TW202604484A - Substituted aryl sulfonamides and compositions and uses thereof - Google Patents

Abstract

The present disclosure provides compounds having Formula I:  and stereoisomers thereof, and pharmaceutically acceptable salts or solvates of said compounds or stereoisomers thereof, wherein M¹, M², M³, M⁴, Z, n, R⁵, R⁶, W, A, and R⁹ are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to inhibit sodium channels (e.g., Na_V1.7) and/or to treat a disorder responsive to the inhibition of a sodium channel (e.g., Na_V1.7). Compounds of the present disclosure may be useful for treating pain.

Description

Substituted arylsulfonamides and their compounds and uses

This disclosure provides substituted aryl sulfonamides (including benzylsulfonamides) and combinations thereof, as well as uses. In some embodiments, the use of the aryl sulfonamides disclosed herein as sodium channel inhibitors (e.g., _NaV 1.7) and methods of treating disorders and diseases involving the inhibition of sodium channels (e.g., _NaV 1.7) are provided. In some embodiments, the uses provide benefits such as pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

Voltage-gated sodium channels are transmembrane proteins that initiate action potentials in nerve, muscle, and other electrically excitable cells, and are essential components of normal sensation, emotion, thought, and movement (Catteral, WA, Nature 409 :988-990 (2001)). This protein family has been extensively studied and shown to participate in many important bodily functions. Members of this protein family are denoted as _NaV1.x , where x = 1 to 9.

One sodium channel is _NaV 1.7. _NaV 1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encoded by the gene SCN9A. _NaV 1.7 is primarily expressed in the peripheral nervous system, particularly in nociceptors, olfactory neurons, and sympathetic neurons. Inhibition or blockade of _NaV 1.7 has been shown to produce analgesic activity. Knockout of _NaV 1.7 expression in nociceptive sensory neurons primarily results in resistance to inflammatory pain (Nassar et al. , Proc Natl Acad Sci USA 24 (34):12706-12711 (2004)). Similarly, loss-of-function mutations in humans result in no difference in congenital pain, with individuals exhibiting resistance to both inflammatory and neuropathic pain (Cox, JJ et al ., Nature 444 :894-898 (2006); Goldberg, YP et al ., Clin. Genet. 71 :311-319 (2007)). Conversely, gain-of-function mutations in _NaV 1.7 have been identified in two heritable human pain disorders (primary acropalatine and familial rectal pain) (Yang, Y. et al ., J. Med. Genet. 41 (3):171-174 (2004)). In addition, the single nucleotide polymorphism (R1150W), which has a very subtle effect on the time and voltage dependence of channel gate control, has a greater impact on pain perception (Estacion, M. et al. , Ann Neurol 66 :862-866 (2009); Reimann, F. et al. , Proc Natl Acad Sci USA 107 :5148-5153 (2010)).

In addition, since _NaV 1.7 preferentially manifests in nociceptors, selective inhibition of _NaV 1.7 can have an increased therapeutic effect on pain without dose-limiting side effects.

Therefore, there is still a need to develop sodium channel inhibitors (such as _NaV 1.7 inhibitors) that can be used to treat pain and related diseases and conditions.

In one embodiment, this disclosure relates to compounds having Formula I (also referred to herein as compounds of this disclosure): I ; or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein: ^M1 is selected from N and ^CR1 ; ^M2 is selected from N and ^CR2 ; ^M3 is selected from N and ^CR3 ; ^M4 is selected from N and ^CR4 ; each of ^R1 , ^R2 , ^R3 and ^R4 is independently selected from hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, (C1-C6) halogenated alkyl, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 - _C6 ) alkoxy, (C3-C6) alkyl, or ( _C3 - _C6) alkyl. ^R5 is independently selected from halogen, substituted ( _C1 - _{C6) alkyl and (C1-C6} ) halogenated alkyl, substituted ( _C3 - _C6 ) cycloalkyl, substituted ( _C1 - _C6 ) alkoxy, substituted ( _C3 - _C6 ) cycloalkyl, substituted ( _C1 - _C6 ) alkoxy, substituted ( _C3 - _{C6 )} cycloalkyloxy, substituted ( _{C6 - C14} ) aryl, substituted heterocyclic and substituted heteroaryl, or two twin Rs. ^R5 , together with the atoms it is attached to, forms a ( _C3 - _C6 ) cycloalkyl group, which may be substituted, or ^R5 is a _C1 alkyl group, which forms a bond with each of the two carbons of the ring to which it is attached; n is 0, 1, or 2; ^R9 is selected from hydrogen, ( _C1 - _C6 ) alkyl, and ( _C6 - _C14 ) aryl-( _C1 - _C6 ) alkyl-, which may be substituted; A is a heteroaryl group, which may be substituted; Z is selected from N and ^CRZ ; ^RZ is selected from hydrogen and ( _C1 - _C6 ) alkyl; ^R6 is selected from hydrogen, halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl, and ( _C3 - _C6) alkyl-, which may be substituted. Cycloalkyl, (C1-C6)alkoxy, ( _C3 - _C6 )cycloalkyloxy, ( _C6 - _C14 )aryl, (C6-C14) heterocyclic, and ( _C1 - _C14 ) heteroaryl are selected from ^R8R7N- , ^R8R7N- (C1-C6)alkyl-, R8R7N- _{(C3-C6)cycloalkyl-, R8R7N-(C3-C6)cycloalkyl-(C1-C6)alkyl-, (C1-C6) heterocyclic, and (C1} ^- _{C6 )} ^{alkyl- (} _C1 ^- _{C6 )} ^{cycloalkyl, or R8R7N- (} _C3 - _C6 )cycloalkyl-(C1-C6)alkyl-, ( _C1 - _C14 ) alkyl-(C1-C14)cyclo ... ⁶ and W, together with the atoms they are attached to ^{, form R8R7N- (} _C3 - _C7 )cycloalkyl- ^{, R8R7N-} ( _C1 - _C6 )alkyl-( _C3 - _C7 )cycloalkyl-, or, where applicable, a substituted heterocyclic group; and each of ^R7 and ^R8 is independently selected from hydrogen, where applicable, a substituted ( _C1 - _C6 )alkyl, where applicable, a substituted ( _C3 - _C6 )cycloalkyl, where applicable, a substituted heterocyclic group, where applicable, a substituted ( _C6 - _C14 )aryl-( _C1 - _C6 )alkyl-, ( _C1 - _C6 )halogenated alkyl, or, where applicable, a substituted ( _C1 - _C6 )alkyl-O-(C ₁ - _C6 )alkyl- and ( _C3 - _C6 )cycloalkyl- ( _C1 - _C6 )alkyl-, or ^R7 and ^R8 together with the atoms to which they are attached to form heterocyclic groups as appropriate.

In some embodiments, this disclosure relates to a pharmaceutical composition comprising the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure relates to a method for inhibiting one or more sodium channels in an individual of need, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, this disclosure relates to a method for treating a disease or condition in an individual of need associated with the inhibition of one or more sodium channels, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, one or more sodium channels are Na _V 1.7.

In some embodiments, the inhibition or inhibition of one or more sodium channels is selective inhibition or selective inhibition of Na _V 1.7.

In some cases, the disease or symptom is selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itching, and combinations thereof.

Additional embodiments and advantages of this disclosure will be set forth in part in the description which follows, and will be derived from the description or may be understood by practicing this disclosure. The embodiments and advantages of this disclosure will be realized and obtained by means of the elements and combinations specifically pointed out in the appended claims.

It should be understood that the foregoing invention and the following detailed description are merely illustrative and explanatory, and do not limit the invention as claimed.

In one embodiment, this disclosure relates to compounds having Formula I (also referred to herein as compounds of this disclosure): I ; or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein: ^M1 is selected from N and ^CR1 ; ^M2 is selected from N and ^CR2 ; ^M3 is selected from N and ^CR3 ; ^M4 is selected from N and ^CR4 ; each of ^R1 , ^R2 , ^R3 and ^R4 is independently selected from hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, (C1-C6) halogenated alkyl, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 - _C6 ) alkoxy, (C3-C6) alkyl, or ( _C3 - _C6) alkyl. ^R5 is independently selected from halogen, substituted ( _C1 - _{C6) alkyl and (C1-C6} ) halogenated alkyl, substituted ( _C3 - _C6 ) cycloalkyl, substituted ( _C1 - _C6 ) alkoxy, substituted ( _C3 - _C6 ) cycloalkyl, substituted ( _C1 - _C6 ) alkoxy, substituted ( _C3 - _{C6 )} cycloalkyloxy, substituted ( _{C6 - C14} ) aryl, substituted heterocyclic and substituted heteroaryl, or two twin Rs. ^R5 , together with the atom it is attached to, forms a ( _C3 - _C6 ) cycloalkyl group, which may be substituted, or two twin ^R5s together with the atom they are attached to form a ( _C3 - _C6 ) cycloalkyl group, or ^R5 is a _C1 alkyl group, which forms a bond with each of the two carbons of the ring to which it is attached; n is 0, 1, or 2; ^R9 is selected from hydrogen, ( _C1 - _C6 ) alkyl, and ( _C6 - _C14 ) aryl-( _C1 - _C6 ) alkyl-, which may be substituted; A is a heteroaryl group, which may be substituted; Z is selected from N and ^CRZ ; ^RZ is selected from hydrogen and ( _C1 - _C6 ) alkyl; ^R6 is selected from hydrogen, halogen, and ( _C1 - _C6 ) alkyl, which may be substituted. ( _C1 - _C6 ) alkyl, (C1-C6) halogenated, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) substituted, (C1-C6) alkoxy, ⁽ _C3 - _C6 ) cycloalkyloxy, ( _C6 - ^C14 ₎ aryl, _{( C6} ^- _{C14 )} ^{heterocyclic , and} ( ^C6 _- ^C14 ₎ heteroaryl are _all substituted _. )alkyl-, optionally substituted heterocyclic group and optionally substituted heterocyclic-( _C1 - _C6 )alkyl-, or W is selected from ^R8R7N- , ^R8R7N- (C1-C6)alkyl- ^{, R8R7N-} ( _C3 - _C6 ) ^cycloalkyl- , ^R8R7N- ( _C3 - _C6 ) ^cycloalkyl- ( _C1 - ^C6 )alkyl-, optionally substituted nitrogen-containing heterocyclic group and optionally substituted nitrogen-containing heterocyclic-( _C1 - _{C6 )} alkyl-, or ^R6 and W together with the atoms they are attached to form ^R8R7N- ( _{C3 - C7} )cycloalkyl-, ^R8R7N- ( _C1 - _C6 ^{) ...} _-C6 )alkyl-( _C3 - _C7 )cycloalkyl- or, as appropriate, a substituted heterocyclic group; or ^R6 and W together with the atoms they are attached to form ^R8R7N- ( _C3 - _C7 )cycloalkyl-, ^R8R7N- ( _C1 - _C6 ) ^alkyl- ( _C3 - _C7 )cycloalkyl- or, as appropriate ^, a substituted nitrogen-containing heterocyclic group; or ^R6 is a bond between the carbon it is attached to and ^R5 ; or R5 and W together with the atoms they are attached to form an amine-substituted ( _C3 - _C6 )cycloalkyl or, as appropriate, a substituted heterocyclic group; or ^R5 and ^R6 together with the atoms they are attached to form, as appropriate ^, a substituted ( _C3 - _C6) cycloalkyl group. ^R7 and ^R8 are independently selected from hydrogen, substituted ( _C1 -C6)alkyl, substituted (C3- _C6 )cycloalkyl, substituted heterocyclic, substituted (C6- _C14 )aryl-( _C1 -C6)alkyl-, ( _C1 - _C6 )halogenated alkyl, substituted ( _C1 - _C6 )alkyl- _O- ( _C1 - _C6 )alkyl- and ( _C3 - _C6 )cycloalkyl-( _{C1 - C6} )alkyl-, or ^R7 and _R8 together with ^the atoms _to which they are attached form a substituted heterocyclic group.

In some embodiments, ^M1 , ^M2 , ^M3 and ^M4 are ^CR1 , ^CR2 , ^CR3 and ^CR4 , respectively. In some embodiments, each of ^M1 , ^M2 , ^M3 and ^M4 is N.

In some embodiments, one of ^M1 , ^M2 , ^M3 and ^M4 is N.

In some embodiments, two of ^M1 , ^M2 , ^M3 and ^M4 are N.

In some implementations, three of ^M1 , ^M2 , ^M3 and ^M4 are N.

In some embodiments, ^M1 is N, and ^M2 , ^M3 and ^M4 are ^CR2 , ^CR3 and ^CR4, respectively.

In some embodiments, ^M2 is N, and ^M1 , ^M3 and ^M4 are ^CR1 , ^CR3 and ^CR4, respectively.

In some embodiments, ^M3 is N, and ^M1 , ^M2 and ^M4 are ^CR1 , ^CR2 and ^CR4 , respectively.

In some embodiments, ^M4 is N, and ^M1 , ^M2 and ^M3 are ^CR1 , ^CR2 and ^CR3, respectively.

In some implementations, for .

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently selected from hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) alkoxy, and ( _C1 - _C6 ) alkylthio, as appropriate.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, (C1 _{- C6} )alkyl, ( _C3 - _C6 )cycloalkyl or halogen.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, (C1 _{- C4} )alkyl or halogen.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, chlorine, fluorine, methyl, ethyl or cyclopropyl.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, chlorine or fluorine.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen or fluorine.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, fluorine or methyl.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, fluorine or ethyl.

In some embodiments, each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, fluorine or cyclopropyl.

In some implementations, Department selected from , , , , , , , , , , , , , , , , , and .

In some implementations, Department selected from , , , and .

In some implementations, Department selected from , and .

In some embodiments, ^R1 is selected from hydrogen, halogen, (C1 _{- C6} )alkyl, and ( _C3 - _C6 )cycloalkyl. In some embodiments, ^R1 is selected from hydrogen and halogen. In some embodiments, ^R1 is halogen. In some embodiments, ^R1 is fluorine.

In some implementations, ^R2 is hydrogen.

In some embodiments, ^R3 is selected from hydrogen, halogen, (C1 _{- C6} )alkyl, and ( _C3 - _C6 )cycloalkyl. In some embodiments, ^R3 is selected from hydrogen and halogen. In some embodiments, ^R3 is selected from halogen. In some embodiments, ^R3 is fluorine.

In some embodiments, ^R4 is selected from hydrogen, halogen, ( _C1 - _C6 )alkyl, and ( _C3 - _C6 )cycloalkyl. In some embodiments, ^R4 is selected from halogen. In some embodiments, ^R4 is chlorine. In some embodiments, ^R4 is fluorine. In some embodiments, ^R4 is methyl. In some embodiments, ^R4 is ethyl. In some embodiments, ^R4 is cyclopropyl.

In some embodiments, Z is N. In some embodiments, Z is ^CRZ . In some embodiments, ^RZ is hydrogen, ( _C1 - _C3 )alkyl, or halogen. In some embodiments, ^RZ is hydrogen or methyl. In some embodiments, ^RZ is hydrogen.

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, each ^R5 is independently selected from hydrogen, and optionally substituted ( _C1 - _C6 ) alkyl and ( _{C1 - C6} ⁾ halogenated alkyl. In some embodiments, each ^R5 is independently selected from hydrogen, methyl _{, ethyl} , difluoromethyl, and _{trifluoromethyl} .

In some embodiments, the two descending ^R5s, together with their attached atoms, form a ( _C3 - _C6 ) cycloalkyl group, which may be substituted. In some embodiments, the two descending ^R5s , together with their attached atoms, form a cyclopropyl group. In some embodiments, the two descending ^R5s , together with their attached atoms, form a cyclobutyl group. In some embodiments, the two descending ^R5s , together with their attached atoms, form a cyclopentyl group. In some embodiments, the two descending ^R5s , together with their attached atoms, form a cyclohexyl group.

In some embodiments, W is selected from ^R8R7N- ( _C1 - _C6 ) ^alkyl- , nitrogen-containing heterocyclic group as appropriate, and nitrogen-containing heterocyclic group-( _C1 - _C6 )alkyl- as appropriate.

In some embodiments, W is ^R8R7N- ( _C3 - _C6 )cycloalkyl-. In some embodiments, W is ^R8R7N- ( _C3 - _C6 )cycloalkyl-( _C1 - _C6 )alkyl-. In some embodiments, W is ^a nitrogen ^- containing heterocyclic group, substituted as appropriate. In some embodiments, W is a nitrogen-containing heterocyclic group, substituted as appropriate, -( _C1 - _C6 )alkyl-.

In some implementations, W is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some implementations, W is selected from , , , , , , , and .

In some embodiments, ^R7 and ^R8 are each independently selected from hydrogen, substituted ( _C1 - _C6 ) alkyl, substituted ( _C3 - _C6 ) cycloalkyl and ( _C1 - _C6 ) halogen.

In some embodiments, ^R7 and ^R8 are each, as appropriate, substituted ( _C1 - _C6 ) alkyl groups.

In some embodiments, ^R7 is a ( _C1 - _C6 ) alkyl group, which may be substituted, and ^R8 is hydrogen.

In some embodiments, ^R7 is, where appropriate, a substituted ( _C3 - _C6 ) cycloalkyl group and ^R8 is hydrogen.

In some embodiments, ^R7 is a substituted ( _C1 - _C6 ) alkyl and ^R8 is a substituted ( _C3 - _C6 ) cycloalkyl.

In some embodiments, ^R7 is a ( _C1 - _C6 ) alkyl group that is substituted as appropriate and ^R8 is a ( _C1 - _C6 ) halogen.

In some embodiments, ^R7 and ^R8 are each independently selected from methyl, _d3 -methyl, ethyl, d5 _- ethyl, propyl, tributyl, neopentyl, 1,1-difluoromethyl, 2,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl-2-yl, 2-fluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, cyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, bicyclo[1.1.1]pentyl-1-yl, cyclobutyl, spiro[2.3]hexyl-5-yl, 3-(difluoromethyl)cyclobutyl and benzyl.

In some embodiments, ^R7 and ^R8 are ( _C1 - _C6 ) alkyl groups.

In some embodiments, ^R7 and ^R8, together with the atoms to which they are attached, form heterocyclic groups that are, where appropriate, substituted.

In some embodiments, ^R7 and ^R8 together with the atoms to which they are attached form, where appropriate, a substituted aza-cyclobutyl, a substituted pyrrolidin, a substituted piperidin, a substituted piperazine, a substituted N-morpholino, or a substituted aza-cycloheptyl.

In some implementations, W is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, ^R6 is selected from hydrogen, halogen, ( _C1 - _C6 ) alkyl, (C1-C6) halogenated alkyl, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 - _C6 ) cycloalkyloxy, ( _C6 -C14) aryl, ( _{C6-C14) aryl, (C6 -C14 )} heterocyclic, and (C6-C14) heteroaryl.

In some embodiments, ^R6 is selected from hydrogen, halogen, ( _C1 - _C6 )alkyl, ( _C3 - _C6 )cycloalkyl, ( _C1 - _C6 )alkoxy and, where applicable, substituted ( _C6 - _C14 )aryl.

In some embodiments, ^R6 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, fluorine, _d3- methoxy, methoxy, ethoxy, methoxymethyl, and phenyl. In some embodiments, ^R6 is selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, and phenyl. In some embodiments, ^R6 is hydrogen. In some embodiments, ^R6 is methyl. In some embodiments, ^R6 is ethyl. In some embodiments, ^R6 is cyclopropyl. In some embodiments, ^R6 is methoxy. In some embodiments, ^R6 is phenyl.

In some embodiments, ^R6 and W together with the atoms to which they are attached form ^R8R7N- ( _C3 - _C7 ) ^cycloalkyl- or, where appropriate, a substituted nitrogen-containing heterocyclic group.

In some embodiments, ^R6 and W together with the atoms to which they are attached form ^{R7R8N -} cyclopropyl-, ^R7R8N -cyclobutyl-, ^R7R8N -cyclopentyl-, ^{R7R8N - methyl} -cyclobutyl-, a substituted aza-cyclobutyl-, a substituted pyrrolidyl-, or a substituted ^N -morpholino-.

In some embodiments, ^R6 and W together with the atoms to which they are attached form, where appropriate, a substituted cyclobutyl or a substituted pyrrolidyl group.

In some implementations, for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some implementations, ^R9 is hydrogen.

In some embodiments, A is selected from a substituted thiazolyl group, a substituted benzothiazolyl group, a substituted pyridyl group, a substituted isoxazolyl group, a substituted pyrimidinyl group, and a substituted pyrazinyl group.

In some embodiments, A is selected from a substituted thiazolyl group and a substituted pyridyl group, depending on the case.

In some embodiments, A is a substituted thiazolyl group, depending on the situation.

In some embodiments, A is, where appropriate, a substituted benzothiazolyl group.

In some embodiments, A is a substituted pyridyl group, as appropriate.

In some embodiments, A is an isoxazolyl group, which may be substituted as appropriate.

In some embodiments, A is a substituted pyrimidinyl group, as appropriate.

In some embodiments, A is a substituted pyrazinyl group, as appropriate.

In some implementations, A is selected from , , , , , , , , , , , and .

In some implementations, A is selected from , and .

In some embodiments, the compound may have one or more of the formulas IIa , IIb , IIc , IId , IIe , IIf , IIq , IIr , and IIs : IIa , IIb IIc , IId , IIe If IIq , IIr , IIs , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein: p is selected from 0, 1, 2 and 3; t is selected from 0, 1 and 2; q is selected from 1, 2 and 3, provided that if t is 0, then q is selected from 2 and 3; ^Z1 is selected from ^CR15 and N; ^R12 is selected from hydrogen and, where applicable, a substituted ( _C1 - _C6 ) alkyl group; ^{and R15} is selected from hydrogen,, where applicable, a substituted ( _C1 - _C6 ) alkyl group and ^-NR8R9 .

In some embodiments, p is 0. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

In some implementations, t is 1 and q is 1.

In some implementations, t is 1 and q is 2.

In some implementations, t is 0 and q is 3.

In some embodiments, ^Z1 is CR ¹⁵ .

In some implementations, R ¹⁵ is hydrogen.

In some implementations, ^Z1 is N.

In some embodiments, ^R12 is a ( _C1 - _C6 ) alkyl group. In some embodiments, ^R12 is a methyl group.

In some embodiments, the compound may have one or more of the formulas IIg , IIh , IIi , IIj , IIk , IIm , IIt , IIu , and IIv : IIg , IIh IIi IIj IIk , IIm , IIt 、 IIu , IIv ; or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein: ^R10 and ^R11 are each independently selected from hydrogen, halogen and ( _C1 - _C4 ) alkyl, or ^R10 and ^R11 of formula IIg , IIh and IIt together with the atoms to which they are attached form, where appropriate, a substituted aryl group, where appropriate, a substituted heterocyclic group, where appropriate, a substituted heteroaryl group or where appropriate, a substituted cycloalkyl group; and ^R13 and ^R14 are each independently selected from the group consisting of: hydrogen, halogen, cyano, where appropriate, a substituted ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl, where appropriate, a substituted (C1-C6) alkyl group ... ₍₃ - _C6 )cycloalkyl, ( _C1 - _C6 )alkoxy, (C3- _C6 )cycloalkyloxy, ( _C1 - _C6 )alkylthio, and ( _{C3 - C6} )cycloalkylthio, as appropriate.

In some embodiments, ^R10 and ^R11 in formulas IIg , IIh and IIt together with the atoms to which they are attached form, where appropriate, substituted benzothiazolyl groups.

In some embodiments, ^R10 and ^R11 in formulas IIg , IIh , and IIt are formed together with the atoms to which they are attached: .

In some embodiments, ^R10 and ^R11 are each independently selected from hydrogen, halogen, or, where applicable, a substituted ( _C1 - _C6 ) alkyl group. In some embodiments, ^R10 and ^R11 are each independently selected from hydrogen, methyl, fluorine, chlorine, and bromine. In some embodiments, ^R10 and ^R11 are hydrogen. In some embodiments, ^R10 is hydrogen and ^R11 is halogen. In some embodiments, ^R10 is halogen and ^R11 is hydrogen. In some embodiments, ^R10 is hydrogen and ^R11 is chlorine. In some embodiments, ^R10 is chlorine and ^R11 is hydrogen.

In some embodiments, ^R13 and ^R14 are each independently selected from the group consisting of: hydrogen, halogen, cyano, and, where applicable, substituted ( _C1 - _C6 ) alkyl. In some embodiments, ^R13 and ^R14 are each independently hydrogen, halogen, methyl, ethyl, propyl, or isopropyl.

In some embodiments, R ¹³ is a halogen. In some embodiments, R ¹³ is fluorine, chlorine, or bromine. In some embodiments, R ¹³ is fluorine.

In some implementations, R ¹⁴ is hydrogen.

In some embodiments, the compound may have one or more of the formulas IIn , IIo , IIp , IIw , IIx , and IIy : IIn 、 IIo , IIp , IIw , IIx , IIy , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

The compounds disclosed herein include the compounds listed in Table A, or their pharmaceutically acceptable salts, solvents and stereoisomers.

In some embodiments, the compounds disclosed herein are compounds having one or more of formulas III , IV , or V : III . IV . V , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein A, ^M1 , ^M2 , ^M3 , ^M4 , ^Z1 , ^R6 , ^R7 , ^R8 , ^R12 , p, q and t are as defined herein.

In some embodiments, the compounds disclosed herein are compounds having one or more of formulas VI , VII , or VIII : VI . VII . VIII , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein ^M1 , ^M2 , ^M3 , ^M4 , W, Z, ^R6 , ^R10 , ^R11 , ^R13 , ^R14 and n are as defined herein.

In some embodiments, the compounds disclosed herein are compounds having any one or more of the formulas IX , X , and XI : IX X , XI , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein ^M1 , ^M2 , ^M3 , ^M4 , ^R6 and W are as defined herein.

The compounds disclosed herein include the compounds listed in Table A, or their stereoisomers, or pharmaceutically acceptable salts or solvents of such compounds or their stereoisomers.

Table A Compound number Name 1 5-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2-fluoro-N-(thiazo-2-yl)benzenesulfonamide 2 5-Chloro-4-(3-((dimethylamino)methyl)azacyclobut-1-yl)-2-fluoro-N-(thiazo-2-yl)benzenesulfonamide 3 5-Chloro-2-fluoro-4-(3-(1-methylpiperidin-4-yl)azacyclobut-1-yl)-N-(thiazo-2-yl)benzenesulfonamide 4 3-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazo-2-yl)benzenesulfonamide 13 3-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazo-4-yl)benzenesulfonamide 5 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methylazirmonobutyl-1-yl)-2,6-difluoro-N-(thiazolyl-2-yl)benzenesulfonamide 6 3-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 7 3-Chloro-4-(3-(3-(dimethylamino)propyl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazo-2-yl)benzenesulfonamide 8 3-Chloro-2,6-difluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl)-N-(thiazo-2-yl)benzenesulfonamide 9 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methylaziroxybut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 10 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazolyl-2-yl)benzenesulfonamide 11 3-Chloro-4-[[2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]amino]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (stereomeric compound 1) 12 3-Chloro-4-(3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazo-2-yl)benzenesulfonamide 14 3-Chloro-4-(3-((dimethylamino)methyl)-3-methylazacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 15 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-ethylazinocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 16 3-Chloro-4-(3-cyclopropyl-3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 17 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobutan-1-yl)benzenesulfonamide 18 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobut-1-yl)benzenesulfonamide 19 (3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide 20 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide twenty one 3-Chloro-2,6-difluoro-4-(6-methyl-2,6-diazaspiro[3,4]oct-2-yl)-N-(thiazolyl-2-yl)benzenesulfonamide twenty two 3-Chloro-2,6-difluoro-4-(2,6-diazaspiro[3,4]oct-2-yl)-N-(thiazolyl-2-yl)benzenesulfonamide twenty three 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(1'-methyl-3-phenyl-[3,3'-azidocyclobutane]-1-yl)benzenesulfonamide twenty four 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 25 3-Chloro-2,6-difluoro-4-(6-isopropyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 26 3-Chloro-2,6-difluoro-4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 27 3-Chloro-2,6-difluoro-4-(6-methyl-2,6-diazaspiro[3,4]oct-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 28 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide 29 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 1) 30 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 31 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methylaziroxybutyl-1-yl)-2-fluoro-6-methyl-N-(pyridin-2-yl)benzenesulfonamide 32 3,6-Dichloro-2-fluoro-4-(7-methyl-2,7-diazaspiro[3,6]dec-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 33 3,6-Dichloro-2-fluoro-4-(8-methyl-5-oxa-2,8-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 34 3,6-Dichloro-2-fluoro-4-(5-methyl-2,5-diazaspiro[3.4]oct-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 35 3,6-Dichloro-2-fluoro-4-(6-methyl-2,6-diazaspiro[3,6]dec-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 36 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.5]non-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 1) 37 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.5]non-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 38 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric 1) 39 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 40 3,6-Dichloro-2-fluoro-4-(6-methyl-2,6-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 41 3,6-Dichloro-2-fluoro-4-(5-methyl-2,5-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 42 3,6-Dichloro-2-fluoro-4-(5-methyl-8-oxa-2,5-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 43 3,6-Dichloro-2-fluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl)-N-(pyridin-2-yl)benzenesulfonamide 44 3-Chloro-2-fluoro-6-methyl-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl)-N-(pyridin-2-yl)benzenesulfonamide 45 3,6-Dichloro-2-fluoro-4-(5-methyl-2,5-diazaspiro[3,6]dec-2-yl)-N-(pyridin-2-yl)benzenesulfonamide 46 3,6-Dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 47 3,6-Dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methylaziroxybut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 48 3,6-Dichloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methylazacyclobutan-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 49 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methyl-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric 1) 50 3,6-Dichloro-2-fluoro-4-(3-(2-(4-fluoropiperidin-1-yl)ethyl)-3-methylazidocyclobut-1-yl)-N-(6-fluoropyridin-2-yl)benzenesulfonamide 51 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-(4-methoxypiperidin-1-yl)ethyl)-3-methylazacyclobut-1-yl)benzenesulfonamide 52 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-(3-fluoropyrrolidin-1-yl)ethyl)-3-methylazacyclobut-1-yl)benzenesulfonamide (stereomeric 1) 53 3-Chloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobutan-1-yl)-6-methylbenzenesulfonamide (stereomeric 1) 54 3-Chloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide 55 3,6-Dichloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 56 3,6-Dichloro-4-(3-(2-((3,3-difluorocyclobutyl)(methyl)amino)ethyl)-3-methoxyazinocyclobutyl-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 57 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide 58 3-Chloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methylazacyclobutan-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 59 (R)-3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobut-1-yl)benzenesulfonamide 60 3-Chloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 61 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric 1) 62 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric derivative 2) 63 3-Chloro-4-(5-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric 1) 64 3-Chloro-4-(5-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 65 3,6-Dichloro-4-(5-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 1) 66 3,6-Dichloro-4-(5-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 67 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 68 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 69 3,6-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 70 3,6-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 71 3,6-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 72 3,6-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 73 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 74 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 75 3-Chloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 76 3-Chloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 77 3,6-Dichloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 78 3,6-Dichloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 79 3-Chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric 1) 80 3-Chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric derivative 2) 81 2,3-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 82 2,3-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 83 2,3-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 84 2,3-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 85 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 86 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 87 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(5-(3-methylpiperidin-1-yl)-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 88 3-Chloro-4-(7-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 89 3-Chloro-4-(7-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 90 3-Chloro-4-(7-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 91 3-Chloro-4-(7-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 92 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(7-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 93 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(7-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 94 3-Chloro-2,6-Difluoro-4-(5-(4-fluoropiperidin-1-yl)-2-azaspiro[3.4]oct-2-yl)-N-(6-fluoropyridin-2-yl)benzenesulfonamide 95 3,6-Dichloro-2-fluoro-4-(8-(3-fluoro-3-methylazacyclobut-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl) -N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 96 3,6-Dichloro-2-fluoro-4-(8-(3-fluoro-3-methylazacyclobut-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl) -N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) 97 3-Chloro-2-fluoro- N- (6-fluoropyridin-2-yl)-6-methyl-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric 1) 98 3-Chloro-2-fluoro- N- (6-fluoropyridin-2-yl)-6-methyl-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric derivative 2) 99 3-Chloro-2-fluoro-4-(6-(3-fluoro-3-methylazacyclobut-1-yl)-2-azaspiro[3.5]non-2-yl)-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 1) 100 3-Chloro-2-fluoro-4-(6-(3-fluoro-3-methylazacyclobut-1-yl)-2-azaspiro[3.5]non-2-yl)-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 2) 101 3-Chloro-4-(6-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.5]non-2-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric compound 1) 102 3-Chloro-4-(6-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.5]non-2-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric derivative 2) 103 3-Chloro-2,6-difluoro-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-N-(thiazolyl-4-yl)benzenesulfonamide (stereomeric 1) 104 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methoxypyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-methylbenzenesulfonamide (stereomeric 1) 105 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methoxypyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-methylbenzenesulfonamide (stereomeric 2) 106 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 107 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(-3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 108 4-(8-(1,4-oxazino-4-yl)-5-oxaza-2-azaspiro[3.4]oct-2-yl)-3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 1) 109 4-(8-(1,4-oxazino-6-4-yl)-5-oxaza-2-azaspiro[3.4]oct-2-yl)-3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 2) 110 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(pyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 111 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(pyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 112 3-Chloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 113 3-Chloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 114 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 115 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 116 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric 1) 117 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 118 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 119 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 120 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric 1) 121 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric derivative 2) 122 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric 1) 123 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric derivative 2) 124 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-((R)-3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide 125 3-Chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric 1) 126 3-Chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric derivative 2) 127 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric 1) 128 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereomeric derivative 2) 129 3-Chloro-4-(3-((1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)methyl)-3-methylazacyclobutyl-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 130 3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereomeric 1) 131 3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereomeric derivative 2) 132 3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereomeric 3) 133 3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereomeric derivative 4) 134 3,6-Dichloro-2-fluoro-4-(3-(2-(4-fluoropiperidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-N-(6-fluoropyridin-2-yl)benzenesulfonamide 135 3,6-Dichloro-4-(3-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 136 3,6-Dichloro-4-(3-(2-(3-(difluoromethyl)piperidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 137 3,6-Dichloro-4-(3-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)ethyl)-3-methoxyazabicyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 138 3,6-Dichloro-4-(3-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridine-2-yl)benzenesulfonamide 139 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-(3-fluoropyrrolidin-1-yl)ethyl)-3-methoxyazacyclobut-1-yl)benzenesulfonamide (stereomeric 1) 140 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide 141 5-Chloro-4-(3-(2-(dimethylamino)ethyl)cyclobutyl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereoisomer 1) 142 5-Chloro-4-(3-(2-(dimethylamino)ethyl)cyclobutyl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) 143 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: , , , , , , , and , or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: Or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: , , , , , , , , and , or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: , , , , , , , , , and , or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: Or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: Or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: Or its stereoisomers, or pharmaceutically acceptable salts or solvents of the compound or its stereoisomers.

In some embodiments, the compound has a sodium channel potency of at least 3 μm, at least 2 μm, at least 1 μm, or less than 1 μm, or less than 0.5 μm, or less than 0.01 μm, or less than 0.001 μm, or less than 0.0005 μm, or less than 0.0001 μm. In some embodiments, the sodium channel is Na _V 1.7.

In some embodiments, this disclosure relates to a pharmaceutical composition comprising the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure relates to a method for inhibiting one or more sodium channels (e.g., _NaV 1.7) in an individual of need, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, this disclosure relates to a method for selectively inhibiting _NaV 1.7 in an individual of need, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, this disclosure relates to a method for treating a disease or condition in an individual of need that is associated with the inhibition of one or more sodium channels (e.g., _NaV 1.7), comprising administering to the individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, one or more sodium channels are Na _V 1.7.

In some embodiments, inhibition of one or more sodium channels is selective inhibition or selective inhibition of Na _V 1.7.

In some embodiments, this disclosure relates to a method for treating and selectively inhibiting _NaV 1.7 and not any other sodium channel-related diseases or conditions in mammals, wherein the method comprises administering to an individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, the compounds of this disclosure inhibit one or more sodium channels with IC50 values less than 100 nm, or less than 90 nm, or less than 80 nm, or less than 70 nm, or less than 60 nm, or less than 50 nm, or less than 40 nm, or less than 30 nm, or less than 20 nm, or less than 10 nm, or less than 1 nm, or less than 0.05 nm, or less than 0.01 nm. In some embodiments, the compounds of this disclosure inhibit NaV 1.7 channels with IC50 values less than 100 nm, or less than 90 nm, or less than 80 nm, or less than 70 nm, or less than 60 nm, or less than 50 nm, or less than 40 nm, or less than 30 nm, or less than 20 nm, or less than 10 nm, or less than 1 nm, or less than 0.05 nm, or less than _0.01 nm. The term "IC50" is a measure, known to those skilled in the art, of the amount of compound required to achieve 50% inhibition of the activity of a target sodium channel within a specific time period. In some embodiments, the target sodium channel is _NaV 1.7. Those skilled in the art will understand methods used, for example, by electrophysiological assays, to determine the IC50 of a compound.

In some embodiments, the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, has a Na _V 1.7 to Na _V 1.x (where x is 1, 2, 3, 4, 5, 6 or 8) inhibition ratio of 5 or greater. In some embodiments, the compound of this disclosure, or its stereoisomers, or pharmaceutically acceptable salts or solvents thereof, have an inhibition ratio of Na V 1.7 to Na V 1.x (where x is 1, 2, 3, 4, 5, 6, or 8) of 3 or greater, 3.5 or greater, 4 or greater, 4.5 or greater, 5.5 or greater, 6 or greater, 6.5 or greater, 7 or greater, 7.5 or greater, 8 or greater, 8.5 or greater, 9 or greater, _9.5 or greater, or 10 or greater, or 15 or greater, or 20 or greater, _or 30 or greater, or 40 or greater, or 50 or greater. In some embodiments, the inhibition ratio is Na _V 1.7 to Na _V 1.2. In some embodiments, the inhibition ratio is Na _V 1.7 to Na _V 1.5. In some embodiments, the inhibition ratio is Na _V 1.7 to Na _V 1.6.

In some embodiments, the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, has an inhibition ratio of about 4 to about 7 Na _V 1.7 to Na _V 1.x (where x is 1, 2, 3, 4, 5, 6 or 8). In some embodiments, the compound of this disclosure, or its stereoisomers, or pharmaceutically acceptable salts or solvents thereof, have about 4 to about 5, about 4 to about 6, about 4 to about 8, about 4 to about 9, about 4 to about 10, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 5 to about 9, about 5 to about 10, about 6 to about 7, about 6 to about 8, about 6 to about 9, about 7 to about 8, about 7 to about 9, about 7 to about 10, about 8 to about 9, about 8 to about 10, or about 9 to about 10, or about 10 to about 15, or about 15 to about 20, or about 20 to about 25, or about 25 to about 30, or about 30 to about 35, or about 35 to about 40, or about 40 to about 45, or about 45 to about 50 or greater Na. The inhibition ratio is _NaV 1.7 to _NaV 1.x (where x is 1, 2, 3, 4, 5, 6, or 8). In some embodiments, the inhibition ratio is _NaV 1.7 to _NaV 1.2. In some embodiments, the inhibition ratio is _NaV 1.7 to _NaV 1.5. In some embodiments, the inhibition ratio is _NaV 1.7 to _NaV 1.6.

In some embodiments, the compound of this disclosure, or its stereoisomers, or pharmaceutically acceptable salts or solvents thereof, can inhibit 90% of sodium channels, such as _NaV 1.7, activity. In some embodiments, the compound of this disclosure, or its stereoisomers, or pharmaceutically acceptable salts or solvents thereof, can inhibit about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% of sodium channels, such as _NaV 1.7, activity. In some embodiments, the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, may inhibit about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% of sodium channels, such as _NaV 1.7, activity.

In some embodiments, the compound of this disclosure, or its stereoisomers, or pharmaceutically acceptable salts or solvents thereof, can inhibit about 80% to about 95% of sodium channels, such as _NaV 1.7, activity. In some embodiments, the compound of this disclosure, or its stereoisomers, or pharmaceutically acceptable salts or solvents thereof, can inhibit about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 95%, about 50% to about 98%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 95 ... Sodium channels, such as NaV 1.7, with an activity of 0% to about 98%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, about 70% to about 98%, about 70% to about 99%, about 80% to about 90%, about 80% to about 98%, about 80% to about 99%, about 90% to about 95%, about 90% to about 98%, about 90% to about 99%, about 95% to about 98%, about 95% to about 99%, or about 98% to about ₉₉ %. In some embodiments, the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, may inhibit about 5% to about 15%, about 10% to about 25%, about 15% to about 30%, about 25% to about 45%, about 40% to about 60%, about 50% to about 100%, about 5% to about 100%, about 15% to about 100%, or about 25% to about 100% of sodium channels, such as _NaV 1.7, activity.

In some embodiments, after administration, the ratio of the amount of the disclosed compound present in the brain to the blood/plasma ratio ( i.e. , the "brain-to-plasma ratio") is 0.05 or greater. In some embodiments, the brain-to-plasma ratio is 0.1 or greater, 0.2 or greater, 0.4 or greater, 0.6 or greater, 0.8 or greater, 1 or greater, 1.5 or greater, or 2 or greater, or 5 or greater, or 10 or greater or more. Those skilled in the art will understand the methods used to determine the brain-to-plasma ratio, such as by measuring the concentration of the compound in the blood/plasma and measuring the concentration of the compound in the brain.

In some embodiments, the brain-to-plasma ratio is about 0.01 to about 1. In some embodiments, the brain-to-plasma ratio is about 0.01 to about 0.05, about 0.01 to about 0.2, about 0.01 to about 0.4, about 0.01 to about 0.6, about 0.01 to about 0.8, about 0.01 to about 1, about 0.01 to about 1.5, about 0.01 to about 2, about 0.05 to about 0.1, about 0.05 to about 0.2, about 0.05 to about 0.4, about 0.05 to about 0.6, about 0.05 to about 0.8, about 0.05 to about 1, about 0.05 to about 1.5, about 0.05 to about 2, about 0.1 to about 0.2, about 0.1 to about 0.4, about 0.1 to about 0.6, or about 0.1. to about 0.8, about 0.1 to about 1, about 0.1 to about 1.5, about 0.1 to about 2, about 0.2 to about 0.4, about 0.2 to about 0.6, about 0.2 to about 0.8, about 0.2 to about 1, about 0.2 to about 1.5, about 0.2 to about 2, about 0.4 to about 0.6, about 0.4 to about 0.8, about 0.4 to about 1, about 0.4 to about 1.5, about 0.4 to about 2, about 0.6 to about 0.8, about 0.6 to about 1, about 0.6 to about 1.5, about 0.6 to about 2, about 0.8 to about 1, about 0.8 to about 1.5, about 0.8 to about 2, about 1 to about 1.5, about 1 to about 2 or about 1.5 to about 2.

In some embodiments, after administration, the amount of the compound disclosed herein, Kp _,u, is 0.05 or greater, or 0.1 or greater, or 0.2 or greater, or 0.3 or greater, or 0.4 or greater, or 0.5 or greater, or 0.6 or greater, or 0.7 or greater, or 0.8 or greater, or 0.9 or greater, or 1 or greater. Those skilled in the art will understand the methods used to determine the brain/plasma ratio, such as by measuring the concentration of the compound in the blood/plasma, measuring the concentration of the compound in the brain, measuring the free fraction of the compound in the brain homogenate, and measuring the free fraction of the compound in the blood/plasma homogenate.

In some embodiments, the disease or symptom is selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itching, and combinations thereof.

In some embodiments, this disclosure relates to a method of treating an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof.

In some embodiments, this disclosure relates to a compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent compound thereof, for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

In some embodiments, this disclosure relates to the use of a compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent compound thereof, for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

In some embodiments, this disclosure relates to the use of a compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent compound thereof, for the manufacture of a medicament for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

In some embodiments, pain is selected from the following groups: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, paroxysmal pain, neurocystic pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

For the purposes of this disclosure, the term "alkyl" as used alone or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing one to twelve carbon atoms ( i.e., _C1-12 alkyl) or a specified number of carbon atoms ( i.e. , _C1 alkyl (such as methyl), _C2 alkyl (such as ethyl), _C3 alkyl (such as propyl or isopropyl, etc.)). The alkyl group may suitably be selected from straight-chain _C1-10 alkyl, branched _C3-10 alkyl, straight-chain _C1-6 alkyl, branched _C3-6 alkyl, straight-chain _C1-4 alkyl, branched _C3-4 alkyl, straight-chain or branched _C3-4 alkyl. The alkyl group may be partially or completely deuterated, i.e. , one or more hydrogen atoms of the alkyl group are replaced by deuterium atoms. Non-limiting illustrative _C1-10 alkyl groups include methyl (including _{-CD3 ,} where D is deuterium), ethyl ₍ including _-CD2CD3 ), propyl, isopropyl, butyl, dibutyl, tributyl , isobutyl , 3-pentyl, hexyl , heptyl, octyl, nonyl, and decyl. Non-limiting illustrative _C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, dibutyl , tributyl , isobutyl , pentyl, and hexyl.

