-(3, 4, 5-trimethoxyphenyl)vinyl]phenoxy]carbonyl -methyl -amino]ethyl-methyl- carbamoyl]oxymethyl]prop-2-enoic acid (100 mg, 0.179 mmol, 55.02% yield). LCMS (ESI) m/z: [M+H]+ 559.4.
[0443] Step 6: To a solution of 2-[[2-[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]ethyl-methyl- carbamoyl]oxymethyl]prop-2-enoic acid (76 mg, 0.136 mmol) in DCM (4 mL) was added 1- chloro-N,N,2-trimethyl-prop-l-en-l -amine (36 mg, 0.273 mmol). The reaction was stirred at 25 °C for 1 h. The reaction was used directly in the next step. LCMS (ESI) m/z: [M+H]+ 573.4.
[0444] Step 7: To a solution of 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-l-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (31 mg, 0.054 mmol) and 2,6-dimethylpyridine (12 mg, 0.109 mmol) in DCM (3 mL) was added [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N-[2-[2- chlorocarbonylallyloxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (21 mg, 0.036 mmol). The reaction was stirred at 25 °C for 1 h. The mixture was purified by silica gel column chromatography (MeOH: DCM=10:l) to give the residue which was further purified by Prep- HPLC to give 2-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-l- carbonyl)allyl (2-methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenyl) ethane- 1,2- diylbis(methylcarbamate) (4.2 mg, 0.003 mmol, 10.41% yield). ^ NMR (400 MHz, DMSO-t/e) 8 7.77 (s, 1H), 7.42 - 6.95 (m, 5H), 6.86 (d, ,7 = 10.2 Hz, 3H), 6.52 (d, ,7= 20.7 Hz, 2H), 5.62 - 5.43 (m, 1H), 5.32 (s, 1H), 4.81 - 4.59 (m, 3H), 4.36 (td, .7= 9.7, 8.9, 4.4 Hz, 1H), 4.19 - 3.98 (m, 3H), 3.79 (d, J = 15.0 Hz, 7H), 3.73 (s, 1H), 3.65 (s, 2H), 3.64 - 3.50 (m, 6H), 3.45 (s, 2H), 3.06 (s, 1H), 3.00 - 2.88 (m, 5H), 2.86 (d, J= 10.7 Hz, 1H), 2.55 (d, J= 9.7 Hz, 1H), 2.39 - 2.33 (m, 6H), 2.16 (q, J= 8.5 Hz, 1H), 2.01-1.89 (m, 2H), 1.70 - 1.59 (m, 3H), 1.25 (d, J= 9.3 Hz, 4H). LCMS (ESI) m/z: [M+H]+ 1108.7.
[0445] Step /: To a solution of [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] (4-nitrophenyl) carbonate (500 mg, 1.040 mmol) in DCM (5 mL) were added tert-butyl (2S)-2- (methylaminomethyl)pyrrolidine-l -carboxylate (289 mg, 1.350 mmol) and DIEA (403 mg, 3.120 mmol, 0.542 ml) at 25 °C. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to provide a residue which was purified by silica gel column chromatography (PE:EtOAc=3:l) to give tert-butyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (500 mg, 0.898 mmol, 86.49% yield) as a transparent oil. LCMS (ESI) m/z: [M+H]+ 556.6. [0446] Step 2: To a suspension of tert-butyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (500 mg, 0.898 mmol) in DCM (3 mL) was added TF A (1.5 g, 13.070 mmol, 1 mL). The reaction mixture was stirred at 25 °C for i h. The crude product was purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B: Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give [2-methoxy-5-[(Z)-2- (3,4,5-trimethoxyphenyl)vinyl]phenyl] N-methyl-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (278 mg, 0.609 mmol, 67.79% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 457.3.
[0447] Step 3: A mixture of [2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenyl] N- methyl-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate (130 mg, 0.285 mmol), tert-butyl 2- (hydroxymethyl)prop-2-enoate (68 mg, 0.427 mmol), triphosgene (84 mg, 0.285 mmol), and pyridine (113 mg, 1.420 mmol) in DCM (10 mL) was stirred at 0 °C for 5 min. The mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1/2 EtOAc/PE) to afford 2-tert-butoxycarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l -carboxylate (70 mg, 0.109 mmol, 38.37% yield). LCMS (ESI) m/z: [M+H]+ 641.5.
[0448] Step 4: A suspension of 2-tert-butoxycarbonylallyl (2S)-2-[[[2-methoxy-5-[(Z)-2- (3,4,5-trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carboxylate (150 mg, 0.234 mmol) in formic acid (2 mL) was stirred at 50 °C for 16 hours. The crude product was purified by reverse-phase column (Mobile phase: A: 0.5% Formic acid in water, B : Acetonitrile; B from 5% to 95% in 10 min) and the fractions containing the product were combined and lyophilized to give 2-[[(2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carbonyl]oxymethyl]prop-2-enoic acid (80 mg, 0.137 mmol, 58.45% yield) as a white solid.
LCMS (ESI) m/z: [M+H]+ 585.4.
[0449] Step 5 To a solution of 2-[[(2S)-2-[[[2-methoxy-5-[(Z)-2-(3,4,5- trimethoxyphenyl)vinyl]phenoxy]carbonyl-methyl-amino]methyl]pyrrolidine-l- carbonyl]oxymethyl]prop-2-enoic acid (33 mg, 0.056 mmol) in DCM (5 mL) was added 1-chloro- N,N,2-trimethyl-prop-l-en-l -amine (15 mg, 0.113 mmol). The resulting mixture was stirred at rt for 1 hour. The reaction was quenched with MeOH. The mixture was concentrated and used directly in the next step. [0450] Step 6 To a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-l -yl]-2-[[(2S)-
1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-arnine (48 mg, 0.845 mmol) in DCM (5 mL) were added 2-chlorocarbonylallyl (2S)-2-[[[2-methoxy-5- [(Z)-2-(3, 4, 5-trimethoxyphenyl)vinyl]phenoxy]carbonyl -methyl -amino]methyl]pyrrolidine-l - carboxylate (34 mg, 0.056 mmol) and 2,6-lutidine (24 mg, 0.225 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 10 min. The mixture was concentrated and purified by prep-TLC and prep-HPLC to afford 2-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-
2-yl)-6-chloro-8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3- methylpiperazine- l-carbonyl)allyl (2S)-2-((((2-methoxy-5-((Z)-3,4,5-trimethoxystyryl) phenoxy) carbonyl)(methyl)amino)methyl)pyrrolidine-l -carboxylate (29 mg, 0.026 mmol). 'H NMR (400 MHz, DMSO-d6) 8 7.79 (d, J = 6.7 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 7.01 (m, 2H), 6.86 (d, J = 11.8 Hz, 2H), 6.58 - 6.45 (m, 4H), 5.59 - 5.46 (m, 1H), 5.33 (s, 1H), 4.67 (d, J = 30.6 Hz, 3H), 4.37 (m, 1H), 4.29 - 3.97 (m, 5H), 3.82 - 3.71 (m, 4H), 3.62 (m, 9H), 3.00 (s, 2H), 2.91 (m 3H), 2.55 (d, J = 8.5 Hz, 3H), 2.41 - 2.31 (m, 6H), 2.16 (m, 1H), 1.97 - 1.73 (m, 5H), 1.72 - 1.56 (m, 3H), 1.28 (m, 3H). LCMS (ESI) m/z: [M+H]+ 1134.7.
Example 19: Preparation of Compound 19
[0451] Step 7: To a solution of 2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]aniline (300 mg, 0.842 mmol) in DCM (8 mL) was added triphosgene (149 mg, 0.505 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. Then TEA (255 mg, 2.530 mmol) was added. The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. The mixture was concentrated to provide a residue that was directly used in next step. LCMS (ESI) m/z: [M+H]+ 383.2.
[0452] Step 2'. To a solution of 4-(3-isocyanato-4-methoxy-phenyl)-5-(3,4,5- trimethoxyphenyl)isoxazole (300 mg, 0.785 mmol) in DCM (5 mL) were added tert-butyl 2- (hydroxymethyl)prop-2-enoate (186.18 mg, 1.18 mmol) and TEA (158 mg, 1.570 mmol). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide a residue which was purified by silica gel column chromatography (PE:EtOAc=3:l) to give tert-butyl 2-[[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2-enoate (80 mg, 0.148 mmol, 18.86% yield) as a colorless oil. LCMS (ESI) m/z: [M+H]+ 541.3.
[0453] Step 3 To a solution of tert-butyl 2-[[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2-enoate (80 mg, 0.148 mmol) in DCM (2 mL) was added TFA (1.5 g, 13.070 mmol, 1 m ). The reaction mixture was stirred at 25 °C for 2 hours under air atmosphere. Then the mixture was concentrated to provide a residue which was purified by Cis reverse column chromatography (ACN: 1420=3: 1) to give 2- [[2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamoyloxymethyl]prop-2- enoic acid (50 mg, 0.103 mmol, 69.74% yield) as a white solid. LCMS (ESI) m/z: [M+H]+ 485.3. [0454] Step 4: To a solution of 2-[[2-methoxy-5-[5-(3,4,5-trimethoxyphenyl)isoxazol-4- yl]phenyl]carbamoyloxymethyl]prop-2-enoic acid (10 mg, 0.021 mmol) in DCM (1 mL) was added l-chloro-N,N,2-trimethyl-prop-l-en-l -amine (13 mg, 0.103 mmol). The reaction mixture was stirred at 25 °C for 30 mins under air atmosphere. Then the mixture was concentrated to provide a residue which was directly used in next step. LCMS (ESI) m/z: [M+H]+ 521.5.
[0455] Step 5: To a solution of 2-chlorocarbonylallyl N-[2-methoxy-5-[5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl]phenyl]carbamate (45 mg, 0.089 mmol) in DCM (1.93 mL) were added 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-l-yl]-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (76 mg, 0.134 mmol) and lutidine (83 mg, 0.775 mmol). The reaction mixture was stirred at 25 °C for 10 mins under air atmosphere. Then the mixture was purified by silica gel column chromatography (DCM: MeOH=10:l) to give 2-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro- 8-fluoro-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3 -methylpiperazine- 1- carbonyl)allyl (2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)carbamate (25.7 mg, 0.024 mmol, 27.76% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 8 8.80 (s, 2H), 7.75 (d, J = 15.5 Hz, 2H), 7.22 (dd, J = 8.5, 2.2 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.97 - 6.78 (m, 4H), 6.50 (s, 1H), 5.59 (s, 1H), 5.35 (s, 1H), 4.71 (d, J = 14.0 Hz, 3H), 4.37 (ddd, J = 10.7, 8.6, 4.6 Hz, 1H), 4.16 (ddd, J = 41.9, 31.5, 25.0 Hz, 4H), 3.81 (s, 3H), 3.69 (s, 3H), 3.67 (s, 6H), 3.25 - 3.05 (m, 2H), 2.95 (d, J = 5.3 Hz, 1H), 2.61 - 2.53 (m, 2H), 2.42 - 2.30 (m, 6H), 2.17 (q, J = 8.5 Hz, 1H), 1 .99 - 1 .87 (m, 1H), 1 .76 - 1 .56 (m, 3H), 1 .28 (dd, J = 11 .8, 6.6 Hz, 3H). LCMS (ESI) m/z: [M+H]+ 1034.5.
Example 20: Preparation of Compound 22
[0456] Step 1 To a solution of 6 (from Example 54, 100.0 mg, 170.0 pmol, 1.0 equiv.) inDCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 4 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water and lyophilized to give 2 (90.0 mg, crude) as a yellow solid. LCMS(ESI)[M+1]+ =527.2, tR =1.429 min.
[0457] Step 2: To a solution of 2 (110.0 mg, 210.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 3 (55.7 mg, 420.0 pmol, 2.0 equiv.). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The reaction was used in the next step without further purification. LCMS(ESI) [M+MeOH-35]+ = 541.3, tR = 1.594 min.
[0458] Step 3: To a solution of 4 (100.0 mg, 180.0 pmol, 1.0 equiv.) in DCM (2 mL) were added a solution of Int-R-2 (167.2 mg, 180.0 pmol, 1.0 equiv.) in DCM (3 mL) and 2,6-lutidine (117.9 mg, 1080.0 pmol, 6.0 equiv.). The mixture was stirred at RT for 10 minutes. LCMS showed the reaction was complete, and the reaction was purified by flash chromatography and then prep- HPLC to give 5 (40.0 mg, 30.0 pmol, yield: 17.6%) as a yellow solid. LCMS(ESI) [M+l]+ = 1236.4, tR = 1.717 min.
[0459] Step 4 To a solution of 5 (80.0 mg, 60.0 pmol, 1.0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete, and the reaction was purified by prep-HPLC to give Compound 22 (35.0 mg, 30.0 pmol, yield: 47.6%) as a yellow solid. LCMS(ESI) [M+l]+ = 1136.6, tR = 1.310 min. Column: Shim-Pack Scepter C18, 33*3.0 mm, 3 um. Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05, Solvent B: CH3CN. Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). 'H NMR (400 MHz, DMSO) 8 8.13 (s, 2H), 7.74 (s, 1H), 7.37 - 7.09 (m, 4H), 6.93 (s, 2H), 6.73 (s, 1H), 5.87 - 5.47 (m, 4H), 5.38 (s, 1H), 4.85 (s, 2H), 4.71 - 4.44 (m, 4H), 3.98 - 3.57 (m, 18H), 3.43 (s, 1H), 3.32 - 3.11 (m, 2H), 2.93 - 2.70 (m, 3H), 2.64 - 2.52 (m, 2H), 2.46 (s, 3H), 2.37 - 2.26 (m, 1H), 2.24 - 1.94 (m, 3H), 1.23 (s, 3H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1% TFA); phase B: CH3CN.
Example 21: Preparation of Compound 22’
[0460] Step 1 To a solution of 6 (from Example 54, 100.0 mg, 170.0 pmol, 1.0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 4 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water and lyophilized to give 2 (90.0 mg, crude) as a yellow solid. LCMS(ESI)[M+1]+ =527.2, tR =1.429 min.
[0461] Step 2: To a solution of2 (110.0 mg, 210.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 3 (55.7 mg, 420.0 pmol, 2.0 equiv.). The mixture was stirred at RT for 2 h, LCMS showed the reaction was complete, and the reaction was used in the next step without further purification. LCMS(ESI) [M+MeOH-35]+ = 541.3, tR = 1.594 min.
[0462] Step 3 To a solution of 4 (93.0 mg, 170.0 pmol, 1.0 equiv.) in DCM (2 mL) was added a solution of Int-R-1 (124.2 mg, 170.0 pmol, 1.0 equiv.) in DCM (3 mL) and 2,6-lutidine (109.7 mg, 1020.0 pmol, 6.0 equiv.). The mixture was stirred at RT for 10 minutes. LCMS showed the reaction was complete, and the reaction was purified by flash column chromatography to give 5 (100.0 mg, 80.0 pmol, yield: 47.3%) as a yellow solid. LCMS(ESI) [M+l]+ = 1236.4, tR = 1.623 min.
[0463] Step 4 To a solution of 5 (100.0 mg, 80.0 pmol, 1.0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete, and the reaction was purified by prep-HPLC to give Compound 22’ (42.0 mg, 40.0 pmol, yield: 45.7%) as a yellow solid. LCMS(ESI) [M+l]+ = 1136.4, tR = 1.416 min. Column: Shim-Pack Scepter C18, 33*3.0 mm, 3 um. Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05, Solvent B: CH3CN. Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). ’H NMR (400 MHz, DMSO-d6) 5 8.14 (s, 2H), 7.89 (s, 1H), 7.34 - 7.12 (m, 4H), 6.95 (s, 2H), 6.76 (s, 1H), 5.86 - 5.74 (m, 2H), 5.68 - 5.50 (m, 2H), 5.40 (s, 1H), 4.85 (s, 2H), 4.57 (s, 2H), 4.27 (s, 1H), 4.07 - 3.63 (m, 19H), 3.37 - 3.00 (m, 3H), 2.81 (s, 3H), 2.67 - 2.54 (m, 2H), 2.47 (s, 3H), 2.39 - 2.28 (m, 1H), 2.26 - 1.96 (m, 3H), 1.36 - 1.10 (m, 3H). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wave length: 220 nm/254 nm; phase A: H2O (0.1% TFA); phase B: ACN; TIME: 17.5 min.
Example 22: Preparation of Compound 28
[0464] Step 1 A solution of 1 (90.0 g, 576.2 mmol, 1.0 equiv.), 2 (57.1 g, 633.8 mmol, 1.1 equiv.) and sodium carbonate (91.6 g, 864.3 mmol, 1.5 equiv.) in H2O (1200 m ) was stirred at room temperature for 2 days. TLC showed the reaction was complete. The suspension was filtered and the cake was dried in vacuo to give 3 (60.0 g, 329.2 mmol, yield: 57.1%) as a colorless solid. ’H NMR (400 MHz, DMSO-d6) 8 12.49 (s, 1H), 2.73 (tt, J = 19.4, 7.6 Hz, 4H), 2.58 (t, J= 7.4 Hz, 2H), 2.46 (s, 3H).
[0465] Step 2: To a solution of 3 (68.0 g, 373.1 mmol, 1.0 equiv.) in DCE (170 mb) was added POCI3 (300 mb, 3731.3 mmol, 10.0 equiv.). The reaction mixture was stirred at 90 °C for 2 h. LCMS showed the reaction was complete. The solution was poured into ice water (800.0 mL), and the pH was adjusted to 7-8 with potassium carbonate. The resulting solution was extracted with ethyl acetate (400 mLxl), and the organic phase was concentrated to dryness to obtain 4 (60.0 g, 284.0 mmol, yield: 76.1%) as a yellow solid. LCMS (ESI) [M+l] + = 201.3, tR = 1.062 min.
[0466] Step 3: A mixture of 4 (40.0 g, 139.5 mmol, 1.0 equiv.) and 5 (25.8 g, 153 4 mmol, 1.1 equiv.) in anhydrous isopropyl alcohol (300.0 mL) with a catalytic amount of HC1 (concentrated, 3 drops) was stirred at 50 °C for 8 h. The reaction mixture was monitored by TLC until the reaction was complete. The solution was diluted with saturated aqueous NaHCO.3 solution to pH 7, filtered, washed with water, and dried to obtain 6 (35.0 g, 105.3 mmol, yield: 75.4%) as an orange solid. 'H NMR (400 MHz, CDCh) 8 9.89 (s, 1H), 9.00 (d, J= 9.4 Hz, 1H), 7.70 (d, J= 3.1 Hz, 1H), 7.28 (d, J= 3.1 Hz, 1H), 7.25 (s, 1H), 3.87 (s, 3H), 2.95 (t, J= 7.8 Hz, 2H), 2.92 - 2.84 (m, 2H), 2.57 (s, 3H), 2.26 - 2.13 (m, 2H).
[0467] Step 4\ To a mixture of 6 (30.0 g, 90.2 mmol, 1.0 equiv.) and Zn (59.0 g, 902.6 mmol, 10.0 equiv.) in DCM (30.0 mb) was added HOAc (10.3 mL, 180.52 mmol). The reaction mixture was stirred at 0 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite and the filtrate was concentrated to obtain 7 (20.0 g, 66.1 mmol, yield: 73.2%) as an orange solid. LCMS (ESI) [M+l] + = 303.3, tR = 0.860 min.
[0468] Step 5: To a mixture of 7 (30.0 g, 99.2 mmol, 1.0 equiv.) and K2CO3 (41.1 g, 297.6 mmol, 3.0 equiv.) in acetone (200.0 mL) was added 8 (15.7 mL, 198.4 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. LCMS showed the reaction was complete. The solution was poured into water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by column chromatography to obtain 9 (10.0 g, 26.4 mmol, yield: 26.6%) as a pale pink solid. LCMS(ESI)[M+1]+ = 379.3, tR = 1.118 min.
[0469] Step 6: To a solution of 9 (10.0 g, 26.3 mmol, 1.0 equiv.) in anhydrous THF (100 mL) was added NaH (60%, 0.95 g, 39.5 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The mixture was poured into ice water. The solid was collected by filtration to give 10 (7.0 g, 20.4 mmol, yield: 77.4%) as a white solid. LCMS(ESI)[M+lf = 343.3, tR = 1.061 min.
[0470] Step 7: To a solution of 10 (9.0 g, 26.2 mmol, 1.0 equiv.) in DMF (50 mL) was added NaH (0.9 g, 39.4 mmol, 1.5 equiv.). Then PMBC1 (4.5 g, 28.9 mmol, 1.1 equiv.) was added. The reaction was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with EA. The filtrate was washed with NaHCO? solution, dried over anhydrous ISfeSCL, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 50-100% EtOAc in petroleum ether to afford 11 (12.0 g, 25.9 mmol, yield: 98.7%) as a colorless oil. LCMS(ESI)[M+1]+ = 463.4, tR = 1.863 min.
[0471] Step 8: To a solution of 11 (14.0 g, 30.2 mmol, 1.0 equiv.) in MeOH (300.0 mL) and H2O (300.0 mL) was added Oxone (83.4 g, 242.1 mmol, 8.0 equiv.) at room temperature. The reaction was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The mixture was poured into aqueous NaHCO? solution and extracted with EtOAc twice. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated to afford crude 12 (7.0 g, 14.1 mmol, yield: 46.7%) as a colorless oil. LCMS(ESI)[M+1]+ = 495.4, tR = 1.562 min.
[0472] Step 9: To a solution of 12 (5.0 g, 10.1 mmol, 1.0 equiv.) in dioxane (80.0 mL) was added CH3NH2/H2O (32.0 mL). The reaction was stirred at 110 °C for 16 h. LCMS showed the reaction was complete. The solution was concentrated in vacuo to give a crude product which was purified by silica gel column chromatography to afford 13 (4.3 g, 9.6 mmol, yield: 95.4%) as a white solid. LCMS(ESI)[M+1]+ = 446.4, tR = 0.913 min.
[0473] Step 10\ To a solution of 13 (500.0 mg, 1.1 mmol, 1.0 equiv.) and DIEA (434.3 mg, 3.3 mmol, 3.0 equiv.) in dioxane (3 mL) was added triphosgene (133.21 mg, 0.4 mmol, 0.4 equiv.). The reaction mixture was stirred at 70 °C for 20 min, then L-4 (0.1 mL, 1.2 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 70 °C for an additional 3 h under nitrogen. LCMS showed the reaction was complete. After cooling to room temperature, the mixture was diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc, and then the combined extracts were dried over anhydrous MgSO4, filtered and evaporated to afford 15 (450.0 mg, 0.7 mmol, yield: 90.7%) as a pale yellow solid.
[0474] Step 11. A solution of 15 (90.0 mg, 0.14 mmol ) in TEA (1 mL) and CF3SO3I I (1.0 mL) was stirred at RT for 2 h LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. And the residue was triturated with H>O: ACN = 20'80 to afford 16 (50.0 mg, 0.1 mmol, yield: 77.1%) as a white solid. LCMS(ESI)[M+1]+ = 454.3, tR = 0.825 min.
[0475] Step 12'. To a solution of 16 (100.0 mg, 0.2 mmol, 1.0 equiv.) in DCM (2.5 mL) and DMF (1.0 mL) were added Int-R (138.5 mg, 0.2 mmol, 1.0 equiv.), DIEA (85.5 mg, 0.6 mmol, 2.0 equiv.) and T3P (140.3 mg, 0.4 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA three times. The organic layer was concentrated under reduced pressure to give a crude product which was purified by prep-TLC and then prep-HPLC to give Compound 28 (4.0 mg, 10.0 pmol, yield: 4.2%) as a white solid. LCMS(ESI)[M+1]+ = 1063.4, tR = 1.628 min. Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: HzO/MeCN/FA = 90:10:0.05 Solvent B: CH3CN; Temperature: 40 °C; Flow Rate: 2.5 mL/min; Run Time: O.Olmin @ 20% B, 1.79min gradient (20-95% B), then 0.7min @ 95% B. ’H NMR (400 MHz, DMSO-d6) 5 10.67 (d, J= 23.5 Hz, 2H), 8.13 (s, 2H), 7.89 (d, J= 30.0 Hz, 1H), 7.28 - 7.11 (m, 2H), 6.87 (d, J= 8.0 Hz, 1H), 6.57 (d, J= 10.2 Hz, 2H), 5.70 (s, 1H), 5.56 (d, J= 51.4 Hz, 1H), 5.39 (s, 1H), 4.84 (s, 3H), 4.58 (d, J= 15.7 Hz, 3H), 4.43 (s, 3H), 4.14 (s, 8H), 3.71 - 3.66 (m, 4H), 3.33 (d, J= 4.3 Hz, 3H), 2.76 (s, 2H), 2.33 (s, 1H), 2.17 (dd, J= 20.6, 12.8 Hz, 4H), 2.03 (s, 1H), 1.85 (s, 2H), 1.27 (d, J= 24.0 Hz, 3H). 19F NMR (377 MHz, DMSO) 5 -74.44 (s), - 116.15 (s), -121.92 (s), -173.00 (d, J = 32.8 Hz). Instrument: E-Prep LC 012 LH-40; Column: Triart C18, 250*20.0 mml.D, 5 pm, 12 nm; Temperature: 25 °C; Inject number: 1; Wave length: 205 nm/254 nm; Phase A: H2O (0.1% FA); Phase B: CH3CN.
