Substituted aryl sulfonamides for use as sodium channel inhibitors

Abstract

The present disclosure provides compounds having Formula I: and the pharmaceutically acceptable salts, solvates, and 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., Nav1.7) and / or to treat a disorder responsive to the inhibition of a sodium channel (e.g., Nav1.7). Compounds of the present disclosure may be useful for treating pain.

Description

SUBSTITUTED ARYL SULFONAMIDES AND COMPOSITIONS AND USES THEREOF BACKGROUND OF THE DISCLOSURE

[0001] The present disclosure provides substituted aryl sulfonamides, including benzenesulfonamides and composition and uses thereof. In some aspects, use of aryl sulfonamides disclosed herein as sodium channel inhibitors (e.g., NaV1.7) and therapeutic methods of treating conditions and diseases wherein inhibition of sodium channels (e.g., NaV1.7) are provided. In some aspects, the use provides a benefit, for example, pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

[0002] Voltage-gated sodium channels are transmembrane proteins that initiate action potentials in nerve, muscle and other electrically excitable cells, and are a necessary component of normal sensation, emotions, thoughts and movements (Catteral, W.A., Nature 409:988-990 (2001)). This family of proteins has been extensively studied and shown to be involved in numerous vital body functions. The members of this family of proteins are denoted NaV1.x, where x=1 to 9.

[0003] The sodium channel NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encoded by the gene SCN9A. NaV1.7 is expressed primarily in the peripheral nervous system, especially in nociceptors, olfactory neurons and sympathetic neurons. The inhibition, or blocking, of NaV1.7 has been shown to result in analgesic activity. Knockout of NaV1.7 expression in a subset of sensory neurons that are predominantly nociceptive results in resistance to inflammatory pain (Nassar, et al., Proc Natl Acad Sci USA 24(34):12706-12711 (2004)). Likewise, loss of function mutations in humans results in congenital indifference to pain, in which the individuals are resistant to both inflammatory and neuropathic pain (Cox, J.J., et al., Nature 444:894-898 (2006); Goldberg, Y.P., et al., Clin. Genet.71:311-319 (2007)). Conversely, gain of function mutations in NaV1.7 have been established in two human heritable pain conditions, primary erythromelalgia and familial rectal pain (Yang, Y., et al., J. Med. Genet.41(3): 171-174 (2004)). A single nucleotide polymorphism (R1150W) that has very subtle effects on the time- and voltage-dependence of channel gating has large effects on painperception (Estacion, M., et al., Ann Neurol 66:862-866 (2009); Reimann, F., et al., Proc Natl Acad Sci USA 107: 5148-5153 (2010)).

[0004] Because NaV1.7 is preferentially expressed in nociceptors, selective inhibition of NaV1.7 may have increased efficacy in treating pain without dose-limiting side effects.

[0005] Thus, there remains a need to develop sodium channel inhibitors (e.g., NaV1.7 inhibitors) useful in the treatment of pain and related diseases and disorders. BRIEF SUMMARY

[0006] In one aspect, the present disclosure relates to compounds having Formula I (also referred to herein as Compounds of the Disclosure):

[0007] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0008] M1is selected from N and CR1;

[0009] M2is selected from N and CR2;

[0010] M3is selected from N and CR3;

[0011] M4is selected from N and CR4;

[0012] each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0013] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6- C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or

[0014] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or

[0015] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0016] R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0017] n is 0, 1 or 2;

[0018] R6is selected from hydrogen, halogen, cyano, hydroxy, optionally substituted (C1- C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

[0019] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0020] R6and W are taken together with the atom to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl, or

[0021] R6is a bond between the carbon to which it is attached and R5, or

[0022] R5and W are taken together with the atoms to which they are attached to form an amine substituted (C3-C6) cycloalkyl or optionally substituted heterocyclyl, or

[0023] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl;

[0024] each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or

[0025] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl;

[0026] A is optionally substituted heteroaryl;

[0027] Z is selected from N and CRZ;

[0028] RZis selected from hydrogen and (C1-C6) alkyl; and

[0029] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-.