For the purposes of this disclosure, the term "substituted alkyl group, as used alone or as part of another group" means an alkyl group as defined above that is unsubstituted or substituted by one, two, or three independent substituents selected from the following: halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogenated alkyl, hydroxyl, alkoxy, halogenalkoxy, aryloxy, arylalkyloxy, alkylthio, carboxyamino, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, hydroxyalkylamino, cycloalkylamino, arylalkylamino, cycloalkyl, heterocyclic, aryl, and heteroaryl. The alkyl group may be a _C1-6 alkyl group, substituted as appropriate. As appropriate, the substituted alkyl group may _be substituted with two substituents or _with one substituent. Non-limiting illustrative examples of substituted alkyl groups as appropriate include _CH2C3H4 , _CH2CH2 - _O - _CH3 and _CH2Ph .

For the purposes of this disclosure, the term "alkenyl," used alone or as part of another group, refers to an alkyl group as defined above that contains one, two, or three carbon-carbon double bonds. The alkenyl group may be selected from _C2-6 alkenyl and _C2-4 alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, dibutenyl , pentenyl, and hexenyl.

For the purposes of this disclosure, the term "alternatively substituted alkenyl" as used alone or as part of another group means an alkenyl group as defined above that is unsubstituted or substituted by one, two or three independent substituents selected from the following: halogen, nitro, halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogenated alkyl, hydroxyl, alkoxy, halogenated alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxyamino, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, cyclic substituted as appropriate, aryl substituted as appropriate, heteroaryl substituted as appropriate or heterocyclic substituted as appropriate.

For the purposes of this disclosure, the term "alkynyl" as used alone or as part of another group refers to an alkyl group as defined above containing one to three carbon-carbon linkages. An alkynyl group may have one carbon-carbon linkage. The alkynyl group may be selected from _C2-6 alkynyl and _C2-4 alkynyl groups. Non-limiting illustrative alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentyynyl, and hexynyl.

For the purposes of this disclosure, the term "substituted alkynyl" as used herein, either alone or as part of another group, means an alkynyl group as defined above that is unsubstituted or substituted by one, two, or three independent substituents selected from the following: halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogenated alkyl, hydroxyl, alkoxy, halogenated alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxyamino, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic.

For the purposes of this disclosure, the term "halogenated alkyl" as used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms. An alkyl group may be substituted with one, two, or three fluorine and/or chlorine atoms. An alkyl group may be substituted with one, two, or three fluorine atoms. Halogenated alkyl groups may be selected from _C1-6 halogenated alkyl groups. Non-limiting illustrative halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl-2-yl, 2-fluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl.

For the purposes of this disclosure, the term "hydroxyalkyl" as used alone or as part of another group refers to an alkyl group substituted with one or more, such as one, two, or three hydroxyl groups. Hydroxyl groups may be selected from monohydroxyalkyl ( i.e., substituted with one hydroxyl group), dihydroxyalkyl ( i.e., substituted with two hydroxyl groups), and _C1-4 hydroxyalkyl groups. Non-limiting illustrative hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxypropyl-2-yl.

For the purposes of this disclosure, the term "alkoxy" or "substituted alkoxy" as used alone or as part of another group refers to a substituted alkyl, substituted cycloalkyl, substituted alkenyl, or substituted alkynyl group attached to a terminal oxygen atom. The alkoxy group may be selected from _C1-6 alkoxy groups and _C1-6 alkyl groups attached to a terminal oxygen atom, such as methoxy, ethoxy, and terbutoxy groups.

For the purposes of this disclosure, the term "alkoxyalkyl" as used alone or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting illustrative alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, third butoxymethyl, isobutoxymethyl, second butoxymethyl, and pentoxymethyl.

For the purposes of this disclosure, the term "haloalkoxy" as used alone or as part of another group refers to a halogenated group attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

For the purposes of this disclosure, the terms "alkylthio" or "as appropriate substituted alkylthio" as used alone or as part of another group refer to a sulfur atom substituted by an alkyl group as appropriate. The alkylthio group may be selected from _C1-4 alkylthio groups. Non-limiting illustrative alkylthio groups include _-SCH3 ( i.e., methylthio) _{and -SCH2CH3} .

For the purposes of this disclosure, the term "cycloalkyl" as used alone or as part of another group refers to a saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbon containing one to three rings having three to twelve carbon atoms ( i.e., _C3-12 cycloalkyl) or a specified number of carbon atoms. A cycloalkyl group may have two rings or one ring. The cycloalkyl group may be selected from _C3-8 cycloalkyl and _C3-6 cycloalkyl groups. The cycloalkyl group may contain one or more carbon-carbon double bonds or one carbon-carbon double bond. Non-limiting illustrative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norcamphenyl, decahydronaphthalene, adamantyl, cyclohexenyl, spiro[2.3]hexane, spiro[2.4]heptane, spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[3.5]nonane, spiro[4.5]decane, and spiro[5.5]undecane.

For the purposes of this disclosure, the term "substituted cycloalkyl group, as it may be" when used alone or as part of another group means a cycloalkyl group as defined above that is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, halogenalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxyamino, sulfonamide, ... Alkyl carbonyl, aryl carbonyl, alkyl sulfonyl, aryl sulfonyl, carboxyl, carboxylalkyl, alkyl, cyclic alkyl (substituent), alkenyl, alkynyl (substituent), heteroaryl (substituent), heterocyclic (substituent), alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxylamino)alkyl, pilylalkyl, (heterocyclic)alkyl, or (heteroaryl)alkyl. Cycloalkyl (substituent) may be substituted with two or one substituent.

For the purposes of this disclosure, the terms "cycloalkyloxy" or "as appropriate substituted cycloalkyloxy," used alone or as part of another group, refer to a cycloalkyl group that is, as appropriate, substituted to a terminal oxygen atom. Exemplary cycloalkyloxy groups include cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

For the purposes of this disclosure, the terms "cycloalkyl thio" or "as appropriate substituted cycloalkyl thio" used alone or as part of another group refer to a cyclic group that is, as appropriate, substituted to a terminal sulfur atom. Exemplary cycloalkyl thio groups include cyclobutyl thio, cyclopentyl thio, and cyclohexyl thio.

For the purposes of this disclosure, the term "heterocyclic" or "heterocyclic group," used alone or as part of another group, refers to a saturated and partially unsaturated ( e.g., containing one or two double bonds) cyclic group containing one, two, or three rings having three to fourteen ring members ( i.e. , 3- to 14-membered heterocyclic groups) and at least one heteroatom. The heterocyclic group may be selected from _C3-14 heterocyclic groups and _C3-8 heterocyclic groups. Each heteroatom is independently selected from a group consisting of oxygen, sulfur (including sulfene and sulfone), and/or nitrogen atoms, and may be quaternarily ammonium-treated. The term "heterocyclic group" is intended to include cyclic urea groups, such as imidazodinyl-2-one; cyclic amide groups, such as β-lactam, γ-lactam, δ-lactam and ε-lactam; and cyclic aminocarbamate groups, such as oxazolidinyl-2-one. The term "heterocyclic" is also intended to include groups having fused, where applicable, substituted aryl groups, such as indololinyl, indololinyl-2-one, and benzo[d]oxazolidinyl-2(3H)-one. The heterocyclic group may be selected from 4-, 5-, 6-, 7-, or 8-membered cyclic groups containing one ring and one or two oxygen and/or nitrogen atoms; 5- or 6-membered cyclic groups containing one ring and one or two nitrogen atoms; or 8-, 9-, 10-, 11-, or 12-membered cyclic groups containing two rings and one or two nitrogen atoms. The heterocyclic group may, as appropriate, be linked to the rest of the molecule via carbon or nitrogen atoms. Non-limiting illustrative heterocyclic groups include 2-oxypyrrolidin-3-yl, 2-imidazolidineone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, azirrocyclobutyl, 8-azirrobis[3.2.1]octane (norhysterosine), 6-azirrospiro[2.5]octane, 6-azirrospiro[3.4]octane, 1,6-diazaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, indololinyl, indololinyl-2-one, and 1,3-dihydro-2H-benzo[d]imidazol-2-one.

For the purposes of this disclosure, the term "substituted heterocyclic group" as used herein, either alone or as part of another group, means a heterocyclic group as defined above that is unsubstituted or substituted with one to four independent substituents selected from the following: halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, halogenalkoxy, aryloxy, arylalkyl. Arylalkyloxy, alkylthio, carboxyamino, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonamide, arylsulfonamide, carboxyl, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxyamino)alkyl, pilylalkyl, (heterocyclic)alkyl, and (heteroaryl)alkyl. Substitution can occur on any available carbon or nitrogen atom and can form a spirocycle.

For the purposes of this disclosure, the term "aryl" as used herein, whether alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring system having six to fourteen carbon atoms ( i.e., _C6-14 aryl). The aryl group may be selected from _C6-14 aryl and _C6-10 aryl. Non-limiting illustrative aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthraceneyl, indyl, azulel, biphenyl, pentophenyl, and fusyl. The aryl group may be selected from phenyl or naphthyl. The aryl group may be phenyl.

For the purposes of this disclosure, the term "substituted aryl group, as used alone or as part of another group herein" means an aryl group as defined above that is unsubstituted or substituted with one to five substituents independently selected from the group consisting of: halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, halogenalkoxy, aryloxy, heteroaryloxy, aralkylaralkyloxy, alkylthio, carboxyamino, sulfonamide Alkyl carbonyl, aryl carbonyl, alkyl sulfonyl, aryl sulfonyl, carboxyl, carboxylalkyl, alkyl, cyclic alkyl (subjective substitution), alkenyl, alkynyl (subjective substitution), heteroaryl (subjective substitution), heterocyclic (subjective substitution), alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxylamino)alkyl, phenylalkyl, (heterocyclic)alkyl, (cycloalkylamino)alkyl, ( _C14 halogenoxy)alkyl, (heteroaryl)alkyl. The alkyl group (subjective substitution) may be a phenyl group (subjective substitution). Depending on the specific case, the substituted phenyl group may have four, three, two, or one substituents. The term "depending on the specific case aryl" is intended to include groups having fused dependently substituted cycloalkyl groups and fused dependently substituted heterocyclic rings. Examples include... .

For the purposes of this disclosure, the term "heteroaryl" or "heteroary" refers to a monocyclic or bicyclic aromatic ring system having 5 to 14 ring atoms ( i.e., _C5-14 heteroaryl) and 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, or sulfur. The heteroaryl group may be selected from _C5-14 heteroaryl and _C3-6 heteroaryl. The heteroaryl group may have three, two, or one heteroatom. The heteroaryl group may be _C5- heteroaryl or C6 _- heteroaryl. Non-limiting illustrative heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianyl, furanyl, benzofuranyl, piperanyl, isobenzofuranyl, benzooxanone, chromenyl, xanthenyl, 2H -pyrroleyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, darazinyl, isoindolyl, 3H -indolyl, indolyl, inzolyl, purinel, isoquinolinyl, quinolinyl, tarazinyl, naphridinyl, alkolinyl, quinazolinyl, pteridinyl, 4aH -Carbazolyl, carbazolyl, β-carbaolinyl, phenazinyl, acridineyl, pyrimidinyl, phenazinyl, thiazolyl, isothiazinyl, phenazinyl, isoxazinyl, furazinyl, triazolyl, tetrazolyl, and phenoxazinyl. The heteroaryl group may be selected from thienyl (e.g., thien-2-yl and thien-3-yl), furanyl ( e.g., 2-furanyl and 3-furanyl), pyrroleyl (e.g., 1H-pyrrole-2-yl and 1H-pyrrole-3-yl), imidazoleyl ( e.g. , 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl ( e.g. , 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridinyl ( e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl ( e.g. , pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl ( e.g. , thiazolyl-2-yl, thiazolyl-4-yl, and thiazolyl-5-yl), isothiazolyl ( e.g. , isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl ( e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl ( e.g. , isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), triazolyl ( e.g., 1,2,4-triazolyl and 1,2,3-triazolyl). The term "hybrid aryl" is also intended to include possible N-oxides. Exemplary N-oxides include pyridinyl N-oxides.

For the purposes of this disclosure, the term "substituted heteroaryl" as used alone or as part of another group means a heteroaryl group as defined above that is unsubstituted or substituted with one to four substituents, such as one or two independently selected from the following substituents: halogen, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, halogenalkoxy, aralkylaryloxy, aralkyloxy, alkylthio, carboxyamino, sulfonamide Alkyl carbonyl, aryl carbonyl, alkyl sulfonyl, aryl sulfonyl, carboxyl, carboxylalkyl, alkyl, cyclic alkyl (substituted as needed), alkenyl, alkynyl (substituted as needed), heteroaryl (substituted as needed), heterocyclic (substituted as needed), alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxylamino)alkyl, pyroalkyl, (heterocyclic)alkyl, (heteroaryl)alkyl, -N(R) ^R16a )( ^R16b ) or -N(H)C(=O) ^-R17 , wherein ^R16a is hydrogen or a _C1-6 alkyl; ^R16b is an alkoxyalkyl, (heterocyclic)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and ^R17 is an alkyl, optionally substituted aryl, or optionally substituted heteroaryl. The optionally substituted heteroaryl may have one substituent. The substituent may be amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclic)alkyl, -N( ^R16a )( ^R16b ) or -N(H)C(=O) ^-R17 . The heteroaryl group may be a pyridyl group, i.e., 2-, 3-, or 4-pyridyl, depending on the situation. Any carbon or nitrogen atom may be substituted.

For the purposes of this disclosure, the term "aryloxy group," used alone or as part of another group, refers to an aryl group that is, where applicable, substituted and attached to a terminal oxygen atom. A non-limiting illustrative aryloxy group is PhO-.

For the purposes of this disclosure, the term "heteroaryloxy" as used alone or as part of another group refers to a heteroaryl group that is, where applicable, substituted and attached to a terminal oxygen atom.

For the purposes of this disclosure, the term "arylalkyloxy" or "arylalkyloxy" as used alone or as part of another group refers to an aryl group attached to a terminal oxygen atom. A non-limiting illustrative arylalkyloxy is _PhCH₂O- .

For the purposes of this disclosure, the term "aralkyl" or "arylalkyl," used alone or as part of another group, refers to an alkyl group substituted with one, two, or three aryl groups, as appropriate. An aralkyl group may be a _C1-4 alkyl group substituted with one aryl group, as appropriate. An aralkyl group may be a ( _C6 - _C14 )aryl-( _C1 - _C6 )alkyl group, as appropriate. Non-limiting illustrative aralkyl groups include benzyl, phenethyl, _-CHPh2 , _-CH2 (4-OH-Ph), and -CH(4-F-Ph) ₂ .

For the purposes of this disclosure, the term "amino group" as used alone or as part of another group refers to _NH2 .

For the purposes of this disclosure, the term "alkylamine" as used alone or as part of another group refers to -NHR ^16c , where R ^16c is a _C1-6 alkyl group. ^{R 16c} may be a _C1-4 alkyl group. Non-limiting illustrative alkylamine groups include -N(H)CH ₃ and N(H)CH _{2CH 3} .

For the purposes of this disclosure, the term "dialkylamino" as used alone or as part of another group refers to -NR ^18a R ¹⁹ , wherein R ¹⁸ and R ¹⁹ are each independently _C1-6 alkyl. R ¹⁸ and R ¹⁹ may each be independently _C1-4 alkyl. Non-limiting illustrative dialkylamino groups include -N(CH ₃ ) ₂ and -N(CH ₃ )CH ₂ CH(CH ₃ ) ₂ .

For the purposes of this disclosure, the term "hydroxyalkylamino" as used alone or as part of another group refers to –NHR ²⁰ , where R ²⁰ is hydroxyalkyl.

For the purposes of this disclosure, the term "cycloalkylamino" as used alone or as part of another group refers to -NR ²¹ R ²² , wherein R ²¹ is a substituted cycloalkyl group as appropriate and R ²² is hydrogen or C ₁₄ alkyl.

For the purposes of this disclosure, the term "aralkylamine" as used alone or as part of another group refers to –NR ²³ R ²⁴ , where R ²³ is an aralkyl group and R ²⁴ is hydrogen or a _C14 alkyl group. Non-limiting illustrative aralkylamine groups include N(H)CH ₂ Ph and N(CH ₃ )CH ₂ Ph.

For the purposes of this disclosure, the term "(amino)alkyl" as used alone or as part of another group refers to an amino group attached to a terminal alkyl group, such as ^{R25 R26} N-, i.e., ^{R25 R26} N-alkyl, wherein ^R25 and ^R26 are each independently selected from hydrogen, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C6 )cycloalkyl, optionally substituted heterocyclic, optionally substituted ( _C6 - _C14 )aryl-( _C1 - _C6 )alkyl, ( _C1 - _C6 )halogenated alkyl, optionally substituted ( _C1 - _C6 )alkyl-O-( _C1 - _C6 )alkyl, and ( _C3 - _C6) alkyl. Cycloalkyl-( _C1 - _C6 )alkyl, or ^R25 and ^R26 together with the atoms to which they are attached to form, as appropriate, heterocyclic groups. Non-limiting examples of (amino)alkyl include: , , , , , , , , , , , , , and .

For the purposes of this disclosure, the term "(amino)cycloalkyl" as used alone or as part of another group refers to an amino group attached to a terminal cycloalkyl group, such ^{as R27R28N-} , i.e., ^R27R28N -cycloalkyl, wherein ^{R27 and R28} are each independently selected from hydrogen, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C6 )cycloalkyl, optionally substituted heterocyclic, optionally substituted (C6- _C14 )aryl-( _C1 -C6)alkyl, ( _C1 - _C6 )halogen, optionally substituted ( _C1 - _C6 )alkyl-O-( _C1 - _C6 )alkyl, and ( _C3 - _C6 )alkyl-O-( _C1 - _C6) alkyl. Cycloalkyl-( _C1 - _C6 )alkyl, or ^R27 and ^R28 together with the atoms to which they are attached to form, as appropriate, heterocyclic groups. Non-limiting examples of (amino)cycloalkyl groups include: , and .

For the purposes of this disclosure, the term "carboxyamino" as used alone or as part of another group refers to the group of the formula C(=O)NR ²⁹ R ³⁰ , wherein R ²⁹ and R ³⁰ are each independently hydrogen, a substituted alkyl group as appropriate, a substituted aryl group as appropriate, or a substituted heteroaryl group as appropriate, or R ²⁹ and R ³⁰ together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic group. R ²⁹ and R ³⁰ may each be independently hydrogen or a substituted alkyl group as appropriate. Non-limiting illustrative carboxyamino groups include -CONH ₂ , -CON(H)CH ₃ , -CON(CH ₃ ) ₂ , and -CON(H)Ph.

For the purposes of this disclosure, the term "sulfonamide" as used alone or as part of ^another group refers to a group of the formula _{SO₂NR₃1R₃2} , wherein ^R₃1 and ^R₃2 are each independently hydrogen, ^a substituted alkyl group as appropriate, or a substituted aryl group as appropriate, or ^R₃1 and ^R₃2 together with the nitrogen to which they are attached form _a 3- to 8-membered heterocyclic group. Non-limiting illustrative sulfonamide groups include _-SO₂NH₂ , _-SO₂N (H) _CH₃ , and _-SO₂N (H)Ph.

For the purposes of this disclosure, the term "alkyl carbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an alkyl group, i.e., -C(=O)-. A non-limiting illustrative alkyl carbonyl group is -COCH ₃ .

For the purposes of this disclosure, the term "aryl carbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an aryl group, i.e., -C(=O)-, where applicable. A non-limiting illustrative aryl carbonyl group is COPh.

For the purposes of this disclosure, the term "alkylsulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with any of the aforementioned alkyl groups, i.e., _-SO₂- . Non-limiting illustrative alkylsulfonyl groups are _{-SO₂CH₃ (} i.e., methylsulfonyl) and _{-SO₂CH₂CH₃} (i.e., _{ethylsulfonyl )} .

For the purposes of this disclosure, the term "arylsulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with any of the aforementioned aryl groups, i.e., _-SO₂- . A non-limiting illustrative arylsulfonyl group is _-SO₂Ph .

For the purposes of this disclosure, the term "carboxyl" as used alone or as part of another group refers to the group of the formula -COOH.

For the purposes of this disclosure, the term "carboxyalkyl" as used alone or as part of another group refers to any of the above-mentioned alkyl groups substituted with -COOH. A non-limiting illustrative carboxyalkyl group is _{-CH₂CO₂H .}

For the purposes of this disclosure, the term "alkyl alkyl" as used alone or as part of another group refers to any of the aforementioned alkyl groups substituted with -SH.

For the purposes of this disclosure, the term "(heterocyclic)(alkyl)" means a heterocyclic group attached to a terminal alkyl group or, where applicable, a substituted heterocyclic group. (Heterocyclic)(alkyl) may be, where applicable, a substituted heterocyclic-( _C1 - _C6 )alkyl. The heterocyclic group may be, for example, aziridine, pyrrolidinyl, or piperidinyl, or an N-methylated derivative thereof. The alkyl group may be _C1-6 alkyl, such as methyl. Non-limiting examples of (heterocyclic)(alkyl) include: .

For the purposes of this disclosure, the term "(alkyl)-O-(alkyl)" refers to an alkoxy group, where applicable, attached to a terminal alkyl group and substituted. (alkyl)-O-(alkyl) can be a ( _C1 - _C6 )alkyl-O-( _C1 - _C6 )alkyl _, where applicable. Non-limiting examples of (alkyl)-O-(alkyl) include _CH3 -O- _CH2CH2- .

For the purposes of this disclosure, the term "(cycloalkyl)(alkyl)" means a cycloalkyl group connected to a terminal alkyl group or, where applicable, a substituted cycloalkyl group. (cycloalkyl)(alkyl) can be ( _C3 - _C6 )cycloalkyl-( _C1 - _C6 )alkyl. A cycloalkyl group can be, for example, cyclopropyl. An alkyl group can be _C1-6 alkyl. Non-limiting examples of (cycloalkyl)(alkyl) include: .

As used in this article, the term "twin" refers to two atoms or groups attached to the same atom. For example, a cyclopropyl group substituted with two twin methyl groups can have the following structure: .

This disclosure covers any of the compounds of this disclosure that are isotopically labeled ( i.e. , radioactively labeled) by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ^2H (or deuterium (D)), ^3H , ^11C , ^13C , ^14C , ^15N , 18O, ^17O , ^31P , ^32P , ^35S , ^18F , and ^36Cl , which are, for example, ^3H , ^11C , and ^14C . This disclosure also provides compositions in which substantially all atoms at one position within the compound of this disclosure are replaced ^by atoms having different atomic masses or mass numbers. This disclosure also provides a composition in which a portion of atoms at one position within the compound of this disclosure are substituted, i.e. , the compound of this disclosure is enriched at positions of atoms with different atomic masses or mass numbers. In one embodiment, this disclosure provides a composition in which the compound of this disclosure has 1 to 8 deuterated hydrogen atoms. In another embodiment, the hydrogen atom of the methyl group is substituted with a deuterium atom. In another embodiment, the hydrogen atom of the ethyl group is substituted with a deuterium atom. The isotopically labeled compound of this disclosure can be prepared by methods known in the art.

The compounds disclosed herein may contain one or more asymmetric centers, and thus may produce mirror isomers, non-mirror isomers, and other stereoisomers. This disclosure is intended to cover all such possible forms, as well as their racemic and resolved forms and mixtures thereof. It should be understood that when the disclosed chemical entity or compound (i.e., the "compound") has at least one symmetric center, this disclosure covers a mirror isomer of a compound that does not contain the corresponding optical isomer, a racemic mixture of the compound, and a mixture rich in a mirror isomer relative to its corresponding optical isomer. When a mixture is rich in a mirror isomer relative to its optical isomer, the mixture contains, for example, at least 50%, 75%, 90%, 95%, 99%, or 99.5% in excess of the mirror isomer. In view of this disclosure, individual mirror isomers can be separated according to methods known in the art. When the compounds described herein contain alkene double bonds or other geometrically asymmetrical centers, they are intended to include both E and Z geometric isomers unless otherwise stated. This disclosure is also intended to cover all tautomers.

As used herein, the term "stereoisomer" is a general term for all isomers of an individual molecule that differ only in the spatial orientation of their atoms. It includes mirror isomers and isomers of compounds that are not mirror images of each other and have more than one palmar center (non-mirror isomers).

The term "palm-shaped center" or "asymmetric carbon atom" refers to a carbon atom connected by four different groups.

The terms "mirror image isomer" and "mirror image isomer" refer to molecules that cannot be superimposed on their mirror image and are therefore optically active. Among them, the mirror image isomer causes the polarization plane to rotate in one direction and its mirror image compound causes the polarization plane to rotate in the opposite direction.

The term "racemic" refers to a mixture of equal fractions of mirror isomers that is optically inactive.

The term "absolute configuration" refers to the spatial arrangement of atoms in a molecular entity (or group) and its stereochemical description, such as R or S.

Unless otherwise instructed, the stereochemical terms and conventions used in this manual are intended to be consistent with those described in Pure & Appl. Chem 68 :2193 (1996).

The term "excess of image isomer" or "ee" refers to a measure of how much one image isomer is present compared to another. For a mixture of R and S image isomers, the excess percentage of image isomer is defined as | R - S |*100, where R and S are the individual moles or weight fractions of the image isomers in the mixture such that R + S = 1. Given the optical rotation of a volatile substance, the excess percentage of image isomer is defined as ([α] _obs / [α] _max )*100, where [α] _obs is the optical rotation of the mixture of image isomers and [α] _max is the optical rotation of the pure image isomer. Excess mirror isomers can be determined using a variety of analytical techniques, including NMR spectroscopy, palmar column chromatography, or optical polarization measurement.

The term "mirror image isomerism" or "mirror image purity" refers to a sample of a palmitic substance in which all molecules (within the detection limit) have the same palmitic meaning.

The term "mirror image isomer enrichment" or "mirror image enrichment" refers to a palm-shaped substance sample with a mirror image isomer ratio greater than 50:50. Compounds that are mirror image isomer enriched can be mirror image isomerically pure.

It should be understood that embodiments of the invention described herein include "consisting of embodiments" and/or "substantially consisting of embodiments". As used herein, unless otherwise indicated, the forms "a", "an" and "the" include a plurality of indicators. The use of the term "or" herein does not imply that alternatives are mutually exclusive.

In this application, unless clearly stated or understood by one skilled in the art, the use of "or" means "and/or". In the context of multiple dependent claims, the use of "or" refers to more than one of the aforementioned independent or dependent claims.

As used herein, the term "about" includes ±10% of the listed values. Therefore, "about 10" means 9 to 11. As will be understood by those skilled in the art, references to "about" values or parameters herein include (and describe) the case referring to the value or parameter itself. For example, a description of "about X" includes a description of "X".

This disclosure covers the preparation and use of salts of the compounds disclosed herein (including non-toxic, pharmaceutically acceptable salts). Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridinium salts, methylpyridinium salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like; and inorganic acid salts, such as hydrochlorides, hydrobromide salts, phosphates, and sulfates. And analogues; organic acids, such as citrates, lactates, tartrates, maleic anhydride, fumarate, amygdalinate, acetates, dichloroacetate, trifluoroacetate, oxalate, formates and analogues; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates and analogues; and amino acids, such as arginine, aspartate, glutamic acid and analogues. As used herein, "medically acceptable salt" means, for example, any salt of the compounds disclosed herein obtained by reaction with an acid or base, which is physiologically tolerable in the target patient ( e.g. , a mammal, such as a human).

Acid addition salts can be formed by mixing a solution of a specific compound of this disclosure with a solution of a pharmaceutically acceptable, non-toxic acid (such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or similar substances). Alkaline salts can be formed by mixing a solution of a compound of this disclosure with a solution of a pharmaceutically acceptable, non-toxic alkali (such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, or similar substances).

This disclosure covers the preparation and use of solvent compounds of the disclosed compounds. Solvent compounds generally do not significantly alter the physiological activity or toxicity of the compounds and are therefore considered pharmacologically equivalents. As used herein, "solvent compound" refers to the combination, physical bonding, and/or solubilization of the disclosed compounds with solvent molecules, such as disolvents, monosolvents, or hemisolvents, wherein the ratio of solvent molecules to the disclosed compounds is approximately 2:1, approximately 1:1, or approximately 1:2. This physical bonding involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvent compounds can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Soluble compounds" encompass both solution phases and separable solvent compounds. The compounds of this disclosure may exist in a solventized form with pharmaceutically acceptable solvents (such as water, methanol, ethanol, and similar substances), and this disclosure is intended to include both solventized and non-solvable forms of the compounds of this disclosure. One type of solvent compound is a hydrate. "Hydrate" refers to a specific subgroup of solvent compounds in which the solvent molecule is water. Solvent compounds are generally used as pharmacological equivalents. The preparation of solvent compounds is known in this art. See, for example, M. Caira et al ., J. Pharmaceut. Sci., 93(3) :601-611 (2004), which describes the preparation of solvent compounds of fluconazole with ethyl acetate and with water. Similar preparations of solvent compounds, semi-solvent compounds, hydrates, and analogues are described by EC van Tonder et al ., AAPS Pharm. Sci. Tech., 5(1) : Article 12 (2004) and AL Bingham et al ., Chem. Commun. 603-604 (2001). A typical non-limiting process for preparing a solvent compound involves dissolving the compound of this disclosure in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and separating the crystals by known methods ( e.g. , filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in the solvent compound crystals.

In some embodiments, the compounds disclosed herein are inhibitors of _NaV 1.7, and the present disclosure provides a method for inhibiting _NaV 1.7 in an individual in need, comprising administering to the individual a therapeutically effective amount of one or more of the compounds disclosed herein.

In embodiments of this disclosure where the compounds are _NaV 1.7 inhibitors, various diseases, disorders, or conditions mediated by _NaV 1.7 can be treated using these compounds. Therefore, this disclosure generally relates to a method for treating diseases, disorders, or conditions in animals suffering from or at risk of suffering from the disease that respond to _NaV 1.7 inhibition, the method comprising administering to the animal an effective amount of one or more of the compounds of this disclosure.

This disclosure further relates to a method for inhibiting _NaV 1.7 in a desired animal, the method comprising administering to the animal a therapeutically effective amount of at least one of the compounds of this disclosure.

As used herein, “treatment” is a method for obtaining a beneficial or desired clinical outcome. As used herein, “treatment” encompasses any administration or application of a therapeutic agent for diseases in mammals (including humans). For the purposes of this disclosure, a beneficial or desired clinical outcome includes, but is not limited to, one or more of the following: relief of one or more symptoms, reduction of the severity of the disease, prevention or delay of the spread of the disease (e.g., metastasis), prevention or delay of disease recurrence, delay or slowing of disease progression, improvement of the disease state, inhibition of the disease or disease progression, inhibition or slowing of the disease or its progression, prevention of its development, and relief (partial or complete). “Treatment” also encompasses the reduction of the pathological consequences of proliferative diseases. The methods presented in this article cover one or more of these treatment approaches. Consistent with the above, terminological treatment does not require the complete removal of all aspects of the condition.

The "therapeutic effective dose" of a substance can vary depending on factors such as an individual's disease state, age, sex, weight, and the substance's ability to elicit the desired response in the individual. Therapeutic effective dose is also the amount at which the beneficial therapeutic effect outweighs any toxic or harmful effects of the substance. Therapeutic effective doses can be administered in one or more doses. Therapeutic effective dose refers to the amount at which the desired therapeutic effect is effectively achieved within the necessary dosage and time frame.

The terms “administer,” “administering,” “administration,” and similar terms refer to methods used to deliver therapeutic agents to the desired biological site of action. Administration techniques that can be used with the agents and methods described herein can be found, for example , in Goodman and Gilman, * The Pharmacological Basis of Therapeutics *, current edition; Pergamon; and Remington's, *Pharmaceutical Sciences *, Mack Publishing Co., Easton, Pa.

The terms "medical formulation" and "medical composition" refer to a formulation which is in a form in which the biological activity of the active ingredient is permitted and which does not contain other components that would be unacceptably toxic to an individual, and which is to be administered to that individual. Such formulations may be sterile.

"Pharmaceutical-acceptable excipients" refer to non-toxic solid, semi-solid, or liquid fillers, thinners, encapsulating materials, formulation aids, or excipients that are routinely used with therapeutic agents in this technology, together constituting a "medical composition" for administration to an individual. Pharmaceutically acceptable excipients are non-toxic to the recipient at the dosage and concentration used and are compatible with other components of the formulation. Pharmaceutically acceptable excipients are suitable for use in the formulation.

"Sterile" preparations are sterile or substantially free of live microorganisms and their spores.

The term "container" means any container and cap suitable for storing, transporting, distributing and/or disposing of pharmaceutical products.

The term "insert" or "package insert" refers to information accompanying a pharmaceutical product that provides a description of how to administer the product, as well as safety and efficacy data necessary for physicians, pharmacists, and patients to make informed decisions about its use. Package inserts are often considered the "label" of a pharmaceutical product.

As used herein, the terms “disease” or “disorder” or “symptom” refer to an ailment requiring and/or desired treatment, and indicate a disorder or dysfunction generally considered to be pathological or functional, and which may manifest itself as a specific sign, symptom, and/or malfunction. As shown below, in some embodiments, the compounds of this disclosure inhibit sodium channels (e.g., _NaV 1.7) and can be used to treat diseases and disorders such as pain, depression, cardiovascular disease, respiratory disease, mental illness, and combinations thereof, wherein inhibition of sodium channels (e.g., _NaV 1.7) provides benefits.

The terms "peptide" and "protein" are used interchangeably and refer to polymers of amino acid residues, not limited to a minimum length. Such polymers of amino acid residues may contain native or non-native amino acid residues and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and polymers containing amino acid residues. This definition covers both full-length proteins and their fragments. These terms also include post-expression modifications of peptides, such as glycosylation, sialylation, acetylation, phosphorylation, and similar modifications. Furthermore, for the purposes of this disclosure, "peptide" refers to a protein that includes modifications to its native sequence, such as deletions, additions, and substitutions (generally conserved in nature), provided that the protein retains the desired activity. Such modifications can be intentional, such as through site-directed mutagenesis, or accidental, such as through mutations in the host that produces the protein or due to errors caused by PCR amplification.

The term "specific binding" to a protein or protein domain is well-known in this art, as are the methods for determining such specific binding. A molecule is said to exhibit "specific binding" or "preferred binding" if it reacts or binds more frequently, rapidly, for a longer duration, and/or with a greater affinity than it does with alternative proteins or domains. It should be understood that a molecule that specifically or preferentially binds to a first protein or domain may or may not specifically or preferentially bind to a second protein or domain. Therefore, "specific binding" or "preferred binding" does not necessarily require (although it may include) exclusive binding. Usually, but not always, the term "binding" refers to preferred binding.

The terms “reduction,” “reduce,” “inhibition,” or “inhibit” refer to the reduction or cessation of any phenotypic characteristic, or the reduction or cessation of the occurrence, extent, or likelihood of that characteristic. “Reduction” or “inhibition” means a decrease, reduction, or cessation of activity, function, and/or quantity compared to a reference. In some embodiments, “reduction” or “inhibition” means the ability to cause a total reduction of 20% or greater. In some embodiments, “reduction” or “inhibition” means the ability to cause a total reduction of 50% or greater. In some embodiments, “reduction” or “inhibition” means the ability to cause a total reduction of 75%, 85%, 90%, 95%, or greater. In some embodiments, the above quantities are inhibited or reduced over a period of time relative to a control.

The terms "individual" or "subject" are used interchangeably in this document to refer to an animal; for example, a mammal, such as a human. In some cases, methods of treatment are provided for mammals, including but not limited to humans, rodents, apes, cats, dogs, horses, cattle, pigs, sheep, goats, laboratory mammals, farm mammals, sporting mammals, and pet mammals. In some instances, "individual" or "subject" refers to an individual or individual who requires treatment for a disease or condition. In some cases, an individual receiving treatment may be a patient, indicating that the individual has been identified as having a condition related to the treatment or is at specific risk of developing that condition.

Method of Use: The compounds of this disclosure can be used to inhibit the activity of sodium channels. In some embodiments, the compounds of this disclosure can be used to inhibit the activity of _NaV 1.7. This disclosure provides a method for inhibiting sodium channels (e.g., _NaV 1.7) in an individual of need, comprising administering to the individual a therapeutically effective amount of the compounds of this disclosure.

This disclosure also provides a method for inhibiting one or more sodium channels, which includes contacting one or more sodium channels with the compound of this disclosure.

In some embodiments, this disclosure provides a method for inhibiting _NaV 1.7, comprising contacting _NaV 1.7 with the compound of this disclosure. In some embodiments, this disclosure provides a method for selectively inhibiting _NaV 1.7, comprising contacting _NaV 1.7 with the compound of this disclosure.

This disclosure also provides a method for treating a disease or condition in an individual of need related to the inhibition of one or more sodium channels (e.g., _NaV 1.7), comprising administering to the individual a therapeutically effective amount of the compound of this disclosure. In some embodiments, this disclosure provides a method for treating a disease or condition in an individual of need related to the selective inhibition of _NaV 1.7, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure.

This disclosure also provides a method for treating diseases or conditions in individuals in need that are associated with the inhibition of one or more sodium channels (e.g., _NaV 1.7), comprising contacting one or more sodium channels with the compound of this disclosure.

This disclosure also provides a method for treating diseases or conditions associated with selective inhibition of _NaV 1.7 in individuals in need, comprising contacting _NaV 1.7 with the compound of this disclosure.

In some embodiments, pain is selected from the following groups: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, childbirth pain, nausea and vomiting, neurocystic pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof. In some embodiments, pain is nociceptive pain. In some embodiments, pain is neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is chronic pain. In some embodiments, the pain is acute pain.

The term "pain" refers to all categories of pain, including but not limited to neuropathic pain, inflammatory pain, nociceptive pain, essential pain, neuropathic pain, orofacial pain, burn pain, burning mouth syndrome, somatic pain, visceral pain, myofibril pain, toothache, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, childbirth pain, contractions, chronic regional pain syndrome (CRPS), reflex sympathetic dystrophy, brachial plexus nerve avulsion, and nerve pain. Bladder disorders, acute pain (e.g., musculoskeletal and postoperative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, familial hemiplegic migraine, headache-related disorders, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, thalamic lesions, nerve root lesions, HIV pain, postherpetic neuralgia, noncardiac chest pain, irritable bowel syndrome, and pain associated with intestinal disorders and indigestion, and combinations thereof.

In some embodiments, the pain is pain associated with a disease or condition, such as with HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, thermal sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease Pain associated with disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal hypotonia, myasthenic syndrome, myotonia, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, thyroid dysfunction It can be used to treat conditions such as hypofunction, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial acropalatine syndrome, primary acropalatine syndrome, familial rectal pain, cancer, epilepsy, partial and generalized tonic-clonic seizures, restless legs syndrome, arrhythmia, fibromyalgia, neuroprotective measures under ischemic conditions caused by stroke or nerve trauma, tachyarrhythmia, and pain related to atrial or ventricular flutter.

In some embodiments, the disease or symptom is selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itching, and combinations thereof. In some embodiments, the disease or symptom is pain.

In some embodiments, the disease or condition is a central nervous system disorder, such as epilepsy, anxiety, depression, and bipolar disorder; a cardiovascular disorder, such as arrhythmia, atrial fibrillation, and ventricular fibrillation; a neuromuscular disorder, such as restless legs syndrome, muscle paralysis, or tetanus; neuroprotective measures for stroke, neurotrauma, and multiple sclerosis; or a pathway disorder, such as erythromycinia and familial rectal pain syndrome. In some implementations, the disease or condition is neuropathy induced by HTV or HIV treatment, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathy secondary to metastatic infiltration, painful obesity, thalamic lesions, hypertension, autoimmune diseases, asthma, drug addiction (e.g., opioids, benzodiazepines, amphetamines, cocaine, alcohol, butane inhalation), Alzheimer's disease, dementia, age-related memory impairment, or Korsakoff syndrome. Syndrome, restenosis, urinary dysfunction, incontinence, Parkinson's disease, cerebral ischemia, neurosis, gastrointestinal diseases, sickle cell anemia, transplant rejection, heart failure, myocardial infarction, reperfusion injury, intermittent claudication, angina, convulsions, respiratory disorders, cerebral or myocardial ischemia, long QT syndrome, catecholamine polymorphic ventricular tachycardia, ophthalmic diseases, spasms, spastic paraplegia, myopathy, myasthenia gravis, paramyotonia Congentia, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, hair loss, anxiety disorder, mental illness, mania, paranoia, seasonal affective disorder, panic disorder, obsessive-compulsive disorder (OCD), phobias, autism, Asperger's syndrome, Retts syndrome, disintegrative disorders, attention deficit disorder, aggression, impulse control disorders, thrombosis, pre-clampsia, congestive heart failure, cardiac arrest, Freidrich's ataxia, spinocerebellar ataxia, myelopathy, radiculopathy, systemic lupus erythematosus Erythematosis, granulomatous disease, oligopontine-cerebellar atrophy, spinocerebellar ataxia, paroxysmal ataxia, muscle fibrosis, progressive globus pallidus, progressive supranuclear nerve palsy and spasm, traumatic brain injury, cerebral edema, hydrocephalus injury, spinal cord injury, neurogenic anorexia, bulimia, Prader-Willi syndrome, obesity, optic neuritis, cataract, retinal hemorrhage, ischemic retinopathy, retinitis pigmentosa, acute and chronic glaucoma, macular degeneration, retinal artery occlusion, chorea, Huntington's disease Chorea, cerebral edema, proctitis, postherpetic neuralgia, analgesia, heat sensitivity, sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-Nyhan syndrome, Brugado syndrome, Liddle syndrome, Crohn's disease, multiple sclerosis and pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabetic neuropathy, peripheral neuropathy, Charcot marie syndrome, arthritis, rheumatoid arthritis, osteoarthritis, chondrocalcinosis, atherosclerosis, paroxysmal hypotonia, myasthenic syndrome, myotonia, myotonic dystrophy, muscular dystrophy, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, mental retardation, hypothyroidism, bipolar Sexual depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial acropalatine syndrome, primary acropalatine syndrome, rectal pain, cancer, epilepsy, partial and generalized tonic-clonic seizures, febrile seizures, absence seizures (petit mal seizures), myoclonic seizures, atonic seizures, paroxysmal seizures, Lennox Gastaut, West syndrome (infantile spasm), multidrug-resistant seizures, seizure prevention (anti-epileptic), familial Mediterranean fever syndrome, gout, restless legs syndrome, arrhythmia, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or nerve trauma, tachyarrhythmia, atrial and ventricular flutter and pain associated with general or local anesthetics.

This disclosure also provides a method for treating an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof, comprising administering to the individual a therapeutically effective amount of the compound of this disclosure.

This disclosure also provides compounds of this disclosure selected from diseases or conditions of pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itching, and combinations thereof for the treatment of individuals in need.

This disclosure also provides for the use of the compounds disclosed herein for the treatment of diseases or conditions selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itch, and combinations thereof in individuals in need.

This disclosure also provides the use of the compounds disclosed herein for the manufacture of a medicament for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itch, and combinations thereof.

Pharmaceutical Compositions The compounds of this disclosure may be administered to mammals as unprocessed chemicals in the absence of any other components, or the compounds of this disclosure may be administered to mammals as part of a pharmaceutical composition containing the compound in combination with a suitable pharmaceutically acceptable excipient or carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and comparisons: Drugfacts Plus, 20th edition (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition; Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd edition, Pharmaceutical Press (2000)). Such excipients may be selected from pharmaceutically acceptable excipients and adjuvants. The terms “pharmaceutical-acceptable carrier,” “pharmaceutical-acceptable excipient,” or “pharmaceutical-acceptable medium” encompass any of the standard pharmaceutical carriers, excipients, solvents, surfactants, or mediums. Standard pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th edition, 1995.

The pharmaceutical composition disclosed herein can be prepared into solid dosage forms, such as tablets, capsules, pills, powders, rhomboid tablets, or small capsules.

The pharmaceutical composition disclosed herein may be prepared as a liquid suspension or solution using liquids (such as oils, water, alcohols, and combinations thereof).

The pharmaceutical composition disclosed herein can be prepared as a sterile injectable preparation, which may be an aqueous or oil-based suspension. Such suspensions can be formulated according to techniques known in this art.

The pharmaceutical composition disclosed herein can be administered orally in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions, or solutions.

The pharmaceutical composition disclosed herein can be administered in the form of a suppository for rectal administration.

The pharmaceutical composition disclosed herein can also be administered topically, especially when the therapeutic target includes areas or organs easily accessible by topical application, including eye diseases, skin diseases, or lower bowel diseases. Topical application to the lower bowel can be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches can also be used. For topical application, the pharmaceutical composition can be formulated into suitable ointments, lotions, or creams containing active ingredients suspended or dissolved in one or more excipients.

The pharmaceutical composition disclosed herein can also be administered to the eye and formulated as a micronized suspension in isotonic, pH-adjusted sterile brine, with or without preservatives (such as benzylalkonium chloride), or preferably as a solution in isotonic, pH-adjusted sterile brine. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated in an ointment (such as petrolatum).

The pharmaceutical composition disclosed herein can also be administered via nasal spray or inhalation. Such compositions are prepared according to techniques well known in pharmaceutical formulation and can be prepared into a solution in brine using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and/or other commonly used solubilizers or dispersants.