Example 23: Preparation of Compound 29
[0476] Step 7: To a solution of 10 (from Example 22, 200.0 mg, 0.4 mmol, 1.0 equiv.) in DMF (2.0 mL) was added NaH (16.1 mg, 0.6 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then L-5 (198.5 mg, 0.9 mmol, 2.0 equiv.) was added and the reaction was stirred at room temperature for an additional 1 h. LCMS showed the reaction was complete. The solution was poured into NH4CI solution and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na?SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 10-50% EtOAc in petroleum ether to afford 3 (300.0 mg, 0.6 mmol, yield: 85.0%) as a colorless oil. LCMS(ESI)[M+1]+ = 586.5, tR = 1 .390 min.
[0477] Step 2 : To a solution of 3 (300.0 mg, 0.51 mmol, 1.0 equiv.) in TFA (1.0 mL) was added trifluoromethanesulfonic acid ( 1.0 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a crude product which was triturated with H2O: ACN :::: 20:80 to afford 4 (150.0 mg, 0.4 mmol, yield: 71.5%) as a white solid. LCMS(ESI)[M+1]+ = 410.4, tR = 0.446 min.
[0478] Step 3 To a solution of 4 (90.0 mg, 0.22 mmol, 1.0 equiv.) in DCM (2.5 mL) and DMF (1.0 mL) were added Int-R (138.5 mg, 0.2 mmol, 1.0 equiv.), DIEA (85.5 mg, 0.6 mmol, 2.0 equiv.) and T3P (140.3 mg, 0.4 mmol, 2.0 equiv.) at 0 °C. The reaction was stirred at 0 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA three times. The organic layer was concentrated under reduced pressure and the residue was purified by prep-TLC and prep-HPLC to give Compound 29 (4.0 mg, 10.0 pmol, yield: 4.3%) as a white solid. LCMS(ESI)[M+1]+ = 1019.2, tR = 1.118 min. Column:YMC-Triart C18, 50*4.6mm, 5 pm; Mobile Phase: Solvent A: FLO/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'HNMR (400 MHz, DMSO) 5 10.74 (s, 1H), 10.60 (s, 1H), 8.13 (s, 2H), 7.90 (s, 1H), 7.30 - 7.21 (m, 1H), 7.17 (t, J= 8.9 Hz, 1H), 6.80 (s, 1H), 6.57 (d, J= 7.7 Hz, 2H), 5.56 (d, J= 53.6 Hz, 1H), 5.24 (s, 2H), 4.82 (s, 1H), 4.56 (s, 2H), 4.46 (s, 3H), 3.87 (s, 6H), 3.30 (s, 4H), 3.16 (s, 4H), 2.68 (d, J= 8.9 Hz, 2H), 2.33 (s, 2H), 2.14 (d, J= 24.5 Hz, 6H), 1.82 (s, 2H), 1.20 (d, J = 31.9 Hz, 5H). 19F NMR (377 MHz, DMSO) 5 -74.44 (s), -116.15 (s), -121.92 (s), -173.00 (d, J= 32.8 Hz). Column: Water s-Xbridge-Prep Phenyl 19*250 mm 5 um; Temperature: 25 °C; Inject number: 2; Wavelength: 254 nm/220 nm; Phase A: H2O (0.1%TFA); Phase B: MeCN; Gradient:
Example 24: Preparation of Compound 32
[0479] Step 1 To a stirred mixture of 3-P1 (from Example 25, 190.0 mg, 295.2 pmol, 1.0 equiv.) in DCM (6.0 mL) was added TFA (3.0 mL). The resulting mixture was stirred at RT for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford 2 (150.0 mg, 255.3 pmol, yield: 86.5%) as a brown solid. LCMS(ESI)[M+1]+ =588.24, tR =1.388 min. [0480] Step 2 To a stirred mixture of 2 (50.0 mg, 85.1 pmol, 1.0 equiv.) and Int-R-2 (62.0 mg, 85.1 pmol, 1.0 equiv.) in CH3CN (3.0 mL) were added TCFH (35.8 mg, 127.6 pmol, 1.5 equiv.) and 1 -methylimidazole (21.0 mg, 255.3 pmol, 3.0 equiv.). The resulting mixture was stirred at -78 °C for 20 min. LCMS showed -30% of desired product formation. The reaction mixture was purified by prep-TLC and prep-HPLC to give 4 (30.0 mg, 23.1 pmol, yield: 27.2%) as a light yellow solid. LCMS(ESI)[M+1]+ =1297.46, tR =1.967 min.
[0481] Step 3: A stirred mixture of 4 (30.0 mg, 23.1 pmol, 1.0 equiv.) in TFA (3.0 mL) and TfOH (0.1 mL) was stirred at 45 °C for 20 min under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep-HPLC to afford Compound 32 (2.3 mg, 2.1 pmol, yield: 9.2%) as a white solid. LCMS(ESI)[M+1]+ =1077.35, tR =1.269 min. Column:YMC-Triart C18, 50*4.6mm, 5um; Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). JH NMR (400 MHz, DMSO- d6) 5 10.86 (s, 1H), 10.66 (s, 1H), 8.14 (s, 2H), 7.88 (s, 1H), 7.25 (dd, J = 8.4, 5.3 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.88 (d, J= 7.8 Hz, 1H), 6.59 (d, J= 8.0 Hz, 2H), 5.57 (d, J= 57.2 Hz, 3H), 5.32 (s, 1H), 4.79 (s, 1H), 4.59 (t, J= 8.7 Hz, 2H), 4.46 (q, J = 16.5 Hz, 2H), 4.18 (d, J= 71.3 Hz, 3H), 3.94 - 3.81 (m, 3H), 3.73 (s, 3H), 3.34 (s, 5H), 2.75 (d, J= 15.7 Hz, 2H), 2.53 (s, 1H), 2.35 - 2.30 (m, 1H), 2.23 - 2.12 (m, 4H), 2.03 (dd, J= 20.5, 13.2 Hz, 2H), 1.87 (s, 2H), 1.46 (s, 3H), 1.26 (d, J= 23.0 Hz, 5H). 19F NMR (377 MHz, DMSO-d6) 6 -74.70 (s), -116.17 (s), -121.97 (s), -172.98 (s). Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wavelength: 220 nm / 254 nm; phase A: H2O (0.1% TFA); phase B: ACN; TIME: 15, 16 min. Example 25: Preparation of Compound 33
[0482] Step 1 To a solution of 10 (from Example 22, 500.0 mg, 1.1 mmol, 1.0 equiv.) in DCM (10.0 mL) and NMP (10.0 mL) were added L-8 (263.3 mg, 1.1 mmol, 1.0 equiv.) and DIEA (435.2 mg, 3.3 pmol, 3.0 equiv.). The reaction was stirred at RT for 16 h. LCMS showed the reaction was complete. The mixture was quenched with H2O and extracted with DCM. The combined organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel to give 3 (racemate, 400.0 mg, 620.0 pmol, yield: 55.4%) as a yellow solid. LCMS(ESI)[M+1]+ =644.7, tR = 2.011 min. The racemate was purified by SFC to give 3-P1 (190.0 mg, 295.0 mmol, 47.5%) and 3-P2 (220.0 mg, 34.1 mmol, 55.0%) as a yellow solid. 3-P1: LCMS(ESI)[M+l]+ = 644.3, tR = 2.011 min. Retention time of SFC: tR = 2.598 min. 3-P2: LCMS(ESI)[M+1]+ =644.4, tR = 2.013 min. Retention time of SFC: tR = 4.011 min. Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak C-IC, 250x30 mm I.D., 5 pm; Mobile phase: A for CO2 and B for IPA(0.1% 7mol/L NFL in MeOH); Gradient: B 55%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 30 min; Injection volume: 3 mL; Number of injection needles: 13; Eluted time: 7 H. The 500 mg sample was dissolved in 15 mL MEOH; [0483] Step 2 To a solution of 3-P2 (210.0 mg, 60.0 pmol, 1 .0 equiv.) in DCM (6.0 mL) was added TFA (2.0 mL). The reaction was stirred at RT for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and used directly in the next step. LCMS(ESI) [M+l]+ = 587.6, tR = 1.019 min.
[0484] Step 3: To a solution of 4 (50.0 mg, 90.0 pmol, 1.0 equiv.) in CH3CN (3.0 mL) were added Int-R-2 (62.0 mg, 90.0 pmol, 1.0 equiv.), TCFH (45.3 mg, 90.0 pmol, 1.0 equiv.), and NMI (182.8 mg, 270.0 qmol, 3.0 equiv.). The reaction was stirred at RT for 1 h. LCMS showed the reaction was complete. The mixture was quenched by H2O and extracted with DCM. The combined organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel to give 5 (10.0 mg, 7.7 qmol, yield: 18.2%) as a yellow solid. LCMS(ESI)[M+1]+ = 1297.9, tR = 1.245 min.
[0485] Step 4 To a solution of 5 (10.0 mg, 7.7 pmol, 1.0 equiv.) in TFA (3.0 mL) was added TfOH (1.0 mL). The reaction was stirred at RT for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep-HPLC to give Compound 33 (2.9 mg, 1.6 pmol, yield: 20.8%) as a yellow solid. LCMS(ESI) [M+l]+ = 1077.3, tR = 1.233 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5um; Mobile Phase: Solvent A: FLO/MeCN/FA = 90:10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min. Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B; 1H NMR (400 MHz, DMSO-d6) 8 10.94 (s, 1H), 10.65 (s, 1H), 8.15 (s, 2H), 7.80 (s, 1H), 7.16 (d, J = 6.8 Hz, 2H), 6.87 (d, J= 7.7 Hz, 1H), 6.59 (d, J= 9.5 Hz, 2H), 5.72 - 5.44 (m, 3H), 5.33 (s, 1H), 4.72 (s, 1H), 4.58 (dd, J= 20.4, 12.3 Hz, 3H), 4.41 (s, 1H), 4.27 (s, 1H), 4.04 (s, 2H), 3.86 (s, 2H), 3.73 (s, 4H), 3.33 (s, 3H), 2.73 (s, 2H), 2.57 (s, 2H), 2.37 - 1.96 (m, 8H), 1.82 (s, 2H), 1.63 (s, 1H), 1.42 (d, J = 33.9 Hz, 4H), 1.25 (d, J = 12.4 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.63 (s), -116.16 (s), -121.84 (s), -172.89 (s). Preparation method: Instrument: E- Prep LC 012 LH-40; Column: XBridge Prep Phenyl 19*250 mm Temperature: 25°C; Inject number : 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN. Example 26: Preparation of Compound 34
[0486] Step 1 A solution of 10-P2 (from Example 43, 200.0 mg, 376.9 pmol, 1.0 equiv.) in formic acid (4.0 mL) was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated under reduced pressure to give crude 2 (150.0 mg, 348.5 pmol, yield: 92.5%) as a colorless oil. LCMS(ESI)[M+1] + = 431.4, tR = 1.311 min.
[0487] Step 2: To a solution of 2 (80.0 mg, 185.9 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 3 (74.5 mg, 557.6 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0488] Step 3: To a solution of 4 (80.0 mg, 178.2 pmol, 1.0 equiv.) in DCM (3.0 mL) were added Int-R-2 (127.3 mg, 178.2 pmol, 1.0 equiv.) and lutidine (57.3 mg, 534.6 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 5 (30.0 mg, 26.3 pmol, yield: 14.8%) as a yellow solid. LCMS(ESI)[M+1] + = 1140.4, tR = 1.936 min.
[0489] Step 4: A solution of 5 (30.0 mg, 26.3 pmol, 1.0 equiv.) in formic acid (2.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0.1% TFA) to give Compound 34 (3.7 mg, 3.6 pmol, yield: 13.5%) as a yellow solid. LCMS(ESI) [M+l] + = 1040.2, tR = 1.806 min. Instrument: LCMS2020 (E-LCMS 015); Column: YMC-Triart C18, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 10.77 (s, 1H), 9.94 (d, J = 45.1 Hz, 1H), 8.14 (s, 1H), 7.93 (d, J = 11.3 Hz, 1H), 7.26 (dd, J = 7.9, 5.3 Hz, 1H), 7.17 (t, J= 8.9 Hz, 1H), 6.83 (d, J= 10.2 Hz, 1H), 6.55 (s, 2H), 6.45 (dt, J = 22.4, 12.2 Hz, 3H), 5.58 (d, J= 51.8 Hz, 1H),
5.47 - 5.30 (m, 2H), 4.74 (dd, J= 46.6, 32.8 Hz, 2H), 4.59 (q, J= 12.3 Hz, 2H), 4.39 - 4.31 (m, 1H), 3.83 (d, J= 5.0 Hz, 2H), 3.77 (s, 4H), 3.66 (s, 1H), 3.63 (s, 3H), 3.61 (s, 9H), 3.36 - 3.26 (m, 2H), 2.58 (d, J= 3.1 Hz, 1H), 2.33 (t, J= 7 A Hz, 1H), 2.25 - 2.13 (m, 2H), 2.12 - 1.94 (m, 2H),
1.47 (d, J= 6.0 Hz, 3H), 1.40 (d, J= 4.6 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.27 (s), - 116.17 (s), -121.91 (s), -173.03 (s). Preparation method: Instrument: LC-LH: Column: XBridge Prep Phenyl 19*250mm; Temperature:25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN. Example 27: Preparation of Compound 35
[0490] Step 1 A solution of 10-P1 (from Example 43, 200.0 mg, 376.9 pmol, 1.0 equiv.) in formic acid (4.0 mL) was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 2 (150.0 mg, 348.5 pmol, yield: 92.5%) as a colorless oil. LCMS(ESI)[M+1] + = 431.2, tR = 1.034 min.
[0491] Step 2'. To a solution of 2 (150.0 mg, 348.5.1 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 3 (139.7 mg, 1045.4 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0492] Step 3: To a solution of 4 (70.0 mg, 155.9 pmol, 1.0 equiv.) in DCM (3.0 mL) were added Int-R-2 (111.4 mg, 155.9 pmol, 1.0 equiv.) and lutidine (50.1 mg, 467.8 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 5 (30.0 mg, 26.3 pmol, yield: 16.9%) as a yellow solid. LCMS(ESI)[M+1] + = 1141.5, tR = 1.912 min.
[0493] Step 4: A solution of 5 (20.0 mg, 17.5 pmol, 1.0 equiv.) in formic acid (2.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0.1% TFA) to give Compound 35 (3.1 mg, 3.0 pmol, yield: 17.0%) as a yellow solid. LCMS(ESI) [M+l] + = 1040.3, tR = 1.905 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 10.73 (s, 1H), 9.95 (d, J = 47.2 Hz, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.22 (dt, J = 17.6, 8.5 Hz, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.54 (s, 2H), 6.52 - 6.30 (m, 3H), 5.57 (d, J = 52.4 Hz, 1H), 5.29 (s, 2H), 4.81 (d, J = 56.8 Hz, 2H), 4.59 (s, 2H), 4.42 (d, ,7 = 12.6 Hz, 1H), 3.82 (s, 2H), 3.78 (s, 4H), 3.66 (s, 1H), 3.63 (s, 3H), 3.58 (s, 9H), 3.31 (s, 2H), 2.33 (s, 2H), 2.18 (s, 2H), 2.05 (d, J= 17.9 Hz, 2H), 1.52 (d, J = 6.1 Hz, 3H), 1.39 (d, J= 6.2 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.12 (s), -116.16 (s), -121.98 (s), -173.06 (s). Preparation method: Instrument: E-Prep LC 024; Column: YMC-Actus Triart Phenyl ,20.0*250mm,5um; Temperature:25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN. Example 28: Preparation of Compound 36
[0494] Step 1 To a stirred mixture of 5-P2 (from Example 29, 150.0 mg, 0.3 mmol, l.O equiv.) in DCM (8.0 mL) was added TFA (4.0 mL). The resulting mixture was stirred under N2 at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford 6 (150.0 mg, crude) as a brown solid. LCMS(ESI)[M+1]+ =497.21, tR =0.672 min.
[0495] Step 2: To a stirred mixture of 6 (70.0 mg, 0.7 mmol, 1.0 equiv.) in DCM (5.0 mb) was added 7 (56.5 mg, 0.4 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 1 h under a N2 atmosphere. LCMS showed the reaction was complete. The resulting mixture was used directly in the next step without purification. LCMS(ES1)[M+I ] =511.22, tR =0.824 min.
[0496] Step 3: To a stirred mixture of 8 (70.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (5.0 m ) were added 2,6-dimethylpyridine (0.1 mL, 0.8 mmol, 6.0 equiv.) and Int-R-2 (99.0 mg, 0.1 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 1 h under a N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column and prep-HPLC to give 9 (30.0 mg, 24.9 pmol, yield: 18.3%) as a light yellow solid. LCMS(ESI)[M+1]+ =1206.43, tR =1.337 min.
[0497] Step 4'. To a stirred mixture of 9 (30.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred under N2 at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep-HPLC to afford Compound 36 (6.9 mg, 6.2 pmol, yield: 25.1%) as a yellow solid. LCMS(ESI)[M+1]+ =1106.38, tR =1.004 min. Column:YMC-Triart C18, 50*4.6mm, 5um; Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: O.Olmin @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). 'H NMR (400 MHz, DMSO-d6) 8 10.87 (s, 1H), 8.14 (s, 4H), 7.86 (s, 1H), 7.24 (dd, J= 8.3, 5.3 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 7.11 (dd, J= 22.2, 8.4 Hz, 2H), 6.71 (d, J= 7.9 Hz, 1H), 5.68 - 5.37 (m, 3H), 5.28 (d, J= 33.9 Hz, 5H), 4.78 (s, 2H), 4.59 (dd, J= 19.3, 11.9 Hz, 3H), 4.23 (s, 2H), 4.04 (s, 4H), 3.84 (s, 2H), 3.79 (s, 4H), 3.31 (d, J= 6.9 Hz, 2H), 3.12 (s, 1H), 2.93 (s, 3H), 2.81 (s, 2H), 2.36 - 2.31 (m, 1H), 2.19 (d, J= 4.6 Hz, 1H), 2.06 (d, J= 11.4 Hz, 2H), 1.86 (s, 2H), 1.33 (s, 6H). 19F NMR (377 MHz, DMSO-d6) 8 -74.23 (s), -116.15 (s), -121.89 (s), -173.04 (s). Instrument: LC-LH; Column: XB ridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wavelength: 220 nm/254 nm; phase A: H2O (0.1% TFA); phase B: ACN; TIME: 16 min. Example 29: Preparation of Compound 37
[0498] Step 1 To a solution of 1 (1.0 g, 3.1 mmol, 1.0 equiv.) in DMF (5.0 mL) were added K2CO3 (1.2 g, 9.3 mmol, 3.0 equiv.) and 2-methylpropan-2-yl bromoacetate (599.5 mg, 3.1 mmol, 1.0 equiv.). The reaction was stirred at 60 °C for 1 hour. LCMS showed the reaction was complete. The mixture was poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous Na SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 2 (400.0 mg, 0.9 mmol, yield: 29.6%) as a black solid. LCMS(ESI)[M+1]+ = 440.2, tR = 1.387 min.
[0499] Step 2: To a stirred mixture of 2 (1.5 g, 3.4 mmol, 1.0 equiv.) in DCM (20.0 mL) was added TFA (10.0 mL). The resulting mixture was stirred at RT for 3 h under a N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep-HPLC to afford 3 (900.0 mg, 2.4 mmol, yield: 68.8%) as a light-yellow solid. LCMS(ESI)[M+1]+ =384.16, tR =0.418 min.
[0500] Step 3: To a stirred mixture of 3 (400 mg, 1.0 mmol, 1.0 equiv.) in dioxane (8.0 mL) were added DIEA (404.5 mg, 3.1 mmol, 3.0 equiv.) and DPPA (430.7 mg, 1.6 mmol, 0.5 equiv.) at RT under N2. The resulting mixture was stirred at 100 °C for 20 min under N2. LCMS showed the reaction was complete. The reaction mixture was used directly in the next step without purification. LCMS(ESI)[M+1]+ =413.19, tR =0.701 min.
[0501] Step 4'. To a stirred mixture of 4 (400.0 mg, 1.1 mmol, 1.0 equiv.) in dioxane (5.0 mL) was added L-l (543.3 mg, 3.2 mmol, 3.0 equiv.). The reaction mixture was stirred at 100 °C for 4 h under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, The residue was purified by silica gel column, prep-HPLC and chiral SFC to afford 5-P1 (150.0 mg, 0.3 mmol, yield: 42.9%) and 5-P2 (150.0 mg, 0.3 mmol, yield: 42.9%) as a yellow solid. LCMS(ESI)[M+1]+ =553.27, tR =1.105 min. Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak AD, 250><30mm I.D., 5pm; Mobile phase: A for CO2 and B for IPA(0.05 % TEA); Gradient: B 25%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 15 min; Injection volume: 1 mL; number of injection needles: 25; Eluted time: 3 H; Peak 1 : 5-P1, retention time: 3.336 min. Peak 2: 5-P2, retention time: 4.022 min.
[0502] Step 5: To a stirred mixture of 5-P1 (150.0 mg, 0.3 mmol, 1.0 equiv.) in DCM (8.0 mL) was added TFA (4.0 mL). The resulting mixture was stirred under N2 at RT for 1 hr. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford 6 (150.0 mg, crude) as a brown solid. LCMS(ESI)[M+1]+ =497.21, tR =0.673 min.
[0503] Step 6 To a stirred mixture of 6 (70.0 mg, 0.7 mmol, 1.0 equiv.) in DCM (5.0 mL) was added 7 (56.5 mg, 0.4 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 1 h under a N2 atmosphere. LCMS showed the reaction was complete. The resulting mixture was used directly in the next step without purification. LCMS(ESI)[M+ I] =511.22, tR =0.819 min.
[0504] Step 7: To a stirred mixture of 8 (70.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (5.0 mL) were added 2,6-dimethylpyridine (0.1 mL, 0.8 mmol, 6.0 equiv.) and Int-R-2 (99.0 mg, 0.1 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 1 h under a N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column and prep-HPLC to give 9 (50.0 mg, 41.4 pmol, yield: 30.5%) as a light yellow solid. LCMS(ESI)[M+1]+ =1206.43, tR =1.299 min.
[0505] Step 8: To a stirred mixture of 9 (50.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep-HPLC to afford Compound 37 (27.9 mg, 25.2 pmol, yield: 60.8%) as a yellow solid. LCMS(ESI)[M+1]+ =1106.38, 1R =0.985 min. (Column:YMC-Triart C18, 50*4.6mm, 5 um, Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN, Temperature: 40°C, Flow Rate: 2.5 mL/min, Method: positive-negative 3 min-l.lcm, Run Time: 0.01 min @ 20% B, 1.79 min gradient (20- 95% B), then 0.7 10.95 (s, 1H), 8.22 (d, J = 61.4 Hz, 4H), 7.85 (s, 1H), 7.25 (dd, J= 8.4, 5.3 Hz, 1H), 7.18 (d, J= 9.2 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.72 (d, J= 8.1 Hz, 1H), 5.58 (d, J= 52.6 Hz, 2H), 5.44 - 5.30 (m, 3H), 5.24 (s, 4H), 4.77 (s, 2H), 4.59 (q, J= 12.0 Hz, 3H), 4.12 (d, J= 72.8 Hz, 4H), 3.92 - 3.82 (m, 2H), 3.79 (s, 4H), 3.65 (s, 1H), 3.33 (dd, J= 25.3, 18.3 Hz, 2H), 3.12 (s, 1H), 2.93 (s, 3H), 2.81 (s, 2H), 2.37 - 2.30 (m, 1H), 2.18 (d, J = 3.4 Hz, 1H), 2.06 (d, J = 10.4 Hz, 2H), 1.90 - 1.81 (m, 2H), 1.29 (s, 6H). 19F NMR (377 MHz, DMSO-d6) 6 -74.29 (s), -116.17 (s), -121.87 (s), -173.03 (s). Instrument: LC- LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wave length: 220 nm / 254 nm; phase A: H2O (0.1% TEA); phase B: ACN; TIME: 15 min.