The pharmaceutical composition intended for in vivo administration can be sterile. This can be easily achieved by filtration, for example, through a sterile filtration membrane.

The pharmaceutical compositions within the scope of this disclosure include all compositions in which the compound of this disclosure is combined with one or more pharmaceutically acceptable excipients. In one embodiment, the compound of this disclosure is present in the composition in an amount sufficient to effectively achieve its intended therapeutic purpose.

The pharmaceutical composition disclosed herein can be administered to any patient who may experience the beneficial effects of the compounds disclosed herein. Most importantly, such patients are mammals, such as humans and other animals, but this disclosure is not intended to be limited to this. In one embodiment, the patient is a human.

In another embodiment, this disclosure provides a kit containing a compound of this disclosure (or a combination of compounds of this disclosure) packaged in a manner facilitating its use in practicing the methods of this disclosure. In one embodiment, the kit includes a compound of this disclosure (or a combination of compounds of this disclosure) packaged in a container (such as a sealed bottle or vessel), wherein a label is affixed to the container or included in the kit, the label describing the use of the compound or combination in practicing the methods of this disclosure. In one embodiment, the compound or combination is packaged in a unit dosage form. The kit may further include a device suitable for dispensing the combination according to a intended dispensing route. In some embodiments, this disclosure provides a kit comprising the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and instructions for administering the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, to an individual in need of treatment of a patient suffering from a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, or combinations thereof. In some embodiments, the disease or condition is pain.

In some embodiments, this disclosure provides a pharmaceutical composition comprising the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having Formula I , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having any or more of the formulas IIa , IIb , IIc , IId , IIe , IIf , IIq , IIr and IIs , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having any or more of the formulas IIg , IIh , IIi , IIj , IIk , IIm , IIt , IIu and IIv , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having any one or more of the formulas IIn , IIo , IIp , IIw , IIx and IIy , or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer, and a pharmaceutically acceptable excipient.

In some embodiments, this disclosure provides a pharmaceutical composition comprising the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is intended to treat an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof. In some embodiments, the disease or condition is pain.

In some embodiments, this disclosure provides a pharmaceutical composition comprising the compound of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is intended for the manufacture of an agent for treating an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof. In some embodiments, the disease or condition is pain.

This disclosure also provides examples of the following numbers.

Example 1. A compound having Formula I , I ; or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein: ^M1 is selected from N and ^CR1 ; ^M2 is selected from N and ^CR2 ; ^M3 is selected from N and ^CR3 ; ^M4 is selected from N and ^CR4 ; each of ^R1 , ^R2 , ^R3 , and ^R4 is independently selected from hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated, ( _C3 - _{C6 )} cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 -C6) cycloalkyloxy, ( _{C1 ...} )alkyl thioyl and, where applicable, substituted ( _C3 - _C6 )cycloalkyl thioyl; each ^R5 is independently selected from halogen,, where applicable, substituted ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl,, where applicable, substituted ( _C3 - _C6 ) cycloalkyl, where applicable, substituted ( _C1 - _C6 ) alkoxy, where applicable, substituted ( _C3 - _C6 ) cycloalkyloxy, where applicable, substituted ( _C6 - _C14 ) aryl, where applicable, substituted heterocyclic and where applicable, or two twin ^R5s together with their attached atoms to form, where applicable, substituted ( _C3 - _C6) ^R5 is a cycloalkyl group, or two twin R5s forming a ( _C3 - _C6 )cycloalkyl group with the atoms they are attached to, or ^R5 is a _C1 alkyl group that forms a bond with each of the two carbons of the ring to which it is attached; n is 0, 1, or 2; ^R9 is selected from hydrogen, ( _C1 - _C6 )alkyl, and ( _C6 - _C14 )aryl-( _C1 - _C6 )alkyl-, depending on the substitution; A is a heteroaryl group, depending on the substitution; Z is selected from N and ^CRZ ; ^RZ is selected from hydrogen and ( _C1 - _C6 )alkyl; ^R6 is selected from hydrogen, halogen, (C1-C6)alkyl, ( _C1 - _C6 )alkyl, ( _C1 -C14)alkyl- _... ) halogenated alkyl, substituted ( _C3 - _C6 ) cycloalkyl, substituted ( _C1 - _C6 ) alkoxy, substituted ( _C3 -C6) cycloalkyloxy, substituted ( _C6 - _C14 ) aryl, substituted heterocyclic, and substituted heteroaryl ^; W is selected from ^R8R7N- , ^R8R7N- ( _C1 - _C6 )alkyl-, ^R8R7N- ( ^C3 - _C6 )cycloalkyl-, ^R8R7N- ( _C3 - _C6 ) ^cycloalkyl- ₍ ^C1 _{- C6 )} R6 may be an alkyl-, a heterocyclic group as appropriate, or a heterocyclic group as appropriate ( _C1 - _C6 )alkyl-, or ^R6 and W together with the atoms to which they are attached form ^R8R7N- ( _C3 - _C7 ) ^cycloalkyl- , ^R8R7N- ( _C1 - _C6 )alkyl-( _C3 - _C7 )cycloalkyl- or ^a heterocyclic group as appropriate, or ^R6 is a bond between the carbon atom to which it is attached and ^R5 , or R5 and W together with the atoms to which they are attached form an amine-substituted ( _C3 - _C6 )cycloalkyl or a heterocyclic group as appropriate, or ^R5 and ^R6 together with the atoms to which they are attached form a ( ^C3 -C6)cycloalkyl group as appropriate ( _C3 - _C6) cycloalkyl-. ^R7 and ^R8 are independently selected from hydrogen, substituted ( _C1 -C6)alkyl, substituted (C3- _C6 )cycloalkyl, substituted heterocyclic, substituted (C6- _C14 )aryl-( _C1 -C6)alkyl-, ( _C1 - _C6 )halogenated alkyl, substituted ( _C1 - _C6 )alkyl- _O- ( _C1 - _C6 )alkyl- and ( _C3 - _C6 )cycloalkyl-( _{C1 - C6} )alkyl-, or ^R7 and _R8 together with ^the atoms _to which they are attached form a substituted heterocyclic group.

Example 2. A compound having Formula I , I ; or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein: ^M1 is selected from N and ^CR1 ; ^M2 is selected from N and ^CR2 ; ^M3 is selected from N and ^CR3 ; ^M4 is selected from N and ^CR4 ; each of ^R1 , ^R2 , ^R3 , and ^R4 is independently selected from hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated, ( _C3 - _{C6 )} cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 -C6) cycloalkyloxy, ( _{C1 ...} )alkyl thioyl and, where applicable, substituted ( _C3 - _C6 )cycloalkyl thioyl; each ^R5 is independently selected from halogen,, where applicable, substituted ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl,, where applicable, substituted ( _C3 - _C6 ) cycloalkyl, where applicable, substituted ( _C1 - _C6 ) alkoxy, where applicable, substituted ( _C3 - _C6 ) cycloalkyloxy, where applicable, substituted ( _C6 - _C14 ) aryl, where applicable, substituted heterocyclic and where applicable, or two twin ^R5s together with their attached atoms to form, where applicable, substituted ( _C3 - _C6) ^R5 is a cycloalkyl group, or two twin R5s forming a ( _C3 - _C6 )cycloalkyl group with the atoms they are attached to, or ^R5 is a _C1 alkyl group that forms a bond with each of the two carbons of the ring to which it is attached; n is 0, 1, or 2; ^R9 is selected from hydrogen, ( _C1 - _C6 )alkyl, and ( _C6 - _C14 )aryl-( _C1 - _C6 )alkyl-, depending on the substitution; A is a heteroaryl group, depending on the substitution; Z is selected from N and ^CRZ ; ^RZ is selected from hydrogen and ( _C1 - _C6 )alkyl; ^R6 is selected from hydrogen, halogen, (C1-C6)alkyl, ( _C1 - _C6 )alkyl, ( _C1 -C14)alkyl- _... ) halogenated alkyl, substituted ( _C3 - _C6 )cycloalkyl, substituted ( _C1 - _C6 )alkoxy, substituted ( _C3 -C6)cycloalkyloxy, substituted ( _C6 - _C14 )aryl, substituted heterocyclic, and substituted heteroaryl; W is selected from ^R8R7N- , ^R8R7N- (C1 ^-C6 ₎ alkyl-, ^R8R7N- ( _C3 - _C6 )cycloalkyl-, substituted ^heterocyclic _{, and substituted heterocyclic-(C1-C6} ⁾ _{alkyl- , or} R ^R6 and W, together with the atoms they are attached to, form ^{R8/ R7} N-( _C3 - _C7 )cycloalkyl-, ^{R8/ R7} N-( _C1 - _C6 )alkyl-( _C3 - _C7 )cycloalkyl-, or, as appropriate, a substituted heterocyclic group; or ^R6 is a bond between the carbon atom to which it is attached and ^R5 ; or ^R5 and W, together with the atoms they are attached to, form an amine-substituted ( _C3 - _C6 )cycloalkyl or, as appropriate, a substituted heterocyclic group; or ^R5 and ^R6, together with the atoms they are attached to, form, as appropriate, a substituted ( _C3 - _C6 )cycloalkyl; and each of ^R7 and ^R8 is independently selected from hydrogen, or, as appropriate, a substituted ( _C1 - _C6) cycloalkyl group. )alkyl, ( _C3 - _C6 )cycloalkyl, (C1-C6) heterocyclic, ( _C6 - _{C14)aryl-(C1-C6} )alkyl-, ( _C1 - _C6 )halogenated alkyl, ( _C1 - _C6 )alkyl-O-( _C1 - _{C6)alkyl- and (C3-C6} )cycloalkyl-( _{C1 - C6} )alkyl-, or ^R7 and ^R8 together with the atoms to which they are attached to form ( _C1 - _C6 ) heterocyclic groups _, as may be substituted.

Example 3. A compound such as that of Example 1 or 2, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein... for .

Example 4. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, (C1 _{- C6} ) alkyl or halogen.

Example 5. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^R1 is a halogen.

Example 6. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^R2 is hydrogen.

Example 7. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^R3 is selected from hydrogen and halogen.

Example 8. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein R ⁴ is a halogen.

Example 9. A compound as described in any of the foregoing examples, or a pharmaceutically acceptable salt, solvent compound, or stereoisomer thereof, wherein... Department selected from , and .

Example 10. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein Z is N.

Example 11. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein W is selected from ^R8R7N- ( _C1 - _C6 )alkyl-, a nitrogen-containing heterocyclic group substituted as appropriate, and ^a nitrogen-containing heterocyclic group-( _C1 - _C6 )alkyl- substituted as appropriate.

Example 12. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein ^R7 and ^R8 are ( _C1 - _C6 ) alkyl groups.

Example 13. A compound as described in any of the foregoing examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein W is selected from... , , , , , , , and .

Example 14. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein ^R6 is selected from hydrogen, halogen, ( _C1 - _C6 )alkyl, ( _C3 - _C6 )cycloalkyl, ( _C1 - _C6 )alkoxy and, where applicable, substituted ( _C6 - _C14 )aryl.

Example 15. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^R6 is selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, and phenyl.

Example 16. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^R6 and W together with the atoms to which they are attached form ^R8R7N- ( _C3 - _C7 ) ^cycloalkyl- or, where applicable, a substituted nitrogen-containing heterocyclic group.

Example 17. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^R6 and W, together with the atoms to which they are attached, form, where appropriate, a substituted cyclobutyl or a substituted pyrrolidyl group.

Example 18. A compound as described in any of the foregoing examples, or a pharmaceutically acceptable salt, solvent compound, or stereoisomer thereof, wherein... for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

Example 19. A compound as described in any of the foregoing examples, or a pharmaceutically acceptable salt, solvent compound, or stereoisomer thereof, wherein... for , or .

Example 20. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein R ⁹ is hydrogen.

Example 21. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein A is selected from a substituted thiazolyl group and a substituted pyridyl group, as appropriate.

Example 22. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein A is selected from... , and .

Example 23. A compound of any of the foregoing embodiments, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, having one or more of the formulas IIa , IIb , IIc , IId , IIe , IIf , IIq , IIr , and IIs , wherein: p is selected from 0, 1, 2, and 3; t is selected from 0, 1, and 2; q is selected from 1, 2, and 3, provided that if t is 0, then q is selected from 2 and 3; ^Z1 is selected from ^CR15 and N; ^R12 is selected from hydrogen and, where applicable, a substituted ( _C1 - _C6 ) alkyl group; and ^R15 is selected from hydrogen,, where applicable, a substituted ( _C1 - _C6 ) alkyl group ^, and ^-NR8R9 .

Example 24. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein p is 1 or 2.

Example 25. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent compound, or stereoisomer thereof, wherein t is 1 and q is 1.

Example 26. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent compound, or stereoisomer thereof, wherein t is 1 and q is 2.

Example 27. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein t is 0 and q is 3.

Example 28. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein ^Z1 is CR ¹⁵ .

Example 29. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein R ¹⁵ is hydrogen.

Example 30. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent compound or stereoisomer thereof, wherein ^Z1 is N.

Example 31. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein R ¹² is methyl.

Example 32. A compound of any of the foregoing embodiments, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, having one or more of the formulas IIg , IIh , IIi , IIj , IIk , IIm , IIt , IIu , and IIv ; wherein: ^R10 and ^R11 are each independently selected from hydrogen, halogen, and ( _C1 - _C4 ) alkyl, or ^R10 and ^R11 of formulas IIg , IIh , and IIt together with the atoms to which they are attached form, where appropriate, a substituted aryl group, a substituted heterocyclic group, a substituted heteroaryl group, or a substituted cycloalkyl group; and ^R13 and R ¹⁴ Each independently chooses from the group consisting of: hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 - _C6 ) cycloalkyloxy, ( _C1 - _C6 ) alkylthio, and ( _C3 - _C6 ) cycloalkylthio.

Example 33. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein ^R10 and ^R11 are hydrogen.

Example 34. A compound of any of the preceding examples, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, wherein R ¹³ is a halogen.

Example 35. A compound of any of the foregoing embodiments, or a pharmaceutically acceptable salt, solvent or stereoisomer thereof, having one or more of the formulas IIn , IIo , IIp , IIw , IIx and IIy .

Example 36. A compound as described in any of the preceding examples, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof, wherein the compound is one of the compounds listed in Table A, or a pharmaceutically acceptable salt, solvent, or stereoisomer thereof.

Example 37. A pharmaceutical combination comprising any of the compounds described in the foregoing embodiments and a pharmaceutically acceptable excipient.

Example 38. A method for inhibiting one or more sodium channels in an individual in need, comprising administering to the individual a therapeutically effective amount of any of the compounds described in the foregoing examples.

Example 39. A method for treating a disease or symptom in an individual of need related to the inhibition of one or more sodium channels, comprising administering to the individual a therapeutically effective amount of any of the compounds described in the foregoing examples.

Example 40. The method of any of the preceding examples, wherein the one or more sodium channels are Na _V 1.7.

Example 41. The method of any of the preceding examples, wherein the inhibition or inhibition of one or more sodium channels is selective inhibition or selective inhibition of Na _V 1.7.

Example 42. The method of any of the preceding examples, wherein the disease or condition is selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

Example 43. A method for treating an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof, comprising administering to the individual a therapeutically effective amount of any of the compounds described in the foregoing examples.

Example 44. A compound of any of the preceding examples, used to treat an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itch, and combinations thereof.

Example 45. Use of a compound as described in any of the preceding examples for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

Example 46. Use of a compound as described in any of the preceding examples for the manufacture of a medicament for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof.

Example 47. The compound, use, or method of any of the foregoing examples, wherein the pain is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, paroxysmal pain, neurocystic pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

Example 48. The compound, use, or method of any of the preceding embodiments, wherein the pain is associated with HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, allodynia, thermal sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, and multiple Pain associated with MS, ALS, diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal hypotonia, myasthenia Syndrome, myotonia, malignant fever, cystic fibrosis, pseudopolyaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial acropalatine syndrome, primary acropalatine syndrome, familial rectal pain, cancer, epilepsy, partial and generalized tonic-clonic seizures, restless legs syndrome, arrhythmia, fibromyalgia, neuroprotective measures under ischemic conditions caused by stroke or nerve trauma, tachyarrhythmia, atrial or ventricular flutter.

Examples General Synthetic Methods In view of this disclosure, the compounds of this disclosure are prepared using methods known to those skilled in the art or by the illustrative methods shown in the general scheme below. In any general scheme, suitable protecting groups may be used in the synthesis. (See Wuts, P. G. M.; Greene, T. W., "Greene's Protective Groups in Organic Synthesis", 4th ed., J. Wiley & Sons, NY, 2007).

Unless otherwise stated, all reagents do not require further purification before use.

Example 1: (R)-5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(thiazolyl-2-yl)benzenesulfonamide Step 1. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide: 5-chloro- N - [ (2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-ylbenzenesulfonamide (0.120 g, 0.260 mmol) was added to a mixture of 2-(azacyclobut-3-yl)-N, N - dimethyl-ethylamine (0.0500 g, 0.248 mmol, hydrochloride) and cesium carbonate (0.405 g, 1.24 mmol) in dimethylformamide (1 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow oily product, 5-chloro- N -[(2,4-dimethoxyphenyl)methyl]-4-[3-[2-(dimethylamino)ethyl]azacyclobut-1-yl]-2-fluoro- N -thiazolyl-2-ylbenzenesulfonamide (0.146 g, crude). MS (ES+) m/z 569.4, 571.4 (M + 1)

Step 2. Preparation of 5-chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide: Trifluoroacetic acid (1.54 g, 13.5 mmol) was added to a solution of 5-chloro- N -[(2,4-dimethoxyphenyl)methyl]-4-[3-[2-(dimethylamino)ethyl]azacyclobut-1-yl]-2-fluoro- N -thiazol-2-yl-benzenesulfonamide (0.146 g, crude) in dichloromethane (10 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extract was washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid)-acetonitrile]; B%: 8–38%, 10 min), followed by repurification by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm ; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 15–45%, 10 min), and finally purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm ; mobile phase: [water (ammonium hydroxide v/v)-acetonitrile]; B%: 9–39%). (min) Repurification. The desired fraction was collected and freeze-dried to give 5-chloro-4-[3-[2-(dimethylamino)ethyl]azacyclobut-1-yl]-2-fluoro- N -thiazolyl-2-ylbenzenesulfonamide as a grayish-white solid (0.0104 g, 0.0233 mmol, 9% yield, 94% purity). MS (ES+) m/z 419.1, 421.1 (M+1). ^1H NMR (400 MHz, _CDCl3 ) δ 7.75 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 4.4 Hz, 1H), 6.48 (d, J = 4.4 Hz, 1H), 5.99 (d, J = 11.6 Hz, 1H). 4.32–4.21 (m, 2H), 3.88–3.79 (m, 2H), 3.09–2.96 (m, 2H), 2.82 (s, 6H), 2.78–2.71 (m, 1H), 2.22–2.16 (m, 2H). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.50 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 4.4 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 12.0 Hz, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.75 (dd, J = 6.0, 8.0 Hz, 2H), 2.64–2.58 (m, 2H), 2.57 (m, 1H), 2.41 (s, 6H), 1.81 (q, J = 7.6 Hz, 2H).

Preparation of 3-chloro-N-(3,4-dimethylbenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (intermediate 1) Step 1. Preparation of N-(3,4-dimethylbenzyl)-6-fluoropyridine-2-amine: (2,4-dimethoxyphenyl)methylamine (17.4 g, 104 mmol) was added to a mixture of 2,6-difluoropyridine (10.0 g, 86.9 mmol) and N -ethyl- N -isopropylpropyl-2-amine (14.6 g, 113 mmol) in dimethyl sulfoxide (70 mL). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature. Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined extract was washed with brine (40 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 0–15% ethyl acetate/petroleum ether gradient, 50 mL/min) to give N- (2,4-dimethoxybenzyl)-6-fluoropyridine-2-amine (22.0 g, 83.9 mmol, 96% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (q, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.51–6.38 (m, 2H), 6.20 (dd, J = 2.4, 8.0 Hz, 1H), 6.11 (dd, J = 2.4, 7.6 Hz, 1H), 4.38 (s, 2H), 3.81 (d, J = 14.4 Hz, 6H).

Step 2. Preparation of 3-chloro-N-(3,4-dimethylbenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide: Methyllithium (1.6 M, 34 mL) was added dropwise to a solution of N- (2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (10.0 g, 38.1 mmol) in tetrahydrofuran (100 mL) at -78 °C. After stirring at 0 °C for 0.5 h, the reaction mixture was cooled to -78 °C and 3-chloro-2,4,6-trifluorobenzenesulfonyl chloride (10.6 g, 40.0 mmol) in tetrahydrofuran (20 mL) was added at -78 °C. The reaction mixture was then heated to 25 °C and stirred again under nitrogen for 12 h. The reactants were quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 0–20% ethyl acetate/petroleum ether solvent gradient, 50 mL/min) to give a yellow solid of 3-chloro- N- (2,4-dimethoxybenzyl)-2,4,6-trifluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (2.02 g, 3.91 mmol, 11% yield, 95% purity). MS (ES+) m/z 513.1, 515.1 (M +23).

The other examples listed in Table 1 are similar in preparation to Example 1 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 1 Example Name and Structure Analysis data 1 5-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2-fluoro-N-(thiazo-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 4.4 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 12.0 Hz, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.75 (dd, J = 6.0, 8.0 Hz, 2H), 2.64–2.58 (m, 2H), 2.57 (m, 1H), 2.41 (s, 6H), 1.81 (q, J = 7.6 Hz, 2H). MS (ES+) m/z 419.1, 421.1 (M + 1) 2 5-Chloro-4-(3-((dimethylamino)methyl)azacyclobut-1-yl)-2-fluoro-N-(thiazo-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 4.4 Hz, 1H), 6.75 (d, J = 4.4 Hz, 1H), 6.39 (d, J = 12.4 Hz, 1H), 4.22 (t, J = 8.0 Hz, 2H), 3.78 (dd, J = 5.6, 8.4 Hz, 2H), 2.90–2.81 (m, 1H), 2.65 (d, J = 7.6 Hz, 2H), 2.25 (s, 6H). MS (ES+) m/z 405.3, 407.3 (M+1) 3 5-Chloro-2-fluoro-4-(3-(1-methylpiperidin-4-yl)azacyclobut-1-yl)-N-(thiazo-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 4.4 Hz, 1H), 6.66 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 12.4 Hz, 1H), 4.16 (t, J = 8.0 Hz, 2H), 3.81 (dd, J = 6.4, 8.0 Hz, 2H), 3.02 (d, J = 11.6 Hz, 2H), 2.39 (s, 4H), 2.27 (t, J = 11.6 Hz, 2H), 1.68 (d, J = 12.0 Hz, 2H), 1.58–1.47 (m, 1H), 1.26–1.08 (m, 2H). MS (ES+) m/z 445.2, 447.2 (M + 1) 4 3-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazo-2-yl)benzenesulfonamide 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.14 (d, J = 4.4 Hz, 1H), 6.69 (d, J = 4.4 Hz, 1H), 6.17 (d, J = 12.4 Hz, 1H), 4.23 (t, J = 8.4 Hz, 2H), 3.79 (d, J = 7.6 Hz, 2H), 2.69–2.65 (m, 1H), 2.62 (dd, J = 6.0, 13.6 Hz, 2H), 2.39 (d, J = 4.4 Hz, 6H), 1.85–1.75 (m, 2H). MS (ES+) m/z 437.0, 439.0 (M +1) 13 3-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazo-4-yl)benzenesulfonamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 5.83–5.76 (m, 1H), 4.29 (t, J = 8.4 Hz, 2H), 3.82 (dd, J = 6.0, 8.0 Hz, 2H), 2.69 (s, 1H), 2.49–2.44 (m, 2H), 2.40 (s, 6H), 1.96–1.86 (m, 2H). MS (ES+) m/z 437.2, 439.2 (M + 1) 5 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methylazirmonobutyl-1-yl)-2,6-difluoro-N-(thiazolyl-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (d, J = 4.4 Hz, 1H), 6.55 (d, J = 4.4 Hz, 1H), 5.76 (d, J = 12.8 Hz, 1H), 3.94 (d, J = 8.0 Hz, 2H), 3.81 (d, J = 8.0 Hz, 2H), 2.63–2.59 (m, 2H), 2.50 (s, 6H), 1.98–1.91 (m, 2H), 1.30 (s, 3H). MS (ES+) m/z 451.2, 453.2 (M + 1) 6 3-Chloro-4-(3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.60–7.47 (m, 1H), 6.63 (dd, J = 2.4, 8.0 Hz, 1H), 6.29 (dd, J = 2.4, 7.6 Hz, 1H), 6.12 (d, J = 11.6 Hz, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.77 (dd, J = 5.6, 8.0 Hz, 2H), 2.72–2.63 (m, 2H), 2.63–2.57 (m, 1H), 2.51 (s, 6H), 1.86 (q, J = 7.6 Hz, 2H). MS (ES+) m/z 449.0, 451.0 (M +1) 9 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methylaziroxybut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 (q, J = 8.4 Hz, 1H), 6.63 (dd, J = 2.0, 8.0 Hz, 1H), 6.30 (d, J = 6.4 Hz, 1H), 6.10 (d, J = 12.8 Hz, 1H), 3.91 (d, J = 8.0 Hz, 2H), 3.79 (d, J = 8.0 Hz, 2H), 2.78 (s, 2H), 2.56 (s, 6H), 1.91–1.83 (m, 2H), 1.22 (s, 3H). MS (ES+) m/z 463.1, 465.1 (M + 1) 10 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazolyl-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 5.85–5.76 (m, 1H), 5.19 (s, 2H), 4.32–4.21 (m, 2H), 4.15 (s, 2H), 3.76 (s, 3H), 2.72–2.51 (m, 1H), 2.39 (d, J = 2.8 Hz, 2H), 2.32–2.06 (m, 6H). MS (ES+) m/z 569.1, 571.1 (M + 1)

Example 7: 3-Chloro-4-(3-(3-(dimethylamino)propyl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazolyl-2-yl)benzenesulfonamide Step 1. Methyl 3-(1-(2-chloro-3,5-difluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)aminesulfonyl)phenyl)azacyclobut-3-yl)propionate was added to a solution of methyl 3-( azacyclobut -3-yl)propionate hydrochloride (0.200 g, 1.11 mmol) and cesium carbonate (1.09 g, 3.34 mmol) in N , N -dimethylformamide (5 mL). The mixture was stirred at 25°C for 12 h. Add ethyl acetate (6 mL) and water (5 mL) and separate the layers. Extract the aqueous phase with ethyl acetate (2 × 6 mL). Wash the combined extract with brine (18 mL), dry with sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, 0–35% ethyl acetate/petroleum ether solvent gradient, 25 mL/min) to obtain methyl 3-(1-(2-chloro-3,5-difluoro-4-( N- (4-methoxybenzyl) -N- (thiazol-2-yl)aminesulfonyl)phenyl)azacyclobut-3-yl)propionate (0.480 g, 0.839 mmol, 76% yield), which was a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.81 (dd, J = 1.6, 12.8 Hz, 1H), 5.20 (s, 2H), 4.35 (t, J = 8.0 Hz, 2H), 3.86 (dd, J = 5.6, 8.0 Hz, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 2.79–2.66 (m, 1H), 2.33 (t, J = 7.2 Hz, 2H), 1.99 (q, J = 7.6 Hz, 2H).

Step 2. 3-Chloro-2,6-difluoro-4-(3-(3-hydroxypropyl)azacyclobut-1-yl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide was added at 0°C to a solution of methyl 3-(1-(2-chloro-3,5-difluoro-4-( N- (4-methoxybenzyl) -N- (thiazol-2-yl)aminesulfonyl)phenyl)azacyclobut-3-yl)propionate (0.480 g, 0.839 mmol) in tetrahydrofuran (8 mL) with lithium aluminum hydroxide (1 M, 1.73 mL). The mixture was heated to 25°C for 2 h. The reaction mixture was quenched at 0°C with sodium sulfate decahydrate (0.8 g). The mixture was stirred at 25°C for 1 h. The mixture was then filtered through diatomaceous earth . The filter cake was washed with tetrahydrofuran (20 mL). The filtrate was concentrated under reduced pressure to obtain 3-chloro-2,6-difluoro-4-(3-(3-hydroxypropyl)azacyclobut-1-yl) -N- (4-methoxybenzyl) -N- (thiazolyl-2-yl)benzenesulfonamide (0.430 g, crude product), which was a yellow oil.

Step 3. 3-Chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-(3-hydroxypropyl)azacyclobut-1-yl)-N-(thiazol-2-yl)benzenesulfonamide was added to a solution of 3-chloro-2,6-difluoro-4-(3-(3-hydroxypropyl)azacyclobut-1-yl) -N- (4-methoxybenzyl) -N- (thiazol-2-yl)benzenesulfonamide (0.300 g, 0.551 mmol) in dichloromethane (6 mL) at 0 °C. The mixture was stirred at 40 °C for 12 h. The reaction mixture was then cooled to room temperature. The mixture was diluted with saturated sodium bicarbonate (7 mL) and dichloromethane (6 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 7 mL). The combined organic extract was washed with brine (25 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, 0–50% ethyl acetate/petroleum ether solvent gradient, 25 mL/min) to give 3-chloro-2,6-difluoro- N- (4-methoxybenzyl)-4-(3-(3-sideoxypropyl)azacyclobut-1-yl) -N- (thiazo-2-yl)benzenesulfonamide (0.150 g, 0.277 mmol, 51% yield), which appeared as a yellow oil. MS (ES+) m/z 542.2, 544.2 (M+1).

Step 4. 3-Chloro-4-(3-(3-(dimethylamino)propyl)azacyclobut-1-yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide was added to a solution of 3-chloro-2,6-difluoro- N- (4-methoxybenzyl)-4-(3-(3-dioxypropyl)azacyclobut-1-yl) -N- (thiazol-2-yl)benzenesulfonamide (0.150 g, 0.277 mmol) and dimethylamine (2 M, 0.410 mL) in dichloromethane (5 mL) with sodium triethoxyborohydride (0.176 g, 0.830 mmol). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 35–65% B, for 10 min). The desired fraction was collected and freeze-dried. The crude product was further purified by preparative HPLC (column: Welch Ultimate XB-CN 250 mm × 50 mm × 10 μm ; mobile phase: [hexane-ethanol (0.1% ammonium hydroxide)]; gradient: 35–70% B, for 15 min). Concentrate the required fraction under reduced pressure to obtain 0.0150 g of 3-chloro-4-(3-(3-(dimethylamino)propyl)azacyclobut-1-yl)-2,6-difluoro- N- (4-methoxybenzyl) -N- (thiazolyl-2-yl)benzenesulfonamide, which is a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 5.87–5.75 (m, 1H), 5.20 (s, 2H), 4.34 (t, J = 8.0 Hz, 2H), 3.88–3.81 (m, 2H), 3.76 (s, 3H), 2.77–2.63 (m, 1H), 2.36–2.32 (m, 2H), 2.28 (s, 6H), 1.70–1.64 (m, 2H), 1.52–1.44 (m, 2H).

Step 5. Add 1 mL of trifluoroacetic acid to a solution of 0.0200 g (0.0350 mmol) of 3-chloro-4-(3-(3-(dimethylamino)propyl)azacyclobut-1-yl)-2,6-difluoro- N- (4-methoxybenzyl) -N- (thiazol-2-yl)benzenesulfonamide (0.0200 g, 0.0350 mmol) in dichloromethane (5 mL). Stir the mixture at 30 °C for 1 h. Concentrate the reaction mixture under reduced pressure. Dilute the residue with dimethyl sulfoxide (1 mL). The mixture was adjusted to pH approximately 8 with ammonium hydroxide (10 wt%). The mixture was purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm ; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 12–42% B, for 10 min) to give a white solid of 3-chloro-4-(3-(3-(dimethylamino)propyl)azacyclobut-1-yl)-2,6-difluoro- N- (thiazolyl-2-yl)benzenesulfonamide (0.00390 g, 0.00856 mmol, 25% yield, 99% purity). MS (ES+) m/z 451.3, 453.3 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.17 (d, J = 4.4 Hz, 1H), 6.72 (d, J = 4.0 Hz, 1H), 6.19 (d, J = 11.6 Hz, 1H), 4.24 (t, J = 8.0 Hz, 2H), 3.76 (dd, J = 6.0, 8.0 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.65–2.60 (m, 1H), 2.53 (s, 6H), 1.63–1.55 (m, 2H), 1.55–1.46 (m, 2H).

Example 8: 3-Chloro-2,6-difluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl)-N-(thiazolyl-2-yl)benzenesulfonamide Step 1. 3-(pyridin-4-ylmethyl)azacyclobutane-1-carboxylate tributyl ester was added to a mixture of 3-methyleneazacyclobutane-1-carboxylate tributyl ester (0.330 g, 1.95 mmol) and tetrahydrofuran (1 mL) under a nitrogen atmosphere, along with 9-boronadicyclo[3.3.1]nonane (0.5 M, 3.9 mL). The mixture was stirred at 60 °C for 12 h. After cooling to room temperature, 1,1'-bis(diphenylphosphino)ferrocene(II) dichloropalladium(II) (0.0800 g, 0.0979 mmol), potassium phosphate (1.24 g, 5.84 mmol), 4-bromopyridine (0.379 g, 1.95 mmol, hydrochloride), tetrahydrofuran (5 mL), and water (0.6 mL) were added. The mixture was stirred at 60 °C for 1 h under microwave conditions. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silicone column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to give 3-(pyridin-4-ylmethyl)azacyclobutane-1-carboxylic acid tributyl ester (0.135 g, 0.543 mmol, 28% yield), which was a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J = 5.6 Hz, 2H), 7.09 (d, J = 5.6 Hz, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.64 (dd, J = 5.2, 8.8 Hz, 2H), 2.95–2.89 (m, 2H), 2.85 (d, J = 8.0 Hz, 1H), 1.44 (s, 9H).

Step 2. Platinum dioxide (0.100 g, 0.440 mmol) was added to a mixture of 3-(pyridin-4-ylmethyl)azidocyclobutane- 1 -carboxylate (0.115 g, 0.463 mmol) and acetic acid (2.5 mL) under a nitrogen atmosphere. The solution was purged three times with hydrogen, and then stirred for 12 h at 25 °C under hydrogen (50 psi). The resulting mixture was dried over diatomaceous earth . The filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give 3-(piperidin-4-ylmethyl)azacyclobutane-1-carboxylic acid tributyl ester (0.110 g, 0.432 mmol, 93% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.01 (t, J = 8.0 Hz, 2H), 3.53 (dd, J = 5.6, 8.0 Hz, 2H), 3.40 (d, J = 1.6 Hz, 1H), 2.83 (s, 2H), 2.63–2.51 (m, 1H), 1.86 (t, J = 8.8 Hz, 1H), 1.76 (s, 2H), 1.61 (s, 3H), 1.48 (s, 2H), 1.43 (s, 9H).

Step 3. Formaldehyde (0.350 g, 4.32 mmol, 37% purity) was added to a mixture of 3-(piperidin-4-ylmethyl)azidocyclobutane- 1 -carboxylate (0.110 g, 0.432 mmol) and methanol (2 mL). The mixture was stirred at 25 °C for 1 h. Then, sodium cyanoboronide (0.0815 g, 1.30 mmol) was added. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain 0.120 g of 3-((1-methylpiperidin-4-yl)methyl)azacyclobutane-1-carboxylic acid tributyl ester, which was a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.34 (s, 3H), 4.00 (t, J = 8.4 Hz, 2H), 3.53 (dd, J = 5.6, 8.4 Hz, 2H), 3.30–3.10 (m, 2H), 3.03 (d, J = 12.0 Hz, 2H), 2.65–2.53 (m, 1H), 2.41 (s, 2H), 2.22–2.08 (m, 2H), 1.69 (d, J = 13.2 Hz, 2H), 1.58 (t, J = 7.2 Hz, 2H), 1.43 (s, 9H), 1.40–1.36 (m, 1H).

Step 4. 4-(azacyclobut-3-ylmethyl)-1-methylpiperidine: A mixture of 3-((1-methylpiperidin-4-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.120 g, 0.447 mmol) in hydrogen chloride/dioxane (4 M, 3 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 4-(azacyclobut-3-ylmethyl)-1-methylpiperidine (0.100 g, crude product, hydrochloride) as a yellow solid. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 4.15–4.10 (m, 2H), 4.01 (s, 3H), 3.86–3.76 (m, 2H), 3.73 (s, 1H), 3.52–3.45 (m, 2H), 3.35 (s, 3H), 2.84 (s, 2H), 1.92 (d, J = 14.0 Hz, 2H), 1.72–1.66 (m, 2H).

Step 5. Cryosulfanilamide (0.795 g, 2.44 mmol) was added to a mixture of 3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl) -N- (thiazo-2-yl)benzenesulfanilamide (0.219 g, 0.488 mmol) and dimethylformamide (3 mL). The mixture was stirred at 25 ° C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was combined with batch EW21562-1353 (0.020 mg starting material 6 ). The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid): 30%-50% B, 9 min]). The desired fraction was collected and freeze-dried to give 3-chloro-2,6-difluoro- N- (4-methoxybenzyl)-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobut-1-yl) -N- (thiazolyl-2-yl)benzenesulfonamide as a white solid (0.0350 g, 0.0586 mmol, 12% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.80 (dd, J = 1.2, 12.8 Hz, 1H), 4.36 (t, J = 8.0 Hz, 2H), 3.88–3.80 (m, 2H), 3.76 (s, 3H), 3.06 (d, J = 11.6 Hz, 2H), 2.84–2.75 (m, 1H), 2.40 (s, 3H), 2.13 (t, J = 11.2 Hz, 2H), 1.73–1.60 (m, 4H), 1.46 (dd, J = 3.2, 12.4 Hz, 2H), 1.36–1.28 (m, 1H).

Step 6. Add 0.5 mL of trifluoroacetic acid to a mixture of 3-chloro-2,6-difluoro-4-(3 - (((1-methylpiperidin-4-yl)methyl)azacyclobut-1-yl) -N- (thiazol-2-yl)benzenesulfonamide (0.0320 g, 0.0535 mmol) and dichloromethane (2.5 mL). Stir the mixture at 25 °C for 12 h. Concentrate the reaction mixture. Dilute the residue with dimethyl sulfoxide (2 mL). The pH was adjusted to 7–8 with diisopropylethylamine. The residue was purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm ; mobile phase: [water (ammonia hydroxide v/v)-acetonitrile]; gradient: 14–44% B, for 9 min). The desired fraction was collected and freeze-dried to give a white solid of 3-chloro-2,6-difluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl) -N- (thiazo-2-yl)benzenesulfonamide (0.0113 g, 0.0222 mmol, 42% yield, 94% purity). MS (ES+) m/z 477.3, 479.3 (M+ 1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.11 (d, J = 4.0 Hz, 1H), 6.65 (d, J = 4.0 Hz, 1H), 6.16 (d, J = 12.0 Hz, 1H), 4.25 (t, J = 8.0 Hz, 2H), 3.71 (d, J = 7.2 Hz, 2H), 3.06 (d, J = 11.6 Hz, 2H), 2.74–2.67 (m, 1H), 2.45 (s, 3H), 2.41–2.32 (m, 2H), 1.67 (d, J = 12.0 Hz, 2H), 1.53 (t, J = 7.2 Hz, 2H), 1.35–1.16 (m, 3H).

Example 11: 3-Chloro-4-[[2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]amino]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide Step 1. 3-(Cyanomethylene)-3-phenyl-aziridine-1-carboxylic acid tributyl ester: A mixture of 3-(cyanomethylene)aziridine-1-carboxylic acid tributyl ester (4.00 g, 20.6 mmol), phenylboronic acid (3.77 g, 30.9 mmol), KOH (1.73 g, 30.9 mmol), rhodium chloride;(1Z,5Z)-cyclooctyl-1,5-diene (0.304 g, 0.618 mmol) in dioxane (80.0 mL) was degassed and purged three times with _N2 . The mixture was then stirred for 1 hr at 100°C under _N2 atmosphere. The reaction mixture was poured into _H2O (80.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic phase was washed with brine (100 mL), dried over _{Na₂SO₄ ,} filtered, and concentrated under vacuum. The residue was purified by column chromatography ( _SiO₂ , petroleum ether: ethyl acetate = 30/1 to 1/1). A yellow solid, 3-(cyanomethyl)-3-phenyl-azacyclobutane-1-carboxylic acid tributyl ester (2.30 g, 8.45 mmol, 41.0% yield), was obtained.

Step 2. Tributyl Reichneronate (2.17 g, 25.3 mmol) was added to a solution of 3-(cyanomethyl)-3-phenyl-aziridine-1-carboxylic acid (2.30 g, 8.45 mmol) in MeOH (23.0 mL) under _N₂ atmosphere. The suspension was degassed and purged three times with _H₂ . The mixture was stirred for 12 hours at 25°C with _H₂ (50 Psi). The mixture was filtered and concentrated under vacuum. 3-(2-aminoethyl)-3-phenyl-azacyclobutane-1-carboxylic acid tributyl ester (2.30 g, 8.32 mmol, 98.5% yield) was obtained as a colorless oil.

Step 3. N-[(2R)-2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]carbamate benzyl ester was added to a solution of 3-(2-aminoethyl)-3-phenyl-azacyclobutane-1-carboxylic acid tributyl ester (1.00 g, 3.62 mmol) in MeOH (7.00 mL) at 0 °C. HCHO (0.734 g, 9.05 mmol, 0.673 mL, 37% purity) and AcOH (0.021 g, 0.361 mmol, 0.020 mL) were stirred at 0 °C for 30 min. Then, _NaBH3CN (0.454 g, 7.24 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 5 hr. The reactants were poured into _H₂O (30.0 mL) and extracted with EtOAc (20.0 mL x 2). The combined organic phases were washed with brine (20.0 mL), dried over _Na₂SO₄ , _filtered , and concentrated under vacuum. The residues were purified by column chromatography ( _SiO₂ , petroleum ether: ethyl acetate = 10/1 to dichloromethane: methanol = 10/1). 3-[2-(dimethylamino)ethyl]-3-phenyl-azacyclobutane-1-carboxylic acid tributyl ester (0.720 g, 2.37 mmol, 65.3% yield) was obtained as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.35 (t, J = 7.6 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.14 - 7.08 (m, 2H), 4.21 (d, J = 8.2 Hz, 2H), 4.01 (d, J = 8.2 Hz, 2H), 2.18 (s, 6H), 2.14 - 2.00 (m, 4H), 1.44 (s, 9H).

Step 4. (N2-Ethyl-N2,4,4-Trimethyl-pentane-1,2-diamine) HCl/EtOAc (4.00 M, 1.50 mL) was added to a solution of 3-[2-(dimethylamino)ethyl]-3-phenyl-aziridine-1-carboxylic acid tributyl ester (0.720 g, 2.37 mmol) in EtOAc (3.50 mL). The mixture was stirred at 25 °C for 0.5 hr. The reactant was concentrated under vacuum. N,N-Dimethyl-2-(3-phenylaziridine-3-yl)ethylamine (0.430 g, 1.79 mmol, 75.5% yield, HCl) was obtained as a white solid.

Step 5. Add Cs₂CO₃ (0.331 g, 1.02 mmol) to a solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[[2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]amino]-2,6-difluoro-N-(6-fluoro- ₂ -pyridyl)benzenesulfonamide (0.200 g, 0.407 mmol) and N,N-dimethyl- _2- (3-phenylazacyclobut-3-yl)ethylamine (0.117 g, 0.488 mmol, HCl) in DMF (1.00 mL). The mixture was stirred at 25°C for 16 hr. The reaction mixture was poured into _H₂O (5.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic phase was washed with brine (10.0 mL), dried over _{Na₂SO₄ ,} filtered, and concentrated under vacuum. The residue was purified by preparative TLC ( _SiO₂ , dichloromethane: methanol = 10/1). 3-Chloro-N-[(2,5-dimethoxyphenyl)methyl]-4-[3-[2-(dimethylamino)ethyl]-3-phenyl-azacyclobut-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide was obtained as a white solid (0.120 g, 0.177 mmol, 43.6% yield). ¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.66 (q, J = 8.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.32 - 7.28 (m, 1H), 7.26 - 7.20 (m, 2H), 7.18 - 7.12 (m, 3.75 ​ (d, J = 3.4 Hz, 6H), 3.50 (s, 2H), 2.23 (s, 9H).

Step 6. Add TFA (0.200 mL) to a solution of 3-chloro-4-[[2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]amino]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (0.120 g, 0.177 mmol) in DCM (1.00 mL). Stir the mixture at 25 °C for 0.5 hr. Pour the reaction mixture into _NaHCO3 (5.00 mL) and extract with DCM (3.00 mL x 3). The combined organic phase was washed with brine (10.0 mL), _dried over _Na₂SO₄ , filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX-C18 (75 * 30 mm _{* 3} μm); mobile phase: [ _H₂O (0.05% _NH₃H₂O + 10 mM _NH₄HCO₃ ) - ACN]; gradient: 20% - 50% B, for 8.0 min). 3-Chloro-4-[3-[2-(dimethylamino)ethyl]-3-phenyl-azacyclobut-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide was obtained as a white solid (0.024 g, 0.045 mmol, 25.7% yield). MS (ES+) m/z 525.2 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.27 - 10.12 (m, 1H), 7.56 (q, J = 8.2 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.32 - 7.21 (m, 3H), 6.64 (dd, J = 7.8, 1.6 Hz, 1H), 6.31 (d, J = 6.6 Hz, 1H), 6.20 (d, J = 12.6 Hz, 1H), 4.32 (s, 4H), 2.50 - 2.43 (m, 8H), 2.36 - 2.22 (m, 2H).

Example 12: 3-Chloro-4-(3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobut-1-yl)-2,6-difluoro-N-(thiazolyl-2-yl)benzenesulfonamide Step 1. 3-(1-(dimethylamino)-2-methyl-1-sideoxyprop-2-yl)azacyclobutane-1-carboxylic acid tert-butyl ester was added to a solution of 2-(1-(tert-butoxycarbonyl)azacyclobut-3-yl)-2-methylpropionic acid (0.500 g, 2.06 mmol) in dichloromethane (5.0 mL) with 1,1'-carbonyldiimidazole (0.400 g, 2.47 mmol). The mixture was stirred at 25 °C for 0.5 h. Then dimethylamine (2 M, 1.6 mL) was added (in tetrahydrofuran). The resulting mixture was stirred at 25 °C for 2.5 h. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1 M hydrochloric acid (2 × 5 mL) and brine (15 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was a yellow oil containing 0.310 g of crude 3-(1-(dimethylamino)-2-methyl-1-sideoxyprop-2-yl)azacyclobutane-1-carboxylic acid tributyl ester. MS (ES+) m/z 271.2 (M + 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.99 (t, J = 9.2 Hz, 2H), 3.64 (dd, J = 6.0, 9.2 Hz, 2H), 3.08–2.99 (m, 7H), 1.43 (s, 9H), 1.28 (s, 6H).

Step 2. 3-(1-(dimethylamino)-2-methylprop-2-yl)azacyclobutane-1-carboxylic acid tributyl ester (0.310 g, 1.15 mmol) (crude product) was added to a solution of 3-(1-(dimethylamino)-2-methyl-1-opyroprop-2-yl)azacyclobutane-1-carboxylic acid tributyl ester (0.310 g, 1.15 mmol) in tetrahydrofuran (6.0 mL) with a boron dimethyl sulfide complex (10 M, 0.3 mL). The mixture was heated under nitrogen at 50 °C for 2 h. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with methanol (20 mL) at 0 °C for 0.5 h. The mixture was stirred at 25°C for 1 h and concentrated under reduced pressure to obtain a residue. The residue was diluted with methanol (15 ml) and refluxed at 80°C for 1 h and concentrated under reduced pressure to obtain a yellow oily substance, 0.300 g of crude 3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobutane-1-carboxylic acid tributyl ester. MS (ES+) m/z 257.1 (M+1).

Step 3. Acetyl chloride (0.459 g, 5.85 mmol) was added to a solution of 3-(1-(dimethylamino)-2-methylprop-2-yl)azacyclobutane-1-carboxylic acid tributyl ester (0.300 g, 1.17 mmol) (crude product) in methanol (3.0 mL). The mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, yielding 2-(azacyclobutane-3-yl) -N , N ,2-trimethylpropane-1-amine (0.280 g, crude product, 2-hydrochloride) as a colorless oil. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 4.13–3.98 (m, 4H), 3.22–3.14 (m, 1H), 3.11 (s, 2H), 2.97 (s, 6H), 1.20 (s, 6H).

Step 4. 3-Chloro-4-(3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobut-1-yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide was added to a solution of 2-(azacyclobut-3-yl) -N , N ,2-trimethylpropyl-1-amine (0.100 g, 0.436 mmol, 2-hydrochloride) (crude) in dimethylformamide (1.0 mL) with 3-chloro-2,4,6-trifluoro- N- (4-methoxybenzyl) -N- (thiazol-2-yl)benzenesulfonamide (0.157 g, 0.349 mmol) and cesium carbonate (0.711 g, 2.18 mmol). The mixture was stirred at 25°C for 12 h. Ethyl acetate (4 mL) and water (4 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 4 mL). The combined extract was washed with brine (8 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by a preparative HPLC column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid)-acetonitrile]; gradient: 28%–48% B (for 2 min). The desired fraction was collected and freeze-dried to give 3-chloro-4-(3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobut-1-yl)-2,6-difluoro- N- (4-methoxybenzyl) -N- (thiazo-2-yl)benzenesulfonamide as a yellow solid (0.0700 g, 0.120 mmol, 27% yield). MS (ES+) m/z 585.2, 587.2 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.82 (dd, J = 1.2, 13.2 Hz, 1H), 5.20 (s, 2H), 4.22–4.12 (m, 2H), 4.05 (t, J = 7.2 Hz, 2H), 3.76 (s, 3H), 2.85–2.74 (m, 1H), 2.27 (s, 6H), 2.09 (s, 2H), 0.90 (s, 6H).

Step 5. Add 1.0 mL of trifluoroacetic acid to a solution of 3-chloro-4-(3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobut-1-yl)-2,6-difluoro- N- (4-methoxybenzyl) -N- (thiazol-2-yl)benzenesulfonamide (0.0700 g, 0.120 mmol) in dichloromethane (10.0 mL). Stir the mixture at 30 °C for 1 h. Concentrate the reaction mixture under reduced pressure. The residue was diluted with dimethylformamide (1.0 mL) and the pH was adjusted to approximately 8 with ammonium hydroxide (10% purity). The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid)-acetonitrile]; gradient: 10%–30% B, for 2 min). The desired fraction was collected and freeze-dried to give 3-chloro-4-(3-(1-(dimethylamino)-2-methylpropyl-2-yl)azacyclobut-1-yl)-2,6-difluoro- N- (thiazo-2-yl)benzenesulfonamide as a white solid (0.00470 g, 0.00892 mmol, 7% yield, 97% purity, formate). MS (ES+) m/z 465.1, 467.1 (M+ 1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.25 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.22 (dd, J = 1.2, 13.2 Hz, 1H), 4.17–4.08 (m, 2H), 4.04–3.94 (m, 2H), 2.77–2.63 (m, 1H), 2.24 (s, 6H), 2.11 (s, 2H), 0.85 (s, 6H).

Example 14: 3-Chloro-4-(3-((dimethylamino)methyl)-3-methylazacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide Step 1. ((1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)aminesulfonyl)-3,5-difluorophenyl)-3-methylazidocyclobut-3-yl)methyl)tert-butyl carbamate) ((3-methylazidocyclobut-3-yl)methyl) tert- butyl carbamate (0.100 g, 0.422 mmol, hydrochloride), 3-chloro- N- (2,4-dimethoxybenzyl)-2,4,6-trifluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.210 g, 0.428 mol) and cesium carbonate (0.550 g, 1.69 mmol) were reacted with N , N -dimethylformamide (2.0... The solution in mL was stirred at 25 °C for 12 h. Ethyl acetate (20 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a yellow oily substance, ((1-(2-chloro-4-( N- (2,4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl)aminesulfonyl)-3,5-difluorophenyl)-3-methylazacyclobut-3-yl)methyl)carbamate tributyl ester (0.300 g, crude). MS (ES+) m/z 671.1, 673.1 (M + 1).

Step 2. 4-(3-(aminomethyl)-3-methylazacyclobut-1-yl)-3-chloro-2,6-difluoro- N- (6-fluoropyridin-2- yl )benzenesulfonamide was added to a solution of 0.300 g (0.447 mmol) of tributyl carbamate in 5.0 mL of dichloromethane. The mixture was stirred at 25 °C for 16 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 23%–53% B, for 10 min). The desired fraction was collected and freeze-dried to give a yellow solid of 4-(3-(aminomethyl)-3-methylazacyclobut-1-yl)-3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.0300 g, 0.0561 mmol, 13% yield, trifluoroacetate). ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 11.76 (s, 1H), 7.87 (q, J = 8.0 Hz, 4H), 6.86 (dd, J = 1.6, 8.0 Hz, 1H), 6.74 (dd, J = 2.4, 8.0 Hz, 1H), 6.27 (d, J = 12.8 Hz, 1H), 4.15 (d, J = 8.8 Hz, 2H), 3.92 (d, J = 8.8 Hz, 2H), 3.10 (s, 2H), 1.32 (s, 3H)

Step 3. 3-Chloro-4-(3-((dimethylamino)methyl)-3-methylazacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide was added to a solution of 4-(3-(aminomethyl)-3-methylazacyclobut-1-yl)-3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.0300 g, 0.0561 mmol, trifluoroacetate) and formaldehyde (0.0460 g, 0.567 mmol) in methanol (2.0 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm ; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 18%–48% B, min). The desired fraction was collected and freeze-dried to give a white solid of 3-chloro-4-(3-((dimethylamino)methyl)-3-methylazacyclobut-1-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.0106 g, 0.0222 mmol, 40% yield, 94% purity). MS (ES+) m/z 449.1, 451.1 (M+ 1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (q, J = 8.0 Hz, 1H), 6.82–6.73 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.26 (d, J = 13.2 Hz, 1H), 4.02–3.88 (m, 4H), 2.57 (s, 2H), 2.24 (s, 6H), 1.33 (s, 3H)

The other examples listed in Table 2 are similar in preparation to Example 14 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 2 Example Name and Structure Analysis data 18 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobut-1-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66–7.41 (m, 1H), 6.70–6.53 (m, 1H), 6.38–6.23 (m, 1H), 6.20–6.07 (m, 1H), 4.34–4.17 (m, 2H), 3.80–3.68 (m, 2H), 3.19–3.11 (m, 2H), 2.76–2.63 (m, 2H), 2.61–2.57 (m, 3H), 1.76–1.64 (m, 2H), 1.55 (s, 2H), 1.46–1.14 (m, 4H). MS (ES+) m/z 489.2, 491.2 (M+1) 19 (3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48 (q, J = 8.4 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.25–6.07 (m, 2H), 4.22–4.14 (m, 2H), 3.81–3.77 (m, 2H), 3.02 (s, 2H), 2.96–2.88 (m, 2H), 2.66 (d, J = 8.4 Hz, 2H), 2.54 (s, 3H), 2.11–1.98 (m, 1H), 1.56–1.43 (m, 1H). MS (ES+) m/z 461.0, 463.0 (M + 1) 20 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.53 (q, J = 8.4 Hz, 1H), 6.62 (dd, J = 2.4, 7.6 Hz, 1H), 6.27 (d, J = 7.2 Hz, 1H), 6.16 (d, J = 12.8 Hz, 1H), 4.19 (td, J = 8.4, 12.0 Hz, 2H), 3.81 (td, J = 5.2, 8.4 Hz, 2H), 3.14 (s, 2H), 3.07–3.00 (m, 2H), 2.73–2.65 (m, 2H), 2.62 (s, 3H), 2.14–2.03 (m, 1H), 1.59–1.46 (m, 1H). MS (ES+) m/z 461.0, 463.0 (M + 1) twenty four 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (q, J = 8.0 Hz, 1H), 6.99 (dd, J = 2.4, 8.0 Hz, 1H), 6.34 (dd, J = 2.8, 7.6 Hz, 1H), 5.64 (d, J = 12.8 Hz, 1H), 4.15–3.95 (m, 4H), 3.29 (s, 3H), 3.09–3.00 (m, 2H), 2.82 (s, 6H), 2.42–2.36 (m, 2H). MS (ES+) m/z 479.0, 481.0 (M + 1)

Example 15: 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-ethylazidocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide Step 1. Red-Al (1.5 M, 3.73 mL, 1.2 eq) was added to a mixture of 3-ethyl- _3- (2-methoxy-2-ethoxy-ethyl)azidocyclobutane-1-carboxylate (1.20 g, 4.66 mmol, 1.0 eq) in THF (10 mL) under N2 atmosphere and at 0 °C. The mixture was then stirred for 3 hr under _N2 atmosphere and at 0 °C. LC-MS (P1: RT = 0.389 min; MS = [M-99] = 128.3) showed complete consumption of the reactants and detection of approximately 98.8% of the desired compound. TLC (plate 1; _I₂ ; _SiO₂ , petroleum ether: ethyl acetate = 2:1; R₁: _R₅ = 0.77; P₁: _R₅ = 0.19) indicated complete consumption of the reactants and formation of a new spot. TLC (plate 2; DNP; _SiO₂ , petroleum ether: ethyl acetate = 2:1; P₁: _R₅ = 0.19) indicated complete consumption of the reactants and formation of a new spot. The reaction mixture was quenched by adding 10 mL of water at 25°C, followed by extraction with EtOAc (8 mL * 3). The combined organic layers were washed with NaCl (10 mL), dried over [ _{Na₂SO₄ ]} , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (plate 2; DNP; _SiO₂ , petroleum ether: ethyl acetate = 2:1; P1: _Rf = 0.19). LCMS (P1: RT = 0.383 min; MS = [M-99] = 128.3) showed detection of approximately 72.6% of the desired compound. The compound 3-ethyl-3-(2-epihydroxyethyl)azacyclobutane-1-carboxylic acid tributyl ester (850 mg, 3.74 mmol, 80.2% yield) was obtained as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) confirmed the obtained compound as the desired compound. MS (ES+) m/z 227.1, 128.3 (M-99).

Step 2. Add AcOH (1.19 mg, 19.8 μmol, 1.13 μL, 0.01 eq) to a solution of 3-ethyl-3-(2-dimethylamino)ethyl)-3-ethylazidocyclobutane-1-carboxylic acid tributyl ester (450 mg, 1.98 mmol, 1.0 eq), _Me₂NH₃ (1.12 g, 9.90 mmol, 1.25 mL, 5.0 eq) in MeOH (10 mL) and stir at 25 °C for 10 min. Then slowly add _NaBH₃CN (622.06 mg, 9.90 mmol, 5.0 eq) at 0 °C. Stir the mixture at 25 °C for 5 hr. LC-MS (EC16103-11-P1A; P1: RT = 0.281 min; MS = [M+1] = 257.2) showed complete consumption of the reactants and detection of the desired compound at approximately 12.6% purity. TLC (plate 1; _I₂ ; _SiO₂ , petroleum ether: ethyl acetate = 0:1; R₁: _Rf = 0.93; P₁: _Rf = 0.07) indicated complete consumption of the reactants and formation of numerous new spots. The reaction mixture was quenched by adding water (10 mL) at 25 °C, followed by extraction with EtOAc (10 mL * 3). The combined organic layers were washed with NaCl (15 mL), dried over [ _Na₂SO₄ ], filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by _column chromatography (plate 1; _I₂ ; _SiO₂ , petroleum ether: ethyl acetate = 0: 1; P₁: _Rf = 0.07). The compound 3-[2-(dimethylamino)ethyl]-3-ethyl-azacyclobutane-1-carboxylic acid tributyl ester (420 mg, 1.64 mmol, 82.7% yield) was obtained as a colorless oil. MS (ES+) m/z 256.2, 257.2 (M +1).

Step 3. HCl/dioxane (6 mL) was added to a solution of 2-(3-ethylazidocyclobut-3-yl)-N,N-dimethylethyl-1-amine 3-[2-(dimethylamino)ethyl]-3-ethyl-azidocyclobutane-1-carboxylic acid tributyl ester (420 mg, 1.64 mmol, 1.0 eq). The mixture was stirred at 25 °C for 2 hr. LC-MS (P1: RT = 0.077 min; MS = [M+1] = 157.2) showed complete consumption of the reactants and detection of the desired compound with approximately 95.3% purity. The reaction mixture was concentrated under reduced pressure to obtain a residue that could be used without purification. The compound 2-(3-ethylazacyclobut-3-yl)-N,N-dimethyl-ethylamine (500 mg, crude, HCl) was obtained as a colorless oil. MS (ES+) m/z 156.1, 157.2 (M+1).

Step 4. Add Cs₂CO₃ (1.78 g, 5.45 mmol, 3.0 eq) to a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-(2-(dimethylamino)ethyl)-3-ethylazidocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridinyl-2-yl)benzenesulfonamide (891 mg, 1.82 mmol, 1.0 eq) and 2-(3-ethylazidocyclobut- ₃ -yl ₎ -N,N-dimethyl-ethylamine (350 mg, 1.82 mmol, 1.0 eq, HCl) in DMF (10 mL). The mixture was stirred at 25°C for 2 hours. LC-MS (P1: RT = 0.431 min; MS = [M+H] = 627.2) showed complete consumption of the reactants and detection of approximately 38.9% of the desired compound. TLC (plate 1; _SiO2 , petroleum ether: ethyl acetate = 0:1; R1: _Rf = 0.91; P1: _Rf = 0.04) indicated incomplete consumption of the reactants and the formation of many new spots. The reaction mixture was quenched by adding water (15 mL) at 25°C and then extracted with EtOAc (15 mL * 3). The combined organic layers were washed with NaCl (15 mL), dried over [ _{Na2SO4 ]} , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (plate 2; _SiO2 , petroleum ether: ethyl acetate = 0: 1; P1: _Rf = 0.04). LCMS (P1: RT = 0.434 min; MS = [M+1] = 627.3) showed P1 to be approximately 80.2% pure. The compound 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[2-(dimethylamino)ethyl]-3-ethyl-azacyclobut-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (250 mg, 398.65 μmol, 21.95% yield) was obtained as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) and ^¹⁹ F NMR (400 MHz, _CDCl₃ ) confirmed that the obtained compound was the desired compound. MS (ES+) m/z 626.1, 627.2 (M +1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (q, J = 8.2 Hz, 1H), 7.16 - 7.26 (m, 2H), 6.64 (dd, J = 8.0, 2.8 Hz, 1H), 6.33 - 6.43 (m, 2H), 5.84 (d, J = 11.6 Hz, 1H), 5.03 - 5.16 (m, 2H), 3.93 (q, J = 8.4 Hz, 4H), 3.75 (d, J = 6.4 Hz, 7H), 2.35 - 2.48 (m, 7H), 1.81 - 1.96 (m, 2H), 1.67 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.6 Hz, 3H).

Step 5. 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-ethylazidocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide: A solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[2-(dimethylamino)ethyl]-3-ethyl-azidocyclobut-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridinyl)benzenesulfonamide (200 mg, 319 μmol, 1.0 eq) in TFA (1 mL) and DCM (1 mL) was stirred at 25°C for 2 hr. LC-MS (P1: RT = 0.340 min; MS = [M+1] = 477.2) showed complete consumption of the reactants and detection of the desired compound with a purity of approximately 91.4%. The reaction mixture was quenched by adding ₅ mL of NaHCO3 at 25 °C, followed by extraction with DCM (3 mL * 3). The combined organic layers were washed with NaCl (5 mL), dried over [ _{Na2SO4 ]} , filtered, and concentrated under reduced pressure to obtain the residue. The residues were purified by preparative HPLC (HCl conditions; column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (HCl) - ACN]; gradient: 15% - 45% B, for 10 min). LCMS (P1: RT = 0.350 min; MS = [M+1] = 477.2) showed the desired compound with a purity of approximately 82.6%. The compound 3-chloro-4-[3-[2-(dimethylamino)ethyl]-3-ethyl-azacyclobut-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (67.3 mg, 133 μmol, 41.7% yield, 94.2% purity) was obtained as a grayish-white solid. LC-MS (P1: RT = 2.908 min; MS = [M+1] = 477.2) showed a detection of approximately 93.8% of the desired compound. HPLC (P1: RT = 2.043 min) showed a detection of approximately 94.2% of the desired compound's purity. ^¹H NMR (400 MHz, MeOD) and ^¹⁹ F NMR (400 MHz, MeOD) confirmed the obtained compound as the desired compound. MS (ES+) m/z 476.1, 477.2 (M + 1). ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.77 (q, J = 8.0 Hz, 1H), 6.92 (dd, J = 7.8, 2.0 Hz, 1H), 6.61 (dd, J =8.0, 2.4 Hz, 1H), 6.14 (dd, J = 13.2, 1.6 Hz, 1H), 3.94 - 4.11 (m, 4H), 3.18 (dt, J = 8.4, 4.4 Hz, 2H), 2.86 - 2.98 (m, 6H), 2.09 (dt, J = 8.4, 4.4 Hz, 2H), 1.70 (q, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).

The other examples listed in Table 3 are similar to those in Example 15 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 3 Example Name and Structure Analysis data 16 3-Chloro-4-(3-cyclopropyl-3-(2-(dimethylamino)ethyl)azacyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 1H NMR (400 MHz, methanol-d ₄ ) δ 7.77 (d, J = 8.0 Hz, 1H), 6.92 (dd, J = 7.8, 1.6 Hz, 1H), 6.61 (dd, J = 8.0, 2.4 Hz, 1H), 6.13 (d, J = 13.2 Hz, 0.97 (m, 1H), 0.53 - 0.65 (m, 2H), 0.29 - 0.45 (m, 2H). MS (ES+) m/z 488.1, 489.2 (M + 1)

Example 17: 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)benzenesulfonamide   Step 1. 3-(1-Methyl-1H-pyrrolo-2-yl)azionitrobutane-1-carboxylic acid tributyl ester was added under nitrogen to a solution of 1-methyl- 1H -pyrrole (2.87 g, 35.3 mmol) and dipotassium sulfonyl sulfate (0.955 g, 3.53 mmol) in dimethyl sulfoxide (7.5 mL) and water (2.5 mL). The mixture was stirred at 70 °C for 12 h. Ethyl acetate (10 mL) and water (10 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 3/1) to give a yellow oily substance, 3-(1-methyl- 1H -pyrrolo-2-yl)azacyclobutane-1-carboxylic acid tributyl ester (0.0800 g, 0.322 mmol, 18% yield, 95% purity). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.58 (t, J = 2.0 Hz, 1H), 6.12–6.05 (m, 2H), 4.31–4.22 (m, 2H), 4.00 (dd, J = 6.8, 8.0 Hz, 2H), 3.83–3.73 (m, 1H), 3.47 (s, 3H), 1.45 (s, 9H).

Step 2. Platinum dioxide (0.0730 g, 0.321 mmol) was added to a mixture of 3-(1-methyl- 1H -pyrrolo-2-yl)azacyclobutane-1-carboxylic acid tributyl ester (0.0800 g, 0.322 mmol) and acetic acid (2.0 mL) under nitrogen atmosphere. The solution was purged three times with hydrogen and then stirred for 12 h at 50 °C under hydrogen atmosphere (50 psi). The reaction mixture was concentrated under reduced pressure to give 0.100 g (crude) of 3-(1-methylpyrrolo-2-yl)azacyclobutane-1-carboxylic acid tributyl ester as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.15–3.96 (m, 2H), 3.76–3.60 (m, 2H), 3.43 (s, 1H), 2.95 (s, 2H), 2.66–2.57 (m, 1H), 2.52 (s, 3H), 1.88 (s, 3H), 1.72 (s, 1H), 1.43 (s, 9H).

Step 3. Acetyl chloride (0.164 g, 2.09 mmol) was added to a solution of 2-(azacyclobut-3-yl)-1 - methylpyrrolidone (0.100 g, 0.416 mmol) (crude) in methanol (4.0 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 2-(azacyclobut-3-yl)-1-methylpyrrolidone (0.0500 g, crude, 2-hydrochloride) as a yellow oil. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 4.31–4.23 (m, 1H), 4.18 (t, J = 8.0 Hz, 2H), 4.12–4.04 (m, 1H), 3.83 (d, J = 8.0 Hz, 1H), 3.74–3.65 (m, 1H), 3.55–3.46 (m, 1H), 3.24–3.15 (m, 1H), 2.91 (s, 3H), 2.46–2.35 (m, 1H), 2.22–2.14 (m, 1H), 2.13–2.03 (m, 1H), 1.92–1.79 (m, 1H).

Step 4. 3-Chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)benzenesulfonamide: 2-(azacyclobut-3-yl)-1-methylpyrrolidone (0.0500 g, 0.235 mmol, 2-hydrochloride), 3-chloro- N- (2,4-dimethoxybenzyl)-2,4,6-trifluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.115 g, 0.234 mmol), and cesium carbonate (0.383 g, 1.18 mmol) are reacted with N , N -dimethylformamide (1.0... The solution in mL was stirred at 25°C for 2 h. Ethyl acetate (5 mL) and water (5 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic extract was washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 3-chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)benzenesulfonamide (0.120 g, crude product), which was a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (q, J = 8.0 Hz, 1H), 7.25–7.21 (m, 2H), 6.63 (dd, J = 2.8, 8.0 Hz, 1H), 6.40–6.36 (m, 2H), 5.85 (dd, J = 1.6, 12.8 Hz, 1H), 5.10 (s, 2H), 4.44–4.37 (m, 1H), 4.29 (t, J = 8.8 Hz, 1H), 4.03–3.94 (m, 2H), 3.79–3.71 (m, 8H), 3.16–3.06 (m, 1H), 2.92 (d, J = 5.2 Hz, 1H), 2.55–2.43 (m, 1H), 2.39–2.32 (m, 3H), 2.01–1.92 (m, 1H), 1.85–1.77 (m, 2H).

Step 5. 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)benzenesulfonamide was added to a solution of 3-chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)benzenesulfonamide (0.120 g, 0.196 mmol) (crude product) in dichloromethane (10.0 mL) with 1.0 mL of trifluoroacetic acid. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with N , N -dimethylformamide (2 mL). The mixture was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid)-acetonitrile]; gradient: 10%–40% B, for 10 min). The desired fraction was collected and freeze-dried to give a white solid of 3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azacyclobutan-1-yl)benzenesulfonamide (0.0096 g, 0.0198 mmol, 10% yield, 95% purity). MS (ES+) m/z 461.0, 463.0 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71–7.56 (m, 1H), 6.68 (d, J = 6.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 12.8 Hz, 1H), 4.32 (t, J = 8.4 Hz, 1H), 4.20 (t, J = 8.4 Hz, 1H), 3.97–3.92 (m, 1H), 3.89 (dd, J = 6.4, 8.4 Hz, 1H), 3.08 (d, J = 3.2 Hz, 1H), 2.91–2.84 (m, 1H), 2.81–2.72 (m, 1H), 2.46–2.42 (m, 1H), 2.37 (s, 3H), 2.03–1.90 (m, 1H), 1.77–1.69 (m, 2H), 1.61–1.50 (m, 1H).

Example 25: 3-Chloro-2,6-difluoro-4-(6-isopropyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(pyridin-2-yl)benzenesulfonamide Step 1. 6-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)aminesulfonyl)-3,5-difluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester was added to a solution of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester (0.100 g, 0.504 mmol) and cesium carbonate (0.493 g, 1.51 mmol) in dimethylformamide (2.0 mL). 3-chloro- N- (2,4-dimethoxybenzyl)-2,4,6-trifluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.248 g, 0.505 mmol) was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate (3 mL) and water (2 mL). The mixture was extracted with ethyl acetate (3 × 2 mL). The combined organic extract was washed with brine (8 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, 0–30% ethyl acetate/petroleum ether solvent gradient, 30 mL/min) to give a colorless oily substance, 6-(2-chloro-4-( N- (2,4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl)aminesulfonyl)-3,5-difluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tributyl ester (0.220 g, 0.326 mmol, 65% yield, 99% purity). MS (ES+) m/z 669.0, 671.0 (M + 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (q, J = 8.0 Hz, 1H), 7.25–7.18 (m, 2H), 6.65 (d, J = 2.8 Hz, 1H), 6.42–6.33 (m, 2H), 5.88 (dd, J = 1.6, 12.4 Hz, 1H), 5.08 (s, 2H), 4.35 (s, 4H), 4.12–4.09 (m, 4H), 3.74 (d, J = 8.0 Hz, 6H), 1.45 (s, 9H).

Step 2. Dichloromethane (10.0 mL) was added to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(2,6-diazaspiro[3.3]hept-2-yl)benzenesulfonamide in 6-(2-chloro-4-( N- (2,4-dimethoxybenzyl) -N- (6-fluoropyridin-2-yl)aminesulfonyl)-3,5-difluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.220 g, 0.326 mmol) in trifluoroacetic acid (1.0 mL). The mixture was stirred at 25 °C for 2 h. Concentration of the reaction mixture under reduced pressure yielded a brown solid, 3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(2,6-diazaspiro[3.3]hept-2-yl)benzenesulfonamide (0.230 g, crude, trifluoroacetate). MS (ES+) m/z 418.9, 420.9 (M+ 1). ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.76 (q, J = 8.0 Hz, 1H), 6.91 (dd, J = 1.6, 8.0 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 6.16 (d, J = 12.0 Hz, 1H), 4.45 (s, 4H), 4.27 (s, 4H)

Step 3. 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(6-isopropyl-2,6-diazaspiro[3.3]hept-2-yl)benzenesulfonamide: A solution of 3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(2,6-diazaspiro[3.3]hept-2-yl)benzenesulfonamide (0.0500 g, 0.0938 mmol, trifluoroacetate), acetone (0.0280 g, 0.482 mmol), acetic acid (0.0170 g, 0.283 mmol) and sodium cyanoboronide (0.0180 g, 0.286 mmol) in methanol (0.5 mL) was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: 14%–44% B, for 9 min). The desired fraction was collected and freeze-dried to give 3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(6-isopropyl-2,6-diazaspiro[3.3]hept-2-yl)benzenesulfonamide (0.0221 g, 0.0418 mmol, 45% yield, 94% purity, hydrochloride). MS (ES+) m/z 461.1, 463.1 (M + 1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.97–11.50 (m, 1H), 11.20–10.70 (m, 1H), 7.86 (q, J = 8.0 Hz, 1H), 6.85 (dd, J = 1.6, 8.0 Hz, 1H), 6.73 (dd, J = 2.4, 8.0 Hz, 1H), 6.37 (d, J = 13.2 Hz, 1H), 4.54 –4.27 (m, 4H), 4.18 (s, 4H), 3.38–3.35 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H)

The other examples listed in Table 4 are similar in preparation to Example 25 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 4 Example Name and Structure Analysis data 26 3-Chloro-2,6-difluoro-4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.59–7.49 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 4.4 Hz, 1H), 6.22 (d, J = 12.0 Hz, 1H), 4.27 (s, 4H), 3.84 (s, 4H), 2.54 (s, 3H). MS (ES+) m/z 433.0, 435.0 (M + 1) 27 3-Chloro-2,6-difluoro-4-(6-methyl-2,6-diazaspiro[3,4]oct-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO- d ₆ + HCl) δ 11.8 (s, 1H), 11.4 (s, 1H), 7.85 (q, J = 8.0 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 6.28 (d, J = 12.8 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.26 (s, 2H), 4.15 (d, J = 8.8 Hz, 1H), 3.79–3.75 (m, 1H), 3.51–3.47(m, 1H), 3.28–3.19 (m 1H), 3.10–2.98 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.44–2.33 (m, 1H), 2.29–2.20 (m, 1H). MS (ES+) m/z 447.0, 449.0 (M + 1) 28 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (s, 1H), 7.71–7.53 (m, 1H), 6.66 (dd, J = 2.0, 8.0 Hz, 1H), 6.47–6.32 (m, 1H), 6.19 (d, J = 13.2 Hz, 1H), 4.19 (s, 2H), 4.08 (s, 2H), 2.92–2.85 (m, 1H), 2.36 (ddd, J = 2.8, 7.6, 10.0 Hz, 2H), 2.25 (s, 6H), . MS (ES+) m/z 461.1, 463.1 (M + 1) 2.16–2.06 (m, 2H) 29 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 1) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.64 (q, J = 8.0 Hz, 1H), 6.84 (dd, J = 2.0, 8.0 Hz, 1H), 6.43 (dd, J = 2.4, 8.0 Hz, 1H), 6.06 (dd, J = 1.6, 13.2 Hz, 1H), 4.14–4.00 (m, 4H), 3.01 (t, J = 8.0 Hz, 1H), 2.52 (s, 6H), 2.30 (dd, J = 7.6, 13.2 Hz, 1H), 2.10–1.99 (m, 2H), 1.98–1.85 (m, 2H), 1.78–1.63 (m, 1H). MS (ES+) m/z 475.1, 477.1 (M + 1) 30 3-Chloro-4-(6-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.69 (q, J = 8.0 Hz, 1H), 6.87 (dd, J = 2.0, 8.0 Hz, 1H), 6.50 (dd, J = 2.4, 8.0 Hz, 1H), 6.08 (dd, J = 1.6, 13.2 Hz, 1H), 4.20–4.00 (m, 4H), 3.21 (t, J = 8.4 Hz, 1H), 2.64 (s, 6H), 2.36 (dd, J = 7.6, 13.2 Hz, 1H), 2.16–2.02 (m, 2H), 2.01–1.89 (m, 2H), 1.81–1.68 (m, 1H). MS (ES+) m/z 475.1, 477.1 (M + 1) 31 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methylaziroxybutyl-1-yl)-2-fluoro-6-methyl-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (m, 1H), 6.7 - 6.62 (m, 1H), 6.49 (s, 1H), 6.17 (s, 1H), 3.98 - 3.85 (d, J = 8.1 Hz, 2H), 3.85 - 3.73 (d, J = 8.1 Hz, 2H), 2.65 - 2.58 (m, 2H), 2.58 - 2.54 (m, 2H), 2.4 - 2.24 (m, 6H), 1.81 - 1.68 (m, 2H), 1.22 (s, 3H). MS (ES+) m/z 459.20, 461.2 (M + 1). 32 3,6-Dichloro-2-fluoro-4-(7-methyl-2,7-diazaspiro[3,6]dec-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR: 400 MHz, CDCl3- d ) δ 10.41 (br s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.57 - 6.59 (m, 1H), 6.31 (s, 1H), 6.27 (br d, J = 6.0 Hz, 1H), 3.89 (q, J = 6.8 Hz, 4H), 2.97 (br s, 4H), 2.60 (s, 3H), 2.05 (br s, 2H), 1.90 - 1.92 (m, 2H), 1.69 (br s, 2H). MS (ES-) m/z 491.0 (M+1). 33 3,6-Dichloro-2-fluoro-4-(8-methyl-5-oxa-2,8-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR: EC28542-225-P1A2 (400 MHz, CDCl3- d ) δ 7.72 (q, J = 8.0 Hz, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 6.62 (dd, J = 2.0, 8.0 Hz, 1H), 6.22 (d, J = 1.6 Hz, 1H), 4.19 (d, J = 9.2 Hz, 2H), 4.09 (d, J = 9.2 Hz, 2H), 3.72 - 3.70 (m, 2H), 2.57 (s, 2H), 2.40 - 2.38 (m, 2H), 2.32 (s, 3H). MS (ES-) m/z 478.9 (M+1). MS (ES-) m/z 463.0 (M+1). 34 3,6-Dichloro-2-fluoro-4-(5-methyl-2,5-diazaspiro[3.4]oct-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR: EC28542-255-P1B (400 MHz, DMSO-d ₆ ) δ 11.74 (br s, 1H), 7.82 (q, J = 8.0 Hz, 1H), 6.81 (br d, J = 7.6 Hz, 1H), 6.67 (dd, J = 2.0, 8.0 Hz, 1H), 6.44 (s, 1H), 4.33 (br d, J = 9.2 Hz, 2H), 4.04 (br d, J = 9.2 Hz, 2H), 2.64 (br t, J = 6.8 Hz, 2H), 2.37 (s, 3H), 2.03 (t, J = 7.2 Hz, 2H), 1.70-1.65 (m, 2H).

Example 35: 3,6-Dichloro-2-fluoro-4-(6-methyl-2,6-diazaspiro[3.6]dec-2-yl)-N-(pyridin-2-yl)benzenesulfonamide Step 1. 6-Methyl-2,6-diazaspiro[3.6]decane-2-carboxylate tributyl ester was added to a solution of 2,6-diazaspiro[3.6]decane-2-carboxylate (450.0 mg, 1.87 mmol) and formaldehyde (1.52 g, 37.0% purity, 18.75 mmol) in DCM (5.0 mL). The mixture was stirred at 20 °C for 18 h. The solution was quenched with 5 mL of saturated _NaHCO3 solution. DCM (10 mL) and water (10 mL) were added, and the layers were separated. The aqueous phase was extracted with DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 6-methyl-2,6-diazaspiro[3.6]decane-2-carboxylic acid tributyl ester (400.0 mg, 1.57 mmol, 83.9% yield) as a viscous oil. MS (ES+) m/z 255.2 (M+1).

Step 2. Acetyl chloride (490.22 mg, 6.29 mmol) was added to 5 ml of stirred MeOH at 0 °C. After stirring for 5 min, MeOH (1 ml) containing tert-butyl 6-methyl-2,6-diazaspiro[3.6]decane-2-carboxylate (400.0 mg, 1.57 mmol) was added and the solution was stirred at 20 °C for 6 h. The solution was concentrated under vacuum to obtain 6-methyl-2,6-diazaspiro[3.6]decane dihydrochloride (320.0 mg, 90.0% purity, 1.27 mmol, 80.7% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.28 - 11 (m, 1H), 9.67 - 9.21 (m, 2H), 4.3 - 4.18 (m, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.76 - 3.58 (m, 3H), 3.36 (dd, J = 13.7, 8.5 Hz, 1H), 3.28 - 3.18 (m, 1H), 3.13 - 3 (m, 1H), 2.78 (d, J = 4.6 Hz, 3H), 2.26 - 2.16 (m, 1H), 2 - 1.88 (m, 1H), 1.86 - 1.51 (m, 4H). MS (ES+) m/z 155.2 (M + 1).

Step 3. 3,6-Dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-methyl-2,6-diazaspiro[3.6]dec-2-yl)benzenesulfonamide was stirred in DMSO (5 mL) with methyl-2,6-diazaspiro[3.6]decane dihydrochloride 3 (115 mg, 90.0% purity, 390 μmol) and DIPEA (152.79 mg, 1.18 mmol). After stirring for 3 min, 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzene-1-sulfonamide (200.0 mg, 394.24 μmol) was added to the mixture, and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with EtOAc (10 ml) and washed with saturated _NaHCO3 aqueous solution (5 ml) and water (5 ml). Concentration of the organic phase under reduced pressure yielded 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoropyridin-2-yl)-4-6-methyl-2,6-diazaspiro[3,6]dec-2-ylphenyl-1-sulfonamide (240.0 mg, 94.0% purity, 351.64 μmol, 89.2% yield). MS (ES+) m/z 641.2, 643.2, 645.2 (M+ 1).

Step 4. 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-methyl-2,6-diazaspiro[3.6]dec-2-yl)benzenesulfonamide was added to a solution of 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoropyridin-2-yl)-4-6-methyl-2,6-diazaspiro[3.6]dec-2-ylbenzene-1-sulfonamide (240.0 mg, 94.0% purity, 351.64 μmol) in DCM (2 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched at 0 °C with saturated sodium bicarbonate solution (0.5 mL). The mixture was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (column: XBridge BEH C18 100x19 mm, 5 μm; precipitate: 0-65% _H₂O /ACN/0.1% _NH₄OH ) to obtain 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-6-methyl-2,6-diazaspiro[3.6]dec-2-ylphenyl-1-sulfonamide (102.0 mg, 98.0% purity, 203.43 μmol, 57.8% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.77 - 7.65 (m, 1H), 6.78 - 6.67 (m, 1H), 6.59 - 6.47 (m, 1H), 6.36 (s, 1H), 3.97 (d, J = 9.3 Hz, 2H), 3.9 - 3.79 (m, 2H), 2.91 - 2.75 (m, 2H), 2.66 - 2.55 (m, 2H), 2.41 (s, 3H), 1.86 - 1.73 (m, 2H), 1.65 - 1.55 (m, 2H), 1.55 - 1.44 (m, 2H). MS (ES+) m/z 491.2, 493.2, 495.2 (M + 1).

The other examples listed in Table 5 are similar in preparation to Example 35 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 5 Example Name and Structure Analysis data 36 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.5]non-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 1) ¹ H NMR (400 MHz, DMSO- d ₆ + HCl) δ 11.8 (s, 1H), 11.4 (s, 1H), 7.85 (q, J = 8.0 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 6.28 (d, J = 12.8 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.26 (s, 2H), 4.15 (d, J = 8.8 Hz, 1H), 3.79–3.75 (m, 1H), 3.51–3.47(m, 1H), 3.28–3.19 (m 1H), 3.10–2.98 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.44–2.33 (m, 1H), 2.29–2.20 (m, 1H). MS (ES+) m/z 447.0, 449.0 (M + 1) 37 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.5]non-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.41 (s, 1H), 7.78 (q, J = 8.0 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.68–6.55 (m, 1H), 6.28 (d, J = 13.6Hz, 1H), 4.23–4.00 (m, 2H), 3.88 (dd, J = 8.4, 15.6 Hz, 2H), 2.37–2.18 (m, 7H), 1.98–1.87 (m, 1H), 1.68–1.56 (m, 2H), 1.55–1.34 (m, 4H), 1.22 (dd, J = 3.6, 8.0 Hz, 1H). MS (ES+) m/z 489.0, 491.0 (M + 1) 38 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.62 (q, J = 8.0 Hz, 1H), 6.78 (dd, J = 2.0, 8.0 Hz, 1H), 6.45 (dd, J = 2.0, 7.6 Hz, 1H), 6.07 (d, J = 12.8 Hz, 1H), 4.54 (d, J = 8.8 Hz, 1H), 4.29 (d, J = 8.0 Hz, 1H), 4.17–4.06 (m, 2H), 3.67–3.57 (m, 1H), 2.66 (s, 6H), 2.19 (ddd, J = 2.4, 7.2, 12.8 Hz, 1H), 2.14–2.04 (m, 1H), 2.03–1.93 (m, 1H), 1.90–1.75 (m, 2H), 1.67–1.54 (m, 1H). MS (ES+) m/z 475.0, 477.0 (M + 1) 39 3-Chloro-4-(5-(dimethylamino)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.65 (q, J = 8.0 Hz, 1H), 6.81 (dd, J =2.0, 8.0 Hz, 1H), 6.48 (dd, J = 2.4, 8.0 Hz, 1H), 6.10 (d, J = 12.8 Hz, 1H), 4.53 (d, J = 8.8 Hz, 1H), 4.27 (d, J = 8.4 Hz, 1H), 4.20–4.05 (m, 2H), 3.61 (t, J = 7.2 Hz, 1H), 2.68 (s, 6H), 2.23–2.14 (m, 1H), 2.14–2.06 (m, 1H), 2.04–1.93 (m, 1H), 1.90–1.77 (m, 2H), 1.67–1.54 (m, 1H). MS (ES+) m/z 475.0, 477.0 (M + 1) 40 3,6-Dichloro-2-fluoro-4-(6-methyl-2,6-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR: (400 MHz, DMSO-d6). δ 7.74 (q, J = 8.0 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 7.2 Hz, 1H), 6.37 (s, 1H), 3.93 (d, J = 8.0 Hz, 2H), 3.91 (d, J = 8.0 Hz, 2H), 2.59 (br s, 2H), 2.38 (br s, 2H), 2.29 (s, 3H), 1.60 (br s, 2H), 1.50 - 1.52 (m, 2H). MS (ES-) m/z 477.0 (M+1). 41 3,6-Dichloro-2-fluoro-4-(5-methyl-2,5-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR: (400 MHz, DMSO-d6). δ 7.81 (q, J = 8.4 Hz, 1H), 6.80 (dd, J = 2.0, 8.0 Hz, 1H), 6.66 (dd, J = 2.0, 8.0 Hz, 1H), 6.45 (d, J = 0.8 Hz, 1H), 4.33 (br d, J = 9.6 Hz, 2H), 3.88 (br d, J = 9.2 Hz, 2H), 2.43 - 2.48 (m, 2H), 2.34 (s, 3H), 1.70 - 1.77 (m, 2H), 1.45 (br s, 4H). MS (ES-) m/z 477.0 (M+1). 42 3,6-Dichloro-2-fluoro-4-(5-methyl-8-oxa-2,5-diazaspiro[3.5]non-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ^1H NMR: (400 MHz, DMSO- _d6 ). δ 11.7 (s, 1H), 7.85 (q, J = 8.4 Hz, 1H), 6.83 (dd, J = 1.6, 7.6 Hz, 1H), 6.71 (dd, J = 1.6, 8.0 Hz, 1H), 6.48 (s, 1H), 4.36 (d, J = 9.6 Hz, 2H), 3.88 (d, J = 9.6 Hz, 2H), 3.63 (s, 2H), 3.60 - 3.57 (m, 2H), 2.43 - 2.41 (m, 2H), 2.34 (s, 3H). 43 3,6-Dichloro-2-fluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 - 7.39 (m, 1H), 6.59 - 6.47 (m, 1H), 6.28 (s, 1H), 6.19 (m, 1H), 4.29 - 4.19 (m, 2H), 3.78 - 3.66 (m, 2H), 3.12 - 2.95 (m, 2H), 2.75 - 2.65 (m, 1H), 2.65 - 2.58 (m, 1H), 2.38 - 2.27 (m, 3H), 1.71 - 1.58 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 - 1.04 (m, 4H). MS (ES+) m/z 505.20, 507.2, 509.2 (M + 1). 44 3-Chloro-2-fluoro-6-methyl-4-(3-((1-methylpiperidin-4-yl)methyl)azacyclobutan-1-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.68 - 7.53 (m, 1H), 6.69 - 6.56 (m, 1H), 6.47 - 6.34 (m, 1H), 6.14 (s, 1H), 4.25 (t, J = 7.9 Hz, 2H), 3.77 - 3.65 (m, 2H), 3.01 - 2.79 (m, 2H), 2.77 - 2.65 (m, 1H), 2.56 (s, 3H), 2.33 (d, J = 12.4 Hz, 3H), 2.25 - 2.08 (m, 2H), 1.68 - 1.56 (m, 2H), 1.51 (t, J = 6.7 Hz, 2H), 1.32 - 1.06 (m, 3H). MS (ES+) m/z 485.20, 487.20 (M + 1). 45 3,6-Dichloro-2-fluoro-4-(5-methyl-2,5-diazaspiro[3,6]dec-2-yl)-N-(pyridin-2-yl)benzenesulfonamide ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.78 - 11.57 (m, 1H), 7.74 - 7.52 (m, 1H), 6.74 - 6.56 (m, 1H), 6.39 (m, 2H), 4.02 - 3.95 (d, J = 6.4 Hz, 2H), 3.91 (d, J = 6.4 Hz, 2H), 2.72 - 2.65 (m, 2H), 2.27 (d, J = 1.6 Hz, 3H), 2.01 - 1.93 (m, 2H), 1.63 - 1.56 (m, 2H), 1.53 (s, 4H). MS (ES+) m/z 491.38, 493 (M + 1).