Example 30: Preparation of Compound 38
[0506] Step 1. To a solution of 6-P2 (from Example 31, 120 mg, 210.0 pmol, 1.0 equiv.) in DCM (4 mL) was added TFA (0.8 mL). The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The mixture was diluted with EA and concentrated to give 4 (103 mg, 0.2 mmol, yield: 95.0%) as a yellow solid. LCMS(ESI)[M-1]‘ = 527.3, tR = 1.269 min.
[0507] Step 2'. To a solution of 7 (103.0 mg, 0.2 mmol, 1.0 equiv.) in DCM (2 mL) was added 8 (78.4 mg, 60.0 pmol, 3.0 equiv.). Then a mixture of Int-R-2 (142.4 mg, 195.8 pmol, 1.0 equiv.) and Lutidine (73.3 mg, 70.0 pmol, 1.0 equiv.) in DCM (0.5 mL) was added. The resulting mixture was stirred at RT for 10 min. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give 10 (40.0 mg, yield: 16.5%) as a yellow solid. LCMS(ESI)[M+1]+ = 1236.7, tR = 1.527 min.
[0508] Step 3: To a solution of 10 (40.0 mg, 32.3 pmol, 1.0 equiv.) in DCM (3 mL) was added TFA (0.6 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was diluted with EA and concentrated. The residue was purified by prep-HPLC (TFA) to give Compound 38 (17.2 mg, yield: 46.9%) as a yellow solid. LCMS(ESI)[M+1]+ = 1136.4, tR = 1.112 min. Instrument: LCMS 2020 (E-LCMS 028); Column: YMC-Triart C18, 50*4.6 mm, 5 urn; Mobile Phase: Solvent A: FhO/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B; 'H NMR (400 MHz, DMSO-t76) 8 10.79 (s, 1H), 8.98 - 8.63 (m, 1H), 8.12 (s, 2H), 7.74 - 7.37 (m, 2H), 7.30 - 7.15 (m, 2H), 6.87 (s, 2H), 6.71 - 6.29 (m, 1H), 5.67 - 4.99 (m, 6H), 4.55 - 4.34 (m, 4H), 4.31 - 4.06 (m, 4H), 3.92 - 3.63 (m, 13H), 3.52 - 3.13 (m, 3H), 2.93 - 2.78 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.37 (m, 3H), 2.17 (s, 2H), 2.00 (s, 1H), 1.57 - 1.46 (m, 2H), 1.43 - 1.20 (m, 2H), 1.16 - 1.00 (m, 2H). 19F NMR (377 MHz, DMSO-r76) 8 -74.34 (s, IF), - 116.18 (s, IF), -122.12 (s, IF), -173.04(s, IF). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wavelength: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: MeCN; TIME: 16.5 min.
Example 31: Preparation of Compound 39
[0509] Step 7: To a solution of 1 (700.0 mg, 1.9 mmol, 1.0 equiv.) in DMF (7 mL) was added NaH (118.3 mg, 2.9 mmol, 1.5 equiv.). The mixture was stirred at 0 °C for 30 min. Then 2 (573.8 mg, 2.9 mmol, 1.5 equiv.) was added. The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The mixture was poured into an aqueous NFUCl solution and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give 2 (670.0 mg, 1.4 mmol, 72.4%) as a yellow solid. LCMS(ESI)[M+1]+ = 470.4.
[0510] Step 2 To a solution of 3 (670.0 mg, 1.4 mmol) in DCM (6.7 mL) was added TFA (2.1 mL). The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The solvent was removed in vacuo to give crude 4 (590 mg), which was used directly in the next step without purification. LCMS(ESI)[M-1]’ = 412.4.
[0511] Step 3: To a solution of 4 (590.0 mg, 1.4 mmol, 1.0 equiv.) and DIEA (276.7 mg, 2.1 mmol, 1.5 equiv.) in dioxane (2 mL) was added DPPA (589.1 mg, 2.1 mmol, 1.5 equiv.). The mixture was stirred at 100 °C for 10 min. Then L-l (737.3 mg, 4.2 mmol, 3.0 equiv.) was added. The mixture was stirred at 100 °C for 2 h. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography to give 6 (racemate, 350 mg, 0.6 mmol, yield: 42.1%) as a white solid. The racemate was separated by chiral SFC to give 6-P1 (120 mg, 0.2 mmol) and 6-P2 (120 mg, 0.2 mmol). LCMS(ESI)[M+1]+ = 583.3, tR = 1.770 min. Preparative separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak C-IG, 250><30mm I.D., 5pm; Mobile phase: A for CO2 and B for MEOH; Gradient: B 35%; Flow rate:60 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Run time: 15 min; Cycle-time:8 min; Injection volume: 1.1 mL; Number of injection needles: 17; Eluted time: 4H. Peak 1: 6-P1, retention time: 1.649 min. Peak 2: 6-P2, retention time: 2.211 min.
[0512] Step 4 To a solution of 6-P1 (120 mg, 210.0 pmol, 1.0 equiv.) in DCM (4 mL) was added TFA (0.8 mL). The mixture was stirred at RT for Ih. LCMS showed the reaction was complete. The mixture was diluted with EA and concentrated under reduced pressure to give 7-P1 (105 mg, 199.6 pmol, yield: 96.8%) as a yellow solid. LCMS(ESI)[M-1]' = 527.4, tR = 1.271 min. [0513] Step 5: To a solution of 7-P1 (105 mg, 199.6 pmol, 1.0 equiv.) in DCM (2 mL) was added 8 (79.9 mg, 60.0 pmol, 3.0 equiv.). The mixture was stirred at RT for 40 min. LCMS (quenched with MeOH) showed the reaction was complete. Then a mixture of Int-R-2 (145.2 mg, 199.6 pmol, 1.0 equiv.) and lutidine (74.7 mg, 70.0 pmol, 3.5 equiv.) in DCM (0.5 mL) was added. The resulting mixture was stirred at RT for 10 min. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give 10 (45 mg, 36.4 pmol, 18.3%) as a yellow solid. LCMS(ESI)[M+1]+ = 1236.6, tR = 1.556 min.
[0514] Step 6: To a solution of 7 (45.0 mg, 40.0 pmol, 1.0 equiv.) in DCM (3 mL) was added TFA (0.6 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was diluted with EA and concentrated. The residue was purified by prep-HPLC (TFA) to give Compound 39 (25.8 mg, yield: 62.4%) as a yellow solid. LCMS(ESI)[M+1]+ = 1136.4, tR = 1.323 min. Instrument: LCMS 2020 (E-LCMS 012); Column: YMC -Triart C18, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: FLO/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.0 Imin @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. *HNMR (400 MHz, DMSO-c/6) 5 10.78 (s, 2H), 8.71 (s, IH), 8.13 (s, 2H), 7.87
- 7.59 (m, IH), 7.39 - 7.05 (m, 4H), 6.91 (s, 2H), 6.71 - 6.45 (m, IH), 5.72 - 5.19 (m, 6H), 4.86
- 4.38 (m, 7H), 4.30 - 4.08 (m, 2H), 3.99 - 3.82 (m, 3H), 3.79 - 3.59 (m, 12H), 3.21 - 2.83 (m, 2H), 2.64 - 2.51 (m, 2H), 2.33 - 2.26 (m, 1H), 2.24 - 2.10 (m, 2H), 2.07 - 1.97 (m, 1H), 1.46 - 1.18 (m, 4H), 0.84 (s, 2H). 19F NMR (377 MHz, DMSO</6) 8 -74.34 (s, IF), -116.18 (s, IF), - 122.12 (s, IF), -173.04(s, IF). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wavelength: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: MeCN; TIME: 16.5 min.
Example 32: Preparation of Compound 40
[0515] Step 1 To a solution of 6-P2 (from Example 33, 60.0 mg, 108.4 pmol, 1.0 equiv.) in DCM (2.0 mL) was added TFA (1.0 mL) and the mixture was stirred at RT for 3 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 2 (50.0 mg, 100.4 pmol, yield: 92.7%) as a yellow solid. LCMS(ESI)[M+1] + = 498.4, tR = 1.687 min.
[0516] Step 2'. To a solution of 2 (50.0 mg, 100.4 pmol, 1.0 equiv.) in DCM (2.0 mL) was added 3 (40.2 mg, 301.2 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0517] Step 3: To a solution of 4 (50.0 mg, 96.9 pmol, 1.0 equiv.) in DCM (2.0 mL) were added Int-R-2 (70.6 mg, 96.9 pmol, 1.0 equiv.) and lutidine (31.2 mg, 290.7 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 6 (30.0 mg, 24.9 pmol, yield: 25.6%) as a yellow solid. LCMS(ESI)[M+1] + = 1207.5, tR = 1.823 min.
[0518] Step 4 To a solution of 6 (30.0 mg, 24.9 pmol, 1.0 equiv.) in DCM (2.0 mL) was added TFA (1.0 mL), and the mixture was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give the crude product, which was purified by prep-HPLC (0.1% TFA) to give Compound 40 (9.0 mg, 8.1 pmol, yield: 39.3%) as a yellow solid. LCMS(ESI) [M+l] + = 1107.4, tR = 1.605 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ’H NMR (400 MHz, DMSO)- d6 8 8.13 (s, 2H), 7.85 (d, J= 23.1 Hz, 1H), 7.71 (s, 1H), 7.25 (dd, J= 8.1, 5.0 Hz, 2H), 7.17 (t, J = 8.9 Hz, 1H), 7.08 (s, 2H), 6.91 (dd, J = 8.7, 2.1 Hz, 1H), 5.81 (d, J = 19.9 Hz, 2H), 5.52 (d, J = 11.9 Hz, 1H), 4.74 (d, J= 23.7 Hz, 2H), 4.56 (d, J= 4.3 Hz, 2H), 4.12 - 4.01 (m, 2H), 3.89 (d, J = 14.4 Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.74 (s, 6H), 3.66 - 3.44 (m, 2H), 3.30 (dt, J= 14.2, 7.1 Hz, 1H), 3.16 (dd, J= 12.2, 10.2 Hz, 1H), 2.68 - 2.56 (m, 2H), 2.54 (s, 3H), 2.47 (t, J= 5.3 Hz, 2H), 2.33 - 1.98 (m, 4H), 1.70 (s, 3H), 1.21 (d, J = 21.4 Hz, 3H). 19F NMR (377 MHz, DMSO- d6) 5 -74.50 (s), -116.19 (s), -121.97 (s), -173.07 (s). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature:25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 33: Preparation of Compound 41
[0519] Step 1 To a solution of L1AIH4 (18.5 g, 487.3 mmol, 5.0 equiv.) in dioxane (300.0 mL) was added a solution of 1 (20.0 g, 97.5 mmol, 1.0 equiv.) in dioxane at 0 °C. The mixture was stirred at 110 °C for 18 h, LCMS showed the reaction was complete. The reaction was quenched with water and 15% aqueous NaOH solution, then filtered. The filtrate was extracted with EA. The organic layer was washed with brine, dried over Na2SCU and concentrated. The residue was purified by flash chromatography to give 2 (13.0 g, 80.6 mmol, yield: 82.75%) as a white solid. LCMS(ESI)[M+1] + = 162.1, tR =1.387 min.
[0520] Step 2: To a solution of 2 (10.0 g, 62.1 mmol, 1.0 equiv.) and ZnCh (62.1 mL, 2.0 M, 2.0 equiv.) in DCM (20.0 mL) was added EtMgBr (80.7 mL, 1.0 M, 1.3 equiv.) at RT. The mixture was stirred at RT for 1 h, then a solution of 3 (21.4 g, 93.2 mmol, 1.5 equiv.) in DCM (20.0 mL) was added slowly. The mixture was stirred at RT for another 1 h, then AICI3 (12.4 g, 93.2 mmol, 1.5 equiv.) was added. The mixture was stirred at RT for another 18 h. 30% conversion in LCMS was observed. The mixture was diluted with water and DCM. The organic layer was separated and concentrated. The residue was purified by flash chromatography to give 4 (4.0 g, 11.3 mmol, yield: 18.1%) as a yellow solid. LCMS(ESI)[M+1] + = 356.4, tR = 1.255 min. [0521] Step 3: To a solution of 4 (2.0 g, 5.6 mmol, 1.0 equiv.) in THF (20.0 mL) was added NaH (0.23 g, 5.6 mmol, 1.0 equiv.) at 0 °C and the mixture was stirred for 2 h. Then 5 (1.9 g, 5.6 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at RT for an additional 2 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give 6-P1 (350.0 mg, 632.9 pmol, yield: 27.3%) and 6-P2 (350 mg, 632.9 pmol, yield: 27.3%) as a yellow oil. LCMS(ESI)[M+1] + = 554.5, tR = 2.147 min. SFC method: Preparative separation method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak C-IC, 250><30mm I.D., 5pm; Mobile phase: A for CO2 and B for MeOH; Gradient: B 15%; Flow rate: 40 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220nm; Cycle-time: 16min; Injection volume: 1 mL; Number of injection needles: 19; Eluted time: 2H. The 1000 mg sample was dissolved in 20mL MEOH; Peak 1 : 6-P1, retention time: 2.057 min. Peak 2: 6-P2, retention time: 2.424 min.
[0522] Step 4: To a solution of 6-P1 (60.0 mg, 108.4 pmol, 1.0 equiv.) in DCM (2.0 mL) was added TFA (1.0 mL) and the mixture was stirred at RT for 3 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 7 (50.0 mg, 100.4 pmol, yield: 92.7%) as a yellow solid. LCMS(ESI)[M+1] + = 498.4, tR = 1.584 min.
[0523] Step 5: To a solution of 7 (50.0 mg, 100.4 pmol, 1.0 equiv.) in DCM (2.0 mL) was added 8 (40.2 mg, 301.2 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0524] Step 6: To a solution of 9 (50.0 mg, 96.9 pmol, 1.0 equiv.) in DCM (5.0 mL) were added Int-R-2 (70.6 mg, 96.9 pmol, 1.0 equiv.) and lutidine (31.2 mg, 290.7 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 11 (30.0 mg, 24.9 pmol, yield: 25.6%) as a yellow solid. LCMS(ESI)[M+1] + = 1207.4, tR = 1.892 min.
[0525] Step 7: A solution of 11 (30.0 mg, 24.9 pmol, 1.0 equiv.) in DCM (2.0 mL) was added TFA (1.0 mL) and the mixture was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give the crude product, which was purified by prep-HPLC (0.1% TFA) to give Compound 41 (8.7 mg, 7.9 pmol, yield: 47.4%) as a yellow solid. LCMS(ESI) [M+l] + = 1107.3, tR = 1.655 min. Instrument: LCMS2020 (E-LCMS 015); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ' H NMR (400 MHz, DMSO- d6) 5 8.13 (s, 2H), 7.83 (s, 1H), 7.71 (d, J= 2.2 Hz, 1H), 7.25 (t, J= 7.5 Hz, 2H), 7.17 (t, J= 8.9 Hz, 1H), 7.08 (s, 2H), 6.91 (dd, J = 8.7, 2.3 Hz, 1H), 5.86 - 5.78 (m, 2H), 5.52 (d, J = 11.9 Hz, 1H), 4.56 (q, J= 12.1 Hz, 2H), 4.38 - 4.07 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.75 (s, 6H), 3.66 - 3.55 (m, 2H), 3.53 - 3.41 (m, 1H), 3.34 - 3.26 (m, 1H), 2.61 (s, 2H), 2.54 (s, 3H), 2.47 (s, 2H), 2.33 - 2.02 (m, 4H), 1.69 (d, J= 6.5 Hz, 3H), 1.26 (d, J = 22.2 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 5 -74.04 (s), -116.17 (s), -121.93 (s), -173.05 (s). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature:25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 34: Preparation of Compound 42 [0526] Step 1 To a stirred mixture of 4-P2 (from Example 37, 60.0 mg, 108.2 pmol, l .O equiv.) in DCM (1.0 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. LCMS showed the reaction was complete. The mixture was concentrated to afford 2 (50.0 mg, crude) as a light yellow solid. LCMS(ESI)[M+1]+ = 499.3, tR = 1.472 min.
[0527] Step 2: To a stirred mixture of 2 (40.0 mg, crude, 1.0 equiv.) in DCM (1.0 mL) was added 3 (32.2 mg, 240.8 pmol, 3.0 equiv.) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The mixture was used directly in the next step. LCMS(ESI)[M+1]+ = 513.3 (in MeOH), tR = 1.753 min.
[0528] Step 3: To a stirred mixture of 4 (40.0 mg, crude, 1.0 equiv.) in DCM (2.0 mL) were added Int-R-2 (84.5 mg, 116.1 pmol, 1.5 equiv.) and 2, 6-lutidine (49.8 mg, 464.3 pmol, 6.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by TLC (5% MeOH in DCM) to give 6 (35.0 mg, 28.9 pmol, yield: 37.4%) as a yellow solid. LCMS(ESI)[M+ I ] = 1208.6, tR = 1.533 min.
[0529] Step 4: To a stirred mixture of 6 (35.0 mg, 28.9 pmol, 1.0 equiv.) in MeOH (2.0 mL) was added HC1 in MeOH (4M, 1.0 mL). The resulting mixture was stirred at room temperature for 0.5 h under a N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound 42 (25.6 mg, 23.1 pmol, yield: 79.8%) as a yellow solid. LCMS(ESI)[M+1]+ = 1108.4, tR = 1.531 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ MeCN/ FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/ min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ‘HNMR (400 MHz, DMSO-d6) 8 10.74 (s, 1H), 8.81 (s, 1H), 8.76 - 8.59 (m, 1H), 8.13 (s, 2H), 7.86 (s, 1H), 7.76 (s, 1H), 7.27 - 6.97 (m, 6H), 6.89 (s, 2H), 5.67 - 5.22 (m, 5H), 4.85 - 4.70 (m, 2H), 4.63 - 4.53 (m, 4H), 3.89 - 3.86 (m, 1H), 3.82 (s, 3H), 3.78 - 3.72 (m, 2H), 3.69 (s, 3H), 3.67 (s, 6H), 3.32 - 3.28 (m, 1H), 3.19 - 3.10 (m, 1H), 2.34 - 2.30 (m, 1H), 2.21 - 2.12 (m, 2H), 2.06 - 2.00 (m, 1H), 1.44 - 1.33 (m, 6H). 19F NMR (377 MHz, DMSO-d6) 8 - 74.50 (s), -116.17 (s), -121.92 (s), -173.05 (s). Preparation method: Instrument: E-Prep LC 024; Column: YMC Cl 8 250*21.2 mm 5um; Temperature: 25°C; Inject number: 1 ; Wave Length: 254 nm/220 nm; Phase A: H2O (0.1%TFA); Phase B: CH3CN.
Example 35: Preparation of Compound 43 [0530] Step 1 To a stirred mixture of 5 (from Example 37, 50.0 mg, crude, 1 .0 equiv.) in DCM (2.0 mL) was added 6 (21.6 mg, 162.5 pmol, 1.5 equiv.) at 0 °C under N2. The reaction mixture was stirred at room temperature for 0.5 hour. LCMS showed the reaction was complete. The mixture was used directly in the next step without purification. LCMS(ESI)[M+1]+ = 513.4 (in MeOH), tR = 1.737 min.
[0531] Step 2: To a stirred mixture of 7 (50.0 mg, crude, 1.0 equiv.) in DCM (1.0 mL) were added Int-R-2 (105.8 mg, 145.3 pmol, 1.5 equiv.) and 2,6-lutidine (0.06 mL, 484.5 pmol, 5.0 equiv.) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous ISfeSCU and concentrated under reduced pressure to give the crude product, which was purified by prep-TLC (5% MeOH in DCM) to give 9 (25.0 mg, 20.7 pmol, yield: 17.8%) as a yellow solid. LCMS(ESI)[M+1]+ = 1208.6, tR = 1.536 min.
[0532] Step 3: To a stirred mixture of 9 (25.0 mg, 20.7 pmol, 1.0 equiv.) in MeOH (3.0 mL) was added HC1 in MeOH (4M, 3.0 mL). The resulting mixture was stirred at room temperature for 0.5 h under a N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to give Compound 43 (16.0 mg, 2.9 pmol, yield: 69.8%) as a yellow solid. LCMS(ESI)[M+1]+ = 1108.4, tR = 1.688 min. Instrument: LCMS2020 (E-LCMS 015); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ MeCN/ FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/ min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B.'H NMR (400 MHz, DMSO-d6) 5 10.78 (s, 1H), 8.81 (m, 2H), 8.13 (s, 2H), 7.93 - 7.72 (m, 2H), 7.24 (m, 3H), 7.13 (m, 1H), 6.88 (m, 2H), 5.57 (m, 2H), 5.41 (m, 1H), 5.29 (s, 1H), 4.76 (s, 2H), 4.57 (m, 2H), 4.33 - 4.00 (m, 6H), 3.69 (s, 3H), 3.66 (s, 6H), 3.19 (m, 3H), 2.69 - 2.55 (m, 2H), 2.32 (m, lH), 2.15 (m, 2H), 2.08 - 2.00 (m, 1H), 1.43 - 1.16 (m, 8H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave Length: 254 nm/220 nm; Phase A: H2O (0.1%TFA); Phase B: CH3CN. Example 36: Preparation of Compound 44
[0533] Step I: To a solution of 4-P2 (from Example 37, 50.0 mg, 0.1 mmol, 1.0 equiv.) in
DCM (10.0 mL) was added TFA(3.0 mL). The reaction was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 5 (45.3 mg, 0.1 mmol) as a yellow oil. LCMS(ESI)[M+1]+ = 499.2, tR = 1.578 min.
[0534] Step 2'. To a stirred mixture of 5 (45.3 mg, 105.2 pmol, 1.0 equiv.) in DCM (1.0 mL) was added 6 (85.8 mg, 317.0 pmol, 3.0 equiv.), and the reaction mixture was stirred at RT for 1 hour under N2. LCMS showed the reaction was complete. The solution was used directly in the next step. LCMS(ESI)[M+1]+ = 513.2 (Methyl ester), tR = 1.865 min.
[0535] Step 3: A solution of 7 (66.5 pmol, 1.0 equiv.) in DCM were added 2,6-lutidine (35.3 mg, 322.4 pmol, 5.0 equiv.) and Int-D (35.0 mg, 66.5 pmol, 1.0 equiv.). The reaction mixture was stirred at RT for 1 h under N2. LCMS showed the reaction was complete. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SC>4 and concentrated to dryness. The mixture was purified by prep-TLC (DCM/MeOH = 15: 1) to give 8 (15.0 mg, 12.4 pmol, yield: 6.3%) as a light yellow solid. LCMS(ESI)[M+1]+ = 1125.3, tR = 1.507 min.
[0536] Step 4'. To a stirred mixture of 8 (15.0 mg, 11.4 pmol, 1.0 equiv.) in DCM (1.0 mL) was added HC1 in MeOH (4.0 M, 2.0 mL) and the reaction mixture was stirred at RT for 30 min. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep- HPLC to give Compound 44 (8.1 mg, 7.5 pmol, yield: 60.5%) as a yellow solid. LCMS(ESI)[M+1]+ = 1081.3, tR = 1.322 min. Instrument: LCMS2020 (E-LCMS 015); Column: YMC-Triart C18, 50*4.6mm, 5um; Mobile Phase: Solvent A: H2O/ACN/FA= 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'H NMR (400 MHz, DMSO-d6) 8 10.86 (s, 1H), 9.13 (s, 1H), 8.88 - 8.55 (m, 2H), 8.07 - 7.93 (m, 1H), 7.78 (s, 1H), 7.52 - 7.37 (m, 2H), 7.25 - 7.06 (m, 3H), 6.90 (s, 2H), 5.56 (dd, J= 54.2, 17.2 Hz, 4H), 4.84 - 4.41 (m, 7H), 3.79 - 3.62 (m, 15H), 3.32 (s, 1H), 2.68 - 2.53 (m, 3H), 2.38 - 1.98 (m, 5H), 1.90 - 1.65 (m, 4H), 1.43 (s, 3H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN. Example 37: Preparation of Compound 45
[0537] Step 1 To a solution of 1 (3.2 g, 9.0 mmol, 1.0 equiv.) and DIEA (3.5 g, 27.0 mmol, 3.0 equiv.) in dioxane (32.0 mL) was added triphosgene (1068.2 mg, 3.6 mmol, 0.4 equiv.) at 0 °C. The mixture was stirred at 100 °C for 10 min. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, then diluted with EtOAc and purified by column chromatography on silica gel (0-50% EtOAc in PE) to give 2 (1.7 g, 4.5 mmol, yield: 49.4%) as a colorless oil. LCMS(ESI)[M+1]+ = 383.2, tR = 1.812 min.