Example 46: 3,6-Dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide Step 1. 2-(3-methoxyazinocyclobut-3-yl)ethyl-1-ol hydrochloride was added to a solution of 3-(2-hydroxyethyl)-3-methoxyazinocyclobutane-1-carboxylic acid tributyl ester (500 mg, 2.16 mmol) in dichloromethane (11 mL) with hydrogen chloride (4 N dioxane solution, 11 mL). The reaction mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give 2-(3-methoxyazinocyclobut-3-yl)ethyl-1-ol hydrochloride (385 mg, quantitative yield, crude product) as a yellow oil. ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 9.49 (d, J = 47.5 Hz, 2H), 4.22 (s, 2H), 3.91-3.80 (m, 4H), 3.46 (t, J = 6.4 Hz, 2H), 3.16 (s, 3H), 2.00 (t, J = 6.4 Hz, 2H).

Step 2. 3,6-Dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3-methoxyazinocyclobut-1-yl)benzenesulfonamide: In a procedure similar to Step 1 of Example 25, N,N-dimethylformamide (5.9 mL) containing 3,6-dichloro- N -[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (600 mg, 1.18 mmol) is converted into a grayish-white solid of 3,6-dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- [6-fluoropyridin-2-yl]-2,4-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (500 mg, 1.18 mmol). -(6-Fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3-methoxyazacyclobut-1-yl)benzenesulfonamide (630 mg, 87% yield). MS (ES+) m/z 533.2 (M+1), 535.2 (M+1). ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.93 (q, J = 8.3 Hz, 1H), 7.13-7.06 (m, 2H), 6.90 (dd, J = 8.0, 2.7 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.47-6.43 (m, 2H), 5.03 (s, 2H), 4.47-4.46 (m, 1H), 4.24-4.18 (m, 4H), 3.74 (d, J = 12.7 Hz, 6H), 3.51-3.48 (m, 2H), 3.19 (s, 3H), 2.00-1.97 (m, 2H).

Step 3. 3,6-Dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-ethoxyethyl)azacyclobut-1-yl)benzenesulfonamide: Dissolve 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3-methoxyazacyclobut-1-yl)benzenesulfonamide (630 mg, 1.02 mmol) in dichloromethane (5.1 mL) and add Dess–Martin periodinane (454 mg, 1.07 mmol). Stir the reaction mixture at ambient temperature for 4 hours. The mixture was diluted with ethyl acetate and a saturated sodium bicarbonate aqueous solution. The organic layer was separated and washed sequentially with an aqueous sodium thiosulfate solution (20 mL) and brine (25 mL), then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3,6-dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-sideoxyethyl)azacyclobut-1-yl)benzenesulfonamide (630 mg, quantitative yield, crude product) as a colorless solid. MS (ES+) m/z 616.2, 618.2 (M+1). ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 9.65 (t, J = 2.0 Hz, 1H), 8.09-8.01 (m, 1H), 7.93 (q, J = 8.3 Hz, 1H), 7.12 (dd, J = 7.9, 2.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.0, 2.7 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.5, 2.4 Hz, 1H), 5.04 (s, 2H), 4.35 (q, J = 8.1 Hz, 4H), 3.74 (d, J = 13.1 Hz, 6H), 3.24 (s, 3H), 3.05 (d, J = 1.9 Hz, 2H)

Step 4. Add N-methylmethylamine to a solution of 3,6-dichloro- N-( 2,4-dimethoxybenzyl)-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1- yl )-2-fluoro- N- (6-fluoropyridin-2- yl )benzenesulfonamide (100 mg, 0.162 mmol) in tetrahydrofuran (0.81 mL); followed by N -methylmethylamine; hydrochloride (33 mg, 0.406 mmol), then triethylamine (0.091 mL, 0.649 mmol). 0.540 mL, 0.162 mmol) and titanium isopropoxide (IV) (0.540 mL, 0.162 mmol). The reaction mixture was stirred at 25 °C for 20 hours. Then sodium cyanoboronide (0.81 mL, 0.81 mmol, 1N in dioxane) was added, and the reaction mixture was stirred for another hour. The reaction mixture was diluted with ethyl acetate (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3,6-dichloro- N-( 2,4-dimethoxybenzyl)-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazacyclobut-1-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (106 mg, quantitative yield), which was a yellow oil. MS (ES+) m/z 645.4, 647.2 (M+1).

Step 5. Add 0.81 mL of trifluoroacetic acid to a solution of 3,6-dichloro-4-(3- ( 2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro- N- (6-fluoropyridin-2- yl )benzenesulfonamide (106 mg, 0.162 mmol) in dichloromethane (0.81 mL). Stir the reaction mixture at 25°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient dissolution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fraction was collected and freeze-dried to give 3,6-dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazacyclobut-1-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide as a grayish-white solid (27.2 mg, 0.045 mmol, 28% yield, 98% purity). MS (ES+) m/z 495.0, 497.0 (M+1). ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.47-7.41 (m, 1H), 6.52 (dd, J = 7.9, 2.6 Hz, 1H), 6.34 (t, J = 2.1 Hz, 1H), 6.15 (dd, J = 7.6, 2.7 Hz, 1H), 4.07-4.01 (m, 4H), 3.19 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 2.41 (s, 6H), 2.10-2.06 (m, 2H).

The other examples listed in Table 6 are similar in preparation to Example 46 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 6 Example Name and Structure Analysis data 47 3,6-Dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methylaziroxybut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.48 (q, J = 8.6 Hz, 1H), 6.55 (dd, J = 8.0, 2.5 Hz, 1H), 6.25 (d, J = 1.2 Hz, 1H), 6.20 (dd, J = 7.7, 2.7 Hz, 1H), 3.91 (d, J = 8.0 Hz, 2H), 3.79 (d, J = 8.0 Hz, 2H), 2.68-2.64 (m, 2H), 2.47 (d, J = 14.5 Hz, 6H), 1.86-1.82 (m, 2H), 1.23 (s, 3H); MS (ES+) m/z 479.2, 481.2 (M+2) 48 3,6-Dichloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methylazacyclobutan-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.55 (q, J = 8.5 Hz, 1H), 6.63 (dd, J = 7.9, 2.4 Hz, 1H), 6.33-6.31 (m, 1H), 6.24 (d, J = 1.1 Hz, 1H), 3.91 (d, J = 8.1 Hz, 2H), 3.80 (d, J = 8.1 Hz, 2H), 3.22-3.19 (m, 2H), 2.97-2.93 (m, 2H), 2.89 (s, 2H), 1.93-1.89 (m, 2H), 1.72 (t, J = 7.2 Hz, 2H), 1.23 (s, 3H), 1.10 (s, 6H); MS (ES+) m/z 533.2, 535.2 (M+2) 49 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methyl-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobut-1-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.60 (q, J = 8.5 Hz, 1H), 6.66 (dd, J = 7.9, 2.3 Hz, 1H), 6.37 (dd, J = 7.7, 2.4 Hz, 1H), 6.30 (d, J = 1.2 Hz, 1H), 3.95 (d, J = 8.2 Hz, 2H), 3.84 (d, J = 8.2 Hz, 2H), 3.21-3.14 (m, 2H), 2.77-2.74 (m, 2H), 2.44-2.36 (m, 1H), 2.17-2.11 (m, 1H), 1.91-1.88 (m, 2H), 1.73-1.67 (m, 4H), 1.23 (s, 3H), 0.98 (ddd, J = 12.9, 9.3, 3.4 Hz, 1H), 0.86 (d, J = 6.6 Hz, 3H); MS (ES+) m/z 533.2, 535.2 (M+2) 50 3,6-Dichloro-2-fluoro-4-(3-(2-(4-fluoropiperidin-1-yl)ethyl)-3-methylazidocyclobut-1-yl)-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.82 (q, J = 8.3 Hz, 1H), 6.81 (dd, J = 7.9, 2.0 Hz, 1H), 6.67 (dd, J = 8.0, 2.4 Hz, 1H), 6.38 (d, J = 1.3 Hz, 1H), 4.88-4.73 (m, 1H), 4.03 (d, J = 8.4 Hz, 2H), 3.91 (d, J = 8.4 Hz, 2H), 2.93-2.73 (m, 6H), 2.01-1.94 (m, 1H), 1.94-1.84 (m, 5H), 1.25 (s, 3H); MS (ES+) m/z 537.2, 539.2 (M+2) 51 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-(4-methoxypiperidin-1-yl)ethyl)-3-methylazacyclobut-1-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.65 (q, J = 8.3 Hz, 1H), 6.68 (dd, J = 8.0, 2.1 Hz, 1H), 6.46-6.43 (m, 1H), 6.31 (d, J = 0.8 Hz, 1H), 3.95 (d, J = 8.2 Hz, 2H), 3.84 (d, J = 8.2 Hz, 2H), 3.32-3.28 (m, 1H), 3.23 (s, 3H), 2.98-2.96 (m, 2H), 2.72-2.67 (m, 2H), 2.65-2.55 (m, 2H), 1.92-1.83 (m, 4H), 1.60-1.54 (m, 2H), 1.23 (s, 3H); MS (ES+) m/z 549.2, 551.2 (M+2) 52 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-(3-fluoropyrrolidin-1-yl)ethyl)-3-methylazacyclobut-1-yl)benzenesulfonamide (stereomeric 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.79 (q, J = 8.3 Hz, 1H), 6.78 (dd, J = 7.9, 2.0 Hz, 1H), 6.63 (dd, J = 8.0, 2.4 Hz, 1H), 6.36 (d, J = 1.1 Hz, 1H), 5.34-5.17 (m, 1H), 4.01 (d, J = 7.9 Hz, 2H), 3.90-3.87 (m, 2H), 3.13-3.07 (m, 1H), 3.03-2.97 (m, 1H), 2.91-2.79 (m, 1H), 2.68-2.58 (m, 3H), 2.21-2.10 (m, 1H), 2.02-1.89 (m, 1H), 1.85-1.78 (m, 2H), 1.24 (s, 3H); MS (ES+) m/z 523.2, 525.2 (M+2) 53 3-Chloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobutan-1-yl)-6-methylbenzenesulfonamide (stereomeric 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 10.54 (s, 1H), 7.83 (q, J = 8.3 Hz, 1H), 6.79 (dd, J = 7.9, 1.9 Hz, 1H), 6.67 (dd, J = 8.0, 2.4 Hz, 1H), 6.29 (s, 1H), 4.13 (q, J = 8.6 Hz, 4H), 3.40-3.34 (m, 2H), 3.22 (s, 3H), 2.96-2.95 (m, 2H), 2.74-2.65 (m, 1H), 2.65-2.62 (m, 3H), 2.48-2.41 (m, 1H), 2.30-2.17 (m, 2H), 1.82-1.61 (m, 4H), 1.08-0.98 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H); MS (ES+) m/z 529.2, 531.2 (M+2) 54 3-Chloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.75 (q, J = 8.3 Hz, 1H), 6.73 (dd, J = 7.9, 2.0 Hz, 1H), 6.58-6.56 (m, 1H), 6.25 (s, 1H), 4.10 (s, 4H), 3.20 (d, J = 3.0 Hz, 3H), 3.07-3.04 (m, 2H), 2.85-2.75 (m, 4H), 2.61 (s, 3H), 2.13-2.09 (m, 2H), 1.67 (dd, J = 9.3, 5.2 Hz, 2H), 1.08 (s, 6H); MS (ES+) m/z 529.2 (M+1), 531.2 (M+1) 55 3,6-Dichloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.65-7.59 (m, 1H), 6.68 (dd, J = 7.9, 2.2 Hz, 1H), 6.41-6.36 (m, 2H), 4.09 (q, J = 8.5 Hz, 4H), MS ( ES+) m/z 549.1 (M+1), 551.0 (M+1) 56 3,6-Dichloro-4-(3-(2-((3,3-difluorocyclobutyl)(methyl)amino)ethyl)-3-methoxyazinocyclobutyl-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.87 (q, J = 8.2 Hz, 1H), 6.84 (dd, J = 7.9, 1.9 Hz, 1H), 6.72 (dd, J = 8.0, 2.3 Hz, 1H), 6.47 (d, J = 1.2 Hz, MS ( ES +) m/z 571.0 (M+1), 573.0 (M+1) 57 3-Chloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.69 - 7.58 (m, 1H), 6.7 - 6.58 (m, 1H), 6.48 - 6.37 (m, 1H), 6.22 (s, 1H), 4.03 (m, 4H), 3.16 (s, 3H), 2.57 (s, 3H), 2.5 (m, 2H), 2.31 (s, 4H), 2.07 - 1.93 (m, 2H). MS (ES+) m/z 475.00, 477.00, 476.00 (M + 1). 58 3-Chloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methylazacyclobutan-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H NMR (500 MHz, CD ₃ OD) δ 7.49 - 7.39 (m, 1H), 6.65 (dd, J = 8, 1.9 Hz, 1H), 6.17 (dd, J = 7.8, 2.3 Hz, 1H), 5.95 (d, J = 12.6 Hz, 1H), 3.84 (dd, J = 54.6, 8 Hz, 4H), 2.92 (s, 2H), 2.74 - 2.47 (m, 4H), 1.97 - 1.83 (m, 2H), 1.7 (t, J = 7 Hz, 2H), 1.28 (s, 3H), 1.12 (s, 6H). MS (ES+) m/z 517.20, 519.20 (M + 1). 134 3,6-Dichloro-2-fluoro-4-(3-(2-(4-fluoropiperidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.82 (q, J = 8.2 Hz, 1H), 6.80 (dd, J = 7.9, 1.9 Hz, 1H), 6.68-6.65 (m, 1H), 6.45 (dd, J = 4.3, 0.7 Hz, 1H), 1.11 (dd, J = 9.3, 5.3 Hz, 2H); MS (ES+) m/z: 553.0 (M + 1), 555.0 (M + 1). 135 3,6-Dichloro-4-(3-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.86 (q, J = 8.2 Hz, 1H), 6.83 (dd, J = 7.9, 1.8 Hz, 1H), 6.72 (dd, J = 8.0, 2.3 Hz, 1H), 6.48 (t, J = 0.4 Hz, MS (ES+) m/z : 571.0 (M + 1), 573.0 (M + 1). 136 3,6-Dichloro-4-(3-(2-(3-(difluoromethyl)piperidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.87-7.81 (m, 1H), 6.85-6.80 (m, 1H), 6.71-6.68 (m, 1H), 6.46-6.45 (m, 1H), 6.14-5.84 (m, 1H), 4.21-4.10 (m, 3H), 3.43-3.26 (m, 2H), 3.23-3.17 (m, 3H), 3.17-3.01 (m, 2H), 2.71-2.61 (m, 1H), 2.42-2.27 (m, 2H), 2.19-2.05 (m, 3H), 1.80-1.71 (m, 2H), 1.59-1.48 (m, 1H), 1.28-1.16 (m, 1H); MS (ES+) m/z: 585.0 (M + 1), 587.0 (M + 1). 137 3,6-Dichloro-4-(3-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)ethyl)-3-methoxyazabicyclobut-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.84-7.78 (m, 1H), 6.81-6.78 (m, 1H), 6.67-6.62 (m, 1H), 6.43-6.40 (m, 1H), 4.16-4.08 (m, 4H), 3.19-3.14 (m, 3H), 3.07-3.00 (m, 2H), 2.72-2.67 (m, 2H), 2.45-2.38 (m, 2H), 2.32-2.27 (m, 2H), 1.96-1.89 (m, 2H); MS (ES+) m/z: 569.0 (M + 1), 571.0 (M + 1). 138 3,6-Dichloro-4-(3-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2-fluoro-N-(6-fluoropyridine-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.74-7.72 (m, 1H), 6.74-6.71 (m, 1H), 6.55-6.53 (m, 1H), 6.43 (d, J = 0.9 Hz, 1H), 4.14-4.08 (m, 4H), 3.18 (s, 3H), 2.91-2.81 (m, 2H), 2.69-2.66 (m, 2H), 2.43-2.40 (m, 2H), 2.26-2.17 (m, 2H), 1.99-1.95 (m, 2H); MS (ES+) m/z : 557.0 (M + 1), 559.0 (M + 1). 139 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.75-7.69 (m, 1H), 6.73-6.71 (m, 1H), 6.55-6.50 (m, 1H), 6.42 (d, J = 1.0 Hz, 1H), 5.29-5.12 (m, 1H), 4.15-4.07 (m, 4H), 3.17-3.15 (m, 3H), 2.98-2.81 (m, 4H), 2.73-2.60 (m, 1H), 2.45-2.37 (m, 1H), 2.19-2.05 (m, 1H), 2.04-1.98 (m, 2H), 1.96-1.80 (m, 1H); MS (ES+) m/z: 539.0 (M + 1), 541.0 (M + 1).

Example 59 (R)-3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobut-1-yl)benzenesulfonamide Step 1. Add 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxyazinocyclobutane to a solution of 2-(3-methoxyazinocyclobut-3-yl)ethanol hydrochloride (410 mg, 2.45 mmol) in dichloromethane (5.01 mL) along with tert-butyldimethylsilyl chloride (387 mg, 2.57 mmol) and triethylamine (1.0 mL, 7.34 mmol). Stir the reaction mixture at 25 °C for 12 hours. After completion, quench the reaction mixture with water (30 mL) and extract with dichloromethane (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxyazinon-cyclobutane (390 mg, 65% yield), a pale yellow oil. MS (ES+) m/z 245.9 (M+1); no UV absorbance was detected by DAD under standard LCMS conditions. ^¹H -NMR (400 MHz; DMSO-d6): δ 3.64 (t, J = 6.8 Hz, 2H), 3.10–3.08 (m, 4H), 1.99–1.91 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H).

Step 2. 4-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxyazacyclobut-1-yl)-3-chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide was converted to a crude residue (0.876 g, quantitative yield) in a procedure similar to that in Example 25, Step 1, without further purification, and proceeded to the next step. MS (ES+) m/z 716.4 (M+1).

Step 3. 3-Chloro- N- (2,4-Dimethoxybenzyl)-2,6-Difluoro- N- (6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3-methoxyazacyclobut-1-yl)benzenesulfonamide: The crude starting material (1.00 g, 1.396 mmol) was dissolved in tetrahydrofuran (11.6 mL), and tetrabutylammonium fluoride (2.79 mL, 1 M tetrahydrofuran solution) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 45 minutes, and the reaction was confirmed to be complete by LCMS. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with saturated sodium bicarbonate aqueous solution (25 mL), water (3 × 25 mL), and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient dissolution of 5% to 95% ethyl acetate in heptane to give 3-chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3-methoxyazacyclobut-1-yl)benzenesulfonamide (0.676 g, 80% yield). MS (ES+) m/z 602.2, 604.2 (M+1).

Step 4. 3-Chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-hydroxyethyl)-3-methoxy-azinobutyl-1-yl)benzenesulfonamide: In a similar experimental procedure to Step 3 of Example 46, 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3-methoxy-azinobutyl-1-yl)benzenesulfonamide (675 mg, 1.12 mmol) is converted into a colorless solid of 3-chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro- N- -(6-Fluoropyridin-2-yl)-4-(3-methoxy-3-(2-elyoxoethyl)azacyclobutan-1-yl)benzenesulfonamide (370 mg, 55% yield). MS (ES+) m/z 600.2, 602.2 (M+1).

Step 5. (R)-3-chloro- N- (2,4-dimethoxybenzyl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3- methoxy -3-(2-(3-methylpiperidin-1-yl) ethyl )azacyclobut-1-yl)benzenesulfonamide was converted into a crude title compound (198 mg, quantitative yield) as a yellow oil in a procedure similar to that in Example 46, Step 4. MS (ES+) m/z 683.4, 685.4 (M+1).

Step 6. Add trifluoroacetic acid (1.5 mL) and 1,3,5-trimethoxybenzyl (49.0 mg, 0.292 mmol) to a solution of (R)-3-chloro - 2,6-difluoro- N- (6-fluoropyridin-2- yl )-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azidocyclobut-1-yl)benzylsulfonamide (198 mg, 0.291 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient dissolution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fraction was collected and freeze-dried to give a colorless solid of (R)-3-chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azacyclobut-1-yl)benzenesulfonamide (108.6 mg, 0.204 mmol, 70% yield, 100% purity). MS (ES+) m/z 533.2 (M+1), 535.2 (M+1). ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.69 (q, J = 8.3 Hz, 1H), 6.76 (dd, J = 7.9, 2.2 Hz, 1H), 6.49 (dd, J = 7.8, 2.2 Hz, 1H), 6.25 (d, J = 12.7 Hz, 1H), 4.08 (q, J = 8.6 Hz, 4H), 3.38-3.31 (m, 2H), 3.20 (s, 3H), 2.98-2.86 (m, 2H), 2.69-2.63 (m, 1H), 2.39 (t, J = 11.6 Hz, 1H), 2.32-2.22 (m, 2H), 1.89-1.63 (m, 4H), 1.07-0.97 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H).

The other examples listed in Table 7 are similar in preparation to Example 59 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silicone chromatography, reversed-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 7 Example Name and Structure Analysis data 60 3-Chloro-4-(3-(2-(3,3-dimethylpyrrolidin-1-yl)ethyl)-3-methoxyazinocyclobut-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.67 (q, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.0, 2.3 Hz, 1H), 6.47 (dd, J = 7.8, 2.0 Hz, 1H), 6.19 (d, J = 12.8 Hz, 1H), 4.05 (q, J = 8.7 Hz, 4H), 3.42-3.38 (m, 2H), 3.20 (s, 3H), 3.12-3.08 (m, 4H), 2.26-2.22 (m, 2H), 1.79 (t, J = 7.3 Hz, 2H), 1.12 (s, 6H); MS (ES+) m/z 533.2, 535.1 (M+1)

Examples 61 and 62: 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-((R)-6-((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereoisomers 1 and 2) Step 1. 2-Zazaspiro[3.5]nonyl-6-one hydrochloride was added to a solution of 6-lateral-2-azaspiro[3.5]nonane-2-carboxylic acid tributyl ester (400 mg, 1.67 mmol) in dichloromethane (8.4 mL) with hydrogen chloride (4 N dioxane solution, 8.4 mL, 33.4 mmol). The reaction mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give 2-azaspiro[3.5]nonyl-6-one hydrochloride (319 mg, quantitative yield, crude product) as a yellow oil. ¹ H NMR (400 MHz; DMSO- d ₆ ) δ 9.42 (d, J = 48.8 Hz, 2H), 3.74-3.68 (m, 2H), 3.64-3.58 (m, 2H), 2.65 (s, 2H), 2.21 (t, J = 6.7 Hz, 2H), 1.98 (t, J = 5.9 Hz, 2H), 1.75-1.69 (m, 2H).

Step 2. 3,6-Dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-sideoxy-2-azaspiro[3.5]non-2-yl)benzenesulfonamide was converted into a colorless solid 3,6-dichloro- N- (2,4-dimethoxyphenyl)methyl]-2,4-difluoro- N-(6-fluoro-2-pyridinyl)benzenesulfonamide (220 mg, 0.434 mmol) in a similar experimental procedure to Example 25, Step 1, by converting 2.2 mL of DMF containing 3,6-dichloro-N -[(2,4-dimethoxyphenyl)methyl ]-2,4-difluoro-N- ( 6-fluoro-2-pyridinyl)benzenesulfonamide (220 mg, 0.434 mmol). -(6-Fluoropyridin-2-yl)-4-(6-Sideoxy-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (0.176 g, 65% yield). MS (ES+) m/z 626.2 (M+1), 628.2 (M+1). ¹ H NMR (400 MHz; CDCl ₃ ): δ 7.65 (q, J = 8.1 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 7.9, 1.9 Hz, 1H), 6.61 (dd, J = 8.0, 3.0 Hz, 1H), 6.41 (d, J = 7.3 Hz, 2H), 6.18 (d, J = 1.6 Hz, 1H), 5.19 (s, 2H), 4.02 (q, J = 6.3 Hz, 4H), 3.78 (d, J = 3.3 Hz, 6H), 2.66 (s, 2H), 2.37 (t, J = 6.6 Hz, 2H), 2.05 (dd, J = 7.7, 4.9 Hz, 2H), 1.94-1.88 (m, 2H).

Step 3. 3,6-Dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide was converted into a yellow oily substance, 3,6-dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-sideoxy-2-azaspiro[3.5]non-2- yl )benzenesulfonamide (175 mg, 0.279 mmol ) , in a procedure similar to that in Example 46, step 4. -(6-Fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (198 mg, quantitative yield, crude product). MS (ES+) m/z 709.4, 711.3 (M+1).

Step 4. Add trifluoroacetic acid (1.41 mL) and 1,3,5-trimethoxybenzylbenzene (47.0 mg, 0.279 mmol ) to a solution of 3,6-dichloro-2- fluoro - N- (6-fluoropyridin-2-yl)-4-(6-(( R )-3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (198 mg, 0.279 mmol) in dichloromethane (1.41 mL). The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient dissolution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fraction was collected and freeze-dried to give 3,6-dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-(( R )-3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide as a colorless solid (97.3 mg, 0.158 mmol, 56% yield, 98% purity). MS (ES+) m/z 559.2 (M+1), 561.2 (M+1). ¹ H NMR (400 MHz; DMSO-d6) δ 7.62 (q, J = 8.4 Hz, 1H), 6.67 (dd, J = 8.0, 2.2 Hz, 1H), 6.42-6.39 (m, 1H), 6.31 (d, J = 1.0 Hz, 1H), 4.00-3.98 (m, 1H), 3.91-3.83 (m, 3H), 3.26-3.17 (m, 2H), 2.96-2.92 (m, 1H), 2.72-2.64 (m, 1H), 2.45-2.39 (m, 1H), 2.32-2.24 (m, 1H), 1.89-1.70 (m, 7H), 1.37-1.23 (m, 3H), 1.07-0.96 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H).

Step 5. Separation of 3,6-dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereoisomers 1 and 2) using a palmar SFC (column: Daicel Chiralpak AD column (250 × 30 mm, 10 μm)) to isolate stereoisomers 3,6-dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (0.0350 g, 0.0578 g) (mmol). Mobile phase: 55% ethanol (0.1% ammonium hydroxide) in supercritical carbon dioxide. Flow rate: 70 g/min. Cycle time: 2.6 min. Back pressure: 100 bar to maintain carbon dioxide in the supercritical flow. UV: 220 nm). Two peaks were separated.

Peak 1 was purified by preparative HPLC (column: Waters xbridge 150 mm × 25 mm × 10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; gradient: 38%-58% B, for 8.0 min) (retention time = 1.385 min). The fraction was concentrated and freeze-dried to give 3,6-dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereoisomer 1) as a colorless solid (0.0022 g, 0.0039 mmol, 98% purity, 99% ee). MS (ES+) m/z 559.2, 561.2, 563.2 (M + 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56–7.47 (m, 1H), 7.11–7.05 (m, 1H), 6.40–6.31 (m, 1H), 6.08 (s, 1H), 3.91–3.75 (m, 3H), 3.71–3.61 (m, 1H), 3.54–3.39 (m, 2H), 3.19–3.04 (m, 1H), 2.69–2.62 (m, 1H), 2.44 (d, J = 2.8 Hz, 1H), 2.36–2.25 (m, 3H), 2.18–2.07 (m, 2H), 2.00–1.95 (m, 1H), 1.91–1.84 (m, 2H), 1.80 (d, J = 13.2 Hz, 2H), 1.67–1.60 (m, 1H), 1.28 (d, J = 4.4 Hz, 1H), 1.01–0.94 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).

Peak 2 was purified by preparative HPLC (column: Phenomenex Luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 29%-49% B, after 10.0 min) (retention time = 1.852 min). The fraction was concentrated and freeze-dried to give 3,6-dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric 2) as a colorless solid (0.0046 g, 0.0081 mmol, 99% purity, 98% ee). MS (ES+) m/z 559.1, 561.1, 563.1 (M + 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58–7.47 (m, 1H), 7.07 (dd, J = 2.0, 8.0 Hz, 1H), 6.37 (dd, J = 2.4, 7.6 Hz, 1H), 6.07 (s, 1H), 3.87 (td, J = 9.2, 18.0 Hz, 3H), 3.73–3.63 (m, 1H), 3.62–3.52 (m, 1H), 3.45–3.35 (m, 1H), 3.26–3.17 (m, 1H), 2.77–2.59 (m, 3H), 2.56–2.34 (m, 2H), 2.20–2.04 (m, 2H), 2.02–1.95 (m, 1H), 1.95–1.86 (m, 2H), 1.85–1.76 (m, 2H), 1.67 (t, J = 12.4 Hz, 1H), 1.34 (s, 1H), 0.96 (d, J = 6.4Hz, 4H).

The other examples listed in Table 8 are similar in preparation to those in Examples 61 and 62 (as described above), with appropriate starting materials substituted where necessary and experimental conditions modified as appropriate according to common sense. Purification was carried out by silica gel chromatography, reverse-phase preparation HPLC, or supercritical fluid chromatography (SFC).