[0538] Step 2: To a solution of 2 (1.7 g, 4.5 mmol, 1.0 equiv.) in dioxane (17.0 mL) was added L-l (2.3 g, 13.4 mmol, 3.0 equiv ). The reaction mixture was stirred at 100 °C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (0-100% EtOAc in PE) to give 680 mg of racemate, which was further purified by SFC separation to give 4-P1 (240.0 mg, 433.0 pmol, yield: 9.6%) and 4-P2 (210.0 mg, 379.0 pmol, yield: 8.4%) as a colorless oil. 'H NMR (400 MHz, DMSO-d6) 8 8.81 (s, 1H), 8.68 (s, 1H), 7.83 (s, 1H), 7.21 (dd, J = 8.4, 2.2 Hz, 1H), 7.12 (d, J= 8.5 Hz, 1H), 6.91 (s, 2H), 6.11 (s, 1H), 5.86 (s, 1H), 5.47 (m, 1H), 3.85 (s, 3H), 3.73 (d, J = 8.5 Hz, 3H), 3.68 (s, 6H), 1.44 (d, J = 8.4 Hz, 9H), 1.34 (d, J = 6.5 Hz, 3H). Instruments: Shimadzu E-UC 01; Injection Volume: 0.5 uL; Column temperature: 40 °C; AB PR: 10 MPa; Mobile phase: A: CO2 B: MeOH (0.05% DEA v/v); Peak 1: Int-4-Pl, retention time: 1.635 min. Peak 2: Int-4-P2, retention time: 3.483 min.
[0539] Step 3 To a stirred mixture of 4-P1 (240.0 mg, 433.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour under a N2 atmosphere. LCMS showed the reaction was complete. The mixture was concentrated to afford 5 (240.0 mg, crude) as a light yellow solid. LCMS(ESI)[M+1]+ = 499.2, tR = 1.453 min. [0540] Step 4: To a stirred mixture of 5 (50.0 mg, crude, 1.0 equiv.) in DCM (2.0 mL) was added 6 (18.0 mg, 135.4 pmol, 1.5 equiv.) under nitrogen at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hour. LCMS showed the reaction was complete. The mixture was used directly in the next step without purification. LCMS(ESI)[M+1]+ = 513.4 (in MeOH), tR = 1.794 min.
[0541] Step 5 To a stirred mixture of 7 (45.0 mg, crude, 1.0 equiv.) in DCM (1.0 mL) were added Int-D (84.3 mg, 130.9 pmol, 1.5 equiv.) and 2,64utidine (0.06 mL, 436.0 qmol, 5.0 equiv.) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at room temperature for 0.5 hour. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by prep-TLC (5% MeOH in DCM) to give 9 (25.0 mg, 22.2 pmol, yield: 25.7%) as a yellow soild. LCMS(ESI)[M+1]+ = 1125.5, tR = 1.544 min.
[0542] Step 6: To a stirred mixture of 9 (25.0 mg, 22.2 pmol, 1.0 equiv.) in MeOH (3.0 mL) was added HC1 in MeOH (4 M, 3.0 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound 45 (3.1 mg, 2.9 pmol, yield: 12.9%) as a yellow solid. LCMS(ESI)[M+1]+ = 1081.8, tR= 1.468 min. Instrument: LCMS2020 (E-LCMS 013); Column: Shim-Pack Scepter C18, 33*3.0 mm, 3 um; Mobile Phase: Solvent A: H2O/ MeCN/ FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/ min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ’H NMR (400 MHz, DMSO-d6) 8 10.79 (s, 1H), 10.21 (s, 1H), 9.14 (m, 1H), 8.81 (m, 1H), 8.69 (m, 1H), 7.99 (m, 1H), 7.77 (s, 1H), 7.48 (m, 1H), 7.41 (m, 1H), 7.19 (m, 2H), 7.11 (m), 6.89 (s, 2H), 5.55 (m, 4H), 4.77 - 4.38 (m, 7H), 3.87 (m, 3H), 3.81 (s, 4H), 3.68 (m, 11H), 3.31 (s, 1H), 2.33 (s, 1H), 2.23 - 2.12 (m, 2H), 2.04 (s, 1H), 1.75 (m, 4H), 1.42 (s, 3H), 1.23 (s, 1H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: Triart C18, 250*20.0 mml. D., 5 um,12nm; Temperature: 25°C; Inject number: 1; Wave length: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 38: Preparation of Compound 46
[0543] Step 1 To a solution of 1 (1.0 g, 3.1 mmol, 1.0 equiv.) in DMF (5.0 mL) were added K2CO3 (1.2 g, 9.3 mmol, 3.0 equiv.) and 2-methylpropan-2-yl bromoacetate (599.5 mg, 3.1 mmol, 1.0 equiv.). The reaction was stirred at 60 °C for 1 hour. LCMS showed the reaction was complete. The mixture was poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 2 (400.0 mg, 0.9 mmol, yield: 29.6%) as a black solid. LCMS(ESI)[M+1]+ = 440.2, tR = 1.387 min.
[0544] Step 2: To a solution of 2 (400.0 mg, 0.9 mmol, 1 .0 equiv.) in DCM (8.0 mL) was added TFA (4.0 mL). The reaction was stirred at 60 °C for 18 hours. LCMS showed the reaction was complete. The mixture was concentrated to give 3 (320.0 mg, 0.8 mmol, yield: 91.7%) as black oil. LCMS(ESI)[M-56]+ = 384.2, tR = 1.358 min.
[0545] Step 3: To a solution of 3 (200.0 mg, 0.5 mmol, 1.0 equiv.) in toluene (5.0 mL) were added TEA (0.2 mL, 1.6 mmol, 3.0 equiv.) and DPPA (172.7 mg, 0.6 mmol, 1.1 equiv.). The reaction was stirred at 100 °C for 1 hour. Then L-4 (165.4 mg, 1.0 mmol, 2.0 equiv.) was added and the reaction was stirred at 100 °C for an additional 1.0 h under a N2 atmosphere. TLC showed the reaction was complete. The reaction mixture was poured into water and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel to give 5 (50.0 mg, 0.1 mmol, yield: 17.8%) as a yellow oil. LCMS(ESI)[M+1]+ = 539.3, tR = 1.175 min.
[0546] Step 4: A solution of 5 (50.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (10.0 mL) and TFA (3.0 mL) was stirred at 25 °C for 2.0 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated to give 6 (45.3 mg, 0.1 mmol, yield: 100%) as a yellow oil. LCMS(ESI)[M+1]+ = 483.6, tR = 0.682 min.
[0547] Step 5 To a stirred mixture of 6 (45.3 mg, 105.2 pmol, 1.0 equiv.) in DCM (1.0 mL) was added 7 (85.8 mg, 317.0 pmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h under N2. LCMS showed the reaction was complete. The resulting mixture was used directly in the next step. LCMS(ESI)[M+1]+ =497.3 (methyl ester), tR =0.846 min.
[0548] Step 6: To a solution of 8 (66.5 pmol, 1.0 equiv. From step.5) in DCM were added 2,6- Lutidine (35.3 mg, 322.4 pmol, 5.0 equiv.) and Int-R (35.0 mg, 66.5 pmol, 1.0 equiv.). The resulting mixture was stirred at RT for 1 h under N2. LCMS showed the reaction was complete. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep-TLC (DCM/MeOH = 15:1) to give 9 (15.0 mg, 12.4 pmol, yield: 6.3%) as a light yellow solid. LCMS(ESI)[M+1]+ = 1192.3, tR = 0.985 min.
[0549] Step 7: To a stirred mixture of 9 (15.0 mg, 11.4 pmol, 1.0 equiv.) in DCM (1.0 mL) was added HC1 in MeOH (4.0 M, 2.0 mL), and the resulting mixture was stirred at RT for 30 min. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by prep-HPLC to give Compound 46 (2.1 mg, 1.5 pmol, yield: 20.5%) as a yellow solid. LCMS(ESI)[M+1]+ =1092.4, tR =0.981 min. Instrument: LCMS2020 (E-LCMS 015); Column: YMC-Triart Cl 8, 50*4.6mm, 5um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B.’H NMR (400 MHz, DMSO-d6) 8 10.89 (s, 1H), 8.14 (s, 2H), 7.89 (d, J = 28.1 Hz, 1H), 7.41 - 6.85 (m, 3H), 6.45 (d, J = 206.5 Hz, 1H), 5.83 - 4.98 (m, 4H), 4.90 - 4.51 (m, 4H), 4.33 - 3.62 (m, 13H), 3.32 (s, 9H), 2.97 - 2.60 (m, 6H), 2.47 - 1.55 (m, 6H), 1.27 (d, J= 28.8 Hz, 3H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 39: Preparation of Compound 47
[0550] Step To a solution of 1 (500.0 mg, 1.4 mmol, 1.0 equiv.) and DIEA (542.9 mg, 4.2 mmol, 3.0 equiv.) in dioxane (8.0 mL) was added triphosgene (166.5 mg, 0.5 mmol, 0.4 equiv.) at 0 °C. The reaction mixture was stirred at 100 °C for 10 min. LCMS showed the reaction was complete. The reaction mixture was used in the next step without further purification. LCMS(ESI) [M+l]+ = 415.4, tR = 1.565 min.
[0551] Step 2'. To a solution of 2 (500.0 mg, 1.3 mmol, 1.0 equiv.) in dioxane (8.0 mL) was added L-4 (620.6 mg, 3.9 mmol, 3.0 equiv.). The reaction mixture was stirred at 100 °C for 18 h. LCMS showed 40% of the desired product. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give 4 (220.0 mg, 350.0 pmol, yield: 26.5%) as a yellow oil. LCMS(ESI) [M-56]+ = 485.2, tR = 1.969 min.
[0552] Step 3: To a solution of 4 (220.0 mg, 410.0 pmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure to give crude 5 (202.0 mg, 380.0 pmol, yield: 92.2%) as a yellow oil. LCMS(ESI) [M+l]+ = 485.3, tR = 1.390 min. [0553] Step 4 To a solution of 5 (40.0 mg, 80.0 pmol, 1 .0 equiv.) in DCM (5.0 mL) was added 6 (33.1 mg, 250.0 pmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was used in the next step without further purification. LCMS(ESI) [M+l]+ = 499.3, tR = 1.752 min.
[0554] Step 5: To a solution of 7 (40.0 mg, 80.0 pmol, 1.0 equiv.) in DCM (5.0 mL) were added 2,6-Lutidine (51.1 mg, 480.0 pmol, 6.0 equiv.) and Int-R-2 (57.9 mg, 80.0 pmol, 1.0 equiv.). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction was purified by column chromatography on silica gel and prep-HPLC to give 9 (25.0 mg, 20.0 pmol, yield: 26.3%) as a yellow solid. LCMS(ESI) [M+l]+ = 1194.4, tR = 1.787 min.
[0555] Step 6: To a solution of 9 (25.0 mg, 20.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and the residue was prep-HPLC to give Compound 47 (11.2 mg, 10.0 pmol, yield: 48.9%) as a white solid. LCMS(ESI) [M+l]+ =
1094.4, tR = 1.508 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart C18, 50*4.6 mm, 5 urn; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Time: 0.01 min @ 20% B, 1.79 min gradient (20- 95% B), then 0.7 min @ 95% B; ‘HNMR (400 MHz, DMSO-d6) 5 10.75 (s, 1H), 8.81 (d, J= 6.4 Hz, 2H), 8.13 (s, 2H), 7.79 (d, J= 52.6 Hz, 2H), 7.28 - 7.11 (m, 4H), 6.88 (s, 2H), 5.57 (t, J= 26.5 Hz, 2H), 5.36 (s, 1H), 4.74 (s, 4H), 4.58 (t, J= 9.6 Hz, 2H), 4.20 (s, 2H), 4.05 (s, 1H), 3.87 (s, 1H), 3.82 (s, 3H), 3.80 - 3.71 (m, 2H), 3.70 (s, 3H), 3.67 (s, 6H), 3.64 (s, 1H), 3.53 - 3.34 (m, 1H), 3.15 (s, 1H), 2.57 (d, J - 4.0 Hz, 1H), 2.47 (s, 1H), 2.32 (dd, J = 7.5, 5.6 Hz, 1H), 2.17 (td, J =
12.4, 6.9 Hz, 2H), 2.03 (s, 1H), 1.34 (d, J= 6.5 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.26 (s), -116.17 (s), -121.92 (s), -173.05 (s). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wave length: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: CH3CN; TIME: 18 min. Example 40: Preparation of Compound 48
[0556] Step 1 A solution of 8-P2 (from Example 41, 200.0 mg, 377.4 pmol, 1.0 equiv.) in formic acid (3.0 mL) was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 2 (140.0 mg, 325.6 pmol, yield: 86.3%) as a colorless oil. LCMS(ESI)[M+NH4] + = 448.4, tR = 1.362 min. [0557] Step 2 To a solution of 2 (140.0 mg, 325.2 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 3 (130.4 mg, 975.7 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0558] Step 3: To a solution of 4 (120.0 mg, 267.3 pmol, 1.0 equiv.) in DCM (5.0 mL) were added Int-N (175.8 mg, 267.3 pmol, 1.0 equiv.) and lutidine (85.9 mg, 801.8 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography to give 6 (40.0 mg, 37.4 pmol, yield: 14.0%) as a yellow solid. LCMS(ESI)[M+1] + = 1070.5, tR = 1.482 min.
[0559] Step 3: A solution of 6 (40.0 mg, 37.4 pmol, 1.0 equiv.) in formic acid (2.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0. 1% TFA) to give Compound 48 (8.3 mg, 8.1 pmol, yield: 21.6%) as a yellow solid. LCMS(ESI) [M+l] + = 1026.5, tR = 1.306 min. Instrument: LCMS2020 (E-LCMS 012); Column: YMC-Triart C18, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. JH NMR (400 MHz, DMSO-d6) 5 10.82 (s, 1H), 10.23 (s, 1H), 9.38 - 8.77 (m, 2H), 7.99 (dd, J= 9.1, 6.0 Hz, 1H), 7.48 (t, J= 9.0 Hz, 1H), 7.42 (d, .7= 2.3 Hz, 1H), 7.22 - 7.17 (m, 1H), 6.70 - 6.60 (m, 2H), 6.58 - 6.47 (m, 4H), 5.61 (d, J= 18.8 Hz, 1H), 5.48 (s, 2H), 5.29 (d, J = 8.7 Hz, 1H), 5.01 (d, J = 22.3 Hz, 2H), 4.65 - 4.54 (m, 3H), 3.85 (d, J= 10.4 Hz, 2H), 3.76 (dd, J= 14.6, 7.5 Hz, 8H), 3.61 (s, 3H), 3.56 (s, 6H), 3.32 (dd, J= 13.0, 5.5 Hz, 1H), 3.16 - 3.06 (m, 2H), 2.43 - 2.24 (m, 2H), 2.23 - 1.77 (m, 4H), 1.38 (d, J= 5.9 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.41 (s), -110.60 (s), -139.84 (d, J= 80.5 Hz), -172.93 (d, J= 26.8 Hz). Preparation method: Instrument: E-Prep LC 010 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature:25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 41: Preparation of Compound 49
[0560] Step 1: To a solution of 5 (from Example 43, 14.0 g, 83.3 mmol, 1.0 equiv.) in DCM
(200.0 mL) were added DIEA (21.5 g, 166.7 mmol, 2.0 equiv.) and MOMC1 (10.0 g, 125.0 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at RT for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give 2 (1.5 g, 7.1 mmol, yield: 8.5%) as a yellow oil. LCMS(ESI)[M+1] + = 213.1, tR = 1.055 min.
[0561] Step 2: To a solution of 2 (1.5 g, 7.1 mmol, 1.0 equiv.) in DMF (20.0 mL) were added IH-imidazole (965.6 mg, 14.2 mmol, 2.0 equiv.) and TBSC1 (1.1 g, 7.1 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at RT for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give 3 (1.7 g, 5.2 mmol, yield: 73.7%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 59.97 (s, 1H), 7.33 (t, J= 1A Hz, 1H), 6.73 (d, J= 8.9 Hz, 1H), 4.87 (s, 2H), 3.71 (s, 3H), 3.31 (d, J = 12.2 Hz, 3H), 0.81 (s, 9H), -0.00 (s, 6H).
[0562] Step 3: To a solution of 3 (from Example 43, 3.5 g, 7.8 mmol, 1.5 equiv.) in THF (20.0 mL) was added n-BuLi (4.9 mL, 7.8 mmol, 1.5 equiv.) at -78°C, and the mixture was stirred for 30 min under N2. Then 3 (1.7 g, 5.2 mmol, 1.0 equiv.) was dissolved in dry THF and added dropwise to the reaction mixture, which was stirred for 2 h. The reaction was quenched with water, and THF was evaporated under reduced pressure. The aqueous solution was extracted with EtOAc, and the organic phase was washed with water and brine, dried with Na2SC>4, and evaporated under reduced pressure. The residue was purified by flash silica chromatography to give 5 (1.6 g, 3.3 mmol, yield: 62.6%) as a yellow oil. LCMS(ESI)[M+1] + = 491.3, tR = 2.183 min.
[0563] Step 4: To a solution of 5 (1.6 g, 3.3 mmol, 1.0 equiv.) in THF (20.0 mL) was added TBAF (1.0 M in THF, 4.9 mL, 4.9 mmol, 1.5 equiv.). The mixture was stirred at RT for 1 h under N2. The reaction was quenched with water, the mixture was extracted with EtOAc, and the organic phase was washed with water and brine, dried with Na2SO4, and evaporated under reduced pressure. The residue was purified by flash silica chromatography to give 6 (420.0 mg, 1.1 mmol, yield: 34.2%) as a yellow oil. *H NMR (400 MHz, DMSO-d6) 8 8.84 (s, 1H), 6.83 (d, J= 8.6 Hz, 1H), 6.52 (d, J = 10.8 Hz, 3H), 6.44 (t, J = 9.8 Hz, 2H), 5.00 (s, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 3.57 (s, 6H), 3.47 (s, 3H).
[0564] Step 5: To a solution of 6 (600.0 mg, 1.6 mmol, 1.0 equiv.) and L-7 (555.2 mg, 3.2 mmol, 2.0 equiv.) in DMSO (6.0 mL) were added Pd2(dba)s (29.2 mg, 31.9 pmol, 0.02 equiv.) and LI (N,N'-[(lR,2R)-l,2-Diphenyl-l,2-ethanediyl]bis[2-diphenylphosphinobenzamide]; CAS: 138517-62-1 , 75.37 mg, 95.6 pmol, 0.06 equiv.). The mixture was stirred at 30 °C for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash silica chromatography and SFC separation to give 8-P1 (150.0 mg, 282.7 pmol, yield: 17.7%) and 8-P2 (200.0 mg, 376.9 pmol, yield: 23.7%) as a yellow oil. LCMS(ESI) [M+18] + = 548.6, tR = 1.460 min. SFC method: Preparative separation method; Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak C-IC, 250><30mm I.D., 5 pm; Mobile phase: A for CO2 and B for MEOH; Gradient: B 10%; Flow rate:60 mL/min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength:220nm; Cycle-time: 15min; Injection volume: 0.4mL; Number of injection needles: 45; Eluted time: 10H. The 500mg sample was dissolved in 18mL MEOH. Peak 1 : 8-P1, retention time: 3.236 min. Peak 2: 8-P2, retention time: 3.640 min.
[0565] Step 6: A solution of 8-P1 (150.0 mg, 283.0 pmol, 1.0 equiv.) in formic acid (3.0 mL) was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 9 (120.0 mg, 279.1 pmol, yield: 98.6%) as a colorless oil. LCMS(ESI)[M+18] + = 448.5, tR = 1.360 min.
[0566] Step 7: To a solution of 9 (120.0 mg, 278.8 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 10 (111.8 mg, 836.3 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0567] Step 8: To a solution of 11 (100.0 mg, 222.7 pmol, 1.0 equiv.) in DCM (5.0 mL) were added Int-N (146.5 mg, 222.7 pmol, 1.0 equiv.) and Lutidine (71.6 mg, 668.2 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography to give 13 (30.0 mg, 28.1 pmol, yield: 12.6%) as a yellow solid. LCMS(ESI)[M+1] + = 1070.5, tR = 1.493 min.
[0568] Step 9: A solution of 13 (30.0 mg, 28.1 pmol, 1.0 equiv.) in formic acid (2.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0.1% TFA) to give Compound 49 (12.9 mg, 12.6 pmol, yield: 44.9%) as a yellow solid. LCMS(ESI) [M+l] + = 1026.4, tR = 1.299 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ’H NMR (400 MHz, DMSO-d6) 8 10.83 (s, 1H), 10.24 (s, 1H), 9.14 (d, J = 25.7 Hz, 2H), 7.99 (dd, J= 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.41 (s, 1H), 7.19 (d, J= 2.3 Hz, 1H), 6.64 (dt, J= 8.6, 6.1 Hz, 2H), 6.58 (d, J= 1.5 Hz, 2H), 6.51 (dd, J = 18.4, 9.8 Hz, 2H), 5.57 (d, J= 51.3 Hz, 2H), 5.42 (s, 1H), 5.38 (s, 1H), 4.95 (d, J= 30.1 Hz, 2H), 4.60 (d, J= 12.8 Hz, 3H), 4.05 (d, J= 13.5 Hz, 2H), 3.86 (d, J= 23.1 Hz, 4H), 3.74 (s, 4H), 3.61 (s, 3H), 3.56 (s, 6H), 3.35 - 3.27 (m, 1H), 3.19 - 3.09 (m, 2H), 2.42 - 2.24 (m, 2H), 2.23 - 1.99 (m, 4H), 1.40 (t, J= 6.4 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.50 (s), -110.62 (d, J = 11.1 Hz), -139.83 (d, J= 11.3 Hz), -172.94 (d, J= 25.8 Hz). Preparation method: Instrument: E- Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature:25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 42: Preparation of Compound 50
[0569] Step 1 A solution of 10-P2 (from Example 43, 150.0 mg, 282.7 pmol, 1.0 equiv.) in FA (3.0 mL) was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 2 (120.0 mg, 279.1 pmol, yield: 98.6%) as a colorless oil. LCMS(ESI)[M+1] + = 431.4, tR = 1.433 min.
[0570] Step 2: To a solution of 2 (120.0 mg, 279.1 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 3 (111.8 mg, 837.2 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0571] Step 3: To a solution of 4 (120.0 mg, 267.3 pmol, 1.0 equiv.) in DCM (5.0 mL) were added Int-N (175.8 mg, 267.3 pmol, 1.0 equiv.) and lutidine (85.9 mg, 801.8 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography to give 6 (50.0 mg, 46.8 pmol, yield: 17.5%) as a yellow solid. LCMS(ESI)[M+1] + = 1070.4, tR = 1.791 min. [0572] Step 4 A solution of 6 (50.0 mg, 46.8 pmol, 1.0 equiv.) in formic acid (2.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0. 1% TFA) to give Compound 50 (8.4 mg, 8.2 pmol, yield: 17.5%) as a yellow solid. LCMS(ESI) [M+l] + = 1026.5, tR = 1.240 min. Instrument: LCMS2020 (E-LCMS 012); Column: YMC-Triart C18, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 1H NMR (400 MHz, DMSO-d6) 5 10.80 (s, 1H), 10.24 (s, 1H), 9.72 (d, J =
12.2 Hz, 1H), 9.19 (t, J = 15.2 Hz, 1H), 8.06 - 7.93 (m, 1H), 7.48 (t, J = 9.0 Hz, 1H), 7.42 (d, J =
2.2 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.54 (s, 2H), 6.51 - 6.37 (m, 3H), 5.67 - 5.40 (m, 2H), 5.30 (d, J = 9.8 Hz, 1H), 5.02 (d, J = 21.0 Hz, 1H), 4.71 (d, J = 6.1 Hz, 1H), 4.61 (d, J = 12.6 Hz, 2H), 4.49 (d, J = 9.5 Hz, 2H), 4.36 (d, J = 11.9 Hz, 2H), 4.05 - 3.92 (m, 4H), 3.83 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 3.58 (s, 6H), 3.32 (d, J = 7.5 Hz, 1H), 3.26 - 3.13 (m, 2H), 2.59 (dd, J = 17.4, 8.6 Hz, 2H), 2.35 - 2.04 (m, 4H), 1.48 (d, J = 6.8 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.47 (s), -110.62 (d, J = 25.8 Hz), -139.90 (d, J = 32.0 Hz), - 172.94 (d, J = 28.1 Hz). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250mm; Temperature:25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 43: Preparation of Compound 51
Compound 51
[0573] Step 1 To a solution of 1 (10.0 g, 50.5 mmol, 1.0 equiv.) in DCM (15.0 mL) was added PBr3 (13.6 g, 50.5 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred atRT for 2 h under N2. LCMS showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure to give crude 2 (6.0 g, 23.1 mmol, yield: 45.7%) as a white solid. LCMS(ESI)[M+H] + = 263.2, tR = 1.354 min.
[0574] Step 2: To a solution of 2 (4.0 g, 15.4 mmol, 1.0 equiv.) in THF (50.0 mL) was added PPh3 (4.0 g, 15.4 mmol, 1.0 equiv.). The mixture was stirred at 70 °C for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure to give crude 3 (5.0 g, 11.2 mmol, yield: 73.43%) as a white solid.
[0575] Step 3: To a solution of 4 (100.0 g, 509.68 mmol, 1.0 equiv.) in DCM (150.0 mL) was added BC13 (1.0 L, 1019.36 mmol, 2.0 equiv.) at 0°C. The mixture was stirred at RT for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous ISfeSCL and concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography to give 5 (55.0 g, 327.1 mmol, yield: 64.2%) as a yellow solid. 1H NMR (400 MHz, CDC13) 8 11.11 (s, 1H), 9.75 (s, 1H), 7. 14 (d, J= 8.7 Hz, 1H), 6.62 (d, J= 8.7 Hz, 1H), 5.53 (s, 1H), 3.98 (s, 3H).
[0576] Step 4: To a solution of 5 (15.0 g, 89.2 mmol, 1.0 equiv.) in DMF (200.0 mL) were added IH-imidazole (12.2 g, 178.4 mmol, 2.0 equiv.) and TBSC1 (13.5 g, 89.2 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at RT for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give 6 (15 g, 53.1 mmol, yield: 59.5%) as a yellow solid. 1H NMR (400 MHz, CDC13) 8 10.87 (s, 1H), 9.55 (s, 1H), 6.98 (d, J= 8.7 Hz, 1H), 6.39 (d, J= 8.7 Hz, 1H), 3.71 (s, 3H), 0.86 (s, 9H), 0.00 (s, 6H).
[0577] Step 5: To a solution of 6 (15.0 g, 53.1 mmol, 1.0 equiv.) in DCM (200.0 mL) were added DIEA (13.7 g, 106.2 mmol, 2.0 equiv.) and M0MC1 (6.4 g, 80.5 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at RT for 16 h under N2. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give 7 (16.0 g, 49.0 mmol, yield: 92.3%) as a yellow oil. LCMS(ESI)[M+1] + = 327.4, tR = 2.161 min.
[0578] Step 6: To a solution of 3 (32.7 g, 73.5 mmol, 1.5 equiv.) in THF (200.0 mL) was added n-BuLi (46.0 mL, 73.5 mmol, 1.5 equiv.) at -78 °C, and the mixture was stirred for 30 min under N2. Then 7 (16.0 g, 49.0 mmol, 1.0 equiv.) was dissolved in dry THF and added dropwise to the reaction mixture, which was then stirred for 2 h. The reaction was quenched with water, and the THF was evaporated under reduced pressure. The mixture was extracted with EtOAc, and the organic phase was washed with water and brine, dried with Na2SC>4, and evaporated under reduced pressure. The residue was purified by flash silica chromatography to give 8 (20.0 g, 40.8 mmol, yield: 83.2%) as a yellow oil. 1H NMR (400 MHz, CDC13) 8 6.61 (d, J = 8.6 Hz, 1H), 6.53 (d, J = 11.9 Hz, 1H), 6.37 (s, 2H), 6.36 (d, J= 3.4 Hz, 1H), 6.33 (s, 1H), 5.01 (s, 2H), 3.67 (s, 3H), 3.61 (s, 3H), 3.50 (s, 6H), 3.40 (s, 3H), 0.87 (s, 8H), 0.00 (s, 5H).
[0579] Step 7: To a solution of 8 (20.0 g, 40.8 mmol, 1.0 equiv.) in THF (200.0 mL) was added TBAF (44.8 mL, 44.84 mmol, 1.1 equiv ). The mixture was stirred at RT for 1 h under N2. The reaction was quenched with water. The mixture was extracted with EtOAc, and the organic phase was washed with water and brine, dried with Na2SO4, and evaporated under reduced pressure. The residue was purified by flash silica chromatography to give 9 (15.0 g, 39.9 mmol, yield: 97.8%) as a yellow oil. LCMS(ESI)[M+1] + = 377.4, tR = 1.414 min.
[0580] Step 8: To a solution of 9 (15.0 g, 39.9 mmol, 1.0 equiv.) in DMF (150.0 mL) were added L-2 (15.0 g, 63.8 mmol, 1.6 equiv.) andK^CCh (16.5 g, 119.6 mmol, 3.0 equiv.). The mixture was stirred at RT for 16 h under N2. The reaction was quenched with water. The mixture was extracted with EtOAc, and the organic phase was washed with water and brine, dried with Na2SO4, and evaporated under reduced pressure. The residue was purified by flash silica chromatography and SFC separation to give 10-P1 (700.0 mg, 1.3 mmol, yield: 33.1%) and 10-P2 (700 mg, 1.3 mmol, yield: 33.1%) as a yellow oil. 10-P1: LCMS(ESI) [M+18] + = 548.5, tR = 2.050 min. Instrument: LCMS2020 (E-LCMS 012); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 urn; Mobile Phase: Solvent A: H2O/ACN/FA= 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 10-P2: LCMS(ESI) [M+18] + = 548.6, tR = 2.033 min. Instrument: LCMS2020 (E-LCMS 012); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. SFC method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak C-IG, 250x30mm I D., 5pm; Mobile phase: A for CO2 and B for EtOH; Gradient: B 10%; Flow rate:60 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength:254nm; Cycle-time: 13 min; Injection volume: 0.4 mL; Number of injection needles: 130; Eluted time: 30 H. The 2100mg sample was dissolved in 40 mL ETOH. Peak 1 : 10-P1, retention time: 2.065 min. Peak 2: 10-P2, retention time: 2.347 min. [0581] Step 9: A solution of 10-P1 (150.0 mg, 282.7 pmol, 1.0 equiv.) in formic acid (3.0 mL) was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 11 (120.0 mg, 279.1 pmol, yield: 98.6%) as a colorless oil. LCMS(ESI)[M+ 1 ] + = 431.4, tR = 1.417 min.
[0582] Step 10: To a solution of 11 (120.0 mg, 279.1 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 12 (111.8 mg, 837.2 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification. [0583] Step 11 : To a solution of 13 (120.0 mg, 267.3 pmol, 1 .0 equiv.) in DCM (5.0 mL) were added Int-N (175.8 mg, 267.3 pmol, 1.0 equiv.) and lutidine (85.9 mg, 801.8 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 15 (30.0 mg, 28.1 pmol, yield: 10.5%) as a yellow solid. LCMS(ESI)[M+1] + = 1070.4, tR = 1.638 min.
[0584] Step 12 A solution of 15 (30.0 mg, 28.1 pmol, 1.0 equiv.) in formic acid (2.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0.1% TFA) to give Compound 51 (6.0 mg, 5.9 pmol, yield: 20.9%) as a yellow solid. LCMS(ESI) [M+l] + = 1026.5, tR = 1.415 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 10.80 (s, 1H), 10.21 (s, 1H), 9.63 (d, J = 15.8 Hz, 1H), 9.16 (d, J= 23.4 Hz, 1H), 8.00 (dd, J = 9.2, 6.0 Hz, 1H), 7.48 (t, J= 8.8 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 3.1 Hz, 2H), 6.52 - 6.36 (m, 3H), 5.65 - 5.48 (m, 1H), 5.40 (d, J= 6.4 Hz, 1H), 5.26 (d, J= 12.8 Hz, 1H), 5.15 (d, J= 8.0 Hz, 1H), 4.73 (dd, J= 13.0, 7.2 Hz, 1H), 4.65 - 4.58 (m, 2H), 4.44 (dd, J= 45.1, 10.3 Hz, 2H), 4.14 (dd, ,/ = 24.8, 14.8 Hz, 2H), 3.87 (d, J= 6.4 Hz, 4H), 3.77 (d, J= 4.1 Hz, 4H), 3.62 (s, 3H), 3.58 (d, 1.4 Hz, 6H), 3.32 (s, 1H), 3.17 (d, J= 7.1 Hz, 2H), 2.33 (dd, J= 11.5, 6.0 Hz,
2H), 2.26 - 2.00 (m, 4H), 1.49 (d, J= 6.1 Hz, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -74.37 (s), -110.59 (s), -139.90 (d, J = 134.6 Hz), -172.92 (d, J = 34.3 Hz). Preparation method: Instrument: E-Prep LC 024LH-40; Column: YMC Cl 8250*21.2 mm 5 um; Temperature:25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN. Example 44: Preparation of Compound 52
[0585] Step 1 To a solution of 1 (10.0 g, 42.2 mmol, 1.0 equiv.) in anhydrous THF (10.0 mL) was added n-BuLi (20.2 mL, 50.6 mmol, 1.2 equiv.) at -70 °C. The reaction was stirred at -70 °C for 1 h. Then 2 (9.9 g, 50.6 mmol, 1.2 equiv.) was added. The mixture was stirred at RT for an additional 1.5 h. LCMS showed the reaction was complete. The reaction mixture was quenched with water and extracted with EA (30 mL x 3). The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated with PE: EA = 2: 1 to afford 3 (6.0 g, 16.9 mmol, yield: 40.1%) as a white solid. LCMS(ESI)[M+1]+ = 336.1, tR = 1.668 min.
[0586] Step 2: To a solution of 3 (5.0 g, 14.1 mmol, 1.0 equiv.) in DCM (50.0 mL) was added the Dess-Martin reagent (8.9 g, 21.1 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with EA. The filtrate was washed with NaHCCL solution, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 10-50% EtOAc in petroleum ether to afford 4 (4.0 g, 11.3 mmol, yield: 80.4%) as a colorless solid. LCMS(ESI)[M+1]+ = 352.1, tR = 1.617 min
[0587] Step 3: To a mixture of 5 (10.0 g, 53.4 mmol, 1.0 equiv.), B2?in2 (20.3 g, 80.2 mmol, 1.5 equiv.) and KOAc (10.4 g, 106.9 mmol, 2.0 equiv.) in dioxane (100.0 mL) was added Pd(PPh3)Ch (3.7 g, 5.3 mmol, 0.1 equiv.). The reaction mixture was backfilled with nitrogen three times, then heated to 90°C and stirred for 6 h under a nitrogen atmosphere. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSCU, filtered and evaporated. The crude product was purified by flash silica gel column chromatography to afford 6 (8.0 g, 34.1 mmol, yield: 63.9%) as a yellow solid. LCMS(ESI)[M+1]+ = 235.2, tR = 1.574 min.
[0588] Step 4.' To a mixture of 6 (4.0 g, 11.3 mmol, 1.0 equiv.), 4 (3.9 g, 17.0 mmol, 1.5 equiv.), Pd(PPhs)4 (1.3 g, 1.1 mmol, 0.1 equiv.) in dioxane (40.0 mL) and H2O (8.0 mL) was added Na2CCh (2.4 g, 22.7 mmol, 2.0 equiv.). The reaction mixture was backfilled with nitrogen three times, then heated to 100 °C and stirred for 4 h under nitrogen. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash silica gel column chromatography to afford 7 (2.6 g, 6.8 mmol, yield: 60.3%) as a yellow solid. LCMS(ESI)[M+1]+ = 380.3, tR = 1.500 min
[0589] Step 5: To a solution of 7 (500.0 mg, 1.3 mmol, 1.0 equiv.) in DMF (8.0 mL) were added K2CO3 (546.3 mg, 0.6 mmol, 3.0 equiv.) and L-2 (437.0 mg, 1.9 mmol, 1.5 equiv.) at 0 °C. The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The solution was poured into water and extracted with EA. The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by flash silica column chromatography to afford 3 (600.0 mg, 1.1 mmol, yield: 87.6%) as a colorless solid. LCMS(ESI)[M+1]+ = 520.5, tR = 2.178 min.
[0590] Step 6: To a solution of 8 (550.0 mg, 1.0 mmol, 1.0 equiv.) in DCM (10.0 mL) was added TFA (2.0 mL, 1.1 mmol) at 25 °C. The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to give 9 (500.0 mg, 0.9 mmol, yield: 91.7%) as a colorless oil. LCMS (ESI) [M+l] + = 464.2, tR = 1.762 min.
[0591] Step 7: To a solution of 9 (50.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (2.0 mL) and DMF (2.0 mL) were added Int-S (81.2 mg, 0.1 mmol, 1.0 equiv.), DIEA(41.8 mg, 0.3 mmol, 3.0 equiv.) and T3P (68.6 mg, 0.2 mmol, 2.0 equiv.) at 0 °C. The reaction was stirred at 0 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured into water and extracted with EA three times. The organic layer was concentrated under reduced pressure, and the residue was purified by prep-TLC and prep-HPLC to give 10 (40.0 mg, 0.1 mmol, yield: 34.5%) as a white solid. LCMS(ESI)[M+1]+ = 1198.6, tR = 1.724 min. [0592] Step 8: To a solution of 10 (50.0 mg, 0.1 mmol, 1 .0 equiv.) in DCM (5.0 mL) was added TFA (2.0 mL) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was purified by prep-TLC and prep-HPLC to give Compound 52 (15.0 mg, 0.01 mmol, yield: 31.1%) as a yellow solid. LCMS(ESI)[M+1]+ = 1098.4, tR = 1.342 min. JH NMR (400 MHz, DMSO-d6) 8 10.75 (s, 1H), 8.22 (dd, J = 7.9, 3.0 Hz, 1H), 8.17 - 7.92 (m, 4H), 7.85 (d, J = 1.6 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.33 (d, J= 8.6 Hz, 1H), 7.21 (ddd, J= 26.0, 13.0, 6.0 Hz, 3H), 6.96 (d, J = 8.7 Hz, 1H), 5.65 (d, J = 17.9 Hz, 2H), 5.46 (d, J= 32.0 Hz, 2H), 4.97 (s, 1H), 4.78 (s, 3H), 4.67 - 4.49 (m, 3H), 4.45 (d, J= 13.2 Hz, 1H), 4.20 (d, J = 12.2 Hz, 2H), 3.91 (s, 1H), 3.89 (s, 3H), 3.83 (s, 1H), 3.76 (s, 1H), 3.74 (s, 3H), 3.50 (s, 3H), 3.47 (d, J= 5.2 Hz, 1H), 3.31 (s, 2H), 3.10 (s, 2H), 2.33 (d, J = 1A Hz, 1H), 2.27 - 1.94 (m, 6H). 19F NMR (377 MHz, DMSO) 8 -74.53 (s), -116.16 (d, J = 4.1 Hz), -121.81 (s), -173.01 (s). Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25 °C; Inject number: 1; Wave length: 254 nm/220 nm; Phase A: H2O (0.1%TFA); Phase B: CH3CN.
Example 45: Preparation of Compound 53 [0593] Step 1 To a solution of 6 (from Example 54, 100.0 mg, 170.0 pmol, 1 .0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 4 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water and lyophilized to give 7 (90.0 mg, crude) as a yellow solid. LCMS(ESI)[M+1]+ =527.2, tR =1.429 min.
[0594] Step 2: To a solution of 7 (110.0 mg, 210.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 8 (55.7 mg, 420.0 pmol, 2.0 equiv.). The mixture was stirred at RT for 2 h, LCMS showed the reaction was complete. The reaction was used in the next step without further purification. LCMS(ESI) [M+MeOH-35]+ = 541.3, tR = 1.594 min.
[0595] Step 3 To a solution of 9 (80.0 mg, 150.0 pmol, 1.0 equiv.) in DCM (2 mL) was added a solution of Int-S-2 (132.6 mg, 180.0 pmol, 1.2 equiv.) in DCM (2 mL) and 2,6-lutidine (156.9 mg, 1500.0 pmol, 10.0 equiv.). The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete, and the reaction was purified by flash column chromatography to give 10 (32.0 mg, 30.0 pmol, yield: 17.2%) as a yellow solid. LCMS(ESI) [M+l]+ = 1261.4, tR = 1.601 min.
[0596] Step 4'. To a solution of 10 (32.0 mg, 30.0 pmol, 1.0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete, and the reaction was purified by prep-HPLC to give Compound 53 (4.7 mg, 9.0 pmol, yield: 15.9%) as a yellow solid. LCMS(ESI) [M+l]+ = 1161.3, tR = 1.431 min. (Column: Shim- Pack Scepter C18, 33*3.0mm, 3um. Mobile Phase: Solvent A: FEO/MeCN/FA = 90: 10:0.05, Solvent B: CH3CN. Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). 'H NMR (400 MHz, DMSO-d6) 8 8.25 - 7.90 (m, 3H), 7.36 - 7.07 (m, 4H), 6.90 (s, 2H), 6.76 (d, J= 7.7 Hz, 1H), 5.86 - 5.33 (m, 5H), 5.05 - 4.76 (m, 3H), 4.65 - 4.45 (m, 3H), 3.89 - 3.84 (m, 2H), 3.80 - 3.67 (m, 15H), 3.53 - 3.40 (m, 1H), 3.37 - 3.25 (m, 1H), 3.14 (s, 1H), 3.03 (s, 2H), 2.87 - 2.71 (m, 3H), 2.64 - 2.53 (m, 2H), 2.43 (s, 3H), 2.39 - 2.33 (m, 1H), 2.24 - 1.93 (m, 4H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1% TFA); phase B: CH3CN. Example 46: Preparation of Compound 54
[0597] Step I To a solution of 1 (1 .0 g, 6.3 mmol, 1 .0 equiv.) in dioxane (15 mL) were added 2 (1.2 g, 12.6 mmol, 2.0 equiv.) and DIEA (2.4 g, 18.9 mmol, 3.0 equiv.). The mixture was stirred at 100 °C for 18 h, LCMS showed 50% conversion. The reaction was concentrated and the residue was purified by prep-HPLC (water/CFLCN) to give 3 (470.0 mg, 2.2 mmol, yield: 34.5%, unstable, dissolved in toluene and used directly). LCMS(ESI) [M-55]+ = 160.3, tR = 1.003 min.
[0598] Step 2: To a solution of 3 (470.0 mg, 2.2 mmol, 1.0 equiv.) in toluene (10 mL) were added MgSO4 (3.0 g) and paraformaldehyde (78.6 mg, 2.6 mmol, 1.2 equiv.) at 0 °C, then TMSC1 (711.6 mg, 6.5 mmol, 3.0 equiv.) was added slowly. The mixture was stirred at RT for 2 h. Then the mixture was filtered and the filtrate was concentrated at 25 °C to give crude 4 as a colorless oil (used directly without purification).
[0599] Step 3: To a solution of 5 (400.0 mg, 1.1 mmol, 0.5 equiv.) in DMF (10 mL) was added CS2CO3 (756.1 mg, 2.2 mmol, 1.0 equiv ). The mixture was stirred at 0 °C for 30 min, then 4 (612.0 mg, 2.2 mmol, 1.0 equiv.) in DMF (2.0 ml) was added. The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete, the reaction was purified by reversed-phase combi flash to give 6 (100.0 mg, 170.0 pmol, yield: 7.4%) as a white solid. LCMS(ESI) [M+l]+ = 583.2, tR = 1.866 min. Column: Shim-Pack Scepter C18, 33*3.0mm, 3 pm. Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05, Solvent B: CH3CN. Run Time: O.Olmin @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). ’H NMR (400 MHz, DMSO-d6) 8 7.30 (d, J= 8.7 Hz, 2H), 6.97 (s, 2H), 6.77 (dd, J = 8.7, 2.0 Hz, 1H), 6.15 (s, 1H), 5.78 (s, 3H), 4.78 (s,21H), 3.85 - 3.66 (m, 12H), 2.78 (s, 3H), 2.45 (s, 3H), 1.42 (s, 9H). Instrument: E-Prep LC 012 LH-40; Column: UniHybrid 5-120 C8 21.2*250 mm; Temperature: 25 °C; Inject number: 1; Wavelength: 254 nm/ 220 nm; phase A: H2O (0.1% NH4HCO3); phase B: CH3CN.
[0600] Step 4'. To a solution of 6 (100.0 mg, 170.0 pmol, 1.0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 4 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water and lyophilized to give 7 (90.0 mg, crude) as a yellow solid. LCMS(ESI)[M+1]+ =527.2, tR =1.429 min.
[0601] Step 5: To a solution of 7 (110.0 mg, 210.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 8 (55.7 mg, 420.0 pmol, 2.0 equiv.). The mixture was stirred at RT for 2 h, LCMS showed the reaction was complete. The compound was used in the next step without further purification. LCMS(ESI) [M+MeOH-35]+ = 541.3, tR = 1.594 min.
[0602] Step 6: To a solution of 9 (133.0 mg, 240.0 pmol, 1.0 equiv.) in DCM (2 mL) was added a solution of Int-S-1 (183.8 mg, 240.0 pmol, 1.0 equiv.) in DCM (2 mL) and 2,6-lutidine (156.9 mg, 1440.0 pmol, 6.0 equiv.). The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete, and the reaction was purified by flash to give 5 (40.0 mg, 30.0 pmol, yield: 12.9%) as a yellow solid. LCMS(ESI) [M+l]+ = 1261.4, tR = 1.714 min.
[0603] Step 7: To a solution of 10 (35.0 mg, 30.0 pmol, 1.0 equiv.) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The reaction was purified by prep-HPLC to give Compound 54 (10.0 mg, 10.0 pmol, yield: 31.0%) as a yellow solid. LCMS(ESI) [M+l]+ = 1161.4, tR = 1.319 min. (Column: Shim- Pack Scepter C18, 33*3.0mm, 3 pm. Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05, Solvent B: CH3CN. Method: positive-negative 3 min-100-1800.1cm. Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B). 'H NMR (400 MHz, DMSO-d6) 5 8.04 (d, J= 70.9 Hz, 3H), 7.42 - 7.07 (m, 4H), 6.95 (s, 2H), 6.74 (s, 1H), 5.88 - 5.67 (m, 2H), 5.65 - 5.32 (m, 3H), 5.00 - 4.75 (m, 3H), 4.62 - 4.49 (m, 4H), 4.16 - 4.04 (m, 2H), 3.94 - 3.66 (m, 17H), 3.31 (s, 2H), 2.84 (s, 3H), 2.63 (d, J = 12.4 Hz, 1H), 2.54 (s, 1H), 2.45 (s, 3H), 2.36 - 2.30 (m, 1H), 2.24 - 1.97 (m, 4H). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1% TFA); phase B: CH3CN.
Example 47: Preparation of Compound 55
[0604] Step 1 To a mixture of 5-P2 (from Example 50, 90.0 mg, 170.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 2 (68.1 mg, 0.5 mmol, 3.0 equiv.). The mixture was stirred at RT for 1 h. LCMS (quenched with MeOH) showed the reaction was complete. The mixture was used directly in the next step. For the methyl ester: LCMS(ESI)[M+1]+ = 544.3, tR = 1.653 min.
[0605] Step 2'. To a solution of2 (93.15 mg, 170.0 pmol, 1.0 equiv.) in DCM (2 mL) was added a mixture of Int-R-2 (128.0 mg, 170.0 pmol, 1.0 equiv.) and lutidine (72.9 mg, 0.7 mmol, 4.0 equiv.) in DCM (0.5 mL). The mixture was stirred at RT for 10 min. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give 4 (100.0 mg, yield: 30.2%) as a yellow solid. LCMS(ESI)[M+1]+ = 1264.4, tR = 1.839 min. [0606] Step 3 To a solution of 4 (100 mg, 0.05 mmol, 1 .0 equiv.) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was diluted with EA and purified by prep-HPLC (TFA) to give Compound 55 (10.6 mg, yield: 28. 8%) as a yellow solid. LCMS(ESI)[M+1]+ = 1164.5, tR = 1.452 min. Instrument: LCMS 2020 (E-LCMS 012); Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/MeCN/FA= 90: 10:0.05 Solvent B: CH3CN; Temperature: 40 °C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. JH NMR (400 MHz, DMSO-r/e) 8 10.71 (s, 1H), 10.33 (s, 1H), 8.18 - 8.05 (m, 4H), 7.92 - 7.87 (m, 1H), 7.84 - 7.78 (m, 1H), 7.75 - 7.66 (m, 2H), 7.48 - 7.36 (m, 3H), 7.26 - 7.19 (m, 1H), 7.15 (t, J = 8.8 Hz, 1H), 6.31 (s, 2H), 5.63 - 5.44 (m, 3H), 5.34 (s, 1H), 5.01 (s, 1H), 4.61 - 4.54 (m, 2H), 4.34 - 4.28 (m, 2H), 4.04 - 3.98 (m, 1H), 3.90 - 3.81 (m, 2H), 3.75 (s, 2H), 3.71 - 3.64 (m, 2H), 3.48 (s, 1H), 3.29 (s, 2H), 3.16 - 3.06 (m, 1H), 2.94 (t, J = 6.5 Hz, 2H), 2.63 - 2.54 (m, 3H), 2.36 - 2.31 (m, 1H), 2.23 - 2.11 (m, 2H), 2.07 - 1.98 (m, 1H), 1.51 (d, J = 6.6 Hz, 3H). 19F NMR (377 MHz, DMSO-tZ6) 8 -74.42 (s, IF), -116.15 (s, IF), -121.83 (s, IF), -173.01(s, IF). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wave length: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: MeCN; TIME: 19.25 min.