Table 8 Example Name and Structure Analysis data 63 3-Chloro-4-(5-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.83 - 7.71 (m, 1H), 6.8 - 6.72 (m, 1H), 6.65 - 6.53 (m, 1H), 6.39 (s, 1H), 4.65 - 4.57 (m, 1H), 4.12 - 3.98 (m, 3H), 2.84 - 2.69 (m, 1H), 2.28 - 2.12 (m, 1H), 1.96 - 1.77 (m, 3H), 1.63 - 1.53 (m, 1H), 1.53 - 1.45 (m, 2H), 1.00 (s, 6H). MS (ES+) m/z 531.2, 532.2, 533.2, 534.2 (M + 1). 64 3-Chloro-4-(5-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.82 - 7.71 (m, 1H), 6.8 - 6.7 (m, 1H), 6.65 - 6.55 (m, 1H), 6.39 (s, 1H), 4.65 - 4.58 (m, 1H), 4.14 - 3.97 (m, 1H), 2.84 - 2.66 (m, 1H), 2.23 (s, 3H), 1.95 - 1.79 (m, 4H), 1.61 - 1.55 (m, 1H), 1.54 - 1.47 (m, 2H), 1 (s, 6H). MS (ES+) m/z 531.2, 532.2, 533.2, 534.2 (M + 1). 65 3,6-Dichloro-4-(5-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 1) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.63 - 11.43 (m, 1H), 7.82 - 7.75 (m, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.65 - 6.59 (m, 1H), 6.42 (s, 1H), 4.66 - 4.57 (m, 1H), 4.18 - 4 (m, 3H), 2.15 (s, 6H), 1.91 - 1.75 (m, 3H), 1.54 - 1.44 (m, 1H). MS (ES+) m/z 477.2, 479.2, 481.2 (M + 1). 66 3,6-Dichloro-4-(5-(dimethylamino)-2-azaspiro[3.3]hept-2-yl)-2-fluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.63 - 11.4 (m, 1H), 7.83 - 7.71 (m, 1H), 6.76 (d, J = 7.7 Hz, 1H), 6.65 - 6.57 (m, 1H), 6.4 (s, 1H), 4.64 - 4.56 (m, 1H), 4.16 - 3.96 (m, 3H), 2.6 - 2.53 (m, 2H), 2.14 (s, 6H), 1.89 - 1.73 (m, 3H), 1.52 - 1.42 (m, 1H). MS (ES+) m/z 477.2, 479.2, 481.2 (M + 1). 67 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, MeOD- d 4) δ 7.75 (q, J = 8.0 Hz, 1H), 6.87 (dd, J = 2.0, 7.6 Hz, 1H), 6.57 (dd, J = 2.4, 8.0 Hz, 1H), 6.42 (d, J = 1.6 Hz, 1H), 4.70 (d, J = 9.6 Hz, 1H), 4.27–4.21 (m, 1H), 4.20–4.11 (m, 2H), 3.91 (dt, J = 5.2, 8.8 Hz, 1H), 3.78 (q, J = 8.4 Hz, 1H), 3.27 (dd, J = 5.2, 7.6 Hz, 2H), 2.80–2.69 (m, 1H), 2.55 (s, 1H), 2.15–2.06 (m, 1H), 2.06–2.00 (m, 1H), 2.00–1.93 (m, 1H), 1.92 (s, 1H), 1.74–1.66 (m, 2H), 1.64 (dd, J = 3.2, 6.8 Hz, 1H), 1.61–1.48 (m, 1H), 0.80 (d, J = 6.4 Hz, 3H); MS (ES+) m/z 547.2 (M+1), 549.2 (M+1), 551.2 (M+1) 68 3,6-Dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) 1H NMR (400 MHz, MeOD- d 4) δ 7.74 (q, J = 8.0 Hz, 1H), 6.87 (dd, J = 2.0, 7.6 Hz, 1H), 6.56 (dd, J = 2.4, 8.0 Hz, 1H), 6.42 (d, J = 1.6 Hz, 3.25 ​ ​ (dd, J = 5.2, 7.6 Hz, 2H), 2.84–2.74 (m, 1H), 2.52 (d, J = 12.6 Hz, 1H), 2.27–2.17 (m, 1H), 2.08 (dd, J = 5.6, 8.0 Hz, 1H), 2.01–1.91 (m, 1H), 1.77–1.66 (m, 2H), 1.66–1.55 (m, 3H), 0.86 (d, J = 6.8 Hz, 3H); MS (ES+) m/z 547.2 (M+1), 549.2 (M+1), 551.2 (M+1) 69 3,6-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) 1H NMR (400 MHz, CDCl3) δ 7.72 (q, J = 8.0 Hz, 1H), 7.23 (dd, J = 1.6, 8.0 Hz, 1H), 6.61 (dd, J = 2.4, 8.0 Hz, 1H), 6.20 (s, 1H), 4.79–4.65 (m, 1H), 4.28 (s, 2H), 4.02–3.85 (m, 2H), 3.84–3.75 (m, 1H), 2.81 (t, J = 6.8 Hz, 1H), 2.74–2.60 (m, 2H), 2.41 (d, J = 8.0 Hz, 1H), 2.31–2.20 (m, 1H), 2.11–2.02 (m, 1H), 1.96–1.84 (m, 1H), 1.56 (t, J = 6.8 Hz, 2H), 1.05 (d, J = 10.0 Hz, 6H); MS (ES+) m/z 547.2, 549.2, 551.2 (M + 1) 70 3,6-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (q, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 4.79–4.61 (m, 1H), 4.28 (s, 2H), 4.01–3.87 (m, 2H), 3.80 (q, J = 8.4 Hz, 1H), 2.89–2.75 (m, 1H), 2.74–2.61 (m, 2H), 2.46–2.38 (m, 1H), 2.28 (d, J = 5.6 Hz, 1H), 2.14–2.02 (m, 1H), 1.98–1.86 (m, 1H), 1.56 (s, 2H), 1.06 (d, J = 9.6 Hz, 6H); MS (ES+) m/z 547.2, 549.2, 551.2 (M + 1) 71 3,6-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (q, J = 8.0 Hz, 1H), 7.21 (dd, J = 1.6, 8.0 Hz, 1H), 6.59 (dd, J = 2.4, 8.0 Hz, 1H), 6.20 (s, 1H), 4.69 (d, J = 9.2 Hz, 1H), 4.22 (s, 2H), 4.14 (d, J = 9.2 Hz, 1H), 3.94 (dt, J = 4.8, 8.8 Hz, 1H), 3.77 (q, J = 8.4 Hz, 1H), 3.09 (t, J = 6.4 Hz, 1H), 2.23 (s, 6H), 2.06–1.91 (m, 2H); MS (ES+) m/z 493.0, 495.0, 497.0 (M + 1) 72 3,6-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (q, J = 8.0 Hz, 1H), 7.24–7.15 (m, 1H), 6.58 (dd, J = 2.0, 8.0 Hz, 1H), 6.20 (s, 1H), 4.71 (d, J = 8.8 Hz, 1H), 4.22 (s, 2H), 4.15 (d, J = 9.2 Hz, 1H), 3.95 (dt, J = 5.2, 8.8 Hz, 1H), 3.78 (q, J = 8.4 Hz, 1H), 3.12 (dd, J = 2.8, 9.2 Hz, 1H), 2.46 (s, 6H), 2.07–1.92 (m, 2H); MS (ES+) m/z 493.1, 495.1, 497.1 (M + 1) 73 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 1H NMR (400 MHz, MeOD- d ₄ ) δ 7.76 (q, J = 8.0 Hz, 1H), 6.92 (dd, J = 1.6, 7.6 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 6.22–6.15 (m, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.27–4.12 (m, 3H), 3.91 (dt, J = 4.8, 8.8 Hz, 1H), 3.78 (q, J = 8.4 Hz, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.60 (d, J = 10.0 Hz, 1H), MS (ES+ ) m/z 531.2, 533.2 (M + 1) 74 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.67 (q, J = 8.0 Hz, 1H), 6.83 (dd, J = 2.0, 8.0 Hz, 1H), 6.50 (dd, J = 2.4, 8.0 Hz, 1H), 6.09 (dd, J = 1.2, 13.2 Hz, 1H), 4.60 (d, J = 9.6 Hz, 1H), 4.17–4.00 (m, 3H), 3.82 (dt, J = 5.2, 8.8 Hz, 1H), 3.74–3.63 (m, 1H), 2.72 (d, J = 10.8 Hz, 1H), 2.49–2.42 (m, 1H), 2.24–2.11 (m, 1H), 2.05–1.90 (m, 2H), 1.71 (t, J = 10.8 Hz, 1H), 1.59–1.49 (m, 3H), 1.19 (s, 2H), 0.84–0.80 (m, 1H), 0.77 (d, J = 6.4 Hz, 3H); MS (ES+) m/z 531.2, 533.2 (M + 1) 75 3-Chloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (q, J = 8.0 Hz, 1H), 7.25 (dd, J = 1.6, 8.0 Hz, 1H), 6.62 (dd, J = 2.4, 8.0 Hz, 1H), 5.90 (d, J = 13.2 Hz, 1H), 4.37 (d, J = 8.4 Hz, 2H), 4.18–3.93 (m, 2H), 3.84–3.67 (m, 1H), 3.54–3.44 (m, 1H), 2.92–2.82 (m, 1H), 2.82–2.71 (m, 1H), 2.65–2.54 (m, 1H), 2.52–2.45 (m, 2H), 1.88–1.75 (m, 2H), 1.60–1.52 (m, 2H), 1.51–1.44 (m, 2H), 1.03–0.89 (m, 6H); MS (ES+) m/z 545.2, 547.2 (M+1) 76 3-Chloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (q, J = 8.0 Hz, 1H), 7.24 (dd, J = 2.0, 8.0 Hz, 1H), 6.61 (dd, J = 2.4, 8.0 Hz, 1H), 5.89 (dd, J = 1.2, 13.2 Hz, 1H), 4.36 (d, J = 8.8 Hz, 2H), 4.14–3.94 (m, 2H), 3.78–3.67 (m, 1H), 3.53–3.42 (m, 1H), 2.90–2.81 (m, 1H), 2.80–2.71 (m, 1H), 2.57 (dd, J = 3.2, 8.8 Hz, 1H), 2.52–2.42 (m, 2H), 1.87–1.72 (m, 2H), 1.60–1.51 (m, 2H), 1.49–1.42 (m, 2H), 1.02–0.84 (m, 6H); MS (ES+) m/z 545.2, 547.2 (M + 1) 77 3,6-Dichloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.73 (q, J = 8.0 Hz, 1H), 6.86 (dd, J = 1.6, 8.0 Hz, 1H), 6.56 (dd, J = 2.4, 7.6 Hz, 1H), 6.43 (d, J = 1.6 Hz, 1H), 4.39 (dd, J = 9.6, 16.8 Hz, 2H), 4.10 (dd, J = 9.6, 17.2 Hz, 2H), 3.82–3.70 (m, 1H), 3.65–3.51 (m, 1H), 2.95–2.80 (m, 2H), 2.65–2.49 (m, 3H), 1.90–1.72 (m, 2H), 1.68–1.50 (m, 2H), 1.45 (q, J = 7.2 Hz, 2H), 0.98–0.85 (m, 6H); MS (ES+) m/z 561.2, 563.2, 565.2 (M+1) 78 3,6-Dichloro-4-(9-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)-2-fluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.75 (q, J = 8.0 Hz, 1H), 6.87 (dd, J = 1.6, 8.0 Hz, 1H), 6.58 (dd, J = 2.4, 8.0 Hz, 1H), 6.49 (s, 1H), 4.49 (bd, J = 9.2 Hz, 1H), 4.36 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 4.14 (d, J = 9.2 Hz, 1H), 3.93–3.84 (m, 1H), 3.83–3.72 (m, 1H), 3.29–3.12 (m, 3H), 1.10 ​ ​ (d, J = 13.6 Hz, 6H); MS (ES+) m/z 561.2, 563.2, 565.2 (M+1) 79 3-Chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric 1) 1H NMR (400 MHz, DMSO- d 6) δ 7.64–7.47 (m, 1H), 6.62 (d, J = 6.8 Hz, 1H), 6.36–6.22 (m, 1H), 6.21–6.05 (m, 1H), 4.01–3.76 (m, 4H), 3.23–3.00 (m, 2H), 2.98–2.72 (m, 1H), 2.34–2.14 (m, 2H), 1.86 (d, J = 9.2 Hz, 2H), 1.81–1.62 (m, 5H), 1.62–1.49 (m, 2H), 1.43–1.17 (m, 4H), 0.86 (d, J = 6.4 Hz, 3H); MS (ES+) m/z 543.2, 545.2 (M+1) 80 3-Chloro-2,6-Difluoro- N- (6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80–7.60 (m, 1H), 6.80–6.66 (m, 1H), 6.62–6.37 (m, 1H), 6.28–6.14 (m, 1H), 4.09–3.81 (m, 4H), 3.15–2.91 (m, 2H), 2.83–2.68 (m, 1H), 2.35–2.23 (m, 2H), 1.96–1.84 (m, 3H), 1.81–1.55 (m, 6H), 1.40–1.22 (m, 4H), 0.88 (d, J = 5.6 Hz, 3H); MS (ES+) m/z 543.2, 545.2 (M+1) 81 2,3-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.79–11.43 (m, 1H), 7.83 (q, J = 8.0 Hz, 1H), 6.82 (dd, J = 1.6, 7.6 Hz, 1H), 6.68 (dd, J = 2.0, 8.0 Hz, 1H), 6.52 (d, J = 13.6 Hz, 1H), 4.60 (d, J = 9.6 Hz, 1H), 4.22 (d, J = 9.6 Hz, 1H), 4.10 (dd, J = 9.2, 19.6 Hz, 2H), 3.84 (dt, J = 5.2, 8.4 Hz, 1H), 3.69 (q, J = 8.4 Hz, 1H), 3.25–3.19 (m, 1H), 2.15 (s, 6H), 2.01–1.86 (m, 2H). MS (ES+) m/z 493.2, 495.2, 497.2 (M+1) 82 2,3-Dichloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87–11.50 (m, 1H), 7.83–7.62 (m, 1H), 6.72 (dd, J = 2.0, 4.4 Hz, 1H), 6.62–6.42 (m, 2H), 4.55 (d, J = 9.2 Hz, 1H), 4.18 (d, J = 9.6 Hz, 1H), 4.12–4.02 (m, 2H), 3.87–3.79 (m, 1H), 3.73–3.65 (m, 1H), 3.17 (dd, J = 5.2, 6.8 Hz, 1H), 2.12 (s, 6H), 1.98–1.85 (m, 2H). MS (ES+) m/z 493.2, 495.2, 497.2 (M+1) 83 2,3-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (q, J = 8.0 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.60 (dd, J = 1.6, 8.0 Hz, 1H), 6.03 (d, J = 13.6 Hz, 1H), 4.69 (d, J = 8.8 Hz, 1H), 4.28 (s, 2H), 3.97–3.87 (m, 2H), 3.85–3.74 (m, 1H), 2.80 (t, J = 8.0 Hz, 1H), 2.67 (q, J = 7.2 Hz, 2H), 2.44–2.25 (m, 2H), 2.13–2.02 (m, 1H), 1.96–1.85 (m, 1H), 1.55 (t, J = 7.2 Hz, 2H), 1.05 (d, J = 9.2 Hz, 6H). MS (ES+) m/z 547.1, 549.1, 551.1 (M + 1) 84 2,3-Dichloro-4-(8-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (q, J = 8.0 Hz, 1H), 7.21 (dd, J = 1.6, 8.0 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 6.03 (d, J = 13.6 Hz, 1H), 4.69 (d, J = 9.6 Hz, 1H), 4.28 (s, 2H), 3.98–3.87 (m, 2H), 3.86–3.73 (m, 1H), 2.80 (t, J = 8.0 Hz, 1H), 2.74–2.59 (m, 2H), 2.41 (d, J = 8.3 Hz, 1H), 2.27 (d, J = 8.4 Hz, 1H), 2.13–2.00 (m, 1H), 1.97–1.82 (m, 1H), 1.55 (t, J = 7.2 Hz, 2H), 1.05 (d, J = 9.2 Hz, 6H). MS (ES+) m/z 547.1, 549.1, 551.1 (M + 1) 85 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (q, J = 8.0 Hz, 1H), 7.25–7.16 (m, 1H), 6.61 (dd, J = 2.0, 8.0 Hz, 1H), 6.05 (d, J = 13.2 Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 4.25–4.14 (m, 2H), 4.12 (d, J = 9.2 Hz, 1H), 3.91 (dt, J = 5.6, 8.4 Hz, 1H), 3.82–3.73 (m, 1H), 3.20 (dd, J = 4.4, 7.6 Hz, 1H), 2.68–2.60 (m, 1H), 2.42 (d, J = 11.2 Hz, 1H), 2.16–2.05 (m, 1H), 2.01–1.91 (m, 1H), 1.90–1.81 (m, 2H), 1.67–1.61 (m, 2H), 1.50–1.43 (m, 1H), 0.89–0.78 (m, 5H). MS (ES+) m/z 547.1, 549.1 (M + 1) 86 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (q, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.05 (d, J = 13.2 Hz, 1H), 4.63 (d, J = 9.2 Hz, 1H), 4.19 (s, 2H), 4.09 (d, J = 9.2 Hz, 1H), 3.92 (dt, J = 5.2, 8.4 Hz, 1H), 3.77 (q, J = 8.4 Hz, 1H), 3.16 (dd, J = 5.2, 7.6 Hz, 1H), 2.69 (d, J = 11.2 Hz, 1H), 2.41 (d, J = 9.6 Hz, 1H), 2.18–2.04 (m, 2H), 1.94–1.84 (m, 1H), 1.70–1.64 (m, 2H), 1.61–1.54 (m, 2H), 0.85 (d, J = 6.4 Hz, 5H). MS (ES+) m/z 547.1, 549.1 (M + 1) 87 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(5-(3-methylpiperidin-1-yl)-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.84 (q, J = 8.2 Hz, 1H), 6.83 (dd, J = 7.9, 1.2 Hz, 1H), 6.70-6.67 (m, 1H), 6.35-6.31 (m, 1H), 4.44-4.42 (m, 1H), 4.10-4.05 (m, 3H), 3.05-2.93 (m, 2H), 2.88-2.83 (m, 1H), 2.46-2.42 (m, 1H), 2.32 (tdd, J = 13.1, 10.6, 2.7 Hz, 1H), 2.09-2.00 (m, 2H), 1.82-1.73 (m, 2H), 1.67-1.64 (m, 3H), 1.58-1.50 (m, 2H), 1.41-1.34 (m, 1H), 1.04-0.97 (m, 1H), 0.84 (d, J = 6.4 Hz, 3H). MS (ES+) m/z 529.2, 531.2 (M+2) 88 3-Chloro-4-(7-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77–7.66 (m, 1H), 7.25–7.19 (m, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.88 (d, J = 12.4 Hz, 1H), 4.30 (s, 2H), 4.22 (s, 2H), 3.98 (t, J = 7.6 Hz, 1H), 3.76–3.68 (m, 1H), 2.88 (quin, J = 7.2 Hz, 1H), 2.35 (dd, J = 7.2, 13.2 Hz, 1H), 2.24 (s, 6H), 2.14 (dd, J = 7.6, 13.2 Hz, 1H); MS (ES+) m/z 477.1, 479.1 (M + 1) 89 3-Chloro-4-(7-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75–7.66 (m, 1H), 7.25–7.19 (m, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 5.88 (dd, J = 1.2, 12.8 Hz, 1H), 4.30 (s, 2H), 4.22 (s, 2H), 3.98 (dd, J = 6.8, 8.8 Hz, 1H), 3.73 (dd, J = 7.2, 8.4 Hz, 1H), 2.90 (quin, J = 7.2 Hz, 1H), 2.36 (dd, J = 7.2, 13.2 Hz, 1H), 2.24 (s, 6H), 2.14 (dd, J = 7.6, 12.8 Hz, 1H); MS (ES+) m/z 477.1, 479.1 (M + 1) 90 3-Chloro-4-(7-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81–7.67 (m, 1H), 7.23 (dd, J = 2.0, 8.0 Hz, 1H), 6.61 (dd, J = 2.4, 8.0 Hz, 1H), 5.87 (dd, J = 1.6, 12.8 Hz, 1H), 4.33–4.18 (m, 4H), 3.97–3.89 (m, 1H), 3.86–3.78 (m, 1H), 3.04–2.90 (m, 1H), 2.75–2.57 (m, 2H), 2.44–2.31 (m, 2H), 2.30–2.22 (m, 2H), 1.61 (t, J = 6.4 Hz, 2H), 1.09 (s, 6H); MS (ES+) m/z 531.2, 533.2 (M + 1) 91 3-Chloro-4-(7-(3,3-dimethylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (q, J = 8.0 Hz, 1H), 7.25–7.21 (m, 1H), 6.62 (dd, J = 2.4, 8.0 Hz, 1H), 5.88 (d, J = 12.4 Hz, 1H), 4.36–4.20 (m, 4H), 3.97–3.90 (m, 1H), 3.87–3.74 (m, 1H), 3.05–2.90 (m, 1H), 2.75–2.58 (m, 2H), 2.44–2.33 (m, 2H), 2.31–2.22 (m, 2H), 1.66–1.60 (m, 2H), 1.09 (s, 6H); MS (ES+) m/z 531.2, 533.2 (M + 1) 92 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(7-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) 1H NMR (400 MHz, CDCl3) δ 7.71 (q, J = 8.0 Hz, 1H), 7.22 (dd, J = 1.6, 7.6 Hz, 1H), 6.61 (dd, J = 2.4, 8.0 Hz, 1H), 5.91–5.84 (m, 1H), 4.29 (s, 2H), 4.21 (s, 2H), 4.01 (t, J = 7.6 Hz, 1H), 3.80–3.68 (m, 1H), 3.01–2.89 (m, 1H), 2.88–2.78 (m, 1H), 2.74–2.64 (m, 1H), 2.42 (dd, J = 7.6, 12.4 Hz, 1H), 2.24 - 2.08 (m, 1H), 2.01–1.83 (m, 1H), 1.80–1.51 (m, 5H), 0.88 (d, J = 6.0 Hz, 4H); MS (ES+) m/z 531.3, 533.3 (M+1) 93 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(7-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.72 (q, J = 7.6 Hz, 1H), 7.23 (dd, J = 1.6, 8.0 Hz, 1H), 6.62 (dd, J = 2.4, 8.0 Hz, 1H), 5.92–5.84 (m, 1H), 4.29 (s, 2H), 4.21 (s, 2H), 4.02 (t, J = 7.6 Hz, 1H), 3.81–3.64 (m, 1H), 3.03–2.73 (m, 2H), 2.68–2.53 (m, 1H), 2.44–2.33 (m, 1H), 2.12 (d, J = 4.0 Hz, 1H), 1.87 (dd, J = 2.4, 4.4 Hz, 1H), 1.73–1.58 (m, 5H), 0.92–0.80 (m, 4H); MS (ES+) m/z 531.3, 533.3 (M+1) 94 3-Chloro-2,6-difluoro-4-(5-(4-fluoropiperidin-1-yl)-2-azaspiro[3.4]oct-2-yl)-N-(6-fluoropyridin-2-yl)benzenesulfonamide ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.82 (q, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.0, 1.9 Hz, 1H), 6.68-6.65 (m, 1H), 6.32-6.28 (m, 1H), 4.73-4.55 (m, 1H), 4.38 (d, J = 8.5 Hz, 1H), 4.07-4.02 (m, 2H), 3.99-3.97 (m, 1H), 2.97 (t, J = 7.2 Hz, 1H), 2.61-2.55 (m, 2H), 2.43-2.32 (m, 2H), 2.23-2.18 (m, 1H), 2.01-1.96 (m, 1H), 1.89-1.76 (m, 2H), 1.75-1.50 (m, 5H), 1.41-1.31 (m, 1H). MS (ES+) m/z 533.2, 535.2 (M+2) 95 3,6-Dichloro-2-fluoro-4-(8-(3-fluoro-3-methylazacyclobut-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl) -N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 11.73 (s, 1H), 7.85 (q, J = 8.2 Hz, 1H), 6.83 (dd, J = 7.9, 1.8 Hz, 1H), 6.71-6.68 (m, 1H), 6.49 (d, J = 1.1 Hz, 1H), 4.53 (d, J = 9.5 Hz, 1H), 4.26 (d, J = 9.5 Hz, 1H), 4.16-4.13 (m, 1H), 3.97 (d, J = 9.3 Hz, 1H), 3.80 (td, J = 8.3, 5.1 Hz, 1H), 3.72 (q, J = 7.8 Hz, 1H), 3.42-3.38 (m, 3H), 3.33-3.26 (m, 4H), 3.05 (t, J = 6.8 Hz, 1H), 2.04-1.96 (m, 1H), 1.69-1.60 (m, 1H), 1.50 (d, J = 22.3 Hz, 3H); MS (ES+) m/z 537.2, 539.2 (M + 1) 96 3,6-Dichloro-2-fluoro-4-(8-(3-fluoro-3-methylazacyclobut-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl) -N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 11.74 (s, 1H), 7.85 (q, J = 8.2 Hz, 1H), 6.83 (dd, J = 7.9, 1.9 Hz, 1H), 6.69 (dd, J = 8.0, 2.2 Hz, 1H), 6.49 (d, J = 1.0 Hz, 1H), 4.53 (d , J = 9.3 Hz, 1H), 4.26 (d, J = 9.5 Hz, 1H), 4.15 (d, J = 9.6 Hz, 1H), 3.96 (d, J = 9.3 Hz, 1H), 3.82-3.77 (m, 1H), 3.75-3.69 (m, 1H), 3.42-3.34 (m, 3H), 3.28 (d, J = 8.3 Hz, 1H), 3.04 (t, J = 6.8 Hz, 1H), 2.04-1.95 (m, 1H), 1.69-1.60 (m, 1H), 1.49 (d, J = 22.3 Hz, 3H); MS (ES+) m/z 537.2, 539.2 (M + 1) 97 3-Chloro-2-fluoro- N- (6-fluoropyridin-2-yl)-6-methyl-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.61 (q, J = 8.3 Hz, 1H), 6.62 (dd, J = 7.9, 1.9 Hz, 1H), 6.38-6.36 (m, 1H), 6.15 (s, 1H), 3.90-3.80 (m, 4H), 2.88-2.85 (m, 2H), 2.58 (s, 3H), 2.48-2.42 (m, 1H), 2.30-2.24 (m, 1H), 2.06-1.95 (m, 2H), 1.86-1.83 (m, 1H), 1.75-1.56 (m, 5H), 1.48-1.42 (m, 2H), 1.34-1.20 (m, 3H), 0.91-0.87 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H); MS (ES+) m/z 539.4, 541.3 (M + 1) 98 3-Chloro-2-fluoro- N- (6-fluoropyridin-2-yl)-6-methyl-4-(6-(3-methylpiperidin-1-yl)-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.63-7.57 (m, 1H), 6.63-6.60 (m, 1H), 6.39-6.36 (m, 1H), 6.15 (s, 1H), 3.90-3.80 (m, 4H), 2.88-2.82 (m, 2H), 2.61-2.55 (m, 3H), 2.47-2.42 (m, 1H), 2.29-2.23 (m, 1H), 2.05-1.97 (m, 2H), 1.84 (dd, J = 10.9, 0.3 Hz, 1H), 1.74-1.56 (m, 5H), 1.49-1.43 (m, 2H), 1.34-1.20 (m, 3H), 0.91-0.86 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H); MS (ES+) m/z 539.4, 541.3 (M + 1) 99 3-Chloro-2-fluoro-4-(6-(3-fluoro-3-methylazacyclobut-1-yl)-2-azaspiro[3.5]non-2-yl)-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.80 (q, J = 8.2 Hz, 1H), 6.77 (dd, J = 7.9, 1.9 Hz, 1H), 6.63 (dd, J = 7.9, 2.3 Hz, 1H), 6.19 (s, 1H), 3.95-3.86 (m, 4H), 3.29-3.23 (m, 2H), 3.19-3.06 (m, 2H), 2.60 (s, 3H), 2.09-2.03 (m, 1H), 1.90-1.86 (m, 1H), 1.82-1.79 (m, 1H), 1.64-1.57 (m, 2H), 1.50 (d, J = 22.4 Hz, 3H), 1.42-1.36 (m, 1H), 1.29-1.13 (m, 2H), 0.95-0.85 (m, 1H); MS (ES+) m/z 529.3, 531.3 (M + 1) 100 3-Chloro-2-fluoro-4-(6-(3-fluoro-3-methylazacyclobut-1-yl)-2-azaspiro[3.5]non-2-yl)-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 2) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.80 (q, J = 8.3 Hz, 1H), 6.77 (dd, J = 7.9, 2.0 Hz, 1H), 6.64 (dd, J = 7.9, 2.4 Hz, 1H), 6.19 (s, 1H), 3.95-3.86 (m, 4H), 3.26 (s, 2H), 3.20-3.04 (m, 2H), 2.60 (s, 3H), 2.09-2.03 (m, 1H), 1.91-1.78 (m, 2H), 1.65-1.57 (m, 2H), 1.53 (s, 3H), 1.42-1.36 (m, 1H), 1.29-1.21 (m, 1H), 1.20-1.12 (m, 1H), 0.95-0.85 (m, 1H); MS (ES+) m/z 529.3, 531.3 (M + 1) 101 3-Chloro-4-(6-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.5]non-2-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric compound 1) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.65-7.59 (m, 1H), 6.63-6.61 (m, 1H), 6.40-6.38 (m, 1H), 6.15 (s, 1H), 3.92-3.81 (m, 4H), 2.94-2.86 (m, 2H), 2.61-2.60 (m, 1H), 2.58 (s, 3H), 2.43-2.33 (m, 1H), 2.18-2.14 (m, 1H), 1.85-1.82 (m, 2H), 1.69-1.66 (m, 1H), 1.57 (t, J = 7.1 Hz, 2H), 1.44-1.35 (m, 2H), 1.28-1.11 (m, 3H), 1.05 (s, 6H); MS (ES+) m/z 539.4, 541.3 (M + 1) 102 3-Chloro-4-(6-(3,3-dimethylpyrrolidin-1-yl)-2-azaspiro[3.5]non-2-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric derivative 2) ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.63-7.57 (m, 1H), 6.62-6.60 (m, 1H), 6.36 (dd, J = 7.0, 0.4 Hz, 1H), 6.14 (s, 1H), 3.92-3.82 (m, 4H), 2.98-2.86 (m, 2H), 2.62 (s, 1H), 2.58 (s, 3H), 2.45-2.38 (m, 1H), 2.18-2.15 (m, 1H), 1.87-1.82 (m, 2H), 1.69-1.66 (m, 1H), 1.57 (dd, J = 9.1, 5.0 Hz, 2H), 1.46-1.33 (m, 2H), 1.31-1.18 (m, 3H), 1.05 (s, 6H); MS (ES+) m/z 539.3, 541.3 (M + 1) 103 3-Chloro-2,6-difluoro-4-(8-(3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-N-(thiazolyl-4-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, CD ₃ OD) δ 8.73 (s, 1H), 6.96 (s, 1H), 6.14 (d, J = 13.5 Hz, 1H), 4.67 (d, J = 9.6 Hz, 1H), 4.21 (d, J = 9 Hz, 1H), 4.11 (t, J = 8.3 Hz, 2H), 3.96 - 3.84 (m, 1H), 3.83 - 3.7 (m, 1H), 3.24 (dd, J = 7.7, 5.1 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.57 - 2.44 (m, 1H), 2.26 - 2.14 (m, 1H), 2.14 - 2.02 (m, 1H), 2.02 - 1.86 (m, 1H), 1.78 - 1.52 (m, 5H), 0.86 (d, J = 6.7 Hz, 4H). MS (ES+) m/z 519.0, 521.0 (M + 1). 104 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methoxypyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-methylbenzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.52 (d, J = 2.2 Hz, 1H), 7.88 - 7.75 (m, 1H), 6.77 (s, 1H), 6.69 - 6.62 (m, 1H), 6.28 (s, 1H), 4.53 - 4.47 (m, 1H), 4.25 (s, 1H), 4.15 - 4.08 (m, 1H), 3.96 - 3.9 (m, 1H), 3.86 - 3.76 (m, 2H), 3.73 - 3.65 (m, 1H), 3.12 (s, 3H), 2.96 - 2.88 (m, 1H), 2.83 - 2.73 (m, 1H), 2.58 (s, 3H), 2.44 - 2.37 (m, 2H), 1.97 (d, J = 2.2 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.84 (d, J = 4.2 Hz, 1H), 1.68 - 1.56 (m, 1H). MS (ES+) m/z 529.2, 531.2 (M + 1). 105 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-(3-methoxypyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)-6-methylbenzenesulfonamide (stereomeric 2) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.56 - 11.42 (m, 1H), 7.86 - 7.74 (m, 1H), 6.8 - 6.72 (m, 1H), 6.7 - 6.61 (m, 1H), 6.28 (s, 1H), 4.57 - 4.48 (m, 1H), 4.26 (d, J = 9.9 Hz, 1H), 4.15 (d, J = 9 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.86 - 3.76 (m, 2H), 3.75 - 3.66 (m, 1H), 3.06 - 2.95 (m, 3H), 2.92 - 2.8 (m, 1H), 2.71 - 2.62 (m, 1H), 2.58 (s, 3H), 2.44 - 2.37 (m, 2H), 2.09 - 1.98 (m, 1H), 1.98 - 1.87 (m, 1H), 1.82 (m, 1H), 1.66 - 1.54 (m, 1H). MS (ES+) m/z 529.2, 531.2 (M + 1). 106 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.54 - 11.45 (m, 1H), 7.85 - 7.73 (m, 1H), 6.82 - 6.7 (m, 1H), 6.69 - 6.58 (m, 1H), 6.28 (s, 1H), 4.56 - 4.49 (m, 1H), 4.3 - 4.22 (m, 1H), 4.14 - 4.07 (m, 1H), 3.96 - 3.86 (m, 1H), 3.86 - 3.76 (m, 1H), 3.73 - 3.64 (m, 1H), 2.96 - 2.86 (m, 1H), 2.85 - 2.8 (m, 1H), 2.66 - 2.53 (m, 4H), 2.19 - 1.71 (m, 7H), 1.18 (d, J = 3.8 Hz, 1H), 1.01 - 0.88 (m, 3H). MS (ES+) m/z 513.2, 515.2 (M + 1). 107 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.85 - 7.76 (m, 1H), 6.8 - 6.73 (m, 1H), 6.69 - 6.62 (m, 1H), 6.33 - 6.26 (m, 1H), 4.6 - 4.49 (m, 1H), 4.29 - 4.21 (m, 1H), 4.21 - 4.12 (m, 1H), 3.97 - 3.88 (m, 1H), 3.85 - 3.78 (m, 1H), 3.76 - 3.66 (m, 1H), 2.89 - 2.8 (m, 1H), 2.68 - 2.59 (m, 3H), 2.23 - 1.74 (m, 6H), 1.29 - 1.16 (m, 2H), 0.9 (d, J = 6.4 Hz, 3H). MS (ES+) m/z 513.2, 515.2 (M + 1). 108 4-(8-(1,4-oxazino-4-yl)-5-oxaza-2-azaspiro[3.4]oct-2-yl)-3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.78 - 7.67 (m, 1H), 6.78 (dd, J = 8, 1.7 Hz, 1H), 6.54 (dd, J = 8, 2.3 Hz, 1H), 6.21 (s, 1H), 4.67 (d, J = 9 Hz, 1H), 4.2 - 4.1 (m, 2H), 4.07 (d, J = 8.7 Hz, 1H), 3.99 - 3.9 (m, 1H), 3.81 - 3.64 (m, 4H), 3.53 (dd, J = 7.7, 4.4 Hz, 1H), 2.72 - 2.61 (m, 5H), 2.12 - 1.95 (m, 2H), 1.93 - 1.8 (m, 2H). MS (ES+) m/z 529.2 , 531.2 (M + 1). 109 4-(8-(1,4-oxazino-6-4-yl)-5-oxaza-2-azaspiro[3.4]oct-2-yl)-3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (stereomeric 2) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.72 (q, J = 8 Hz, 1H), 6.78 (dd, J = 7.9, 1.8 Hz, 1H), 6.54 (dd, J = 8, 2.3 Hz, 1H), 6.2 (s, 1H), 4.67 (d, J = 8.7 Hz, 1H), 4.19 - 4.11 (m, 2H), 4.06 (d, J = 8.7 Hz, 1H), 3.97 - 3.89 (m, 1H), 3.82 - 3.62 (m, 4H), 3.53 (dd, J = 7.7, 4.7 Hz, 1H), 2.73 - 2.62 (m, 5H), 2.13 - 1.95 (m, 2H), 1.95 - 1.79 (m, 2H). MS (ES+) m/z 529.2 , 531.2 (M + 1). 110 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(pyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.75 - 7.67 (m, 1H), 6.78 (dd, J = 7.9, 1.8 Hz, 1H), 6.53 (dd, J = 8, 2.3 Hz, 1H), 6.18 (s, 1H), 4.63 (d, J = 9 Hz, 1H), 4.33 (d, J = 9.4 Hz, 1H), 4.2 (d, J = 9.4 Hz, 1H), 3.97 (d, J = 9 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.85 - 3.76 (m, 1H), 2.93 - 2.85 (m, 1H), 2.73 - 2.68 (m, 2H), 2.65 (s, 3H), 2.64 - 2.58 (m, 2H), 2.2 - 2.13 (m, 1H), 1.97 - 1.89 (m, 1H), 1.78 (s, 4H). MS (ES+) m/z 499.2, 501.2 (M + 1). 111 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(pyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.7 (q, J = 8 Hz, 1H), 6.77 (dd, J = 7.9, 1.8 Hz, 1H), 6.51 (dd, J = 7.9, 2.5 Hz, 1H), 6.18 (s, 1H), 4.63 (d, J = 9 Hz, 1H), 4.33 (d, J = 9 Hz, 1H), 4.2 (d, J = 9.7 Hz, 1H), 3.96 (d, J = 9.4 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.84 - 3.76 (m, 1H), 2.9 - 2.85 (m, 1H), 2.73 - 2.67 (m, 2H), 2.65 (s, 3H), 2.64 - 2.57 (m, 2H), 2.2 - 2.12 (m, 1H), 1.97 - 1.88 (m, 1H), 1.78 (s, 4H). MS (ES+) m/z 499.2, 501.2 (M + 1). 112 3-Chloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.75 - 7.66 (m, 1H), 6.91 - 6.83 (m, 1H), 6.52 (dd, J = 7.9, 1.8 Hz, 1H), 6.16 (d, J = 13.1 Hz, 1H), 4.68 (d, J = 9.4 Hz, 1H), 4.24 (d, J = 9 Hz, 1H), 4.13 (dd, J = 9, 5 Hz, 2H), 3.96 - 3.87 (m, 1H), 3.83 - 3.72 (m, 1H), 3.2 (t, J = 6.5 Hz, 1H), 2.25 (s, 6H), 2.08 - 1.95 (m, 2H). MS (ES+) m/z 477.2, 479.2 (M + 1). 113 3-Chloro-4-(8-(dimethylamino)-5-oxa-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivative 2) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.75 - 7.64 (m, 1H), 6.87 (d, J = 6.7 Hz, 1H), 6.55 - 6.47 (m, 1H), 6.16 (d, J = 13.1 Hz, 1H), 4.68 (d, J = 9.7 Hz, 1H), 4.24 (d, J = 9.4 Hz, 1H), 4.13 (dd, J = 8.9, 4.9 Hz, 2H), 3.98 - 3.86 (m, 1H), 3.82 - 3.73 (m, 1H), 3.23 - 3.17 (m, 1H), 2.25 (s, 6H), 2.09 - 1.96 (m, 2H). MS (ES+) m/z 477.2, 479.2 (M + 1). 114 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 1) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.77 - 7.66 (m, 1H), 6.82 - 6.72 (m, 1H), 6.56 - 6.46 (m, 1H), 6.18 (s, 1H), 4.7 - 4.61 (m, 1H), 4.37 - 4.24 (m, 1H), 4.23 - 4.15 (m, 1H), 4.02 - 3.87 (m, 2H), 3.87 - 3.7 (m, 2H), 2.9 - 2.74 (m, 3H), 2.65 (s, 3H), 2.27 - 1.86 (m, 5H), 1.41 - 1.28 (m, 1H), 0.98 (d, J = 6.7 Hz, 2H). MS (ES+) m/z 513.2, 515.2 (M + 1). 115 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(8-(3-methylpyrrolidin-1-yl)-5-oxa-2-azaspiro[3.4]oct-2-yl)benzenesulfonamide (stereomeric 2) ¹ H NMR (500 MHz, CD ₃ OD) δ 7.81 - 7.65 (m, 1H), 6.85 - 6.71 (m, 1H), 6.53 (dd, J = 8, 2.6 Hz, 1H), 6.19 (s, 1H), 4.64 (d, J = 9.6 Hz, 1H), 4.31 (d, J = 9.6 Hz, 1H), 4.19 (d, J = 9.3 Hz, 1H), 4.03 - 3.86 (m, 2H), 3.86 - 3.73 (m, 1H), 3.05 - 2.88 (m, 2H), 2.66 (s, 4H), 2.28 - 1.83 (m, 4H), 1.42 - 1.27 (m, 1H), 1.01 (d, J = 6.7 Hz, 2H). MS (ES+) m/z 513.2, 515.2 (M + 1).

Examples 116 and 117: 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(pyridin-2-yl)benzenesulfonamide (stereomeric derivatives 1 and 2) Step 1. 5-Cyano-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester was added at 0°C to a solution of 5-azospiro[3.4]octane-2-carboxylic acid tert- butyl ester (0.500 g, 2.22 mmol) and 1-((isocyanomethyl)sulfonylurea)-4-methylbenzene (0.865 g, 4.43 mmol) in 1,2-dimethoxyethane (7.5 mL) and methanol (0.5 mL). The mixture was stirred at 25°C for 12 h. The reaction mixture was poured into water (8 mL). The pH was neutralized to 7 with 1 N hydrochloric acid. The mixture was diluted with ethyl acetate (8 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 × 7 mL). The combined organic extract was washed with brine (13 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ethyl acetate/petroleum ether) to give 0.350 g, 1.48 mmol, 67% yield of 5-cyano-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester, which was a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.14 (d, J = 9.2 Hz, 1H), 3.91–3.66 (m, 3H), 2.91–2.82 (m, 1H), 2.14–1.64 (m, 6H), 1.45 (s, 9H).

Step 2. Raney-nickel (0.350 g, 4.09 mmol) was added to a mixture of 5-cyano-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester (0.350 g, 1.48 mmol) in methanol (20.0 mL) and ammonia (5 mL) under nitrogen atmosphere. The solution was purged three times with hydrogen and then stirred at 25°C for 16 h under hydrogen atmosphere (50 psi). The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain 5-(aminomethyl)-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester (0.350 g, crude product) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.92 (d, J = 8.8 Hz, 1H), 3.81–3.66 (m, 2H), 3.58–3.46 (m, 1H), 2.96 (dd, J = 4.4, 12.0 Hz, 1H), 2.56 (dd, J = 9.2, 12.4 Hz, 1H), 1.90–1.82 (m, 4H), 1.65–1.53 (m, 2H), 1.44 (s, 9H), 1.38–1.28 (m, 1H).

Step 3. 5-((dimethylamino)methyl)-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester was added to a solution of 5-(aminomethyl)-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester (0.120 g, 0.499 mmol) and formaldehyde (0.405 g, 4.99 mmol, 37% aqueous solution) in methanol (1.0 mL). Sodium cyanoboronide (0.0950 g, 1.51 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated. The residue was diluted with dichloromethane (3 mL) and sodium bicarbonate (3 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 4 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 0.105 g (crude) of 5-((dimethylamino)methyl)-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester, a yellow oil. MS (ES+) m/z 269.1 (M+ 1).

Step 4. N,N-Dimethyl-1-(2-azaspiro[3.4]oct-5-yl)methylamine In an experimental procedure similar to that in Example 35, Step 2, 5-((dimethylamino)methyl)-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (0.105 g, 391 mmol) was converted into N , N -dimethyl-1-(2-azaspiro[3.4]oct-5-yl)methylamine (0.0950 g, crude, 2-hydrochloride) as a colorless oil. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 4.23–4.10 (m, 2H), 3.91–3.74 (m, 2H), 3.46 (d, J = 12.8 Hz, 1H), 3.17 (t, J = 12.0 Hz, 1H), 2.97 (d, J = 10.4 Hz, 6H), 2.48–2.37 (m, 1H), 2.10–2.03 (m, 2H), 2.01–1.94 (m, 1H), 1.81–1.72 (m, 2H), 1.59–1.48 (m, 1H).

Step 5. 3-Chloro-N-(2,4-dimethoxybenzyl)-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide was converted into a white solid 3-chloro- N- (2,4- dimethoxybenzyl )-4-(5 - ((dimethylamino)methyl)-2-azaspiro[3.4]oct-5-yl)methylamine (0.0950 g, 0.394 mmol, 2-hydrochloride) in a similar experimental procedure to Example 25, Step 1 . 1-(6-Fluoropyridin-2-yl)benzenesulfonamide (0.110 g, 0.159 mmol, 40% yield, 99% purity, formate). MS (ES+) m/z 639.2, 641.2 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (q, J = 8.0 Hz, 1H), 7.26–7.20 (m, 2H), 6.64 (dd, J = 3.2, 8.0 Hz, 1H), 6.43–6.32 (m, 2H), 5.91–5.79 (m, 1H), 5.10 (s, 2H), 4.24 (d, J = 8.8 Hz, 1H), 4.13–4.01 (m, 2H), 3.85 (d, J = 8.4 Hz, 1H), 3.74 (d, J = 6.8 Hz, 6H), 2.56 (dd, J = 4.8, 12.0 Hz, 1H), 2.42–2.28 (m, 7H), 2.09–1.99 (m, 1H), 1.98–1.86 (m, 3H), 1.65 (quin, J = 7.6 Hz, 2H), 1.48–1.36 (m, 1H).

Step 6. 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide was added to a solution of 3-chloro- N- (2,4-dimethoxybenzyl)-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (0.110 g, 0.159 mmol, formate) in dichloromethane (3.0 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm ; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 18%–38% B, for 10 min). The desired fraction was collected and freeze-dried to give 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide as a white solid (0.0500 g, 0.0992 mmol, 62% yield, 97% purity). MS (ES+) m/z 489.0, 491.0 (M + 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (q, J = 8.0 Hz, 1H), 7.12 (dd, J = 2.0, 8.0 Hz, 1H), 6.49 (dd, J = 2.4, 8.0 Hz, 1H), 5.76 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 8.8 Hz, 1H), 4.13–3.94 (m, 2H), 3.83 (d, J = 8.8 Hz, 1H), 2.92–2.84 (m, 1H), 2.56–2.40 (m, 7H), 2.29–2.17 (m, 1H), 2.04–1.81 (m, 3H), 1.74–1.62 (m, 2H), 1.53–1.40 (m, 1H).

Step 7. Purification of 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereoisomerics 1 and 2) by palmar SFC (column: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 μm ); mobile phase: [carbon dioxide-ethanol ((0.1% ammonium hydroxide)]; B%: 30 % , isocratic dissolution mode) (0.0500 g, 0.0992 g) (mmol). Separate and collect the two peaks. Arbitrary partitioning stereochemistry.

The purification peak 1 (retention time = 7.389 min) was obtained by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid)-acetonitrile]; gradient: 23%–43% B, after 10 min) and freeze-dried to obtain a white solid 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric 1) (0.0146 g, 0.0268 mmol, 29% yield, 98% purity, formate, 96% ee). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (q, J = 8.4 Hz, 1H), 7.07 (dd, J = 1.6, 8.0 Hz, 1H), 6.44 (dd, J = 2.4, 8.0 Hz, 1H), 5.72 (d, J = 12.8 Hz, 1H), 4.20 (d, J = 8.8 Hz, 1H), 4.11–3.95 (m, 2H), 3.81 (d, J = 8.8 Hz, 1H), 3.12 (dd, J = 2.4, 12.4 Hz, 1H), 2.73–2.50 (m, 7H), 2.26 (d, J = 6.4 Hz, 1H), 2.02 (dd, J = 7.2, 13.2 Hz, 1H), 1.95–1.80 (m, 2H), 1.69 (quin, J = 7.6 Hz, 2H), 1.49 (dd, J = 7.6, 13.2 Hz, 1H). MS (ES+) m/z 489.1, 491.1 (M + 1).

The sample was purified by palmar SFC (column: DAICEL CHIRALCEL OX (250 mm × 30 mm × 10 μm ); mobile phase: [carbon dioxide-ethanol (0.1% ammonium hydroxide)]; B%: 30%, isocratic dissolution mode), followed by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm ; mobile phase: [water (formic acid)-acetonitrile]; gradient: 24%–44% B, after 8 min) to peak 2 (retention time = 8.310 min) and freeze-dried to obtain a white solid, 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]oct-2-yl)-2,6-difluoro- N -(6-Fluoropyridin-2-yl)benzenesulfonamide (stereomeric 2) (0.0151 g, 0.0277 mmol, 30% yield, 98% purity, formate, 96% ee). MS (ES+) m/z 489.1, 491.1 (M+ 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (q, J = 8.0 Hz, 1H), 7.06 (dd, J = 2.0, 8.0 Hz, 1H), 6.44 (dd, J = 2.4, 8.0 Hz, 1H), 5.71 (d, J = 12.4 Hz, 1H), 4.20 (d, J = 8.8 Hz, 1H), 4.10–3.98 (m, 2H), 3.81 (d, J = 8.4 Hz, 1H), 3.10 (dd, J = 2.8, 12.8 Hz, 1H), 2.67–2.49 (m, 7H), 2.32–2.19 (m, 1H), 2.01 (dd, J = 7.2, 13.2 Hz, 1H), 1.94–1.82 (m, 2H), 1.69 (quin, J = 7.2 Hz, 2H), 1.55–1.43 (m, 1H).

Examples 118 and 119 3-Chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.3]hept-2-yl)-2,6-difluoro- N- (6-fluoropyridin-2-yl)benzenesulfonamide (stereomeric derivatives 1 and 2) were prepared in a similar manner to Examples 116 and 117. Examples 118 and 119 were prepared in a similar manner to Examples 116 and 117.

Example 118: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (q, J = 8.0 Hz, 1H), 7.14–7.05 (m, 1H), 6.36 (dd, J = 2.4, 5.6 Hz, 1H), 5.81 (d, J = 12.0 Hz, 1H), 4.38 (d, J = 8.8 Hz, 1H), 4.11–3.95 (m, 3H), 3.23–3.10 (m, 1H), 2.82–2.71 (m, 1H), 2.65–2.58 (m, 1H), 2.54 (s, 6H), 2.26–2.10 (m, 3H), 1.75–1.62 (m, 1H). MS (ES+) m/z 475.1, 477.1 (M + 1).

Example 119: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60–7.50 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 12.8 Hz, 1H), 4.38 (d, J = 8.4 Hz, 1H), 4.07–4.01 (m, 3H), 3.19 (d, J = 11.6 Hz, 1H), 2.82–2.71 (m, 1H), 2.67–2.60 (m, 1H), 2.56 (s, 6H), 2.25–2.14 (m, 3H), 1.74–1.63 (m, 1H). MS (ES+) m/z 475.1, 477.1 (M + 1)

Examples 120 and 121: 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomers 1 and 2) Step 1. 3-Hydroxyl-3-(1-methyl-2-sideoxypyrrolidin-3-yl)azacyclobutane-1-carboxylate: Degas the mixture of 1-methylpyrrolidin-2-one (3.00 g, 30.2 mmol, 2.94 mL) in tetrahydrofuran (20.0 mL) and purge three times with nitrogen. Then, add di(propyl-2-yl)aminolithium (2 M, 18.2 mL) to the solution at -78 °C. Stir the mixture at -78 °C for 1 hr. Then, under a nitrogen atmosphere, add a solution of 3-sideoxypyrrolidin-1-carboxylate in tetrahydrofuran (15.0 mL) to the solution. The reaction mixture was then stirred at -78°C for 1 hour. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: CD24-WePure Biotech XPT C18 150*25*7 μm; mobile phase: [ _H₂O (0.225% FA)-ACN]; gradient: 23%-53% B, for 13.0 min). The compound 3-hydroxy-3-(1-methyl-2-sideoxypyrrolidin-3-yl)azacyclobutane-1-carboxylic acid benzyl ester (6.20 g, 20.4 mmol, 67.3% yield) was obtained as a white solid. MS (ES-) m/z 305.0 (M+1).

Step 2. 3-Methoxy-3-(1-Methyl-2-ephemerin-3-yl)azidocyclobutane-1-carboxylate: Degas the mixture of 3-hydroxy-3-(1-methyl-2-ephemerin-3-yl)azidocyclobutane-1-carboxylate (5.20 g, 17.1 mmol) in N,N-dimethylformamide (50.0 mL) and tetrahydrofuran (50.0 mL) and purge with nitrogen three times. Then add sodium hydrogen (1.37 g, 34.2 mmol, 60.0% purity) to the solution at 0 °C. Stir the mixture for 1 hr under a nitrogen atmosphere at 0 °C. Iodomethane (4.85 g, 34.2 mmol, 2.13 mL) was then added to the solution at 0 °C, and the mixture was stirred at 20 °C for 15 hr. The reaction mixture was quenched with ammonium chloride (300 mL) and extracted with ethyl acetate (300 mL × 2). The combined layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC hexane:ethyl acetate. The compound 3-methoxy-3-(1-methyl-2-sideoxy-pyrrolidin-3-yl)azacyclobutane-1-carboxylic acid benzyl ester (5.30 g, 16.6 mmol, 97.4% yield) was obtained as a yellow oil. MS (ES-) m/z 319.0 (M+1).

Step 3. Benzyl 3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutane-1-carboxylate: A mixture of 3-methoxy-3-(1-methyl-2-sideoxy-pyrrolidin-3-yl)azacyclobutane-1-carboxylate (1.40 g, 4.40 mmol) in tetrahydrofuran (15.0 mL) was degassed and purged three times with nitrogen. Then, a borane-methyl sulfide complex (10.0 M, 2.20 mL) was added to the solution at 0 °C. The mixture was stirred for 16 hr under nitrogen atmosphere at 25 °C. The reaction mixture was quenched with methanol (30.0 mL). The solution was then concentrated under reduced pressure to remove the solvent. The compound 3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutane-1-carboxylic acid benzyl ester (1.00 g, 3.29 mmol, 74.7% yield) was obtained as a colorless oil. MS (ES-) m/z 305.2 (M+1). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 7.37 - 7.32 (m, 5H), 5.05 (s, 2H), 3.96 - 3.77 (m, 4H), 3.24 (s, 3H), 3.11 - 3.01 (m, 3H), 2.90 - 2.83 (m, 1H), 2.63 (s, 3H), 2.21 - 2.11 (m, 1H), 1.71 - 1.63 (m, 2H).

Step 4. 3-(3-methoxyazidocyclobut-3-yl)-1-methylpyrrolidone was added to a solution of 3-methoxy-3-(1-methylpyrrolidin-3-yl)azidocyclobutane-1-carboxylic acid benzyl ester (500 mg, 1.64 mmol) in tetrahydrofuran (10.0 mL) under nitrogen atmosphere with wet palladium carbon (300 mg, 281 μmol, 10.0% purity). The suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred at 25 °C under hydrogen (15 psi) for 16 hr. The reaction mixture was filtered and the filtrate was concentrated. The compound 3-(3-methoxyazacyclobut-3-yl)-1-methylpyrrolidone (278 mg, 1.63 mmol, 99.4% yield) was obtained as a colorless oil. ^¹H NMR: (400 MHz, DMSO- _d⁶ ) δ 3.50–3.47 (m, 1H), 3.24–3.12 (m, 5H), 2.63–2.56 (m, 1H), 2.47–2.44 (m, 1H), 2.40–2.31 (m, 2H), 2.21 (s, 3H), 1.85–1.65 (m, 2H).

Step 5. 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (stereomeric derivatives 1 and 2) Add triethylamine (329 mg, 3.26 mmol, 453 μL) to a solution of 3-chloro-2,4,6-trifluoro-N-(6-fluoro-2-pyridinyl)-N-[(4-methoxyphenyl)methyl]benzenesulfonamide (500 mg, 1.09 mmol) and 3-(3-methoxyazacyclobut-3-yl)-1-methyl-pyrrolidone (277 mg, 1.63 mmol) in N,N-dimethylformamide (5.00 mL). The mixture was stirred at 20°C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silicon dioxide, dichloromethane: methanol = 10:1, TLC: dichloromethane: methanol = 10:1, _Rf = 0.47 (P1)). The residue was purified by SFC (column: Chiral-OX-30-DAICEL CHIRALCEL OX (250 mm*30 mm, 10 μm); mobile phase: [CO ₂ -EtOH: CAN = 7:3 (0.1% NH ₃ • H ₂ O)]; B%: 42%; isocratic dissolution mode). The compounds 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (stereoisomer 1) (150 mg, 245 μmol, 22.6% yield) and 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (stereoisomer 2) (140 mg, 229 μmol, 21.1% yield) were obtained as colorless oils. LCMS: MS (ES-) m/z 611.4 (M+1).

Step 6. 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomer 1): Add trifluoroacetic acid (3.84 g, 33.7 mmol, 2.50 mL) to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomer 1) (150 mg, 245 μmol) in dichloromethane (2.50 mL). Stir the mixture at 20 °C for 10 min. The reaction mixture was poured into a saturated sodium bicarbonate solution (50.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. By preparative TLC (silicon dioxide, dichloromethane: methanol = 10:1), a white solid compound, 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereoisomer 1) was obtained (63.5 mg, 126 μmol, 51.6% yield, 98.0% purity). MS (ES-) m/z 491.0 (M+1). ^¹H NMR: (400 MHz, DMSO- _d6 ) δ 10.9 (br s, 1H), 7.56 (q, J = 8.4 Hz, 1H), 6.64 (dd, J = 2.0, 8.0 Hz, 1H), 6.31 (br d, J = 6.8 Hz, 1H), 6.25 (br d, J = 12.4 Hz, 1H), 4.14 - 4.08 (m, 4H), 3.26 (s, 3H), 3.20 - 3.10 (m, 2H), 3.01 - 2.95 (m, 3H), 2.66 (s, 3H), 2.09 - 2.06 (m, 1H), 1.84 - 1.75 (m, 1H).

Step 7. 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereomeric version 2): Add trifluoroacetic acid (3.84 g, 33.7 mmol, 2.50 mL) to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereomeric version 2) (140 mg, 229 μmol) in dichloromethane (2.50 mL). Stir the mixture at 20 °C for 10 min. The reaction mixture was poured into a saturated sodium bicarbonate solution (50.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silicon dioxide, dichloromethane: methanol = 10:1). The compound 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobutan-1-yl)benzenesulfonamide (stereoisomer 2) was obtained as a white solid (79.1 mg, 157 μmol, 68.9% yield, 98.0% purity). MS (ES-) m/z 491.1 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.89 (br s, 1H), 7.56 (q, J = 8.4 Hz, 1H), 6.64 (dd, J = 2.0, 8.0 Hz, 1H), 6.31 (br d, J = 6.8 Hz, 1H), 6.25 (br d, J = 12.4 Hz, 1H), 4.14 - 4.07 (m, 4H), 3.26 (s, 3H), 3.20 - 3.10 (m, 2H), 3.01 - 2.96 (m, 3H), 2.64 (s, 3H), 2.09 - 2.04 (m, 1H), 1.82 - 1.75 (m, 1H).

Examples 122 and 123: 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomers 1 and 2) Step 1. 3-Hydroxy-3-(1-methyl-2-ephenothiazine)azinon-1-carboxylic acid benzyl ester was prepared and obtained as a white solid in a similar experimental procedure to Step 1 in Examples 120 and 121 (9.50 g, 29.8 mmol, 96.5% yield). MS (ES-) m/z 319.1 (M+1).

Step 2. 3-Methoxy-3-(1-Methyl-2-ephenothiazinyl)azionicyclobutane-1-carboxylate In a procedure similar to that in Examples 120 and 121, 3-hydroxy-3-(1-methyl-2-ephenothiazinyl)azionicyclobutane-1-carboxylate (5.00 g, 15.7 mmol) was converted into a colorless oily product, 3-methoxy-3-(1-methyl-2-ephenothiazinyl)azionicyclobutane-1-carboxylate (5.20 g, 15.6 mmol, 99.6% yield). MS (ES-) m/z 333.3 (M+1).