Example 48: Preparation of Compound 56
[0607] Step 1 To a mixture of 5-P2 (from Example 50, 90.0 mg, 1701.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 2 (68.1 mg, 0.5 mmol, 3.0 equiv.). The mixture was stirred at RT for 1 h. LCMS (quenched with MeOH) showed the reaction was complete. The mixture was used directly to the next step. For the methyl ester: LCMS(ESI)[M+1]+ = 544.3, tR = 1.653 min.
[0608] Step 2: To a solution of2 (93.15 mg, 170.0 pmol, 1.0 equiv.) in DCM (2 mL) was added a mixture of Int-R-1 (128.0 mg, 170.0 pmol, 1.0 equiv.) and lutidine (72.9 mg, 0.7 mmol, 4.0 equiv.) in DCM (0.5 mL). The mixture was stirred at RT for 10 min. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give 4 (90.0 mg, yield: 29.3%) as a yellow solid. LCMS(ESI)[M+1]+ = 1264.4, tR = 1.359 min. [0609] Step 3 To a solution of 4 (90.0 mg, 0.04 mmol, 1 .0 equiv) in DCM (2 mL) was added TFA (0.5 mL, 0.05 mmol). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was diluted with EA and purified by prep-HPLC (TFA) to give Compound 56 (12.1 mg, yield: 24.3%) as a yellow solid. LCMS(ESI)[M+1]+ = 1164.5, tR = 1.494 min. Instrument: LCMS 2020 (E-LCMS 028); Column: YMC-Triart C18, 50*4.6mm, 5 pm; Mobile Phase: Solvent A: FLO/MeCN/FA = 90: 10:0.05; Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ' H NMR (400 MHz, DMSO-tA) 8 10.68 (s, 1H), 10.34 (s, 1H), 8.14 - 8.01 (m, 4H), 7.92 - 7.85 (m, 1H), 7.81 (s, 1H), 7.72 (d, J= 8.5 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.27 - 7.21 (m, 1H), 7.16 (t, J= 8.8 Hz, 1H), 6.31 (s, 2H), 5.65 - 5.44 (m, 3H), 5.32 (s, 1H), 5.05 (s, 1H), 4.62 - 4.55 (m, 2H), 4.49 - 4.42 (m, 1H), 4.32 - 4.27 (m, 2H), 4.02 (s, 1H), 3.89 - 3.81 (m, 2H), 3.79 - 3.72 (m, 2H), 3.71 - 3.65 (m, 2H), 3.64 - 3.54 (m, 2H), 3.33 - 3.25 (m, 1H), 3.11 - 3.05 (m, 1H), 2.94 (t, .7= 6.5 Hz, 2H), 2.64 - 2.53 (m, 3H), 2.35 - 2.30 (m, 1H), 2.23 - 2.11 (m, 2H), 2.07 - 1.96 (m, 1H), 1.50 (s, 3H). 19F NMR (377 MHz, DMSO-t/e) 8 -74.44 (s, IF), -116.17 (s, IF), -121.99 (s, IF), -172.86(s, IF). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250mm; Temperature: RT; Inject number: 1; Wavelength: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: CH3CN; TIME: 19.5 min.
Example 49: Preparation of Compound 57
[0610] Step 1 To a mixture of 5-P1 (from Example 50, 70 mg, 130.0 pmol, 1.0 equiv.) inDCM (2 mL) was added 2 (53.0 mg, 0.4 mmol, 3.0 equiv.). The mixture was stirred at RT for 1 h. LCMS (quenched with MeOH) showed the reaction was complete. The mixture was used directly in the next step. For the methyl ester: LCMS(ESI)[M+1]+ = 544.3, tR = 1.638 min.
[0611] Step 2: To a solution of 2 (71 .2 mg, 130.0 pmol, 1 .0 equiv.) in DCM (2 mL) was added a mixture of Int-R-2 (97.9 mg, 130.0 pmol, 1.0 equiv.) and lutidine (55.7 mg, 520.0 umol, 4.0 equiv.) in DCM (0.5 mL). The resulting mixture was stirred at RT for 10 min. LCMS showed the reaction was complete. The solution was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give 4 (60.0 mg, 0.05 mmol, yield: 36.5%) as a yellow solid. LCMS(ESI)[M+1]+ = 1264.4, tR = 1.457 min.
[0612] Step 3 To a solution of 4 (60.0 mg, 0.05 mmol, 1.0 equiv.) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was diluted with EA and purified by prep-HPLC (TFA) to give Compound 57 (5.6 mg, yield: 10.1%) as a yellow solid. LCMS(ESI)[M+1]+ = 1164.5, tR = 1.574 min. Instrument: LCMS 2020 (E-LCMS 012); Column: YMC -Triart Cl 8, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/MeCN/FA= 90:10:0.05 Solvent B: CH3CN; Temperature: 40 °C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'H NMR (400 MHz, DMSO-tL) 5 10.69 (s, 1H), 10.40 - 10.25 (m, 1H), 8.15 - 8.04 (m, 4H), 7.92 - 7.86 (m, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.70 (d, J= 8.4 Hz, 2H), 7.49 - 7.34 (m, 3H), 7.25 - 7.18 (m, 1H), 7.14 (t, J= 8.8 Hz, 1H), 6.30 (s, 2H), 5.65 - 5.32 (m, 4H), 5.01 (s, 1H), 4.63 - 4.55 (m, 2H), 4.35 - 4.28 (m, 2H), 4.07 - 4.02 (m, 1H), 3.89 - 3.81 (m, 2H), 3.75 - 3.65 (m, 4H), 3.61 - 3.53 (m, 1H), 3.34 - 3.24 (m, 2H), 3.17 - 3.09 (m, 1H), 2.94 (t, J= 6.5 Hz, 2H), 2.62 - 2.55 (m, 3H), 2.40 - 2.33 (m, 1H), 2.23 - 2.09 (m, 2H), 2.08 - 1.99 (m, 1H), 1.57 - 1.43 (m, 3H). 19F NMR (377 MHz, DMSO- e) 5 -74.39 (s, IF), -116.16 (s, IF), -121.81 (s, IF), -173.01(s, IF). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250mm; Temperature: RT; Inject number: 1; Wavelength: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: CH3CN; TIME: 19.75 min.
Example 50: Preparation of Compound 58
[0613] Step 7: To a solution of 1 (650.0 mg, 1.6 mmol, 1.0 equiv.) and DIEA (811.3 mg, 6.3 mmol, 4.0 equiv.) in dioxane (10 mL) was added triphosgene (0.3 g, 1.0 mmol, 0.6 equiv.). The mixture was stirred at 100 °C for 10 min. LCMS showed the reaction was complete. The mixture was used directly in the next step without purification.
[0614] Step 2 To a solution of 2 (1066.5 mg, 2.6 mmol, 1.0 equiv.) and DIEA (1331.3 mg, 10.3 mmol, 4.5 equiv.) in dioxane (6 mL) was added L-l (1.5 g, 9.4 mmol, 4.0 equiv.). The mixture was stirred at 100 °C for 1 h. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL). The organic layer was concentrated and purified by flash (PE/EA about 1 : 1) to give 4 (790.0 mg, 1 .3 mmol, yield: 52.3%) as a yellow solid.
LCMS(ESI)[M-1]’ =586.3, tR = 1.852 min.
[0615] Step 3 To a solution of 4 (1.2 g, 2.0 mmol, 1.0 equiv.) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at RT for 3 h. LCMS showed the reaction was complete. The mixture was diluted with EA and concentrated to give 5 (racemate, 1.0 g, 1.9 mmol, yield: 92.2%) as a yellow solid, which was separated by SFC to give 280 mg of 5-P1 and 320 mg of 5-P2. LCMS(ESI)[M+1]+ = 530.0, tR = 1.417 min. Preparative separation method: Instrument: SHIMADZU PREP SOLUTION Column: ChiralPak C-IG, 250x30mm I D., 5 pm; Mobile phase: A for CO2 and B for ETOH(0.1% FA); Gradient: B 50%; Flow rate:60 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 15 min; Injection volume: 3.4 mL; Number of injection needles: 13; Eluted time: 3 H; The 1000 mg sample was dissolved in 40 mL MEOH; Peak 1 : 5-P1, retention time: 2.736 min. Peak 2: 5-P2, retention time: 4.055 min.
[0616] Step 4'. To a mixture of 5-P1 (80.0 mg, 150.0 pmol, 1.0 equiv.) in DCM (2 mL) was added 6 (60.6 mg, 450.0 pmol, 3.0 equiv.). The mixture was stirred at RT for 1 h. LCMS (quenched with MeOH) showed the reaction was complete. The mixture was used directly in the next step. LCMS(ESI)[M+1]+ = 544.3, tR = 1.646 min.
[0617] Step 5: To a solution of 7-P1 (82.2 mg, 150.0 pmol, 1.0 equiv.) in DCM (2 mL) were added a mixture Int-R-1 (113.0 mg, 150.0 pmol, 1.0 equiv.) and lutidine (64.3 mg, 0.60 mmol, 4.0 equiv.) in DCM (0.5 mL). The mixture was stirred at RT for 10 min. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by prep-TLC (DCM/MeOH = 10/1) to give 8 (80 mg, 0.04 mmol, 29.5%) as a yellow solid. LCMS(ESI)[M+1]+ = 1264.4, tR = 1.641 min.
[0618] Step 6: To a solution of 8 (80.0 mg, 0.05 mmol, 1.0 equiv.) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was diluted with EA and purified by prep-TLC (DCM/MeOH=10/l) to give a crude product, which was further purified by prep-HPLC (TFA) to give Compound 58 (12.0 mg, 0.01 mmol, 20.4%) as a yellow solid. LCMS(ESI)[M+1]+ = 1164.4, tR = 1.444 min. Instrument: LCMS 2020 (E-LCMS 028); Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: ELO/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. JH NMR (400 MHz, DMSO- e) 8 10.68 (s, 1H), 10.30 (s, 1H), 8.08 (dd, J= 17.7, 9.1 Hz, 4H), 7.92 - 7.87 (m, 1H), 7.81 (d, J= 6.9 Hz, 1H), 7.77 - 7.65 (m, 2H), 7.49 - 7.35 (m, 3H), 7.26 - 7.20 (tn, 1H), 7.16 (t, J = 9.0 Hz, 1H), 6.30 (s, 2H), 5.57 (d, .7 = 40.1 Hz, 3H), 5.34 (s, 1H), 5.03 (s, 1H), 4.57 (s, 2H), 4.49 - 4.42 (m, 1H), 4.35 - 4.26 (m, 2H), 4.05 (s, 1H), 3.89 - 3.82 (m, 1H), 3.80 - 3.73 (m, 2H), 3.70 - 3.66 (m, 2H), 3.62 - 3.55 (m, 1H), 3.27 (s, 1H), 3.18 - 3.06 (m, 2H), 2.94 (t, J = 6.5 Hz, 2H), 2.65 - 2.53 (m, 2H), 2.32 (s, 1H), 2.23 - 2.10 (m, 2H), 2.08 - 1.99 (m, 1H), 1.58 - 1.41 (m, 3H). 19F NMR (377 MHz, DMSO-d6) 6 -74.34 (s, IF), -116.17 (s, IF), -121.98 (s, IF), -172.86 (s, IF). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature: RT; Inject number: 1; Wave length: 220 nm/254 nm; phase A: H2O (0.1%TFA); phase B: CH3CN; TIME: 19.5 min.
Example 51: Preparation of Compound 59
[0619] Step 1 To a solution of 4-P2 (from Example 53, 50.0 mg, 120.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 2 (48.4 mg, 360.0 pmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. Then 2,6-Lutidine (77.6 mg, 720.0 pmol, 6.0 equiv.) and Int-S (136.3 mg, 180.0 pmol, 1.5 equiv.) were added. The reaction was stirred at RT for 1 h. LCMS showed 70% of desired product was formed. The reaction mixture was purified by column chromatography on silica gel to give 3 (60.0 mg, 50.0 pmol, yield: 43.3%) as a yellow solid. LCMS(ESI) [M+l]+ = 1149.4, tR = 1.670 min.
[0620] Step 2 To a solution of 3 (60.0 mg, 50.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 59 (10.1 mg, 10.0 pmol, yield: 18.4%) as a yellow solid. LCMS(ESI) [M+l]+ = 1049.4, tR = 1.378 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC -Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90:10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B; JH NMR (400 MHz, DMSO-d6) 8 10.74 (s, 1H), 8.14 (s, 2H), 8.04 (d, J= 11.3 Hz, 1H), 7.21 (m, J= 27.0, 13.1, 7.1 Hz, 2H), 6.95 - 6.84 (m, 3H), 6.50 (s, 4H), 5.63 (s, 1H), 5.47 (d, J= 22.8 Hz, 2H), 5.22 (d, J = 8.4 Hz, 1H), 4.92 (s, 2H), 4.71 (s, 1H), 4.59 (d, J= 12.2 Hz, 2H), 4.41 (d, J= 13.2 Hz, 1H), 4.24 (s, 2H), 4.01 - 3.81 (m, 3H), 3.76 (t, J = 14.5 Hz, 5H), 3.61 (t, J= 8.4 Hz, 9H), 3.45 (s, 1H), 3.20 - 3.00 (m, 2H), 2.57 (d, J= 21.4 Hz, 1H), 2.34 (d, J = 8.5 Hz, 1H), 2.18 (t, J= 17.3 Hz, 2H), 2.06 (d, J = 9.1 Hz, 1H), 1.32 (d, J= 5.9 Hz, 3H). 19F NMR (377 MHz, DMSO) 8 -74.36 - -74.41 (m), -116.16 (s), -121.92 (d, J= 69.6 Hz), - 172.86 (s). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 52: Preparation of Compound 60 / O Compound 60
[0621] Step 1 To a solution 4-P1 (from Example 54, 50.0 mg, 120.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added 2 (48.4 mg, 360.0 pmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. Then 2,6-Lutidine (77.6 mg, 720.0 pmol, 6.0 equiv.) and Int-S (136.3 mg, 180.0 pmol, 1.5 equiv.) were added. The reaction was stirred at RT for 1 h. LCMS showed 70% of desired product was formed. The reaction mixture was purified by column chromatography on silica gel to give 3 (65.0 mg, 60.0 pmol, yield: 46.9%) as a yellow solid. LCMS(ESI) [M+l]+ = 1149.4, tR = 1.637 min.
[0622] Step 2: To a solution of 3 (65.0 mg, 60.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 60 (13.5 mg, 10.0 pmol, yield: 22.8%) as a yellow solid. LCMS(ESI) [M+l]+ = 1049.3, tR = 1.356 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC -Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90:10:0.05 Solvent B: CH3CN; Temperature: 40 °C; Flow Rate: 2.5 mL/min. Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B; ’H NMR (400 MHz, DMSO) 5 10.81 (s, 1H), 8.14 (s, 2H), 8.02 (d, J = 16.0 Hz, 1H), 7.26 - 7.16 (m, 2H), 6.88 (d, J= 10.6 Hz, 3H), 6.50 (dd, J= 13.2, 9.6 Hz, 4H), 5.53 (dd, J= 49.2, 26.6 Hz, 3H), 5.22 (t, J= 23.0 Hz, 1H), 4.92 (d, J= 28.1 Hz, 2H), 4.72 (s, 1H), 4.59 (d, J= 10.1 Hz, 2H), 4.43 (s, 1H), 4.24 (s, 2H), 3.82 (s, 3H), 3.75 (d, J= 9.5 Hz, 5H), 3.62 (d, J= 9.5 Hz, 9H), 3.54 - 3.49 (m, 1H), 3.05 (s, 2H), 2.60 (s, 1H), 2.34 (d, J= 8.6 Hz, 1H), 2.20 (d, J= 11.6 Hz, 2H), 2.07 (s, 1H), 1.32 (d, J= 4.5 Hz, 3H). 19F NMR (377 MHz, DMSO) 8 - 74.35 (d, J= 9.8 Hz), -116.15 (s), -121.88 (d, J= 57.3 Hz), -172.91 (d, J= 50.8 Hz). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 53: Preparation of Compound 61
Compound 61
[0623] Step 1 To a solution of 3-P2 (from Example 54, 404.0 mg, 860.0 pmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 4-P2 (400.0 mg, 820.0 pmol, yield: 95.6%) as a colorless oil. LCMS(ESI) [M+l]+ = 415.3, tR = 1.583 min.
[0624] Step 2: To a solution of 4-P2 (200.0 mg, 480.0 pmol, 1.0 equiv.) in DCM (5.0 mL) was added 5 (193.4 mg, 1.5 mmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. Then 2,6-Lutidine (0.3 mL, 2.9 mmol, 6.0 equiv.) and Int-N (476.1 mg, 720.0 pmol, 1.5 equiv.) were added. The reaction was stirred at RT for 1 h. LCMS showed 70% of desired product. The reaction mixture was purified by column chromatography on silica gel to give 6 (200.0 mg, 190.0 pmol, yield: 39.3%) as a yellow solid. LCMS(ESI) [M+l]+ = 1054.5, tR = 1.390 min.
[0625] Step 1'. A solution of 6 (200.0 mg, 190.0 pmol, 1.0 equiv.) in formic acid (4.0 mL) was stirred at RT for 3 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 61 (60.0 mg, 60.0 pmol, yield: 31.3%) as a yellow solid. LCMS(ESI) [M+l]+ = 1010.4, tR = 1.265 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'H NMR (400 MHz, DMSO) 5 10.19 (s, 1H), 9.08 (d, J= 16.6 Hz, 1H), 8.14 (s, 1H), 7.98 (dd, J= 9.2, 6.0 Hz, 1H), 7.47 (t, J= 9.0 Hz, 1H), 7.41 (d, J= 2.5 Hz, 1H), 7.20 (s, 1H), 6.98 - 6.81 (m, 3H), 6.50 (s, 4H), 5.63 - 5.29 (m, 2H), 5.24 (d, J= 6.8 Hz, 1H), 4.90 (s, 2H), 4.44 (d, J = 11.5 Hz, 2H), 4.22 - 3.98 (m, 3H), 3.92 (d, J= 20.5 Hz, 1H), 3.76 (s, 5H), 3.61 (d, J= 11.7 Hz, 10H), 3.12 (t, J= 24.5 Hz, 5H), 2.90 - 2.82 (m, 1H), 2.08 (t, J= 24.5 Hz, 3H), 1.83 (dd, J= 23.5, 10.2 Hz, 3H), 1.33 (t, J= 6.4 Hz, 3H). 19F NMR (377 MHz, DMSO) 5 -110.70 (d, J= 13.7 Hz), - 140.14 (d, J= 10.3 Hz), -172.10 (d, J= 20.7 Hz). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25 °C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%FA); phase B: CH3CN.
Example 54: Preparation of Compound 62 [0626] Step 1 To a solution of 1 (2.0 g, 6.3 mmol, 1 .0 equiv.) and L-2 (2.4 g, 10.1 mmol, 1 .6 equiv.) in DMF (50.0 mL) was added K2CO3 (2.6 g, 18.9 mmol, 3.0 equiv.). The reaction mixture was stirred at RT for 16 h. LCMS showed 10% of desired product. The reaction mixture was poured into saturated NaCl and extracted with EA three times. The combined organic layer was washed with water, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-P1 (404.0 mg, 0.9 mmol, yield: 13.6%) and 3-P2 (410.0 mg, 0.9 mmol, yield: 13.8%), both as colorless oils. LCMS(ESI) [M-56]+ = 415.2, tR = 2.232 min. 3-P1: JH NMR (400 MHz, DMSO-d6) 8 6.93 (d, J = 8.4 Hz, 1H), 6.86 (d, J= 1.8 Hz, 1H), 6.72 (d, J= 1.8 Hz, 1H), 6.50 (s, 2H), 6.46 (d, J= 9.6 Hz, 2H), 5.99 (s, 1H), 5.70 (s, 1H), 4.89 (d, J= 6.3 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 3.58 (s, 6H), 1.38 (d, J= 4.5 Hz, 9H), 1.30 (d, J= 6.3 Hz, 3H). 3-P2: JH NMR (400 MHz, DMSO-d6) 8 6.93 (d, J= 8.3 Hz, 1H), 6.86 (d, J= 1.7 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 6.50 (s, 2H), 6.46 (d, J = 9.6 Hz, 2H), 5.99 (s, 1H), 5.70 (s, 1H), 4.89 (d, J= 6.4 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 3.58 (s, 6H), 1.37 (s, 9H), 1.30 (d, J= 6.3 Hz, 3H).
[0627] Preparative separation method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPakC-IG, 250><30mm I.D., 5 pm; Mobile phase: A for CO2 and B for EtOH; Gradient: B 16%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 13 min; Injection volume: 1 mL; Number of injection needles: 25; Eluted time: 5 H ; The 1100 mg sample was dissolved in 23 mL EtOH. Retention time of 3- Pl: 1.168 min. Retention time of3-P2: 1.415 min.
[0628] Step 2 To a solution of 3-P1 (404.0 mg, 860.0 pmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 4-P1 (400.0 mg, 820.0 pmol, yield: 95.6%) as a colorless oil. LCMS(ESI) [M+l]+ = 415.3, tR = 1.585 min.
[0629] Step 3: To a solution of 4-P1 (200.0 mg, 480.0 pmol, 1.0 equiv.) in DCM (5.0 mL) was added 5 (193.4 mg, 1.5 mmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. Then 2,6-Lutidine (0.3 mL, 2.9 mmol, 6.0 equiv.) and Int-N (476.1 mg, 720.0 pmol, 1.5 equiv.) were added. The reaction was stirred at RT for 1 h. LCMS showed 70% of desired product. The reaction mixture was purified by column chromatography on silica gel to give 6 (200.0 mg, 190.0 pmol, yield: 39.3%) as a yellow solid. LCMS(ESI) [M+l]+ = 1054.4, tR = 1.363 min. [0630] Step 4 A solution of 6 (200.0 mg, 190.0 pmol, 1 .0 equiv.) in formic acid (4.0 mL) was stirred at RT for 3 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 62 (84.5 mg, 80.0 pmol, yield: 44.1%) as a yellow solid. LCMS(ESI) [M+l]+ = 1010.4, tR = 1.270 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart Cl 8, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40 °C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ’H NMR (400 MHz, DMSO-d6) 6 10.19 (s, 1H), 9.08 (d, J= 19.4 Hz, 1H), 8.14 (s, 1H), 7.98 (dd, J= 9.2, 6.0 Hz, 1H), 7.47 (t, J= 9.0 Hz, 1H), 7.41 (d, J= 2.5 Hz, 1H), 7.20 (s, 1H), 6.96 - 6.84 (m, 3H), 6.59 - 6.47 (m, 4H), 5.41 (d, J= 33.1 Hz, 2H), 5.23 (s, 1H), 4.92 (d, J= 16.6 Hz, 2H), 4.57 - 4.34 (m, 2H), 4.27 - 3.97 (m, 3H), 3.91 (d, J= 8.4 Hz, 1H), 3.78 (t, J= 13.0 Hz, 5H), 3.66 - 3.57 (m, 10H), 3.10 (dd, J= 25.0, 10.5 Hz, 5H), 2.86 (dd, J= 14.6, 7.8 Hz, 1H), 2.08 (t, J = 24.1 Hz, 3H), 1.83 (dd, J= 23.0, 10.3 Hz, 3H), 1.34 (s, 3H). 19F NMR (377 MHz, DMSO) 8 - 110.69 (d, J = 9.3 Hz), -140.14 (d, J = 36.1 Hz), -172.09 (d, J = 22.2 Hz). Preparation method: Instrument: E-Prep LC 012 LH-40; Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%FA); phase B: CH3CN.
Example 55: Preparation of Compound 63
[0631] Step 7: To a solution of 1 (600.0 mg, 1.6 mmol, 1.0 equiv.) and DIEA (599.4 mg, 4.7 mmol, 3.0 equiv.) in dioxane (20.0 mL) was added triphosgene (367.7 mg, 1.2 mmol, 0.8 equiv.) at 0 °C. The reaction was stirred at 100 °C for 10 min. LCMS showed the reaction was complete. The reaction mixture was used in the next step without further purification. LCMS(ESI) [M+l]+ = 446.2, tR = 1.562 min.
[0632] Step 2'. To a solution of 2 (688.8 mg, 4.4 mmol, 1.0 equiv.) in dioxane (15.0 mL) was added L-4 (1.9 g, 13.2 mmol, 3.0 equiv.). The reaction mixture was stirred at 100 °C for 1 h. LCMS showed 60% of the desired product. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give 4 (400.0 mg, 630.0 pmol, yield: 43.4%) as a white solid. LCMS(ESI) [M+l]+ = 572.3, tR = 1.875 min.
[0633] Step 3 To a solution of 4 (400.0 mg, 0.7 mmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at RT for 2 hrs. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give 5 (200.0 mg, 390.0 pmol, yield: 55.4%) as a solid. LCMS(ESI) [M+l]+ = 516.3, tR = 1.458 min.
[0634] Step 4 To a solution of 5 (60.0 mg, 120.0 pmol, 1.0 equiv.) in DCM (2.0 mL) was added 6 (46.7 mg, 350.0 pmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was used directly to the next step without further purification. LCMS(ESI) [M+l]+ = 530.2, tR = 1.680 min.
[0635] Step 5 To a solution of 7 (90.0 mg, 170.0 pmol, 1.0 equiv.) in DCM (3.0 mL) were added 2,6- lutidine (0.1 mL, 1.1 pmol, 6.0 equiv.) and Int-S (131.5 mg, 170.0 pmol, 1.0 equiv.). The reaction was stirred at RT for 10 min. LCMS showed 40% of desired product. The reaction mixture was purified by prep-TLC to give 9 (50.0 mg, 40.0 pmol, yield: 22.9%) as a yellow solid. LCMS(ESI) [M+l]+ = 1251.3, tR = 1.524 min.
[0636] Step 6: To a solution of 9 (50.0 mg, 40.0 pmol, 1.0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 63 (7.9 mg, 10.0 pmol, yield: 17.2%) as a white solid. LCMS(ESI) [M+l]+ = 1150.3, tR = 1.310 min. Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05; Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'H NMR (400 MHz, DMSO) 5 10.74 (s, 1H), 10.34 (s, 1H), 8.15 - 8.08 (m, 4H), 7.91 - 7.70 (m, 4H), 7.44 (dt, J= 7.7, 5.3 Hz, 3H), 7.26 - 7.14 (m, 2H), 6.32 (s, 2H), 5.66 (d, J = 29.9 Hz, 2H), 5.49 (s, 1H), 4.89 (s, 3H), 4.65 (s, 2H), 4.55 (dd, J= 21.5, 9.1 Hz, 3H), 4.32 (d, J= 10.7 Hz, 2H), 4.00 (s, 2H), 3.86 - 3.67 (m, 6H), 3.59 (s, 1H), 3.11 (s, 2H), 2.95 (t, J= 6.5 Hz, 2H), 2.70 - 2.58 (m, 1H), 2.48 - 2.33 (m, 1H), 2.14 (dt, J= 35.0, 11.7 Hz, 3H). 19F NMR (377 MHz, DMSO) 5 -74.32 (s), -116.16 (d, J= 4.2 Hz), -121.81 (s), -173.00 (s). Preparation method: Column: X Bring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1 ; Wave length: 254 nm/220 nm; phase A: H2O (0.1% TFA); phase B: CH3CN.
Example 56: Preparation of Compound 64
[0637] Step 1 To a solution of 1 (1.2 g, 3.1 mmol, 1.0 equiv.) and DIEA (0.4 g, 9.3 mmol, 3.0 equiv.) in dioxane (10 mL) was added triphosgene (0.5 g, 1.5 mmol, 0.5 equiv.) at RT. The mixture was stirred at 100 °C for 10 min. LCMS (quenched with MeOH) showed the starting material was consumed. Then L-l (820.8 mg, 4.8 mmol, 3.0 equiv.) was added. The resulting mixture was stirred at 100°C for an additional 1 h. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (50 mL). The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography (PE/EA about 1 :1) to give 3 (400.0 mg, 0.7 mmol, yield: 43.4%) as a yellow solid. LCMS(ESI)[M+1]+ = 586.3, tR = 1.854 min. [0638] Step 2: To a solution of 3 (400.0 mg, 0.7 mmol, 1 .0 equiv.) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at RT for 4 h. LCMS showed the reaction was complete. The mixture was diluted with EA (30 mL) and concentrated. The residue was lyophilized to give 4 (350.0 mg, crude) as a yellow solid. LCMS(ESI)[M+1]+ = 530.3, tR = 1.416 min.
[0639] Step 3 To a solution of 4 (60.0 mg, 0.1 mmol, 1.0 equiv.) in DCM (2 mL) was added 5 (22.7 mg, 0.2 mmol, 2.0 equiv.). The mixture was stirred at RT for 1 h. LCMS (quenched with MeOH) showed the reaction was complete. The mixture was used directly in the next step. LCMS(ESI)[M+1]+ = 544.1, tR = 1.627 min.
[0640] Step 4'. To a solution of 6 (60.3 mg, 0.1 mmol, 1.0 equiv.) in DCM (8 mL) was added a mixture of Int-R (80.1 mg, 0.1 mmol, 1.0 equiv.) and Lutidine (23.6 mg, 0.2 mmol, 2.0 equiv.) in DCM (0.5 mL). The mixture was stirred at RT for 15 min. LCMS showed the reaction was complete. The mixture was diluted with DCM (100 mL) and washed with brine (80 mL). The organic layer was concentrated and purified by flash chromatography (DCM/MeOH from 98/2 to 90/10) to give 8 (90.0 mg, -40% purity, 0.03 mmol, yield: 26.4%) as an off-white solid. LCMS(ESI)[M+1]+ = 1239.2, tR = 1.588 min.
[0641] Step 5 To a solution of 8 (90 mg, -40% purity, 0.03 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The mixture was diluted with EA (30 mL) and concentrated. The residue was purified by prep-TLC (DCM/MeOH=8/l) to give Compound 64 (8.4 mg, 0.01 mmol, yield: 23.3%) as an off-white solid. LCMS(ESI)[M+1]+ = 1139.5, tR = 1.349 min. Column: YMC-Triart Cl 8, 50*4.6mm, 5 pm; Mobile Phase: Solvent A: H2O/MeCN/FA = 90:10:0.05; Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. ‘H NMR (400 MHz, DMSO-t/6) 8 10.32 (s, 1H), 8.17 - 8.03 (m, 3H), 7.90 - 7.86 (m, 1H), 7.86 - 7.78 (m, 1H), 7.77 - 7.67 (m, 2H), 7.51 - 7.32 (m, 3H), 7.30 - 7.22 (m, 1H), 7.18
- 7.09 (m, 1H), 6.31 (s, 2H), 5.61 - 5.16 (m, 4H), 4.88 - 4.67 (m, 1H), 4.33 - 4.01 (m, 4H), 3.74
- 3.59 (m, 3H), 3.20 - 3.00 (m, 3H), 2.94 (t, J= 6.5 Hz, 2H), 2.85 (s, 1H), 2.19 - 1.97 (m, 3H), 1.86 - 1.69 (m, 3H), 1.53 - 1.46 (m, 3H), 1.37 - 1.22 (m, 6H). 19F NMR (377 MHz, DMSO-cA) 8 -116.31 (s, IF), -122.09 (s, IF), -172.19 (s, IF). Example 57: Preparation of Compound 65
[0642] Step 1 To a solution of 5 (from Example 55, 60.0 mg, 120.0 pmol, 1.0 equiv.) in DCM (2.0 mL) was added 2 (46.7 mg, 350.0 pmol, 3.0 equiv.). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was used directly in the next step without further purification. LCMS(ESI) [M+l]+ = 530.2, tR = 1.680 min.
[0643] Step 2: To a solution of 3 (60.0 mg, 110.0 pmol, 1.0 equiv.) in DCM (10.0 mL) were added Int-R (98.8 mg, 130.0 pmol, 1.2 equiv.) and 2,6-Lutidine (72.3 mg, 670.0 pmol, 6.0 equiv.). The reaction mixture was stirred at RT for 1 h. LCMS showed 40% of the desired product formed. The reaction mixture was purified by prep-TLC (DCM:MeOH=9: 1) to give 4 (25.0 mg, 20.0 pmol, yield: 18.2%) as a white solid. LCMS(ESI) [M+l]+ = 1225.2, tR = 1.721 min. [0644] Step 3 To a solution of 4 (25.0 mg, 20.0 pmol, 1 .0 equiv.) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 65 (7.3 mg, 10.0 pmol, yield: 31.8%) as a white solid. LCMS(ESI) [M+l]+ = 1125.1, tR = 1.325 min. Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'HNMR (400 MHz, DMSO) 5 10.71 (s, 1H), 10.35 (s, 1H), 8.14 - 8.08 (m, 3H), 7.95 - 7.79 (m, 3H), 7.71 (d, J= 8.7 Hz, 2H), 7.43 (dt, J= 15.0, 9.1 Hz, 3H), 7.27 - 7.14 (m, 2H), 6.31 (s, 2H), 5.67 (s, 1H), 5.64 - 5.32 (m, 2H), 4.88 (s, 3H), 4.57 (s, 2H), 4.19 (d, J = 58.7 Hz, 3H), 3.72 (dt, J= 12.3, 11.1 Hz, 6H), 3.39 (s, 4H), 3.32 - 3.30 (m, 2H), 2.94 (t, J= 6.5 Hz, 2H), 2.33 (s, 1H), 2.17 (s, 2H), 2.05 - 1.98 (m, 1H), 1.33 (dd, J = 30.2, 6.6 Hz, 3H). 19F NMR (377 MHz, DMSO) 8 -73.54 (d, J = 12.9 Hz), -116.16 (s), -121.95 (s), -172.97 - -173.02 (m). Preparation method: Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN.
Example 58: Preparation of Compound 66
Compound 66
[0645] Step 1 To a solution of 1 (100.0 mg, 320.0 pmol, 1.0 equiv.), L-6 (108.9 mg, 630.0 pmol, 2.0 equiv.) and PPI13 (124.4 mg, 470.0 pmol, 1.5 equiv.) in tetrahydrofuran (3.0 mL) was added DIAD (95.9 mg, 470.0 pmol, 1.5 equiv.) at 0 °C. The reaction mixture was backfilled with N2 three times and stirred at 0 °C for 3 h. LCMS showed 50% of desired product was detected. The reaction mixture was poured into saturated NaCl and extracted with EA three times. The combined organic layer was washed with water, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3 (100.0 mg, 180.0 pmol, yield: 57.1%) as a colorless oil. LCMS(ESI) [M-56]+ = 415.3, tR = 1.954 min. ’H NMR (400 MHz, DMSO-d6) 5 6.98 - 6.91 (m, 2H), 6.90 - 6.85 (m, 2H), 6.73 (q, J= 7.2 Hz, 2H), 6.57 (d, J= 3.3 Hz, 2H), 6.49 (d, J= 6.2 Hz, 1H), 4.49 (s, 2H), 3.72 (s, 3H), 3.64 - 3.61 (m, 9H), 1.82 (s, 3H), 1.44 (s, 9H).
[0646] Step 2'. To a solution of 3 (200.0 mg, 360.0 pmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (2.0 mL), the reaction mixture was stirred at rt for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude 4 (150.0 mg, 310.0 pmol, yield: 85.2%) as a yellow oil. LCMS(ESI) [M+l]+ = 415.3, tR = 1.452 min.
[0647] Step 3 To a solution of 4 (100.0 mg, 240.0 pmol, 1.0 equiv ), Int-N (158.9 mg, 240.0 pmol, 1.0 equiv.) and DIEA (93.4 mg, 720.0 pmol, 3.0 equiv.) in DCM (4.0 mL) and DMF (1.0 mL) was added T3P (153.5 mg, 480.0 pmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS showed 50% of the desired product. The reaction mixture was poured into saturated NaCl and extracted with EA three times. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and prep-TLC (DCM:MeOH=10:l) to give 6 (20.0 mg, 20.0 pmol, yield: 7.9%) as a yellow oil. LCMS(ESI) [M+l]+ = 1054.3, tR = 1.349 min. [0648] Step 4'. A solution of 6 (20.0 mg, 20.0 pmol, 1.0 equiv.) in FA (3.0 mL) was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound 66 (3.2 mg, 3.2 pmol, yield: 16.7%) as a white solid. LCMS(ESI) [M+l]+ = 1010.3, tR = 1.305 min. Instrument: Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/MeCN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time : 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. 'H NMR (400 MHz, DMSO) 8 10.77 (s, 1H), 10.23 (s, 1H), 9.17 (d, J = 21.3 Hz, 1H), 8.00 (dd, J = 9.1, 6.0 Hz, 1H), 7.46 (dd, J = 21.6, 12.5 Hz, 2H), 7.19 (s, 1H), 6.93 (d, J = 24.4 Hz, 3H), 6.58 (s, 2H), 6.55 - 6.46 (m, 2H),
5.92 (s, 1H), 5.56 (d, J = 52.6 Hz, 1H), 4.89 (s, 1H), 4.66 - 4.54 (m, 4H), 4.43 - 4.27 (m, 1H),
3.92 (s, 1H), 3.90 - 3.84 (m, 2H), 3.74 (d, J= 6.7 Hz, 6H), 3.63 (s, 9H), 3.34 - 3.29 (m, 2H), 3.17 (s, 2H), 2.54 (s, 2H), 2.33 (s, 2H), 2.26 - 1.97 (m, 4H), 1.79 (s, 3H). 19F NMR (377 MHz, DMSO) 8 -74.07 (s), -110.56 (d, J= 8.2 Hz), -139.72 (s), -172.97 (s). Preparation method: Column: XBring Prep Phenyl 19*250 mm; Temperature: 25°C; Inject number: 1; Wave length: 254 nm/220 nm; phase A: H2O (0.1%FA); phase B: CH3CN.
Example 59: Preparation of Compound 67
[0649] Step 7: To a solution of 1 (300.0 mg, 950.0 pmol, 1.0 equiv.) and L-2 (334.5 mg, 1.4 mmol, 1.5 equiv.) in DMF (8.0 mL) was added K2CO3 (393.2 mg, 2.8 mmol, 3.0 equiv.), the reaction mixture was stirred at RT for 18 h. LCMS showed 40% of the desired product was detected. The reaction mixture was poured into saturated NaCl and extracted with EA three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3 (150.0 mg, 320.0 pmol, yield: 33.6%) as a colorless oil. LCMS(ESI) [M-56]+ = 415.3, tR = 2.040 min. 'H NMR (400 MHz, DMSO-d6) S 6.93 (d, J= 8.4 Hz, 1H), 6.85 (dd, J = 8.2, 1.8 Hz, IH), 6.72 (d, J= 1.7 Hz, 1H), 6.50 (s, 2H), 6.45 (t, J= 10.3 Hz, 2H), 5.99 (s, 1H), 5.70 (s, 1H), 4.89 (q, J= 6.0 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 3.58 (s, 6H), 1.37 (s, 9H), 1.30 (d, J = 6.3 Hz, 3H).
[0650] Step 2'. To a solution of 3 (150.0 mg, 320.0 pmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at RT for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the crude 4 (120.0 mg, 290.0 pmol, yield: 90.8%) as a colorless oil. LCMS(ESI) [M+l]’ = 415.3, tR = 1.452 min.
[0651] Step 3: To a solution of 4 (120.0 mg, 290.0 pmol, 1.0 equiv.), Int-N (190.4 mg, 290.0 pmol, 1.0 equiv.) and DIEA (112.1 mg, 870.0 pmol, 3.0 equiv.) in DCM (4.0 mL) and DMF (1.0 mL) was added T3P (184.2 mg, 580.0 pmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS showed 50% of the desired product. The reaction mixture was purified by column chromatography on silica gel to give 6 (43.0 mg, 40.0 pmol, yield: 12.7%) as a yellow solid. LCMS(ESI) [M+l]~ = 1054.3, tR = 1.445 min.
[0652] Step 4'. A solution of 6 (43.0 mg, 40.0 pmol, 1.0 equiv.) in formic acid (3.0 mL) was stirred at RT for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give Compound 67 (11.0 mg, 10.0 pmol, yield: 29.7%) as a yellow solid. LCMS(ESI) [M+l]+ = 1010.3, tR = 1.322 min. Instrument: LCMS2020 (E-LCMS 028) Column: YMC-Triart C18, 50*4.6 mm, 5 pm; Mobile Phase: Solvent A: H2O/CH3CN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B. JH NMR (400 MHz, DMSO-d6) 5 10.23 (s, 1H), 9.10 (s, 1H), 8.21 (s, 1H), 7.98 (dd, J= 9.2, 5.9 Hz, 1H), 7.47 (t, J= 9.0 Hz, 1H), 7.40 (d, J= 2.3 Hz, 1H), 7.19 (s, 1H), 7.17 - 6.72 (m, 4H), 6.51 (d, 7= 9.9 Hz, 3H), 5.40 (d, 7= 40.1 Hz, 2H), 5.23 (d, J = 13.6 Hz, 1H), 4.90 (s, 2H), 4.45 (s, 2H), 4.09 (t, 7 = 13.2 Hz, 3H), 3.96 - 3.89 (m, 1H), 3.78 (dd, J= 19.3, 6.4 Hz, 5H), 3.63 (t, J = 10.6 Hz, 10H), 3.06 (dd, 7 = 25.2, 11.4 Hz, 4H), 2.83 (d, 7= 6.7 Hz, 1H), 2.07 (dd, 7= 28.1, 19.5 Hz, 3H), 1.81 (dd, 7= 22.9, 10.4 Hz, 4H), 1.32 (d, 7= 6.3 Hz, 3H). 19F NMR (377 MHz, DMSO) 8 -110.70 (s), -140.21 (s), -172.09 (s). [0653] Preparation method: Instrument: E-Prep LC 012 LH-40; Column: Triart Cl 8,250*20.0 mml. D., 5 pm, 12 nm; Temperature: 25°C; Inject number: 1; Wave length: 205 nm/254 nm; phase
A: H2O (0.1%FA); phase B: CH3CN.
Example 60: Preparation of Compound 68 and Compound 69
[0654] Step 1 To a solution of 1 (420.0 mg, 1.2 mmol, 1.0 equiv) in DMSO (5.0 mL) were added L-7 (674.6 mg, 2.9 mmol, 2.5 equiv), Pd2(dba).3 (21.4 mg, 23.4 pmol, 0.02 equiv) and L (N,N'-[(lR,2R)-l,2-Diphenyl-l,2-ethanediyl]bis[2-diphenylphosphinobenzamide]; CAS: 138517- 62-1, 55.4 mg, 70.3 mmol, 0.06 equiv). The reaction mixture was backfilled with N2 three times and stirred at 30 °C for 18 hrs. LCMS showed the reaction was complete. The reaction mixture was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel and chiral SFC to give 3-P1 (150.0 mg, 293.0 pmol, yield: 24.9%) and 3-P2 (270.0 mg, 527.3 pmol, yield: 44.9%) as white solid. LCMS(ESI)[M+1] " =513.3, tR =1.835 min. Preparative separation method: Instrument: AUNO LC-2000; Column: ChiralPak lG, 250><20mm I.D., 5 pm; Mobile phase: A for Hexane and B for EtOH (0.05% FA); Gradient: B 28%; Flow rate: 22 mL/min; Column temperature: 25°C; Wavelength: 220 nm; Cycle-time: 8 min; Run time: 20 min; Injection volume: 0.3 mL; Number of injection needles: 30; Eluted time: 5 H;
[0655] Step 2: To a solution of 3-P2 (50.0 mg, 97.7 pmol, 1.0 equiv.) in DCM (4.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at RT for 2 h under N2. LCMS showed the starting material was consumed. The reaction was concentrated to give crude 4 (44.0 mg, 96.4 pmol, yield: 98.8%) as a yellow solid. LCMS(ESI)[M+I] + = 457.2, tR = 1.258 min. [0656] Step 3 To a solution of 4 (44.0 mg, 96.4 pmol, 1 .0 equiv.) in DCM (3.0 mL) was added 5 (38.5 mg, 289.2 pmol, 3.0 equiv.). The mixture was stirred at RT for 30 min under N2. LCMS showed the starting material was consumed. The reaction mixture was used directly in the next step without purification.
[0657] Step 4: To a solution of 6 (50.0 mg, 105.3 pmol, 1.0 equiv.) in DCM (3.0 mL) were added Int-S (67.9 mg, 105.3 pmol, 1.0 equiv.) and Lutidine (33.9 mg, 315.9 pmol, 3.0 equiv.). The mixture was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCL and concentrated. The residue was purified by silica gel column chromatography to give 8 (45.0 mg, 41.6 pmol, yield: 39.5%) as a yellow solid. LCMS(ESI)[M+1] + = 1083.3, tR = 1.404 min.
[0658] Step 5: A solution of 8 (45.0 mg, 41.6 pmol, 1.0 equiv.) in formic acid (4.0 mL) was stirred at RT for 2 h under a N2 atmosphere. LCMS showed the starting material was consumed. The solvent was removed in vacuo and the residue was purified by prep-HPLC (0. 1% TFA) to give Compound 68 (24.0 mg, 23.1 pmol, yield: 55.6%) as a yellow solid. LCMS(ESI) [M+l] + = 1039.4, tR = 1.239 min. Instrument: LCMS2020 (E-LCMS 028); Column: YMC-Triart C18, 50*4.6 mm, 5 um; Mobile Phase: Solvent A: H2O/ACN/FA = 90: 10:0.05 Solvent B: CH3CN; Temperature: 40°C; Flow Rate: 2.5 mL/min; Run Time: 0.01 min @ 20% B, 1.79 min gradient (20-95% B), then 0.7 min @ 95% B.'HNMR (400 MHz, DMSO-d6) 8 10.82 (s, 1H), 9.12 (s, 1H), 7.99 (dd, .7= 9.2, 6.0 Hz, 1H), 7.48 (t, ,7= 9.0 Hz, 1H), 7.41 (d, ,7= 2.4 Hz, 1H), 7.27 (d, ,7= 8.6 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J= 8.3 Hz, 2H), 6.97 (s, 2H), 5.58 (d, .7 54.2 Hz, 2H), 5.40 (s, 1H), 4.97 (s, 1H), 4.79 - 4.72 (m, 1H), 4.61 (d, J = 5.1 Hz, 2H), 3.87 (d, J= 6.0 Hz, 2H), 3.78 (d, J= 0.9 Hz, 2H), 3.74 (s, 9H), 3.73 (s, 3H), 3.37 - 3.25 (m, 2H), 2.74 - 2.52 (m, 4H), 2.44 - 2.23 (m, 2H), 2.21 - 1.94 (m, 4H), 1.75 (dd, .7= 8.1, 6.7 Hz, 4H), 1.34 (d, J = 13.9 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) 8 -74.59 (s), -110.56 (s), -139.56 (dd, J = 76.9, 33.7 Hz), -172.98 (s). Preparation method: Instrument: LC-LH; Column: XBridge Prep Phenyl 19*250 mm; Temperature:25°C; Inject number: 1; Wavelength: 254 nm/220 nm; phase A: H2O (0.1%TFA); phase B: CH3CN. [0659] Step 6 Compound 69 was prepared using the methods described in this example, except that 3-P1 from Step 1 was used for Step 2, instead of 3-P2.
Biological Assays
Example Bl: KRASG12C Binding HTRF Assays
[0660] KRASG12C/RAF1 Binding HTRF Assay: Solutions of KRASG12C-GDP (ICE, Cat # E2203T-H47H), S0S1 (ICE, Cat # E2204TH10G), GTP (Sigma, Cat #G8877-25MG), and cRAF (Pharmaron, Cat #ZZY-20190823) are prepared in reaction buffer (40mM HEPES (pH 7.4), 50mM NaCl, lOmM MgCh, 2mM DTT (fresh), 0.01% BSA (fresh)). The final concentrations of KRASG12C-GDP, GTP, S0S1, and cRAF in the reaction mixture are 250 nM, 160 pM, 150 nM, and 50 nM, respectively. The positive reference MRTX1133 is used at a starting concentration of 10 pM, 3-fold diluted. Each concentration of compound (0.05pL in 100% DMSO) is dosed into a 384-well reaction plate in duplicate. 2.5 pL of 2x KRASG12C-GDP enzyme solution is added to the 384-well reaction plates, centrifuged at 1000 rpm for 1 min, and incubated at 25 °C for 15 min. Then, 2.5 pL of a 2x solution of GTP & SOS1 is transferred to the reaction plates, centrifuged at 1000 rpm for 1 min, and incubated at 25 °C for 60 min. Subsequently, 5 pL of 4x cRAF solution is transferred to the reaction plates, centrifuged at 1000 rpm for 1 min, and incubated at 25 °C for 15 min. 10 pL of 2x MAb Anti 6HIS-Tb cryptate (PerkinElmer, Cat# 61HISTLB) & MAb Anti GST-XL665 (PerkinElmer, Cat#61GSTXLB) solution are then transferred to the reaction plates, centrifuged at 1000 rpm for 1 min, and incubated at 25 °C for 1 h. Finally, the HTRF signal (665/620 ratio) is read by the BMG plate reader. IC50 values and nonlinear regression curve fitting is obtained using GraphPad Prism software.