Step 3. Benzyl 3-methoxy-3-(1-methyl-3-piperidinyl)azacyclobutane-1-carboxylate: A mixture of 3-methoxy-3-(1-methyl-2-epheloyl-3-piperidinyl)azacyclobutane-1-carboxylate (2.00 g, 6.02 mmol) in tetrahydrofuran (20.0 mL) was degassed and purged three times with nitrogen. Then, a borane-methyl sulfide complex (10.0 M, 3.61 mL) was added to the solution at 0 °C. The mixture was stirred at 60 °C for 16 hr under nitrogen atmosphere. The reaction mixture was quenched with methanol (30.0 mL). The solution was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (silicon dioxide, commercial hexane: ethyl acetate = 1:1, TLC: commercial hexane: ethyl acetate = 1:1, _Rf = 0.54 (P1)). A colorless oily compound, 3-methoxy-3-(1-methyl-3-piperidinyl)azacyclobutane-1-carboxylate (350 mg, 1.10 mmol, 18.2% yield), was obtained. MS (ES-) m/z 319.2 (M+1). ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.3 -7.31 (m, 5H), 5.04 (s, 2H), 3.99-3.74 (m, 4H), 3.21 (s, 3H), 2.85-2.77 (m, 1H), 2.75-2.71 (m, 1H), 2.63-2.56 (m, 1H), 2.53 (s, 3H), 2.33 (t, J = 11.6 Hz, 1H), 2.10-1.98 (m, 1H), 1.74-1.71 (m, 1H), 1.59-1.55 (m, 2H), 1.20-1.10 (m, 1H).

Step 4. 3-(3-Methoxyazinocyclobut-3-yl)-1-methylpiperidine Under nitrogen, add wet palladium carbon (300 mg, 281 μmol, 10.0% purity) to a solution of 3-methoxy-3-(1-methyl-3-piperidinyl)azinocyclobutane-1-carboxylate (350 mg, 1.10 mmol) in tetrahydrofuran (5.00 mL). Degas the suspension under vacuum and purge several times with hydrogen. Stir the mixture under hydrogen (15 psi) at 25°C for 16 hours. Filter the reaction mixture and concentrate the filtrate. The compound 3-(3-methoxyazinocyclobut-3-yl)-1-methylpiperidine (200 mg, crude product) was obtained as a colorless oil.

Step 5. 3-Chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobut-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (stereomeric derivatives 1 and 2) Add triethylamine (263 mg, 2.60 mmol, 362 μL) to a solution of 3-chloro-2,4,6-trifluoro-N-(6-fluoro-2-pyridinyl)-N-[(4-methoxyphenyl)methyl]benzenesulfonamide (400 mg, 868 μmol) and 3-(3-methoxyazacyclobut-3-yl)-1-methylpiperidine (191 mg, 1.04 mmol) in dimethylformamide (5.00 mL). The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silicon dioxide, dichloromethane: methanol = 10:1). The residue was purified by SFC (Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ • H ₂ O)]; B%: 42%; isocratic dissolution mode). The compounds 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobutan-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (stereoisomer 2) (70.0 mg, 111 μmol, 12.9% yield) and 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobutan-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (stereoisomer 1) (65.0 mg, 103 μmol, 11.9% yield) were obtained as colorless oils. MS (ES-) m/z 625.4 (M+1).

Step 6. Add trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL) to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomeric 1) (70.0 mg, 112 μmol) in dichloromethane (2.00 mL). Stir the mixture at 25 °C for 10 min. The reaction mixture was poured into a saturated sodium bicarbonate solution (50.0 mL) and extracted with ethyl acetate (50 mL × 2). The combined layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. By preparative TLC (silicon dioxide, dichloromethane:methanol = 10:1), a white solid compound, 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomer 1) (24.5 mg, 47.0 μmol, 42.0% yield, 97.0% purity), was obtained. MS (ES-) m/z 505.1 (M+1). ^¹H NMR: (400 MHz, DMSO- _d⁶ ) δ 7.55 (q, J = 8.0 Hz, ¹H), 6.62 (br d, J = 7.2 Hz, ¹H). 6.37-6.30 (m, 1H), 6.19 (br d, J = 12.8 Hz, 1H), 4.18 - 4.00 (m, 4H), 3.26 (s, 3H), 3.23 (br s, 2H), 2.64 (br s, 1H), 2.59 (br s, 3H), 2.22-2.16 (m, 1H), 1.84-1.80 (m, 1H), 1.73-1.62 (m, 2H), 1.29-1.19 (m, 2H).

Step 7. Add trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL) to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereomeric version 2) (65.0 mg, 104 μmol) in dichloromethane (2.00 mL). Stir the mixture at 25 °C for 10 min. LCMS (EC28542-298-P1A) showed a detection of 73.2% of the desired MS (Rt = 0.380 min, MS (ES-) m/z 505.1 (M+1)). The reaction mixture was poured into a saturated sodium bicarbonate solution (50.0 mL) and extracted with ethyl acetate (50 mL × 2). The combined layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (silicon dioxide, dichloromethane:methanol = 10:1, TLC:dichloromethane:methanol = 10:1, _Rf = 0.45 (P1)). A white solid compound, 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomer 2) was obtained (17.8 mg, 34.5 μmol, 33.2% yield, 98.0% purity). MS (ES-) m/z 505.1 (M+1). ¹ H NMR: 400 MHz, DMSO-d ₆ ) δ 7.55 (q, J = 8.0 Hz, 1H), 6.62 (br d, J = 7.2 Hz, 1H), 6.37-6.30 (m, 1H), 6.19 (br d, J = 12.8 Hz, 1H), 4.18 - 4.02 (m, 4H), 3.26 (s, 3H), 3.22 (br s, 2H), 2.62 (br s, 1H), 2.58 (br s, 3H), 2.20 - 2.15 (m, 1H), 1.83-1.80 (m, 1H), 1.73-1.61 (m, 2H), 1.28-1.19 (m, 2H).

Example 124 3,6-Dichloro-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-((R)-3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide Step 1. Add n -butyllithium (18 mL, 45.0 mmol, 2.5 M in hexane) to a solution of 3-methylbut-3-en-1-ol (1.29 g, 15.0 mmol) in tetrahydrofuran (200 mL), followed by dropwise addition of tetrahydrofuran (50 mL) containing N,N,N′,N′ -tetramethylethylenediamine (0.67 mL, 4.50 mmol) at -10 °C. Stir the mixture at this temperature for 1 hour, then add a solution of 3-hydroxy-3-one-1-carboxylate (2.77 g, 16.2 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 0°C for 2 hours. TLC (heptane/ethyl acetate = 7:3) indicated the reaction was complete (Rf = 0.10). The reactants were quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient dissolution of 5% to 90% ethyl acetate in heptane to give 0.67 g, 17% yield, of 3-hydroxy-3-(4-hydroxy-2-methylenebutyl)azacyclobutane-1-carboxylic acid tributyl ester as a colorless oil. ¹ H NMR (400 MHz; CDCl ₃ ): δ 4.97 (dd, J = 17.1, 7.6 Hz, 2H), 3.91-3.80 (m, 5H), 3.74 (t, J = 6.0 Hz, 2H), 3.65-3.57 (m, 1H), 2.33 (t, J = 5.9 Hz, 2H), 1.69-1.58 (m, 1H), 1.44-1.42 (m, 9H).

Step 2. 8-Methylene-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate: 3-Hydroxy-3-(4-Hydroxy-2-methylenebutyl)azacyclobutane-1-carboxylate (667 mg, 2.59 mmol) was dissolved in tetrahydrofuran (4.2 mL), and n -butyllithium (1.7 mL, 2.72 mmol, 2.5 M in hexane) was added dropwise under nitrogen atmosphere at -78°C. Then, a solution of p-toluenesulfonyl chloride (519 mg, 2.72 mmol) in tetrahydrofuran (1 mL) was added dropwise at -78°C. After the addition was complete, the reaction mixture was stirred at 0°C for 30 minutes. n -Butyllithium (1.7 mL, 2.72 mmol, 2.5 M in hexane) was added at 0 °C, and the mixture was heated to ambient temperature and stirred for 4 hours. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. TLC (heptane/ethyl acetate = 75:25) showed the product at Rf = 0.80. The crude material was purified by silica gel column chromatography using a gradient dissolution of 0% to 50% ethyl acetate in heptane to obtain a colorless oily substance, 0.285 g, 46% yield, of tert-butyl 8-methylene-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate. ^¹H NMR (400 MHz; _CDCl₃ ): δ 4.83–4.81 (m, 2H), 3.79 (d, J = 9.4 Hz, 2H), 3.70–3.68 (m, 2H), 3.63 (t, J = 5.6 Hz, 2H), 2.40 (s, 2H), 2.19 (t, J = 5.6 Hz, 2H), 1.44 (s, 9H).

Step 3. Tert-butyl 8-sidekto-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate was added to a solution of 8-methylene-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate (285 mg, 1.19 mmol) and pyridine (0.29 mL, 3.57 mmol) in tert-butanol (12 mL). Sodium periodate aqueous solution (7.1 mL, 3.57 mmol, 0.5 M) was then added, followed by the addition of titanium tetroxide (1.8 mL, 0.0705 mmol, 4 wt% in water). The reaction mixture was stirred at ambient temperature for 16 hours. Then, another portion of sodium periodate aqueous solution (7.1 mL, 3.57 mmol, 0.5 M) was added, and the mixture was stirred for another 4 hours. Brine was added, and the reaction mixture was extracted twice with dichloromethane (2 x 15 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient dissolution of 5% to 70% ethyl acetate in heptane to give a colorless solid of tert-butyl 8-sideoxy-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate (0.213 g, 74% yield). TLC (heptane/ethyl acetate = 70:30) showed Rf = 0.17. ¹ H NMR (400 MHz; CDCl ₃ ): δ 3.93 (dd, J = 11.0, 5.8 Hz, 4H), 3.78-3.75 (m, 2H), 2.69 (s, 2H), 2.46 (t, J = 6.0 Hz, 2H), 1.43 (s, 9H)

Step 4. 5-Oxa-2-azaspiro[3.5]nonane-8-one hydrochloride: Add hydrochloric acid (4.4 mL, 17.7 mmol, aqueous solution) to a solution of 8-side-5-oxa-2-azaspiro[3.5]nonane-2-carboxylic acid (213 mg, 0.883 mmol) in dichloromethane (4.4 mL). Stir the reaction mixture at 25°C for 4 hours. Then concentrate the mixture under reduced pressure, and the resulting residue (152 mg, 98%) can proceed to the next step without further purification.

Step 5. 3,6-Dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-sideoxy-5-oxa-2-azaspiro[3,5]non-2-yl)benzenesulfonamide was converted to 3,6-dichloro- N -[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro- N- (6-fluoropyridin-2-yl) benzenesulfonamide (290 mg, 0.572 mmol ) in an experimental procedure similar to that in Example 25, Step 1. -(6-Fluoropyridin-2-yl)-4-(8-Semi-oxy-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (0.233 g, 65% yield). MS (ES+) m/z 628.2, 630.2 (M+1). ¹ H NMR (400 MHz; DMSO-d ₆ ): δ 7.93 (q, J = 8.2 Hz, 1H), 7.13-7.06 (m, 2H), 6.91 (dd, J = 8.0, 2.7 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.51 (s, 1H), 6.45 (dd, J = 8.4, 2.3 Hz, 1H), 5.03 (s, 2H), 4.24 (q, J = 12.1 Hz, 4H), 3.94 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 2.77 (s, 2H), 2.42 (t, J = 5.9 Hz, 2H).

Step 6. 3,6-Dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-((R)-3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide was administered in a procedure similar to that in Example 46, step 4, by administering 3,6-dichloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(8-sideoxy-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (227 mg, 0.361 mg). The product was converted from 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-((R)-3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (256 mg, quantitative yield, crude product) to a yellow oil. MS (ES+) m/z 712.4, 714.2 (M+1).

Step 7. Add trifluoroacetic acid (1.81 mL) and 1,3,5-trimethoxybenzylbenzene (60.7 mg, 0.361 mmol) to a solution of 3,6-dichloro-2- fluoro - N- (6-fluoropyridin-1- yl )-5-oxa-2-azaspiro[3.5]non-2-yl)benzenesulfonamide (256 mg, 0.359 mmol) in dichloromethane (1.81 mL). The reaction mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient dissolution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fraction was collected and freeze-dried to give the title compound as a colorless solid (114.8 mg, 0.182 mmol, 50% yield, 96% purity). MS (ES+) m/z 561.2 (M+1), 561.3 (M+1). ¹ H NMR (400 MHz; DMSO-d6): δ 7.78 (q, J = 8.2 Hz, 1H), 6.78 (dd, J = 7.9, 1.9 Hz, 1H), 6.62-6.60 (m, 1H), 6.46 (s, 1H), 4.26-4.24 (m, 1H), 4.16 (d, J = 9.6 Hz, 2H), 4.08-4.06 (m, 1H), 3.93-3.89 (m, 1H), 3.47-3.41 (m, 1H), 3.30-3.13 (m, 3H), 2.61-2.56 (m, 1H), 2.43-2.27 (m, 2H), 1.87-1.55 (m, 8H), 1.07-0.94 (m, 2H), 0.89 (d, J = 6.5 Hz, 3H).

Examples 125 and 126: 3-Chloro-2,6-difluoro- N- (6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azacyclobut-1-yl)benzenesulfonamide (stereomeric derivatives 1 and 2) Step 1. 3-Hydroxyl-3-(pyridin-2-ylmethyl)azacyclobutane-1-carboxylic acid tributyl ester was added dropwise to 300 mL of THF containing 2-methylpyridine (5.0 g, 53.73 mmol) at Ar , -70 °C. The mixture was stirred at -70 °C for 3 h to obtain an orange solution. Then, 50 mL of THF containing 9.19 g, 53.73 mmol of 3-sideoxyazacyclobutane-1-carboxylic acid tributyl ester was added dropwise, and the solution was stirred at 20 °C for 2 h to obtain a pale yellow solution. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine (50 mL x 2), _dried over anhydrous _Na₂SO₄ , filtered, and concentrated under vacuum to give 3-hydroxy-3-[(pyridin-2-yl)methyl]azacyclobutane-1-carboxylic acid tributyl ester (7.5 g, 92.0% purity, 26.1 mmol, 48.6% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 4.4 Hz, 1H), 7.71 - 7.6 (m, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.23 - 7.15 (m, 1H), 5.78 (s, 1H), 3.97 - 3.86 (m, 2H), 3.64 - 3.54 (m, 2H), 3.02 (s, 2H), 1.31 (s, 9H). MS (ES+) m/z 265.2 (M + 1).

  Step 2. Tertiary butyl 3-methoxy-3-(pyridin-2-ylmethyl)azacyclobutane-1-carboxylate was added in portions to a solution of 3-hydroxy-3-[(pyridin-2-yl)methyl]azacyclobutane-1-carboxylate (6.4 g, 24.23 mmol) in DMF (50 ml) at 0 °C. Sodium hydroxide (60% in mineral oil, 1070 mg, 26.65 mmol) was added dropwise. After stirring for 2 h, methyl iodoform (4.13 g, 29.07 mmol) was added dropwise to the solution at 0 °C. After stirring for 8 h, the solution was poured into water (50 ml) and diluted with MTBE (100 ml). The organic phase was washed with brine (40 mL x 2), _dried over anhydrous _Na₂SO₄ , filtered, and concentrated under vacuum to give 3-methoxy-3-[(pyridin-2-yl)methyl]azacyclobutane-1-carboxylic acid tributyl ester (5.0 g, 90.0% purity, 16.17 mmol, 66.7% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.54 (d, J = 4.4 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.2 (d, J = 7.7 Hz, 1H), 7.18 - 7.12 (m, 1H), 4.04 - 3.83 (m, 4H), 3.33 (s, 3H), 3.26 (s, 2H), 1.41 (s, 9H). MS (ES+) m/z 279.2 (M + 1).

Step 3. 2-((1-(tert-butoxycarbonyl)-3-methoxyazinocyclobut-3-yl)methyl)-1-methylpyridin-1-onthio-3-methoxy-3-[(pyridin-2-yl)methyl]azinocyclobutane-1-carboxylic acid tert-butyl ester (5.0 g, 90.0% purity, 16.18 mmol) was added to a stirred solution of MeCN (15 ml) with iodomethane (2.98 g, 21.03 mmol) and the solution was stirred at 40 °C for 12 h. The solution was evaporated and treated with MTBE (10 ml) to give 2-(1-[(tert-butoxy)carbonyl]-3-methoxyazacyclobut-3-ylmethyl)-1-methylpyridin-1-onium iodide as a white solid (6.4 g, 96.0% purity, 14.62 mmol, 90.4% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (d, J = 6.2 Hz, 1H), 8.4 - 8.29 (m, 1H), 8 - 7.87 (m, 2H), 4.68 - 4.57 (m, 3H), 4.18 - 4.07 (m, 2H), 4.04 - 3.89 (m, 2H), 3.86 - 3.74 (m, 2H), 3.36 (s, 3H), 1.43 (s, 9H). MS (ES+) m/z 293.2 (M + 1).

Step 4. 3-Methoxy-3-((1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester was added to a solution of 2-(1-[(tert-butoxy)carbonyl]-3-methoxyazacyclobutane-3-ylmethyl)-1-methylpyridin-1-onium iodide (6.4 g, 96.0% purity, 14.62 mmol) in MeOH (100 ml) with sodium borohydride (945.11 mg, 24.85 mmol) and the solution was stirred at 50 °C for 24 h. The solution was diluted with EtOAc (300 ml) and washed with water (50 ml x 2) and brine (50 ml). Concentration of the organic solution under vacuum yielded terbutyl 3-methoxy-3-[(1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methyl]azacyclobutane-1-carboxylate (4.3 g, 87.0% purity, 12.62 mmol, 86.3% yield). MS (ES+) m/z 297.2 (M+1).

Step 5. Tertiary butyl 3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azacyclobutane-1-carboxylate: A mixture of 3-methoxy-3-[(1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methyl]azacyclobutane-1-carboxylate (4.3 g, 87.0% purity, 12.62 mmol) and palladium/carbon (10%, 120 mg) in 30 mL of MeOH was hydrogenated at 1 atm (balloon) and 20°C for 12 h. The catalyst was filtered off and the filtrate was evaporated under vacuum to give tert-butyl 3-methoxy-3-[(1-methylpiperidin-2-yl)methyl]azacyclobutane-1-carboxylate (4.0 g, 87.0% purity, 11.66 mmol, 92.4% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.89 (dd, J = 19.2, 9 Hz, 2H), 3.75 (d, J = 9.1 Hz, 1H), 3.65 (d, J = 9.1 Hz, 1H), 3.45 (s, 2H), 3.21 (d, J = 1.6 Hz, 3H), 2.79 (d, J = 11.3 Hz, 1H), 2.27 (s, 3H), 2.23 - 1.98 (m, 3H), 1.74 - 1.58 (m, 3H), 1.41 (d, J = 1.3 Hz, 9H), 1.31 - 1.13 (m, 2H). MS (ES+) m/z 299.2 (M + 1).

Step 6. 2-((3-methoxyazinocyclobut-3-yl)methyl)-1-methylpiperidine dihydrochloride: In a procedure similar to that in Example 35, Step 2, tert-butyl 3-methoxy-3-[(1-methylpiperidin-2-yl)methyl]azinocyclobutane-1-carboxylate (80.0 mg, 87.0% purity, 233.23 μmol) was converted to 2-[(3-methoxyazinocyclobut-3-yl)methyl]-1-methylpiperidine dihydrochloride (70.0 mg, 90.0% purity, 232.28 μmol, 99.5% yield). MS (ES+) m/z 199.2 (M+ 1).

Step 7. In a similar experimental procedure to Step 3 of Example 35, 2-[(3-methoxy-aziridine-2-yl)methyl]-1-methylpiperidine dihydrochloride (70.0 g/L) is prepared by reacting (S)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidine-2-yl)methyl)aziridine dihydrochloride (70.0 g/L) with ...R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidine-2-yl)methyl)aziridine dihydrochloride (70.0 g/L) with (S)-3-chloro-N-(2,4-dimethoxy-aziridine-3-yl)methyl]-1-methylpiperidine dihydrochloride (70.0 g/L) with (R)-3-chloro-N-(2,4-dimethoxy-aziridine-3-yl)methyl]-1-methylpiperidine dihydrochloride (70.0 g/L) with (R)-3-chloro-N-(2,4-dimethoxy-aziridine dihydrochloride)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidine-2-yl)methyl)aziridine dihydrochloride (70 (mg, 90.0% purity, 317.9 μmol) was converted to crude product. After HPLC purification (column: XBridge BEH C18 100*19mm 5um, mobile phase: _H2O /ACN/0.1% _NH4OH ), racemic 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-3-methoxy-3-[(1-methylpiperidin-2-yl)methyl]azacyclobut-1-ylphenyl-1-sulfonamide (0.06 g, 97% purity) was obtained.

Handheld HPLC (column: Chiralcel OD-H (250 x 20 mm, 5 mkm); mobile phase: hexane (0.5% _NH3 ): IPA: MeOH. flow rate: 20 mL/min) yielded two fractions: Peak 1: 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazacyclobut-1-yl)benzene-1-sulfonamide (stereomeric 1) (20.0 mg, 97.0% purity, 28.99 μmol, 9.1% yield) (Rt = 15.66 min). Analytical SFC: Chiralcel OD-H 250x4.6 mm, 5 μm / mobile phase: 70/15/15 hexane (0.1% EDA)/IPA (0.1% EDA)/MeOH (0.1% EDA). Retention time = 15.66 min; ee = 100%. MS (ES+) m/z 669.2, 671.2 (M + 1). Peak 2: 3-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazacyclobut-1-yl)benzene-1-sulfonamide (stereomeric derivative 2) (21.0 mg, 97.0% purity, 30.44 μmol, 9.6% yield) (Rt = 18.58 min). Analytical SFC: Chiralcel OD-H 250x4.6 mm, 5 μm / mobile phase: 70/15/15 hexane (0.1% EDA)/IPA (0.1% EDA)/MeOH (0.1% EDA). Retention time = 18.58 min; ee = 98.24%. MS (ES+) m/z 669.2, 671.2 (M + 1).

Step 8. Add trifluoroacetic acid (32.95 mg, 289.03 μmol) to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azacyclobut-1-yl)benzenesulfonamide (stereomeric version 1) (20.0 mg, 97.0% purity, 28.99 μmol) in DCM (1 mL). The mixture was stirred at 20°C for 2 h. The reactants were quenched at 0°C with saturated sodium bicarbonate solution (0.5 mL). The mixture was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (column: XBridge BEH C18 100*19mm 5um, mobile phase: [H ₂ O/ACN/0,1%NH ₄ OH]) to obtain pure 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazacyclobut-1-yl)benzene-1-sulfonamide (stereoisomeric 1) (9.6 mg, 18.5 μmol, 64% yield). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.59 - 7.5 (m, 1H), 6.84 - 6.77 (m, 1H), 6.32 (dd, J = 7.7, 2 Hz, 1H), 6 - 5.9 (m, 1H), 4.23 - 4.16 (m, 1H), 4.16 - 4.06 (m, 2H), 4.04 - 3.96 (m, 1H), 3.24 (s, 2H), 2.77 (s, 3H), 2.43 (d, J = 13.7 Hz, 1H), 2.17 (d, J = 26.4 Hz, 1H), 2 - 1.92 (m, 1H), 1.88 - 1.44 (m, 6H). MS (ES+) m/z 519.0, 521.0 (M + 1).

Step 9. Add trifluoroacetic acid (34.7 mg, 304.44 μmol) to a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azacyclobut-1-yl)benzenesulfonamide (stereomeric compound 2) (21.0 mg, 97.0% purity, 30.44 μmol) in DCM (1 mL). The mixture was stirred at 20°C for 2 h. The reactants were quenched at 0°C with saturated sodium bicarbonate solution (0.5 mL). The mixture was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (column: XBridge BEH C18 100*19mm 5um, mobile phase: [H ₂ O/ACN/0,1%NH ₄ OH], flow rate: 30 ml/min) to obtain pure 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazacyclobut-1-yl)benzene-1-sulfonamide (stereoisomeric 2) (10.0 mg, 19.27 μmol, 63.3% yield). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.62 - 7.51 (m, 1H), 6.83 - 6.74 (m, 1H), 6.39 - 6.28 (m, 1H), 6.05 - 5.93 (m, 1H), 4.25 - 4.19 (m, 1H), 4.19 - 4.13 (m, 1H), 4.13 - 4.06 (m, 1H), 4.04 (s, 1H), 3.27 - 3.2 (m, 1H), 2.83 - 2.64 (m, 3H), 2.47 - 2.36 (m, 1H), 2.2 - 2.07 (m, 1H), 1.99 - 1.9 (m, 1H), 1.87 - 1.43 (m, 6H). MS (ES+) m/z 519.0, 521.0 (M + 1).

Examples 127 and 128: 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide (stereoisomers 1 and 2) Step 1. Under nitrogen atmosphere and at -78°C, add dropwise DCM (32.5 mL) containing DMSO (10.4 g, 133 mmol, 10.4 mL, 4.12 eq ) to a solution of (COCl) _₂ (8.44 g, 66.5 mmol, 5.82 mL, 2.06 eq ). Stir for 0.5 hr, then add dropwise DCM (32.5 mL) containing 3-(hydroxymethyl)-3-methyl-azacyclobutane-1-carboxylate (6.50 g, 32.3 mmol, 1.00 eq ) and stir for 0.5 hr. Add 32.5 mL of DCM containing triethylamine (26.0 g, 257 mmol, 35.7 mL, 7.95 eq ) to the mixture and stir the resulting mixture at -78 °C for 0.15 hr, then heat to 20 °C and stir for 1 hr. Quench the reaction mixture by adding water (200 mL) at 20 °C, then extract with DCM (100 mL * 3). Wash the combined layers with brine (200 mL * 2), dry with _{Na₂SO₄ ,} filter, and concentrate under reduced pressure to obtain 6.50 g of crude 3-methoxy-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester as a colorless oil.

Step 2. Add t-BuOK (3.94 g, 35.1 mmol, 1.00 eq) to a solution of methyl 2-dimethoxyphosphoacetate (9.60 g, 52.7 mmol, 7.59 mL, 1.50 eq ) and tributyl 3-methoxy-3-methyl-azacyclobutane-1-carboxylate (7.00 g, 35.1 mmol, 1.00 eq ) in THF (70.0 mL) at 0 °C. Stir the mixture at 20 °C for 1 hr. Quench the reaction mixture by adding water (200 mL) at 0 °C, and then extract with EtOAc (100 mL * 3). The combined layers were washed with brine (200 mL * 2), dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , commercial hexane:ethyl acetate = 100:0 to 94:6) to obtain a colorless oily substance, 3-[(E)-3-methoxy-3-sideoxy-prop-1-enyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (6.50 g, 21.8 mmol, 62.1% yield, 85.7% purity).

Step 3. Degas the mixture of 3-[(E)-3-methoxy-3-sideoxy-prop-1-enyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (6.50 g, 25.5 mmol, 1.00 eq ), _CH3NO2 ( _9.32 g, 153 mmol, 8.27 mL, 6.00 eq ), and DBN (6.32 g, 50.9 mmol, 6.09 mL, 2.00 eq ) in MeOH (80.0 mL) and purge three times with _N2 . Then, stir the mixture at 60°C for 16 hr under _N2 atmosphere. Quench the reaction mixture by adding water (300 mL) at 0°C, and then extract with EtOAc (150 mL * 3). The combined layers were washed with brine (200 mL * 2), dried over [ _Na₂SO₄ ] _, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , commercial hexane:ethyl acetate = 100:0 to 80:20) to give a colorless oily substance, 3-[3-methoxy-1-(nitromethyl)-3-ephthyl-propyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (3.15 g, 9.96 mmol, 39.1% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.30 - 4.52 (m, 2H), 3.74 (dd, J = 8.4, 2.8 Hz, 2H), 3.71 (s, 3H), 3.54 (dd, J = 8.4, 4.8 Hz, 2H), 2.98 - 3.11 (m, 1H), 2.34 - 2.43 (m, 2H), 1.44 (s, 9H), 1.28 (s, 3H).

Step 4. Degas the mixture of 3-[3-methoxy-1-(nitromethyl)-3-ephelopropyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (3.00 g, 9.48 mmol, 1.00 eq ) and Raney-Ni (406 mg, 4.74 mmol, 0.50 eq ) in EtOH (30.0 mL) and purge three times with _H2 . Then stir the mixture at 60 °C for 6 hr under _H2 atmosphere (30 Psi). Filter the reaction mixture and concentrate it under reduced pressure to obtain the residue. The residue was purified by column chromatography ( _SiO2 , DCM: MeOH = 100:0 to 92:8) to obtain a yellow solid, 3-methyl-3-(5-sideoxypyrrolidin-3-yl)azacyclobutane-1-carboxylic acid tributyl ester (400 mg, 1.35 mmol, 14.2% yield, 85.8% purity). ¹ H NMR: (400 MHz, CDCl ₃ ) δ 5.87 (s, 1H), 3.57 (d, J = 8.4 Hz, 2H), 3.45 - 3.52 (m, 2H), 3.40 (t, J = 9.2 Hz, 1H), 2.98 - 3.07 (m, 1H), 2.63 (dt, J = 16.0, 8.4 Hz, 1H), 2.31 (dd, J = 17.2, 9.2 Hz, 1H), 2.02 (dd, J = 17.2, 8.0 Hz, 1H), 1.34 (s, 9H), 1.15 (s, 3H)

Step 5. Add NaH (78.6 mg, 1.97 mmol, 60.0% purity, 2.50 eq) to a solution of 3-methyl-3-(5-sideoxypyrrolidin-3-yl)azacyclobutane-1-carboxylic acid tributyl ester (200 mg, 786 μmol, 1.00 eq ) in THF (4.00 mL) at 0 °C and stir for 0.5 hr at 0 °C. Then add iodomethane (335 mg, 2.36 mmol, 146.9 μL, 3.00 eq ) to the mixture at 0 °C and stir for 0.5 hr at 20 °C. The reaction mixture was quenched by adding _NH₄Cl (10 mL) at 0 °C, then diluted with water (20.0 mL) and extracted with EtOAc (15.0 mL * 3). The combined layers were washed with brine (30.0 mL * ₂ ), dried over [ _Na₂SO₄ ], filtered, and concentrated under reduced pressure to obtain a white solid, 3-methyl-3-(1-methyl-5-sideoxy-pyrrolidin-3-yl)azacyclobutane-1-carboxylic acid tributyl ester (200 mg, crude), without further purification. MS (ES+) m/z 291.0 (M+23), 213.0 (M-55)

Step 6. Replace the solution of 3-methyl-3-(1-methyl-5-sideoxy-pyrrolidin-3-yl)azacyclobutane-1-carboxylic acid tributyl ester (300 mg, 1.12 mmol, 1.00 eq ) in THF (9.00 mL) three times with nitrogen and cool to 0°C in an ice-water bath. Add _BH3 ·THF (1 M, 3.35 mL, 3.00 eq ) dropwise. When the addition is complete, remove the ice bath. Stir the reaction at 60°C for 3 hr. LC-MS (EC26825-223-P1A1, P1: Rt = 2.224 min) showed approximately 0% of reactant 1 remaining and detected approximately 25.2% of the desired compound. The reaction mixture was cooled to 0°C and quenched by dropwise addition of methanol (2.00 mL). The mixture was then evaporated, yielding a yellow oily substance of 3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobutane-1-carboxylic acid tributyl ester (300 mg, crude). MS (ES+) m/z 199.1 (M-55).

Step 7. A mixture of 3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobutane-1-carboxylic acid tributyl ester (300 mg, 1.18 mmol, 1.00 eq ) in DCM (5.00 mL) and TFA (1.00 mL) was stirred at 20 °C for 1 hr. LC-MS (P1: Rt = 1.460 min) showed approximately 0% of reactant 1 residue and approximately 76.7% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure without purification to give 1-methyl-3-(3-methylazacyclobutane-3-yl)pyrrolidone (200 mg, crude) as a yellow oil. MS (ES+) m/z 155.2 (M+1).

Step 8. Add 3-chloro-N-[(3-methylazacyclobut-3-yl)pyrrolidone (197 mg, 1.28 mmol, 2.00 eq ) and Cs₂CO₃ (415 mg, 1.28 mmol, 2.00 eq) to a solution of 1-methyl-3-(3-methylazacyclobut-3-yl)pyrrolidone (197 mg, 1.28 _μmol , 1.00 eq ) in _DMF (5.00 mL ). Stir the mixture at 20 °C for 1 hr. LC-MS (P1: Rt = 1.512 min) showed approximately 0% of reactant 1 remaining and approximately 89.5% of the desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: CD25-WePure Biotech XPT PHS C18 150*25*7μm; mobile phase: [ _H₂O (0.225% FA)-ACN]; gradient: 32%-62% B, for 10.0 min) to obtain a yellow solid product (300 mg, 79.8% yield). LCMS (Rt = 0.501 min) showed that the mass of the desired compound with approximately 100% purity was detected. The residue was further separated using an SFC (EC26825-231-P1A column: Chiral-Cellulose-2-30-Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 μm; mobile phase: [CO ₂ - MeOH: ACN = 7: 3 (0.1% NH ₃ .H ₂ O)]; B%: 45%, isocratic dissolution mode). The residue was obtained as a white solid peak 1: 3-chloro-N-[(3,4-dimethylphenyl)methyl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-4-[3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl]benzenesulfonamide (stereoisomer 1) (125 mg, crude). The residue was also obtained as a white solid peak 2. 3-Chloro-N-[(3,4-dimethylphenyl)methyl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-4-[3-methyl-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl]benzenesulfonamide (stereomeric compound 2) (125 mg, crude). Peak 1: Rt = 1.512 min; MS (ES+) m/z 621.3 (M+1). Peak 2: Rt = 0.501 min; MS (ES+) m/z 621.5 (M+1).

Step 9. A mixture of 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-4-[3-methyl-3-[1-methylpyrrolidin-3-yl]azacyclobut-1-yl]benzenesulfonamide (stereoisomeric compound 1) (120 mg, 204 μmol, 1.00 eq ) in TFA (0.20 mL) and DCM (2.00 mL) was stirred at 20 °C for 0.5 hr. LC-MS (EC26825-251-p1ayj, P1: Rt = 1.157 min) showed no residue of reactant 1 and detected approximately 99.2% of the desired compound. The reaction mixture was diluted with 20.0 _mL of NaHCO3 solution and extracted with DCM (20.0 mL * 3). The combined layers were washed with brine (20.0 mL), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give a white solid of 3-chloro-2-fluoro-N-(6-fluoro-2-pyridinyl)-6-methyl- _4- [3-methyl-3-[1-methylpyrrolidin-3-yl]azacyclobut-1-yl]benzenesulfonamide (stereoisomer 1) (48.0 mg, 101 μmol, 49.7% yield, 99.3% purity). MS (ES+) m/z 471.1 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (q, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.0, 2.0 Hz, 1H), 6.41 (dd, J = 8.0, 2.4 Hz, 1H), 5.91 (s, 1H), 4.05 (dd, J = 16.0, 8.0 Hz, 2H), 3.80 (t, J = 8.8 Hz, 2H), 3.50 (s, 1H), 2.89 - 3.04 (m, 3H), 2.81 (t, J = 9.2 Hz, 1H), 2.63 (s, 3H), 2.51 - 2.62 (m, 4H), 2.03 - 2.14 (m, 1H), 2.02 (s, 1H), 1.75 - 1.89 (m, 1H), 1.32 (s, 3H).

Step 10. A mixture of 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-4-[3-methyl-3-[1-methylpyrrolidin-3-yl]azacyclobut-1-yl]benzenesulfonamide (stereomeric compound 1) (125 mg, 212 μmol, 1.00 eq ) in TFA (0.20 mL) and DCM (2.00 mL) was stirred at 20 °C for 0.5 hr. LC-MS (P1: Rt = 1.776 min) showed approximately 0% residue of reactant 1. Several new peaks appeared on LC-MS and approximately 93.1% of the desired compound was detected. The reaction mixture was quenched by adding _NaHCO3 (10 mL) at 0 °C, then diluted with water (20.0 mL) and extracted with EtOAc (15.0 mL * 3). The combined organic layers were dried over [ _{Na2SO4 ]} , filtered, and concentrated under reduced pressure to give a white solid of 3-chloro-2-fluoro-N-(6-fluoro-2-pyridinyl)-6-methyl-4-[3-methyl-3-[1-methylpyrrolidin-3-yl]azacyclobut-1-yl]benzenesulfonamide (stereoisomer 2) (78.0 mg, 162 μmol, 76.4% yield, 97.9% purity). MS (ES+) m/z 471.1 (M+1). ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 7.61 (q, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.48 (dd, J = 8.0, 2.4 Hz, 1H), 5.93 (s, 1H), 4.05 (dd, J = 14.0, 8.4 Hz, 2H), 3.83 (t, J = 8.4 Hz, 2H), 2.95 - 3.18 (m, 3H), 2.79 - 2.90 (m, 1H), 2.65 (s, 3H), 2.62 (s, 4H), 2.07 - 2.21 (m, 1H), 1.77 - 1.92 (m, 1H), 1.32 (s, 3H), 1.26 (s, 1H)

Example 129: 3-Chloro-4-(3-((1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)methyl)-3-methylazacyclobutyl-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide Step 1. 3-(Iodomethyl)-3-methylazidocyclobutane-1-carboxylic acid tributyl ester: Add KI (15.1 g, 90.9 mmol, 2.00 eq) to a mixture of 3-(bromomethyl)-3-methylazidocyclobutane-1-carboxylic acid tributyl ester (12.0 g, 45.4 mmol, 1.00 eq) and stir at 45 °C for 12 hr. A large amount of white solid precipitate forms. Filter the mixture and concentrate the filtrate under reduced pressure. The oily substance was stirred in isopropyl ether (30 mL) at 20 °C for 1 hr and filtered to remove the solid. The filtrate was concentrated to give a yellow oily substance, 3-(iodomethyl)-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (10.0 g, 32.1 mmol, 70.8% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.71–3.66 (m, 2H), 3.63–3.58 (m, 2H), 3.39 (s, 2H), 1.44 (s, 9H), 1.39 (s, 3H).

Step 2. Add KI (15.1 g, 90.9 mmol, 2.00 eq) to a mixture of 3-(bromomethyl)-3-methyl-azidocyclobutane-1-carboxylic acid tributyl ester (12.0 g, 45.4 mmol, 1.00 eq) and acetone (50.0 mL) and stir at 45 °C for 12 hr. A large amount of white solid precipitate forms. Filter the mixture and concentrate the filtrate under reduced pressure. The oily substance was stirred in isopropyl ether (30 mL) at 20 °C for 1 hr and filtered to remove the solid. The filtrate was concentrated to give a yellow oily substance, 3-(iodomethyl)-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (10.0 g, 32.1 mmol, 70.8% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.71–3.66 (m, 2H), 3.63–3.58 (m, 2H), 3.39 (s, 2H), 1.44 (s, 9H), 1.39 (s, 3H)

Step 3. 3-((1-aminomethoxycyclobutyl)methyl)-3-methylazidocyclobutane-1-carboxylic acid tributyl ester was added slowly to a mixture of 3-[(1-cyanocyclobutyl)methyl]-3-methylazidocyclobutane-1-carboxylic acid tributyl ester (1.00 g, 3.78 mmol, 1.00 eq) and _K₂CO₃ (1.05 g, 7.57 mmol, 2.00 eq) in _DMSO (10.0 mL) at _N₂ and 0 ° _C . _H₂O₂ (1.72 g, 15.1 mmol, 1.45 mL, 30% purity, 4.00 eq) was added. The mixture was heated to 20 °C and stirred for 2 hr. The desired MS was detected by LCMS. The mixture was quenched with _H₂O (50 mL) and extracted with EtOAc (3 * 30 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give a white solid of 3-[(1-aminomethoxycyclobutyl)methyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (985 mg, 3.49 mmol, 92.2% yield). MS (ESI) m/z = 283.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.68-5.40 (m, 2H), 3.73 (d, J = 8.4 Hz, 2H), 3.52 (d, J = 8.4 Hz, 2H), 2.46-2.36 (m, 2H), 2.15 (s, 2H), 2.09-2.01 (m, 2H), 1.97-1.84 (m, 2H), 1.44 (s, 9H), 1.33 (s, 3H).

Step 4. Add NaClO (4.48 g, 3.61 mmol, 3.72 mL, 6% purity, 1.50 eq) to a mixture of 3-[(1-aminocyclobutyl)methyl]-3-methyl-azidocyclobutane-1-carboxylic acid tributyl ester (680 mg, 2.41 mmol, 1.00 eq) in EtOH (10.0 mL) and NaOH (10.0 mL, 15% purity in _H₂O ). Stir the mixture at 20 °C for 2 hr. LCMS (EC25620-258-P1A1) showed the desired MS signal. The mixture was diluted with ethyl acetate (50 mL) and washed with _H₂O (40 mL). The combined layers were washed with brine (50 mL), dried over _Na₂SO₄ , _filtered , and concentrated under vacuum. The oil was purified by silica gel chromatography (100-200 mesh silica gel, commercial hexane:ethyl acetate = 5:1 to 0:1, TLC: commercial hexane:ethyl acetate = 3:1, P1: _Rf = 0.02) to give a yellow oil of 3-[(1-aminocyclobutyl)methyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (395 mg, 1.55 mmol, 64.5% yield). LCMS: RT = 1.472 min, MS (ESI) m/z = 255.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.78 (d, J = 8.4 Hz, 2H), 3.58 (d, J = 8.4 Hz, 2H), 2.14-2.02 (m, 2H), 1.92-1.79 (m, 5H), 1.78-1.65 (m, 3H), 1.44 (s, 9H), 1.34 (s, 3H).

Step 5. Add TEA (680 mg, 6.72 mmol, 936 μL, 3.00 eq) to a mixture of 3-[(1-aminocyclobutyl)methyl]-3-methyl-aziridine-1-carboxylic acid tributyl ester (570 mg, 2.24 mmol, 1.00 eq) and 3,3-dimethyltetrahydrofuran-2,5-dione (316 mg, 2.46 mmol, 278 μL, 1.10 eq) in _CHCl3 (15.0 mL) and stir at 70 °C for 12 hr. CDI (545 mg, 3.36 mmol, 1.50 eq) was then added to the solution and stirred at 70 °C for 3 hr. LCMS (EC25620-260-P1A3) showed detection of the desired MS. The mixture was cooled to 0 °C and 0.5 M HCl (15 mL) was added, followed by extraction with DCM (20 mL x 2). The combined layers were washed with brine (50 mL), dried over _Na₂SO₄ , _filtered , and concentrated under vacuum. The oily substance was purified by silica gel chromatography (100-200 mesh silica gel, commercial hexane:ethyl acetate = 20:1 to 5:1, TLC: commercial hexane:ethyl acetate = 3:1, P1: _Rf = 0.3) to give a yellow oily substance of 3-[[1-(3,3-dimethyl-2,5-dioxy-pyrrolidin-1-yl)cyclobutyl]methyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (620 mg, 1.70 mmol, 75.9% yield). MS (ESI) m/z = 387.2 [M+Na] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.58 (d, J = 8.0 Hz, 2H), 3.44 (d, J = 8.0 Hz, 2H), 2.53-2.44 (m, 4H), 2.43-2.37 (m, 2H), 2.26 (s, 2H), 1.90-1.78 (m, 2H), 1.46 (s, 3H), 1.43-1.39 (m, 9H), 1.29 (s, 6H).

Step 6. Add TFA (1.54 g, 13.5 mmol, 1.00 mL, 9.09 eq) to a mixture of 3,3-dimethyl-1-(1-((3-methylazacyclobut-3-yl)methyl)cyclobutyl)pyrrolidone-2,5-dione and 3-[[1-(3,3-dimethyl-2,5-dioxy-pyrrolidone-1-yl)cyclobutyl]methyl]-3-methyl-azacyclobutane-1-carboxylic acid tributyl ester (540 mg, 1.48 mmol, 1.00 eq) in DCM (5.00 mL) and stir for 0.5 hr at 25 °C. LCMS showed detection of the desired MS. Concentrate the mixture under reduced pressure to give 3,3-dimethyl-1-[1-[(3-methylazacyclobut-3-yl)methyl]cyclobutyl]pyrrolidone-2,5-dione (840 mg, crude, TFA), a brown oil. MS (ESI) m/z = 265.2 [M+H] ⁺ .

Step 7. 3,3-Dimethyl-1-(1-((3-methylazacyclobut-3-yl)methyl)cyclobutyl) _pyrrolidine was slowly added to a mixture of 3,3-dimethyl-1-[1-[(3-methylazacyclobut-3-yl)methyl]cyclobutyl]pyrrolidine-2,5-dione (840 mg, 2.22 mmol, 1.00 eq, TFA) and THF (20.0 mL) at N2, 0°C. The mixture was then slowly heated to 70°C and stirred at _N2 , 70°C for 12 hr. The desired concentration was detected by LCMS. The reaction mixture was quenched by slow addition of _{Na₂SO₄ ·10H₂O (} 20 g) and filtered to remove solids. The filtrate was concentrated without purification to obtain 3,3-dimethyl-1-[1-[(3-methylazacyclobut-3-yl)methyl]cyclobutyl]pyrrolidine (750 mg, crude) as a yellow oil. MS (ESI) m/z = 237.3 [M+H] ^⁺ .

Step 8. Add TEA to a mixture of 3-chloro-N-(3,4-dimethylbenzyl)-4-(3-((1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)methyl)-3-methylazacyclobutyl-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide to 3-chloro-N-[(3,4-dimethylphenyl)methyl]-2,4,6-trifluoro-N-(6-fluoro-2-pyridinyl)benzenesulfonamide (0.45 g, 981 μmol, 1.00 eq) and 3,3-dimethyl-1-[1-[(3-methylazacyclobutyl-3-yl)methyl]cyclobutyl]pyrrolidone (750 mg, 3.17 mmol, 3.24 eq) in DMF (5.00 mL). (248 mg, 2.45 mmol, 341 μL, 2.50 eq) and stirred at 25 °C for 0.5 hr. The mixture was diluted with ethyl acetate (20 mL) and washed with _H₂O (10 mL * 2). The combined layers were washed with brine (10 mL), dried over _Na₂SO₄ , _filtered , and concentrated under vacuum. The oily substance was purified by silicone chromatography (100-200 mesh silicone, commercial hexane: ethyl acetate = 2:1 to 1:1, TLC: commercial hexane: ethyl acetate = 1:1, P1: _Rf = 0.2) to give a yellow oily substance of 3-chloro-N-[(3,4-dimethylphenyl)methyl]-4-[3-[[1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl]methyl]-3-methyl-azacyclobutyl-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridinyl)benzenesulfonamide (360 mg, 533 μmol, 54.4% yield). MS (ESI) m/z = 707.4 [M+H] ⁺ .

Step 9. Add TFA (1.54 g, 13.5 mmol, 1.00 mL, 25.3 eq) to a mixture of 3-chloro-4-(3-((1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)methyl)-3-methylazacyclobutyl-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (360 mg, 533 μmol, 1.00 eq) in DCM (3.00 mL). The mixture was stirred at 25°C for 0.5 hr. LCMS (EC25620-273-P1A1) showed detection of the desired MS. The mixture was concentrated under reduced pressure to obtain an oil. The oil was dissolved in MeOH (10 mL), the solution was filtered to remove solids, and then concentrated. The oily substance was purified by preparative HPLC (column: CD18-Welch Ultimate C18 150*40*7um; mobile phase: [ _H₂O (0.1% TFA)-ACN]; gradient: 18%-48% B, for 17.0 min) to obtain a white solid 3-chloro-4-[3-[[1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl]methyl]-3-methyl-azacyclobutyl-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridinyl)benzenesulfonamide (85.0 mg, 123 μmol, 23.0% yield, 96.9% purity, TFA). m/z = 557.2 (M+H) ^⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.74 (s, 1H), 10.57-9.80 (m, 1H), 7.87 (q, J = 8.0 Hz, 1H), 6.86 (dd, J = 2.0, 8.0 Hz, 1H), 6.74 (dd, J = 2.0, 8.0 Hz, 1H), 6.32 (d, J = 13.2 Hz, 1H), 4.06 (d, J = 3.8 Hz, 4H), 3.70-3.53 (m, 1H), 3.33 (dd, J = 5.2, 10.6 Hz, 2H), 2.87-2.75 (m, 1H), 2.39-2.24 (m, 2H), 2.19-1.99 (m, 5H), 1.95-1.72 (m, 3H), 1.55 (s, 3H), 1.14 (d, J = 17.6 Hz, 6H).

  Examples 130, 131, 132, and 133: 3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereomeric derivatives 1, 2, 3, and 4) Step 1. Add HATU (12.9 g, 34.1 mmol, 1.50 eq), DIEA (8.83 g, 68.2 mmol, 11.9 mL, 3.0 eq), and N-methylmethylamine (2.41 g, 29.5 mmol, 2.7 mL, 1.30 eq, HCl salt) to a solution of 1-tert-butoxycarbonyl-2-methyl-azacyclobutane-3-carboxylic acid (4.90 g, 22.7 mmol, 11.9 mL, 3.0 eq) in DMF (100 mL). Stir the mixture at 25 °C for 2 hr. TLC (commercial hexane:ethyl acetate = 0:1, P1: _Rf = 0.13, ninhydrin) indicated no residue of reactant 1 and detected a major new spot. The reaction mixture was diluted with 100 mL of water and extracted with 400 mL of EtOAc (100 mL * 4). The combined organic layers were washed with 200 mL of water, dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography ( _SiO₂ , commercial hexane:ethyl acetate = 0:1, P1: _Rf = 0.13, commercial hexane:ethyl acetate = 500:1 to 0:1) to give a colorless oily substance, 3-(dimethylaminomethyl)-2-methyl-azacyclobutane-1-carboxylic acid tributyl ester (4.00 g, 16.5 mmol, 72.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.26 (quin, J = 6.0 Hz, 1H), 4.02 - 4.15 (m, 1H), 3.90 (s, 1H), 3.22 (dt, J = 8.8, 6.0 Hz, 1H), 2.84 (s, 3H), 2.82 (s, 3H), 1.37 (s, 12H).

Step 2. The solution of 3-(dimethylaminomethyl)-2-methyl-azacyclobutane-1-carboxylic acid tributyl ester (4.00 g, 16.5 mmol, 1.0 eq) in THF (50.0 mL) was purged three times with nitrogen and cooled to 0°C in an ice-water bath. _BH3 ·THF (1.0 M, 49.5 mL, 3.0 eq) was slowly added dropwise at 0°C until the addition was complete, and the ice bath was removed. The reaction was stirred at 60°C for 3 hr. TLC (commercial hexane:ethyl acetate = 0:1, P1: _Rf = 0.51, ninhydrin) indicated that reactant 1 was not residual and a major new spot was detected. The reactants were cooled to 0°C in an ice-water bath and quenched by adding methanol (40 mL) dropwise. The mixture was then stirred at 60°C for 1 hour. The solvent was then evaporated to give 4.00 g (crude product) of 3-[(dimethylamino)methyl]-2-methyl-azacyclobutane-1-carboxylic acid tributyl ester, which was a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.77 (s, 1H), 3.60 (dd, J = 8.8, 6.8 Hz, 1H), 3.12 - 3.31 (m, 1H), 2.99 (d, J = 4.8 Hz, 2H), 2.65 (dd, J = 13.2, 6.8 Hz, 1H), 2.58 (s, 6H), 1.44 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H).

Step 3. Add TFA (14.4 g, 127 mmol, 9.4 mL, 7.2 eq) to a solution of 3-[(dimethylamino)methyl]-2-methyl-azacyclobutane-1-carboxylic acid tributyl ester (4.00 g, 17.5 mmol, 1.0 eq) in DCM (50.0 mL). Stir the mixture at 20 °C for 1 hr. TLC (commercial hexane: ethyl acetate = 0:1, P1: _Rf = 0.16, ninhydrin) indicated that reactant 1 was not residual and a major new spot was detected. The reaction mixture was concentrated under reduced pressure to remove DCM and TFA, yielding N,N-dimethyl-1-(2-methylazacyclobut-3-yl)methylamine (4.00 g, crude product, TFA salt) as a colorless oil.

Step 4. Mix N,N-dimethyl-1-(2-methylazacyclobut-3-yl)methylamine (995 mg, 4.10 mmol, 2.0 eq, TFA salt), 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (1.00 g, 2.00 mmol, 1.0 eq), _{and Cs₂CO₃} (2.00 g, 6.10 mmol, 3.0 eq) in DMF (20.0 mL), and then stir the mixture at 20 °C for 1 hr. Dilute the reaction mixture with 20 mL of water and extract with 60 mL of EtOAc (20 mL * 3). The combined organic layer was washed with 40 mL of water, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase HPLC (column: CD05-Phenomenex Luna _C18 100*40mm*10um; mobile phase: [H₂O(0.225% FA)-ACN]; gradient: 26%-56% B, for 13.0 min). The compound 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (400 mg, 672 μmol, 32.7% yield) was obtained as a white solid. MS (ES+) m/z: 595.2/596.9 (M+1).

Step 5. Purify 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[ ₃ -[(dimethylamino)methyl]-2-methyl-azacyclobut- ₁ -yl]-2-fluoro-N-(6-fluoro-2 _- pyridyl)-6-methylbenzenesulfonamide (400 mg) using an SFC column: Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 17%, isocratic dissolution mode) to obtain peak 1 at 150 mg and peak 2 at 150 mg.  

The 150 mg peak 1 was purified using an SFC column (Chiral-OX-30-DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [CO ₂ -MeOH: CAN = 7: 3 (0.1% NH ₃ .H ₂ O)]; B%: 40%, isocratic dissolution mode) to obtain 60 mg peak 1 and 60 mg peak 2.  

Peak 2 of 150 mg was purified by SFC (Chiral-OX-30-DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [CO ₂ -MeOH: CAN = 7: 3 (0.1% NH ₃ .H ₂ O)]; B%: 40%, isocratic dissolution mode) to obtain peak 1 of 60 mg and peak 2 of 60 mg.

The following general procedure is used to deprotect four non-mirror isomers.

TFA (153 mg, 1.3 mmol, 0.1 mL, 13.3 eq) was added to a solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (60.0 mg, 100 μmol, 1.0 eq) in DCM (5 mL). The mixture was stirred at 25 °C for 1 hr. TLC indicated that reactant 1 was completely consumed and a new spot was formed. (The reaction mixture was quenched by adding _NaHCO3 solution at 0°C to adjust the pH to approximately 7.0, then filtered, and the filtrate was extracted with 45 mL (15 mL * 3) of DCM. The combined layers were washed with 20 mL of brine, dried over _{Na2SO4 ,} filtered, and concentrated under reduced pressure to obtain the final compound.)

3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereoisomer 1) was obtained as a white solid (19.65 mg, 43.07 μmol, 42.72% yield). MS (ES+) m/z: 445.1/447.0 (M+1) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.75 (q, J = 8.0 Hz, 1H), 6.69 - 6.83 (m, 1H), 6.58 (dd, J = 8.0, 1.6 Hz, 1H), 6.31 (s, 1H), 4.46 (t, J = 8.0 Hz, 1H), 4.03 - 4.21 (m, 1H), 3.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.61 (s, 3H), 2.21 (s, 6H), 1.36 (d, J = 6.0 Hz, 3H), 1.23 (s, 2H).

3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereoisomer 2) was obtained as a white solid (29.1 mg, 64.9 μmol, 64.39% yield, 99.162% purity). MS (ES+) m/z: 445.1/447.0 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77 (q, J = 8.0 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 6.31 (s, 1H), 4.46 (t, J = 8.0 Hz, 1H), 4.04 - 4.24 (m, 1H), 3.57 - 3.63 (m, 1H), 2.60 - 2.64 (m, 3H), 2.56 (s, 1H), 2.24 (s, 6H), 1.36 (d, J = 6.0 Hz, 3H), 1.23 (s, 1H).

3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereoisomer 3) was obtained as a white solid (26.9 mg, 56.4 μmol, 56.0% yield, 93.144% purity). MS (ES+) m/z: 445.1/447.0 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.83 (q, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.0, 1.6 Hz, 1H), 6.67 (dd, J = 8.0, 2.4 Hz, 1H), 6.34 (s, 1H), 4.67 - 4.84 (m, 1H), 4.14 - 4.28 (m, 1H), 4.02 - 4.12 (m, 1H), 3.51 (s, 1H), 3.06 - 3.22 (m, 3H), 2.50 (s, 9H), 1.24 (d, J = 6.4 Hz, 3H).

3-Chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azacyclobut-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methylbenzenesulfonamide (stereoisomer 4) was obtained as a white solid (30.6 mg, 64.0 μmol, 63.4% yield, 92.916% purity). MS (ES+) m/z: 445.1/447.0 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.83 (q, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.0, 2.0 Hz, 1H), 6.68 (dd, J = 8.0, 2.4 Hz, 1H), 6.35 (s, 1H), 4.68 - 4.79 (m, 1H), 4.17 - 4.26 (m, 1H), 4.11 (t, J = 8.0 Hz, 1H), 3.21 - 3.28 (m, 2H), 3.16 (d, J = 9.2 Hz, 1H), 2.69 (s, 6H), 2.63 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H).

Example 140: 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide 2,3-Dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azacyclobut-1-yl)benzenesulfonamide was prepared according to a procedure similar to that used to prepare Examples 120 and 121, providing the title compound as a white solid. (0.12 g, 25% yield): ¹H-NMR (400 MHz; DMSO-d⁶): δ 7.65–7.59 (m, ¹H), 6.67 (dd, J = 8.0, 2.3 Hz, ¹H), 6.47–6.44 (m, ¹H), 6.40–6.38 (m, ¹H), 4.17–4.09 (m, 4H), 3.25 (d, J = 1.0 Hz, 3H), 3.18–3.08 (m, 2H), 3.07–2.91 (m, 3H), 2.64–2.61 (m, 3H), 2.10–2.03 (m, ¹H), 1.80–1.75 (m, ¹H), NH proton signal missing; MS (ES+) m/z: 507.0 (M + H), 509.0 (M + H).

Examples 141 and 142: 5-chloro-4-(3-(2-(dimethylamino)ethyl)cyclobutyl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (stereoisomers 1 and 2) Step 1: Add pyridine (15.9 g, 200 mmol, 16.2 mL, 3.00 eq) and DMAP (1.63 g, 13.4 mmol, 0.20 eq) to a solution of 6-fluoropyridine-2-amine (7.50 g, 66.9 mmol, 1.00 eq) in DCM (75 mL). Then, slowly add 100 mL of DCM containing 4-bromo-5-chloro-2-fluorobenzenesulfonyl chloride (20.6 g, 66.9 mmol, 1.00 eq) at 0 °C. Stir the mixture at 25 °C for 3 hr. Quench the reaction mixture by adding 200 mL of water at 25 °C and filter to obtain a filtrate. Then extract the filtrate with dichloromethane (100 mL * 3). The combined organic layers were washed with hydrogen chloride (1M, 100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO₂ , commercial hexane:ethyl acetate) to give a yellow solid, 4-bromo-5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (20.0 g, 52.1 mmol, 77.9% yield). MS (ES+) m/z 382.9/384.8 (M+1).

Step 2: Add _K₂CO₃ (13.0 g, 93.8 mmol, 2.00 eq) to a solution of 4-bromo-5-chloro-2-fluoro- _N- (6-fluoro-2-pyridyl)benzenesulfonamide (18.0 g, 46.9 mmol, 1.00 eq) in DMF (180 mL). Then add SEM-Cl (9.38 g, 56.3 mmol, 9.96 mL, 1.20 eq) at 0 °C. Stir the mixture at 25 °C for 3 hr. Quench the reaction mixture by adding 400 mL of water at 25 °C, and then extract with ethyl acetate (300 mL * 3). The combined layers were washed with brine (300 mL * 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO2 , commercial hexane:ethyl acetate) to give a white solid compound, 4-bromo-5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-N-(2-trimethylsilethoxymethyl)benzenesulfonamide (20.0 g, 38.9 mmol, 82.9% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.95 - 8.23 (m, 3H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.08 (dd, J = 8.0, 2.4 Hz, 1H), 5.33 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.75 - 0.86 (m, 2H), 0.07 (s, 9H).

Step 3: Add the following to a 100 mL vial equipped with a stirring rod: 4-bromo-5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-N-(2-trimethylsilethoxymethyl)benzenesulfonamide (28.5 g, 55.4 mmol, 1.00 eq), 2-bromo-5,8-dioxane[3,4]octane (13.9 g, 72.1 mmol, 1.30 eq), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (622 mg, 554 μmol, 0.01 eq, CAS: 870987-63-6), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; nickel dichlorodichloro (331 mg, 832 μmol, 0.015 eq, CAS: 1034901-50-2), bis(trimethylsilyl)silyl-trimethyl-silane (13.8 g, 55.5 mmol, 17.1 mL, 1.00 eq; CAS: 1873-77-4), 2,6-dimethylpyridine (11.9 g, 111 mmol, 12.9 mL, 2.00 eq) in DME (600 mL). Seal the vials and place them under nitrogen. The reaction mixture was stirred and irradiated with a blue LED lamp (395 nm, 200 W), and the reaction temperature was maintained at 25°C for 1.5 hours with cooling water. The reaction mixture was quenched by adding water (500 mL) at 25°C, and then extracted with ethyl acetate (200 mL * 3). The combined layers were washed with brine (300 mL * 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography ( _SiO2 , commercial hexane:ethyl) to give a yellow oily compound, 5-chloro-4-(5,8-dioxaspiro[3.4]oct-2-yl)-2-fluoro-N-(6-fluoro-2-pyridyl)-N-(2-trimethylsilethoxymethyl)benzenesulfonamide (19.0 g, 34.7 mmol, 62.6% yield). MS (ES+) m/z 569.2 (M+23). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.02 - 8.13 (m, 1H), 7.87 - 7.98 (m, 1H), 7.52 - 7.64 (m, 1H), 7.34 - 7.41 (m, 1H), 7.02 - 7.08 (m, 1H), 5.35 (d, J = 2.4 Hz, 2H), 3.85 - 3.93 (m, 1H), 3.79 - 3.84 (m, 1H), 3.57 - 3.70 (m, 3H), 3.46 - 3.53 (m, 1H), 3.21 - 3.28 (m, 2H), 2.63 - 2.75 (m, 1H), 2.41 - 2.46 (m, 1H), 2.37 - 2.41 (m, 1H), 0.77 - 0.87 (m, 2H), 0.08 - 0.04 (m, 9H).

Step 4: Dissolve 5-chloro-4-(5,8-dioxaspiro[3.4]oct-2-yl)-2-fluoro-N-(6-fluoro-2-pyridyl)-N-(2-trimethylsilethoxymethyl)benzenesulfonamide (18.0 g, 32.9 mmol, 1.00 eq) in HCOOH (180 mL). Stir the mixture at 50 °C for 12 hr. Concentrate the reaction mixture under reduced pressure to remove the solvent, giving a residue. Dilute the residue with 30 mL of ethyl acetate and adjust the pH to 7-8 with an aqueous sodium bicarbonate solution. Then extract the mixture with ethyl acetate (30 mL * 3). The combined layers were washed with brine (50 mL *1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily compound, 5-chloro-2-fluoro-N-(6-fluoro-2-pyridinyl)-4-(3-sideoxycyclobutyl)benzenesulfonamide (13.0 g, crude). MS (ES+) m/z 372.9 (M+1).

Step 5: Add ethyl 2-(triphenylphosphine)acetate (12.9 g, 36.9 mmol, 1.1 eq) to a solution of 5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-4-(3-sideoxycyclobutyl)benzenesulfonamide (12.5 g, 33.5 mmol, 1.00 eq) in toluene (125 mL). Stir the mixture at 70 °C for 2 hr. Concentrate the reaction mixture under reduced pressure to obtain the residue. The residue was purified by column chromatography ( _SiO₂ , commercial hexane:ethyl acetate) to give a white solid compound, ethyl 2-[3-[2-chloro-5-fluoro-4-[(6-fluoro-2-pyridyl)aminesulfonyl]phenyl]cyclobutylene] (7.00 g, 15.8 mmol, 47.1% yield). MS (ES+) m/z 443.0 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.90 (br s, 1H) 7.82 - 7.97 (m, 2H) 7.63 (br d, J = 11.2 Hz, 1H) 6.92 (br d, J = 7.2 Hz, 1H) 6.75 (br d, J = 6.4 Hz, 1H) 5.71 (br s, 1H) 4.07 (q, J = 7.2 Hz, 2H) 3.87 (dt, J = 16.4, 8.4 Hz, 1H) 3.46 - 3.63 (m, 2H) 2.96 - 3.19 (m, 2H) 1.18 (br t, J = 7.2 Hz, 3H).

Step 6: Add CoCl₂ • 6H₂O (698 mg, 2.94 mmol, 0.20 eq) to a solution of ethyl 2-[3-[ ₂ -chloro- ₅ -fluoro-4-[(6-fluoro-2-pyridyl)aminesulfonyl]phenyl]cyclobutylene]ethyl acetate (6.50 g, 14.7 mmol, 1.00 eq) in EtOH (65 mL). Then slowly add _NaBH₄ (2.78 g, 73.4 mmol, 5.00 eq) at -40 °C. Stir the mixture at -40 °C for 2 hr. Filter the reaction mixture and wash the filter cake with EtOH (30 mL). Then concentrate the filtrate under reduced pressure to obtain the residue. The residue was quenched by adding water (50 mL) at 25°C, followed by extraction with ethyl acetate (50 mL * 3). The combined layers were washed with brine (50 mL * 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily compound, ethyl acetate 2-[3-[2-chloro-5-fluoro-4-[(6-fluoro-2-pyridyl)aminesulfonyl]phenyl]cyclobutyl] (6.00 g, crude). MS (ES+) m/z 445.0 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.75 - 7.87 (m, 1H), 7.46 - 7.61 (m, 1H), 7.19 - 7.41 (m, 1H), 6.56 - 6.70 (m, 1H), 6.19 - 6.36 (m, 1H), 3.98 - 4.09 (m, 2H), 3.81 (quin, J = 8.4 Hz, 1H), 3.47 - 3.61 (m, 1H), 2.51 - 2.64 (m, 2H), 2.39 - 2.49 (m, 2H), 2.21 - 2.36 (m, 1H), 2.08 - 2.20 (m, 1H), 1.72 - 1.87 (m, 1H), 1.13 - 1.20 (m, 3H).

Step 7 Solution 1: {THF, 20.5 ml} containing ethyl acetate 2-[3-[2-chloro-5-fluoro-4-[(6-fluoro-2-pyridyl)aminesulfonyl]phenyl]cyclobutyl] (1.80 g, 4.05 mmol, 1.00 eq)}. Solution 2: {Lithium; Tributoxy(diisobutyl)aluminate (0.5 M, 20.2 mL, 2.5 eq)}. Solution 1 was pumped into flow reactor 1 {FLR1, PFA, coil reactor, 3.175 (1/8") mm, 64.114875 mL, -40.0℃} by pump 1 {S1, P1, 6.366 mL/min}. Solution 2 was pumped into flow reactor 1 {FLR1, PFA, coil reactor, 3.175 (1/8") mm, 64.114875 mL, -40.0℃} by pump 2 {S2, P2, 6.457 mL/min}. The residence time in flow reactor 1 was 5.0 min. The reaction mixture was quenched by adding water (20 mL) and HCl (1 M, 50 mL) at 0 °C, followed by extraction with ethyl acetate (50 mL * 3). The combined layers were washed with brine (50 mL * 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid, 5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-4-[3-(2-epihydroxyethyl)cyclobutyl]benzenesulfonamide (2.00 g, crude), without further purification. MS (ES+) m/z 401.0 (M+1).

Step 8: Add NaBH(OAc)₃ (2.12 g, 9.98 mmol, 2 eq) to a solution of 5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl) _-4- [3-(2-epheloethyl)cyclobutyl]benzenesulfonamide (2.00 g, 4.99 mmol, 1.00 eq), N-methylmethylamine, and hydrochloride (610 mg, 7.48 mmol, 1.50 eq) in DCM (20 mL). Stir the mixture at 25 °C for 2 hr. Quench the reaction mixture by adding 50 mL of water at 25 °C, and then extract with dichloromethane (30 mL * 3). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was wet-milled with MTBE (25 ml) at 25°C for 3 hours. The residue was then filtered and the filter cake was washed with MTBE (25 ml). The filter cake was concentrated under reduced pressure to obtain a crude product (approximately 800 mg). The crude product was purified by column chromatography ( _SiO₂ , dichloromethane:methanol) to obtain peak 1 (approximately 350 mg; P1) and peak 2 (approximately 400 mg; P2) as a white solid. Peak 1 was purified by preparative HPLC (basic conditions: column: CD02-Waters Xbridge BEH C18 100 * 25 mm * 10 μm; mobile phase: [ _H₂O (0.05% _NH₃H₂O )-ACN]; gradient: 7% - 37% B, for 10.0 min) to obtain stereoisomer ₁ (80.0 mg, 186 μmol, 10.0% yield). Peak 2 (stereoisomer 2) was not further purified (400 mg, 930 μmol, 50.0% yield).

Example 141: MS (ES+) m/z 430.1 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.74 (d, J = 6.4 Hz, 1H), 7.42 - 7.52 (m, 1H), 7.29 (d, J = 10.8 Hz, 1H), 6.60 (dd, J = 8.0, 2.4 Hz, 1H), 6.19 (dd, J = 7.6, 2.8 Hz, 1H), 3.59 - 3.72 (m, 1H), 2.86 - 2.93 (m, 2H), 2.72 (s, 6H), 2.13 - 2.23 (m, 3H), 2.03 - 2.12 (m, 2H), 1.83 - 1.92 (m, 2H).

Example 142: MS (ES+) m/z 430.1 (M+1). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77 (d, J = 6.4 Hz, 1H), 7.41 - 7.56 (m, 1H), 7.21 (br d, J = 10.8 Hz, 1H), 6.54 (dd, J = 7.6, 2.4 Hz, 1H), 6.21 (br dd, J = 7.6, 2.4 Hz, 1 H), 3.48 - 3.59 (m, 1H), 2.85 - 2.96 (m, 2H), 2.73 (s, 6H), 2.41 - 2.49 (m, 2H), 2.23 (dt, J = 14.8, 7.2 Hz, 1H), 1.67 - 1.82 (m, 4H).

Example 143 3-Chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide Step 1. Preparation of 3-chloro- N- (2,4-dimethoxybenzyl)-2-fluoro- N- (6-fluoropyridin-2-yl)-4-(3-hydroxyazacyclobutan-1-yl)-6-methylbenzenesulfonamide: A vial containing 3-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)-6-methylbenzenesulfonamide (3.6 g, 7.3 mmol), anhydrous cesium carbonate (5.9 g, 18 mmol), and anhydrous N,N -dimethylformamide (29 mL) was cooled in an ice/water bath. Azacyclobutan-3-ol hydrochloride (1.2 g, 11 mmol) was added to the vial, and the reaction mixture was allowed to heat to ambient temperature. After stirring for 2 h, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated ammonium chloride (2 × 50 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum . The residue was purified by column chromatography by precipitation with heptane containing 10 to 100% ethyl acetate to give the title compound (3.5 g, 89% yield) as a colorless oil: MS (ES+) m/z: 540.0 (M + 1), 542.0 (M + 1).

Step 2. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(3-sideoxyazinocyclobut-1-yl)benzenesulfonamide: Anhydrous dichloromethane (9.2 mL) and oxaloyl chloride (0.191 mL, 2.22 mmol) were added to a flask under a nitrogen atmosphere. The reaction mixture was cooled in a dry ice/acetone bath, and then anhydrous dimethyl sulfoxide (0.35 g, 4.44 mmol) was added. The mixture was stirred at -78°C for 20 min, then a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-hydroxyazacyclobut-1-yl)-6-methylbenzenesulfonamide (1.0 g, 1.9 mmol) in anhydrous dichloromethane (9.2 mL) was added, followed immediately by the addition of triethylamine (0.93 mL, 6.7 mmol). The reaction mixture was heated to ambient temperature and stirred for 2 h. The reaction mixture was diluted with dichloromethane (300 mL) and transferred to a separatory funnel. The organic layer was washed with saturated ammonium chloride (2 × 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum . The compound was ready for the next step without further purification (0.99 g, 100% yield): MS (ES+) m/z: 560.0 (M + Na), 562.0 (M + Na).

Step 3. Preparation of methyl 4-(1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)aminesulfonyl)-3-fluoro-5-methylphenyl)-3-hydroxyazacyclobutan-3-yl)-4-nitrobutyrate: Add ethanol (4 mL), methyl 4-nitrobutyrate (0.41 g, 2.8 mmol), and triethylamine (0.19 g, 1.9 mmol) to a flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(3-sideoxyazacyclobutan-1-yl)benzenesulfonamide (0.99 g, 1.9 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then diluted with ethyl acetate (300 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum . The residue was purified by column chromatography using a gradient dissolution of 10 to 80% ethyl acetate in heptane to give the title compound as a yellow solid (0.64 g, 50% yield): MS (ES+) m/z: 685.2 (M + H), 687.2 (M + H).

Step 4. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-hydroxy-3-(5-sideoxypyrrolidin-2-yl)azacyclobutan-1-yl)-6-methylbenzenesulfonamide: Iron powder (0.72 g, 13 mmol) and glacial acetic acid (15 mL) are added to a flask containing methyl 4-(1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)aminesulfonyl)-3-fluoro-5-methylphenyl)-3-hydroxyazacyclobutan-3-yl)-4-nitrobutyrate (0.64 g, 0.93 mmol). The reaction mixture was heated to 80°C for 12 h and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate (250 mL), filtered through a sodium sulfate bed, and concentrated under vacuum . The residue was purified by column chromatography using a gradient dissolution of 25 to 100% ethyl acetate in heptane, followed by 0 to 20% methanol in ethyl acetate, to give the title compound (0.50 g, 86% yield) as a colorless oil: MS (ES+) m/z: 645.2 (M + Na), 647.2 (M + Na).

Step 5. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methyl-5-sideoxypyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide: Anhydrous N,N,-dimethylformamide (8.6 mL) and methyl iodoform (0.53 g, 3.8 mL) are added to a flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2 -fluoro-N-(6-fluoropyridin-2-yl)-4-(3-hydroxy-3-(5-sideoxypyrrolidin-2-yl)azacyclobut- 1-yl)-6-methylbenzenesulfonamide (0.53 g, 3.8 mmol). mmol), followed by the addition of a 60% sodium hydroxide mineral oil dispersion (0.15 g, 3.8 mmol). The reaction mixture was stirred at ambient temperature for 24 h, and then diluted with ethyl acetate (150 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL), water (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum . The residue was purified by column chromatography using a gradient dissolution of 60 to 100% ethyl acetate in heptane followed by 0 to 20% methanol in ethyl acetate to obtain the title compound (0.46 g, 82% yield) as a colorless oil: MS (ES+) m/z : 673.2 (M + Na), 675.2 (M + Na).

Step 6. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide A flask containing 0.46 g, 0.71 mmol of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methyl-5-sideoxypyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide (6.0 mL) was filled with 9-boronadicyclo[3.3.1]nonane in tetrahydrofuran (6.0 mL). The M solution was heated to 60°C and held for 1 h. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (250 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum . The residue was purified by column chromatography using a gradient dissolution of 10 to 80% ethyl acetate (containing 10% triethylamine and 10% isopropanol) in heptane to give the title compound (0.45 g, 99% yield) as a colorless oil: MS (ES+) m/z: 637.4 (M + H), 639.4 (M + H).

Step 7. Preparation of 3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide A flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azacyclobut-1-yl)-6-methylbenzenesulfonamide (0.45 g, 0.71 mmol) is filled with 1,3,5-trimethoxybenzene (0.119 g, 0.71 mmol), anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in a vacuum . The residue was purified by reverse-phase column chromatography using a gradient dissolution of 5-35% acetonitrile in water containing 0.5% formic acid. After freeze-drying, the title compound (0.13 g, 36% yield) was obtained as a colorless solid: ^¹H -NMR (400 MHz; DMSO- _d⁶ ): δ 7.79 (q, J = 8.3 Hz, 1H), 6.76 (dd, J = 7.9, 2.0 Hz, 1H), 6.62 (dd, J = 7.9, 2.4 Hz, 1H), 6.30 (s, 1H), 4.18 (dd, J = 9.7, 3.4 Hz, 2H), 4.12-4.08 (m, 2H), 3.32 (s, 3H). 3.06–3.01 (m, 1H), 2.93–2.90 (m, 1H), 2.61 (s, 3H), 2.43–2.36 (m, 4H), 2.00–1.93 (m, 1H), 1.73–1.63 (m, 3H), missing NH proton signal; MS (ES+) m/z: 487.2 (M+H), 489.2 (M+H).

Bioassay Example 144: Electrophysiological Assay (In Vivo) Sodium current was measured in whole-cell configuration using patch clamp technology on a Qube 384 (Sophion Bioscience A/S, Copenhagen, Denmark) automated voltage clamp platform. Electrophysiological experiments were performed using HEK293 cells. These HEK293 cells were _stably transfected with a vector containing full-length cDNA encoding one of the following human sodium channel α-units: human _NaV 1.7 (NM_002977); human _NaV 1.1 (NM_006920); human _NaV 1.2 (NM_021007); human _NaV 1.5 (NM_198056); human NaV 1.6 (NM_014191), and co-expressed with the human _NaV β1 unit (NM_199037). Cells were grown at 37°C and 5% _CO2 in a medium containing 10% fetal bovine serum, 1% penicillin-streptomycin-glutamic acid, and 0.5 mg/mL genotypic acid (G418). Recording solutions contained: Intracellular solution (ICS): 5 mM NaCl, 10 mM CsCl, 120 mM CsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid buffer), and 10 mM EGTA (ethylene glycol tetraacetic acid); pH adjusted to 7.2 with CsOH. Extracellular solution (ECS): 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES; pH adjusted to 7.4 with NaOH. The osmotic pressures of all ICS and ECS solutions were adjusted to 300 mOsm/kg and 310 mOsm/kg, respectively, with glucose. For measurement inhibition, the membrane potential was maintained at the voltage at which the channel was completely inactivated. The holding potentials for quantitative compound inhibition were as follows for each NaV channel subtype: _NaV 1.6 (-45 mV), _NaV 1.1 (45 mV), _NaV 1.2 (45 mV), _NaV 1.5 (-60 mV), _NaV 1.7 (-60 mV). The voltage was briefly repolarized to a negative voltage (150 mV) every 10 seconds for 20 milliseconds to allow recovery from rapid inactivation, followed by a pulse to -20 mV for 10 milliseconds to quantify the compound's inhibition of the current. A 20 ms repolarization was sufficient to allow the compound-free channel to fully recover from rapid inactivation, but the compound-bound channel remained blocked. The decrease in the sodium current fraction after washing with the compound for 20 minutes was considered the fraction of sodium channel blockage by the compound. All Qube experiments were conducted at 30 °C ± 2 °C.

Those familiar with this technique should understand that selectivity can be determined by evaluating the ratio of inhibition by Na _V 1.x to Na _V 1.7. If this ratio is ≥5, the compound is considered to be selective.

CNS Exposure: After administration to mice, the brain and plasma levels of the test compound were analyzed by electrospray mass spectrometry. If the brain to plasma exposure ratio was >0.05, the compound was considered to have CNS penetration.

Information on representative compounds disclosed herein is provided in Table 9.

Table 9 * (+) = ＞ 2 μM; (++) = 1-2 μM; (+++) = ＜ 1 μM

The methods, compounds, and compositions described herein have been fully described. Those skilled in the art will understand that they can be carried out under broad and equivalent conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiments thereof. All patents, patent applications, and disclosures cited herein are incorporated herein by reference in their entirety.

Claims (46)

A compound having formula I , I ; or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, wherein: ^M1 is selected from N and ^CR1 ; ^M2 is selected from N and ^CR2 ; ^M3 is selected from N and ^CR3 ; ^M4 is selected from N and ^CR4 ; each of ^R1 , ^R2 , ^R3 and ^R4 is independently selected from hydrogen, halogen, cyano, ( _C1 - _C6 ) alkyl, (C1-C6) halogenated alkyl, ( _C3 - _C6 ) cycloalkyl, ( _C1 - _C6 ) alkoxy, ( _C3 - _C6 ) alkoxy, (C3-C6) alkyl, or ( _C3 - _C6) alkyl. ^R5 is independently selected from halogen, substituted (C1- _C6 ) alkyl, ( _C1 -C6) halogenated, substituted ( _C3 - _C6 ) cycloalkyl, substituted ( _C1 - _C6 ) alkyl, substituted ( _C1 - _C6 ) alkoxy, substituted ( _{C3 - C6 )} cycloalkyl, substituted ( _{C6 - C14} ) aryl, substituted heterocyclic, substituted heteroaryl, or two twin Rs _. ^R5 , together with the atoms it is attached to, forms a ( _C3 - _C6 ) cycloalkyl group, which may be substituted, or ^R5 is a _C1 alkyl group, which forms a bond with each of the two carbons of the ring to which it is attached; n is 0, 1, or 2; ^R9 is selected from hydrogen, ( _C1 - _C6 ) alkyl, and ( _C6 - _C14 ) aryl-( _C1 - _C6 ) alkyl-, which may be substituted; A is a heteroaryl group, which may be substituted; Z is selected from N and ^CRZ ; ^RZ is selected from hydrogen and ( _C1 - _C6 ) alkyl; ^R6 is selected from hydrogen, halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) halogenated alkyl, and ( _C3 - _C6) alkyl-, which may be substituted. Cycloalkyl, (C1-C6)alkoxy, ( _C3 - _C6 )cycloalkyloxy, ( _C6 - _C14 )aryl, (C6-C14) heterocyclic, and ( _C1 - _C14 ) heteroaryl are selected from ^R8R7N- , ^R8R7N- (C1-C6)alkyl-, R8R7N- _{(C3-C6)cycloalkyl-, R8R7N-(C3-C6)cycloalkyl-(C1-C6)alkyl-, (C1-C6) heterocyclic, and (C1} ^- _{C6 )} ^{alkyl- (} _C1 ^- _{C6 )} ^{cycloalkyl, or R8R7N- (} _C3 - _C6 )cycloalkyl-(C1-C6)alkyl-, ( _C1 - _C14 ) alkyl-(C1-C14)cyclo ... ⁶ and W, together with the atoms they are attached to ^{, form R8R7N- (} _C3 - _C7 )cycloalkyl- ^{, R8R7N-} ( _C1 - _C6 )alkyl-( _C3 - _C7 )cycloalkyl-, or, where applicable, a substituted heterocyclic group; and each of ^R7 and ^R8 is independently selected from hydrogen, where applicable, a substituted ( _C1 - _C6 )alkyl, where applicable, a substituted ( _C3 - _C6 )cycloalkyl, where applicable, a substituted heterocyclic group, where applicable, a substituted ( _C6 - _C14 )aryl-( _C1 - _C6 )alkyl-, ( _C1 - _C6 )halogenated alkyl, or, where applicable, a substituted ( _C1 - _C6 )alkyl-O-(C ₁ - _C6 )alkyl- and ( _C3 - _C6 )cycloalkyl- ( _C1 - _C6 )alkyl-, or ^R7 and ^R8 together with the atoms to which they are attached to form heterocyclic groups as appropriate, substituted. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent compound of the compound or a stereoisomer thereof, wherein... for . The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, wherein each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, (C1 _{- C6} ) alkyl or halogen. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein ^R1 is a halogen. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, as described in any of the preceding claims, wherein ^R2 is hydrogen. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, as described in any of the preceding claims, wherein ^R3 is selected from hydrogen and halogen. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein R ⁴ is a halogen. The compound, or its stereoisomer, as described in any of the foregoing claims, or a pharmaceutically acceptable salt or solvent compound or its stereoisomer, wherein Department selected from , and . The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer as described in any of the preceding claims, wherein Z is N. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, wherein W is selected from ^R8R7N- ( _C1 - _C6 )alkyl-, a nitrogen-containing heterocyclic group as appropriate, and ^a nitrogen-containing heterocyclic group as appropriate ( _C1 - _C6 )alkyl-. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of any of the preceding claims, wherein ^R7 and ^R8 are ( _C1 - _C6 ) alkyl groups. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent compound thereof, as described in any of the foregoing claims, wherein W is selected from... , , , , , , , and . The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer, as described in any of the preceding claims, wherein ^R6 is selected from hydrogen, halogen, ( _C1 - _C6 )alkyl, ( _C3 - _C6 )cycloalkyl, ( _C1 - _C6 )alkoxy, and, where applicable, substituted ( _C6 - _C14 )aryl. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, as described in any of the preceding claims, wherein ^R6 is selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, and phenyl. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, wherein ^R6 and W together with the atoms to which they are attached form ^R8R7N- ( ^C3 - _{C7 )} cycloalkyl- or, where applicable, a substituted nitrogen-containing heterocyclic group. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, wherein ^R6 and W, together with the atoms to which they are attached, form, where appropriate, a substituted cyclobutyl or a substituted pyrrolidyl group. The compound, or its stereoisomer, as described in any of the foregoing claims, or a pharmaceutically acceptable salt or solvent compound or its stereoisomer, wherein... for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of any of the preceding claims, wherein R ⁹ is hydrogen. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, as claimed in any of the preceding claims, wherein A is selected from a substituted thiazolyl group and a substituted pyridyl group, as appropriate. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent compound thereof, as described in any of the preceding claims, wherein A is selected from... , and . The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer thereof, having any one or more of the formulas IIa , IIb , IIc , IId , IIe , IIf , IIq , IIr , and IIs : IIa , IIb IIc , IId , IIe If IIq , IIr , IIs , wherein: p is selected from 0, 1, 2 and 3; t is selected from 0, 1 and 2; q is selected from 1, 2 and 3, provided that if t is 0, then q is selected from 2 and 3; ^Z1 is selected from ^CR15 and N; ^R12 is selected from hydrogen and, where applicable, substituted ( _C1 - _C6 ⁾ alkyl; and ^R15 is selected from hydrogen, where applicable, substituted ( _C1 - _C6 ) alkyl and ^-NR8R9 . The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer as described in any of the preceding claims, wherein p is 1 or 2. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer as described in any of the preceding claims, wherein t is 1 and q is 1. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein t is 1 and q is 2. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein t is 0 and q is 3. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, as described in any of the preceding claims, wherein ^Z1 is CR ¹⁵ . The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of any of the preceding claims, wherein R ¹⁵ is hydrogen. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of any of the preceding claims, wherein ^Z1 is N. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein R ¹² is methyl. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or its stereoisomer thereof, having any one or more of the formulas IIg , IIh , IIi , IIj , IIk , IIm, IIt , IIu , and IIv : IIg , IIh IIi IIj , IIk , IIm , IIt 、 IIu , IIv ; wherein: ^R10 and ^R11 are each independently selected from hydrogen, halogen, and ( _C1 - _C4 ) alkyl, or ^R10 and ^R11 in formulas IIg , IIh , and IIt together with the atoms to which they are attached form, where appropriate, a substituted aryl group, a substituted heterocyclic group, a substituted heteroaryl group, or a substituted cycloalkyl group; and ^R13 and ^R14 are each independently selected from the group consisting of: hydrogen, halogen, cyano, where appropriate, a substituted ( _C1 - _C6 ) alkyl, a ( _C1 - _C6 ) halogenated alkyl, where appropriate, a substituted ( _C3 - _C6 ) cycloalkyl, or a substituted ( _C1 - _C6) cycloalkyl group. Alkyloxy, ( _C3 - _C6 )cycloalkyloxy, ( _C1 - _C6 )alkylthio, and ( _C3 - _C6 )cycloalkylthio as appropriate. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or stereoisomer thereof, as described in any of the preceding claims, wherein ^R10 and ^R11 are hydrogen. The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein R ¹³ is a halogen. The compound, or stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of any of the preceding claims, having one or more of the formulas IIn , IIo , IIp , IIw , IIx , and IIy : IIn 、 IIo , IIp , IIw , IIx , IIy . The compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof, as described in any of the preceding claims, wherein the compound is one of the compounds listed in Table A, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvent of the compound or a stereoisomer thereof. A pharmaceutical composition comprising any of the compounds in the preceding claims and a pharmaceutically acceptable excipient. A method for inhibiting one or more sodium channels in an individual in need, comprising administering to the individual a therapeutically effective amount of any of the aforementioned claims. A method for treating a disease or condition in an individual of need that is associated with the inhibition of one or more sodium channels, comprising administering to the individual a therapeutically effective amount of any of the preceding claims of a compound. The method of any of the aforementioned requests, wherein the one or more sodium channels are Na _V 1.7. The method of any of the aforementioned claims, wherein the inhibition or inhibition of one or more sodium channels is selective inhibition or selective inhibition of Na _V 1.7. The method of any of the aforementioned claim 39, wherein the disease or condition is selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itching, and combinations thereof. A method for treating an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, pruritus, and combinations thereof, comprising administering to the individual a therapeutically effective amount of any of the preceding claims. The compound of any of the aforementioned claims is used to treat in an individual of need a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itch, or combinations thereof. Use of a compound as claimed in any of the preceding claims for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itch, and combinations thereof. Use of a compound as claimed in any of the preceding claims, for the manufacture of a medicament for the treatment of an individual in need of a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, mental illness, diabetes, itch, and combinations thereof. The compound, use, or method of any of the preceding claims, wherein the pain is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, paroxysmal pain, neurocystic pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof. The compound, use or method of any of the preceding claims, wherein the pain is related to HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, allodynia, thermal sensitivity, sarcoidosis, irritable bowel syndrome, Crohns disease disease), pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal hypotonia, myasthenic syndrome, myotonia, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, thyroid function Low mood, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial acropain, primary acropain, familial rectal pain, cancer, epilepsy, partial and generalized tonic-clonic seizures, restless legs syndrome, arrhythmia, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or nerve trauma, tachyarrhythmia, atrial or ventricular flutter.