[0661] KRASG12C7SOS1 Binding HTRF Assay: The assay was carried out according to the manual for the HTRF KRASG12C/SOS1 binding kit (PerkinElmer, Cat # 64KRASG12PEG). In brief, working solutions of premixed TAG1-KRASG12C & GTP, TAG2-SOS1, and premixed anti- TAG1 XL665 antibody & anti-TAG2 TB cryptate antibody were prepared respectively in binding domain detection buffer #2. The positive reference MRTX1133 or the tested samples were used at a starting concentration of 10 pM, 3-fold diluted. 0.1 pL of each concentration of compound (final DMSO concentration in the reaction was 1%) was dosed into a 384-well reaction plate in duplicate. After centrifuging the plate at 1000 RPM for 1 min, 2.5 pL of premixed TAG1-KRASG12C & GTP was added into each assay well, followed by plate centrifugation. 2.5 pL of TAG2-SOS1 was then added into each assay well, followed by plate centrifugation and incubation at 25 °C for 15 min. Subsequently, 5 pL of premixed anti-TAGl XL665 antibody & anti-TAG2 TB cryptate antibody was added into each assay well, followed by plate incubation at 25 °C for 3 h. Finally, the HTRF signal (665/620 ratio) was read by a BMG plate reader. IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.
[0662] Results showing biochemical inhibition of KRASO12C by exemplary compounds are provided in Table 2, below. The symbol “+++” indicates an IC50 value of <0.5 pM. The symbol “++” indicates an IC50 value >0.5 pM and <5 pM. The symbol “+” indicates an IC50 value of >5 pM.
Example B2: Cellular Inhibition Assay of KRASG12C
[0663] In-Cell Western assays were conducted in KRASG12C-positive cell lines to demonstrate enhanced KRASG12C inhibition by measuring p-ERK signal. Samples were analyzed using Odyssey CLx.
[0664] On Day 0, MIA Paca-2 cells were seeded in 384-well plates in DMEM supplemented with 10% fetal bovine serum and 1% pen/strep. The cells were then incubated overnight at 37 °C and 5% CO2.
[0665] On Day 1, the cells were treated with DMSO vehicle control or a dose of KRASG12C inhibitor and incubated at 37 °C, 5% CO2 for 3 hours. Afterward, 40 pL of 8% paraformaldehyde solution was added to each well, and the cells were incubated for 20 minutes at room temperature. The paraformaldehyde solution was then removed, and 40 pL of ice-cold methanol was added. The plate was placed at -20 °C for 10 minutes, after which the methanol was removed, and 20 pL of Blocking buffer was added. The plate was incubated at room temperature with shaking for one hour. To each test well, 20 pL of p-ERK antibody (CST 4370) diluted 1 : 1000 and GAPDH antibody (CST#97166s) diluted 1 :2000 in Blocking buffer were added, and the plate was placed at 4 °C overnight.
[0666] On Day 2, the primary antibody solution was removed, and the wells were washed three times with phosphate buffered saline containing 0.1% Tween-20 (PBST). 20 pL of a Goat antiRabbit IRDye800CW secondary antibody (LI-COR 926-32211) diluted 1 :2000 and IRDye 680RD Goat anti Mouse secondary antibody (LI-COR #926-68070) diluted 1 :2000 in Odyssey Blocking Buffer was added. The plate was stored for 1 hour in the dark at room temperature. The secondary antibody solution was removed, and the wells were washed three times with PBST. [0667] The p-ERK signal and the control signal were quantified using a Li-Cor Odyssey machine reading at 800 nm and 700 nm, respectively. The p-ERK/control ratio was used to calculate the inhibition.
[0668] Results showing cellular inhibition of KRASG12C by exemplary compounds are provided in Table 2, below. The symbol “+++” indicates an IC50 value of <0.5 pM. The symbol “++” indicates an IC50 value >0.5 pM and <5 pM. The symbol “+” indicates an IC50 value of >5 pM.
Table 2. Biochemical and Cellular Inhibition of KRASG12C by Provided Compounds
Example B3: Payload Release Assay
[0669] Test samples were prepared in quadruplicate for time points of 0, 1 , 2, and 4 hours. 3.52 pL (1.50 mg/mL) of KRAS(2-158)G12C -GDP was added to 245.48 pL buffer (50 mM HEPES, 10 mM MgCE 1 mM EGTA) in a 0.6 mb tube. 1 pL of the test compound solution (DMSO, 250 pM) was then added to each test sample to start the reaction. Samples were incubated at room temperature for the duration of the assay.
[0670] For negative control samples (i.e. no-enzyme control samples), prepared in quadruplicate for time points of 0, 1, 2, and 4 hours, 249 pL of buffer (50 mM HEPES, 10 mM MgCh 1 mM EGTA) was added to a 0.6 mL tube. 1 pL of the test compound solution (DMSO, 250 pM) was then added to each negative control sample. Samples were incubated at room temperature for the duration of the assay.
[0671] 1000 pL methanol, containing 50 nM ketoprofen as an internal standard, was added individually to test and negative control samples at time points of 0, 1, 2, and 4 hours. Following the addition of the methanol, samples were centrifuged (4 °C 12000 g for 10 minutes), and 100 pL of each sample was diluted with 100 pL of water for analysis of parent and payload compound concentrations.
[0672] Payload and parent compound standard curve samples were prepared analogously to the negative control samples, according to the concentrations outlined in Table 3.
Table 3. Standard Curve Dilutions
Table 4. Test Sample Composition
[0673] The integration of chromatographic peaks, curve fitting, and concentration back- calculation were completed using Analyst software. Curves were fit according to the equation y = ax + b, where a is the slope of the equation, b is the intercept of the equation, x is the sample concentration, y is the peak area of the sample, and the weight coefficient is — . The formula for calculating the concentration of unknown samples is, therefore, x — y — b
[0674] Results demonstrating protein-induced payload release from exemplary compounds that bind to KRASG12C are provided in Table 5, below.
Table 5. Protein-Induced Payload Release of Provided Compounds
Example B4: Cellular Payload Activity Assay
[0675] AlphaLISA assays were utilized to determine the activity of payload in cells by measuring activation of phospho-Histone H3 signal. HEK293T cells with stable expression of KRASG12C or KRASG12D were used as an isogenic cell line pair to determine target-mediated payload release. Samples were analyzed using EnVision™ XCite.
[0676] On Day 1, HEK293T-KRASG12C and HEK293T-KRASG12D cells were seeded at 4K/well in a volume of 50 pL on flat bottom 384-well plates in DMEM supplemented with 10% fetal bovine serum and 1% pen/strep. The cells were then incubated at 37 °C, 5% CO2 overnight. [0677] On Day 2, the cells were treated with DMSO vehicle control or a dose of KRASG12C compound and incubated at 37 °C, 5% CO2 for 4 hours. Each concentration of compound was dosed in duplicate with 10 doses starting at a top dose of 10 pM in a 3.16-fold serial dilution. The medium containing compound was removed and Phospho-Histone H3 (SerlO/Thrll) activity was measured using the AlphaLISA SureFire Ultra Human & Mouse Phospho-Histone H3 (SerlO/Thrll) Detection (Revvity Cat # ALSU-PHISH3): IX Lysis Buffer was prepared by diluting 5X Lysis Buffer (Revvity Cat#ALSU-LB) in water. Acceptor Mix was prepared by adding 141 pL Reaction Buffer 1 (Revvity Cat# ALSU-RB1), 141 pL Reaction Buffer 2 (Revvity Cat# ALSU-RB2), 12 pL Activation Buffer (Revvity Cat# ALSU-AB), and 6 pL AlphaLISA™ CaptSure™ Acceptor Beads (Revvity Cat# ALSU-ACAB). Donor Mix was prepared by adding 6 pL Alpha Streptavidin Donor Beads (Revvity Cat# ALSU-ASDB) to 294 pL Dilution Buffer (Revvity Cat# ALSU-DB). The cells were lysed with 25 pL/well freshly prepared IX Lysis Buffer and incubated with shaking for 30 minutes at room temperature. 10 pL of lysate was transferred to a 384-well OptiplateTM (Revvity Cat# 6007290), and 5 pL of Acceptor Mix was added to the wells. Plates were sealed with adhesive foil and incubated at 25 °C for 1 hour. Subsequently, 5 pL of Donor Mix was added to the well in subdued light, plates were sealed with adhesive foil and incubated at 25 °C for 1 hour.
[0678] The phospho-Histone H3 Signal intensity was recorded on the EnVision™ XCite using 680 nm excitation and 615 nm emission. The signal emission at 615 nM was utilized to determine the extent of phospho-Histone H3 activation.
[0679] Results showing phospho-histone H3 activation by exemplary compounds are provided in Table 6, below. The symbol “+++” indicates an ECso value of <0.5 pM. The symbol “++” indicates an EC50 value >0.5 pM and <5 pM. The symbol “+” indicates an EC 50 value of >5 pM.
Table 6.
[0680] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

or a pharmaceutically acceptable salt thereof, wherein:
KBM is a KRASG12C binding moiety;
Rx is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ry is hydrogen, halogen, cyano, or an optionally substituted group selected from C1-6 aliphatic, C3-7 cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rz is independently hydrogen, halogen, or optionally substituted C1-6 aliphatic;
X is a covalent bond, -O-, -N(RW)-, or -S-;
Rw is hydrogen or optionally substituted C1-6 aliphatic;
L1 is a covalent bond or a linking moiety; and
TPM is a tubulin inhibitor payload moiety.
2. The compound of claim 1, wherein:
L1 is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1.20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or -Cy-; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, C3-7 monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
3. The compound of claim 2, wherein L1 is a covalent bond.
4. The compound of claim 2, wherein L1 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-10 hydrocarbon chain, wherein 1-4 methylene units are optionally and independently replaced by -O-, -S-, -N(R)-, -N=N-, -O-N=, =N-O-, -C(O)-, -C(S)- , -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)N(R)-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, or -N(R)SO2-, and 1-2 methylene units are optionally and independently replaced by -Cy-.
5. The compound of claim 2, wherein L1 is selected from:
wherein:
Lc is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain; the bond labeled X is attached to X; and the bond labeled B is attached to TPM.
6. The compound of claim 2, wherein L1 is selected from: wherein:
Lc is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Ci-6 hydrocarbon chain.
7. The compound of any one of claims 1-6, wherein X is -O-.
8. The compound of any one of claims 1-7, wherein Rx is hydrogen or optionally substituted
Ci-6 aliphatic.
9. The compound of claim 8, wherein Rx is hydrogen.
10. The compound of any one of claims 1 -8, wherein Ry is hydrogen or optionally substituted Ci-6 aliphatic.
11. The compound of claim 10, wherein Ry is hydrogen.
12. The compound of any one of claims 1-11, wherein each Rz is hydrogen.
13. The compound of any one of claims 1-11, wherein one Rz is hydrogen, and one Rz is optionally substituted Ci-6 aliphatic.
14. The compound of any one of claims 1-13, wherein the compound is a compound of Formula II:
II or a pharmaceutically acceptable salt thereof, wherein:
Y is CR2 or N;
R1 is hydrogen, halogen, -OR’, optionally substituted Ci-6 aliphatic, or optionally substituted C -7 cycloaliphatic;
R2 is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic;
R3 is an optionally substituted ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R4 is hydrogen, halogen, -OR’, optionally substituted C1-6 aliphatic, or optionally substituted C3-7 cycloaliphatic; R5 is hydrogen, -OR6, v°\^/Cy1 , -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R6 is optionally substituted Ci-6 aliphatic or optionally substituted monocyclic 3- to 7- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Cy1 and Cy2 are each independently an optionally substituted monocyclic 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L2 is a covalent bond or -N(R’)(CH2)m-;
L3 is a covalent bond or -(CH2)mN(R’)-; each R’ is independently hydrogen or optionally substituted Ci-6 aliphatic;
Ring A is an optionally substituted bivalent ring selected from a monocyclic C3-7 carbocyclylene, a bicyclic C4-10 fused, bridged, or spirocyclic carbocyclylene, a monocyclic 3- to 7-membered heterocyclyl ene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10-membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each m is independently 0, 1, or 2.
15. The compound of claim 14, wherein R1 is hydrogen.
16. The compound of claim 14 or 15, wherein Y is CR2.
17. The compound of claim 16, wherein R2 is halogen.
18. The compound of claim 14 or 15, wherein Y is N.
19. The compound of any one of claims 14-18, wherein R4 is halogen.
20. The compound of any one of claims 14-19, wherein R3 is a ring selected from phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 9- to 10-membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with one or more halogen, -CN, -OH, -NH2, Ci-6 aliphatic, or C1-6 haloaliphatic.
21. The compound of claim 20, wherein R3 is selected from:
22. The compound of any one of claims 14-21, wherein R5 is -OR6, , -O(Ci-4 alkylene)Cy2, or an optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
23. The compound of claim 22, wherein R5 is -O(Ci-4 alkylene)Cy2.
24. The compound of claim 22, wherein R3 is selected from:
25. The compound of claim 22, wherein R6 is Ci-6 alkyl optionally substituted with -N(CI-6 alkyl)2 or monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with Ci-6 alkyl.
26. The compound of claim 20, wherein Cy1 is an optionally substituted monocyclic 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
27. The compound of claim 22 or 23, wherein Cy2 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted bicyclic 6- to 8-membered fused, bridged, or spirocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
28. The compound of any one of claims 14-27, wherein Ring A is an optionally substituted bivalent ring selected from a monocyclic 3- to 7-membered heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and a bicyclic 5- to 10- membered fused, bridged, or spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
29. The compound of claim 28, wherein Ring A is optionally substituted
30. The compound of any one of claims 14-29, wherein L2 is a covalent bond.
31. The compound of any one of claims 14-30, wherein L3 is a covalent bond.
32. The compound of any one of claims 14-27, wherein a moiety is selected from:
33. The compound of any one of claims 14-27, wherein the compound is a compound of Formula Il-b or Il-d: or a pharmaceutically acceptable salt thereof, wherein each R7 is independently optionally substituted Ci-6 aliphatic, or two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and/or spirofused with the ring to which the R7 moieties are attached; and n is 0, 1, 2, 3, 4, 5, or 6.
34. The compound of claim 33, wherein each R7 is independently optionally substituted Ci-6 alkyl.
35. The compound of claim 33, wherein two R7 are taken together to form an optionally substituted 3- to 7-membered ring that is fused, bridged, and/or spirofused with the ring to which the R7 moieties are attached.
36. The compound of any one of claims 33-35, wherein n is 0, 1, or 2.
37. The compound of any one of claims 1-36, wherein the compound is a compound of Formula III:
III or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position; each Ra is independently halogen, -OR33, -N(Raa)2, or optionally substituted Ci-6 aliphatic; each Rb is independently halogen, -ORaa, -N(Rail)2, or optionally substituted Ci-6 aliphatic;
Rc and Rd are each independently hydrogen, halogen or optionally substituted Ci-6 aliphatic; each Raa is independently hydrogen or optionally substituted Ci-6 aliphatic; a is 0, 1, 2, 3, 4, or 5; and b is 0, 1, 2, 3, 4, or 5.
38. The compound of claim 37, wherein at least one Ra is -OR33.
39. The compound of claim 37 or 38, wherein at least one Rb is -ORaa.
40. The compound of any one of claims 37-39, wherein each Rb is -ORaa.
41. The compound of any one of claims 37-40, wherein Re is hydrogen.
42. The compound of any one of claims 37-41, wherein Rd is hydrogen.
43. The compound of any one of claims 37-42, wherein each R33 is independently optionally substituted Ci-6 aliphatic.
44. The compound of any one of claims 37-43, wherein a is 1 or 2.
45. The compound of any one of claims 37-44, wherein b is 3.
46. The compound of any one of claims 37-45, wherein the compound is a compound of Formula Ill-b: or a pharmaceutically acceptable salt thereof.
47. The compound of any one of claims 1-36, wherein the compound is a compound of
Formula IV:
IV or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 5- to 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Re is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic, or two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rf is independently halogen or optionally substituted Ci-6 aliphatic, each Rg is independently halogen, -ORbb, -N(Rbb)2, or optionally substituted Ci-6 aliphatic; each Rbb is independently hydrogen or optionally substituted Ci-6 aliphatic; e is 0, 1, 2, 3, 4, or 5; f is 0, 1, 2, or 3; and g is 0, 1, 2, 3, 4, or 5.
48. The compound of claim 47, wherein Ring Z is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
49. The compound of claim 48, wherein Ring Z is selected from: wherein each ring is substituted with /instances of Rf.
50. The compound of any one of claims 47-49, wherein at least one Re is -ORbb.
51. The compound of any one of claims 47-50, wherein two Re are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heteroaryl or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
52. The compound of any one of claims 47-51, wherein at least one Rs is -ORbb.
53. The compound of any one of claims 47-52, wherein each Rg is -ORbb.
54. The compound of any one of claims 47-53, wherein each Rbb is independently optionally substituted Ci-6 aliphatic.
55. The compound of any one of claims 47-54, wherein e is 1, 2, or 3.
56. The compound of any one of claims 47-55, wherein f is 0.
57. The compound of any one of claims 47-56, wherein g is 3.
58. The compound of any one of claims 47-57, wherein the compound is a compound of or a pharmaceutically acceptable salt thereof.
59. The compound of any one of claims 1-36, wherein the compound is a compound of
Formula V:
V or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Z’ is NH, O, or S; each Rh is independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic;
R' is hydrogen, halogen, optionally substituted Ci-6 aliphatic, or optionally substituted phenyl; each Rk is independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rec is independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.
60. The compound of claim 59, wherein Z1 is NH.
61. The compound of claim 59 or 60, wherein at least one Rh is -ORCC.
62. The compound of any one of claims 59-61, wherein R' is optionally substituted Ci-6 aliphatic or optionally substituted phenyl.
63. The compound of any one of claims 59-62, wherein at least one Rk is -ORec.
64. The compound of any one of claims 59-63, wherein each Rk is -ORCC.
65. The compound of any one of claims 59-64, wherein each Rcc is independently optionally substituted Ci-6 aliphatic.
66. The compound of any one of claims 59-65, wherein h is 1.
67. The compound of any one of claims 59-66, wherein k is 3.
68. The compound of any one of claims 59-67, wherein the compound is a compound of
Formula V-b:
V-b or a pharmaceutically acceptable salt thereof.
69. The compound of any one of claims 1-36, wherein the compound is a compound of Formula V’:
V’ or a pharmaceutically acceptable salt thereof, wherein: each Rh is independently halogen, -ORCC, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rk is independently halogen, -ORce, -N(RCC)2, or optionally substituted Ci-6 aliphatic; each Rce is independently hydrogen or optionally substituted Ci-6 aliphatic; h is 0, 1, 2, 3, or 4; and k is 0, 1, 2, 3, 4, or 5.
70. The compound of claim 69, wherein Rh is methyl.
71. The compound of claim 69 or 70, wherein each Rk is -OR“.
72. The compound of any one of claims 69-71, wherein each Rcc is independently optionally substituted Ci-6 aliphatic.
73. The compound of any one of claims 69-72, wherein h is 1.
74. The compound of any one of claims 69-73, wherein k is 3.
75. The compound of any one of claims 69-74, wherein the compound is a compound of
Formula V’-a: V’-a or a pharmaceutically acceptable salt thereof.
76. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Z2 is CH or N;
Ring Y is phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered carbocyclic ring, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Q is -CH2- or -C(O)-;
W is -CH2-, -CHOH-, -C(O)-, -NH-, or -O-;
Rm is hydrogen, halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rn is independently halogen or optionally substituted Ci-6 aliphatic; each Rp is independently halogen, -ORdd, -N(Rdd)2, or optionally substituted Ci-6 aliphatic; each Rdd is independently hydrogen or optionally substituted Ci-6 aliphatic; n4 is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.
77. The compound of claim 76, wherein Z2 is CH.
78. The compound of claim 76, wherein Z2 is N.
79. The compound of any one of claims 76-78, wherein Ring Y is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
80. The compound of any one of claims 76-78, wherein Ring Y is a 3- to 7-membered carbocyclic ring.
81. The compound of any one of claims 76-80, wherein Q is -C(O)-.
82. The compound of any one of claims 76-81, wherein W is -NH-.
83. The compound of any one of claims 76-82, wherein Rm is -N(H)(Rdd).
84. The compound of any one of claims 76-83, wherein at least one Rp is -ORdd.
85. The compound of any one of claims 76-84, wherein each Rdd is optionally substituted Ci-6 aliphatic.
86. The compound of any one of claims 76-85, wherein n4 is 0.
87. The compound of any one of claims 76-86, wherein p is 1.
88. The compound of any one of claims 76-86, wherein the compound is a compound of
Formula Vl-b or Formula VI-c: or a pharmaceutically acceptable salt thereof.
89. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VII:
VII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
Ring X is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rq is independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci-6 aliphatic; each Rr is independently halogen, -ORee, -N(Ree)2, or optionally substituted Ci-6 aliphatic; each Rs is independently halogen or optionally substituted Ci-6 aliphatic;
Rl is -N(RCC)(CI-4 alkylene)CN; each Ree is independently hydrogen or optionally substituted Ci-6 aliphatic; q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, or 4; and s is 0, 1, or 2.
90. The compound of claim 89, wherein the Ring X is
91. The compound of claim 89 or 90, wherein Rl is -N(H)(CI-4 alkylene)CN.
92. The compound of any one of claims 89-91, wherein q is 0.
93. The compound of any one of claims 89-92, wherein r is 0.
94. The compound of any one of claims 89-93, wherein s is 0.
95. The compound of any one of claims 89-94, wherein the compound is a compound of Formula Vll-b:
VILb or a pharmaceutically acceptable salt thereof.
96. The compound of any one of claims 1-36, wherein the compound is a compound of Formula VIII:
VIII or a pharmaceutically acceptable salt thereof, wherein: the bracketed moiety is attached to the rest of the molecule at any suitable position;
M is a covalent bond or C1-4 alkylene; each Ru is independently halogen, -ORff, -N(Rff)2, or optionally substituted Ci-6 aliphatic; each Rv is independently halogen, -ORft, -N(Rft)2, or optionally substituted Ci-6 aliphatic; each Rft is independently hydrogen or optionally substituted Ci-6 aliphatic;
R88 is hydrogen or optionally substituted Ci.6 aliphatic; u is 0, 1, 2, 3, 4, or 5; and v is 0, 1, 2, 3, or 4.
97. The compound of claim 96, wherein M is a covalent bond.
98. The compound of claim 96 or 97, wherein at least one Ru is -ORff.
99. The compound of any one of claims 96-98, wherein each Rff is independently optionally substituted Ci-6 aliphatic.
100. The compound of any one of claims 96-99, wherein R8S is hydrogen.
101. The compound of any one of claims 96-100, wherein u is 1 or 2.
102. The compound of any one of claims 96-101, wherein v is 0.
103. The compound of any one of claims 96-102, wherein the compound is a compound of
Formula Vlll-b or Formula VIII-c: or a pharmaceutically acceptable salt thereof.
104. The compound of claim 1, wherein the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
105. A pharmaceutical composition, comprising the compound of any one of claims 1-104, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
106. A method of inhibiting tubulin, comprising contacting the compound of any one of claims 1-104 or the composition of claim 105 with a KRAS protein (e.g., KRASO12C).
107. A method of releasing a tubulin inhibitor payload (e.g., a tubulin inhibitor) in a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-104 or the composition of claim 105 with a KRAS protein (e.g., KRASG12C).
108. A method of delivering a tubulin inhibitor payload (e.g., a tubulin inhibitor) to a cell expressing an oncogenic protein (e.g., mutant KRAS, e.g., KRASG12C), comprising contacting the compound of any one of claims 1-104 or the composition of claim 105 with a KRAS protein (e.g., KRASG12C).
109. The method of any one of claims 106-108, wherein the contacting occurs in a cell harboring a KRASG12C mutant protein.
110. The method of any one of claims 106-108, wherein the contacting occurs in a subject (e.g., a human subject).
111. A method, comprising administering the compound of any one of claims 1-104 or the composition of claim 105 to a subject in need thereof.
112. A method of treating a disease, disorder, or condition associated with KRAS (e.g., mutant KRAS, e.g., KRASG12C), comprising administering the compound of any one of claims 1-104 or the composition of claim 105 to a subject in need thereof.
113. The method of claim 112, wherein the disease, disorder, or condition associated with KRAS is a cancer.
114. A method of treating cancer, comprising administering the compound of any one of claims 1-95 or the composition of claim 105 to a subject in need thereof.
115. The method of claim 113 or 114, wherein the cancer is non-small cell lung cancer or colorectal cancer.
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