[0030] In some aspects, the present disclosure relates to a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0031] In some aspects, the present disclosure relates to a method of inhibiting a sodium channel (e.g., NaV1.7) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0032] In some aspects, the present disclosure relates to a method of treating a disease or disorder associated with inhibition of a sodium channel (e.g., NaV1.7) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0033] In some embodiments, the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

[0034] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0035] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed. DETAILED DESCRIPTION OF THE DISCLOSURE

[0036] In one aspect, the present disclosure relates to compounds having Formula I (also referred to herein as Compounds of the Disclosure):

[0037] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0038] M1is selected from N and CR1;

[0039] M2is selected from N and CR2;

[0040] M3is selected from N and CR3;

[0041] M4is selected from N and CR4;

[0042] each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0043] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6- C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or

[0044] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl or

[0045] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0046] R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0047] n is 0, 1 or 2;

[0048] R6is selected from hydrogen, halogen, cyano, hydroxy, optionally substituted (C1- C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

[0049] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0050] R6and W are taken together with the atom to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl, or

[0051] R6is a bond between the carbon to which it is attached and R5, or

[0052] R5and W are taken together with the atoms to which they are attached to form an amine substituted (C3-C6) cycloalkyl or optionally substituted heterocyclyl, or

[0053] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl;

[0054] each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or

[0055] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl;

[0056] A is optionally substituted heteroaryl;

[0057] Z is selected from N and CRZ;

[0058] RZis selected from hydrogen and (C1-C6) alkyl; and

[0059] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-.

[0060] In some embodiments, a Compound of the Disclosure is a compound having Formula Ia:Ia;

[0061] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0062] M1is selected from N and CR1;

[0063] M2is selected from N and CR2;

[0064] M3is selected from N and CR3;

[0065] M4is selected from N and CR4;

[0066] each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0067] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6- C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or

[0068] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl;

[0069] n is 0, 1 or 2;

[0070] R6is selected from hydrogen, halogen, optionally substituted (C1-C6) alkyl, (C1- C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

[0071] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0072] R6and W are taken together with the atom to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl;

[0073] each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or

[0074] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl;

[0075] A is optionally substituted heteroaryl;

[0076] Z is selected from N and CRZ;

[0077] RZis selected from hydrogen and (C1-C6) alkyl; and

[0078] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-.

[0079] In some embodiments, M1, M2, M3, and M4are CR1, CR2, CR3, and CR4, respectively. In some embodiments, each of M1, M2, M3, and M4is N. In some embodiments, one of M1, M2, M3, and M4is N. In some embodiments, two of M1, M2,M3, and M4are N. In some embodiments, three of M1, M2, M3, and M4are N. In some embodiments, M1is N, and M2, M3, and M4are CR2, CR3, and CR4, respectively.

[0080] In some embodiments, M2is N, and M1, M3, and M4are CR1, CR3, and CR4, respectively. In some embodiments, M3is N, and M1, M2, and M4are CR1, CR2, and CR4, respectively. In some embodiments, M4is N, and M1, M2, and M3are CR1, CR2, and CR3, respectively.

[0081] In some embodiments,.

[0082] In some embodiments, each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, and optionally substituted (C1-C6) alkylthio. In some embodiments, each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkoxy, and optionally substituted (C1-C6) alkylthio. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, or halogen. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, (C1-C4) alkyl, or halogen. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, chloro, fluoro, methyl, ethyl, or cyclopropyl. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, chloro, fluoro, methyl, or ethyl. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, chloro, or fluoro. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen or fluoro. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, fluoro, or methyl. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, fluoro, or ethyl. In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, fluoro, or cyclopropyl.

[0083] In some embodiments, R1is selected from: i. hydrogen, halogen, C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. hydrogen and halogen; or iii. halogen.

[0084] In some embodiments, R2is hydrogen.

[0085] In some embodiments, R3is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. hydrogen and halogen; or iii. halogen.

[0086] In some embodiments, R4is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. halogen and (C1-C6) alkyl; or

[0087] iii. halogen.

[0088] In some embodiments,, ,.

[0089] In some embodiments,is selected from

[0090] In some embodiments,.

[0091] In some embodiments, R1is selected from hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl. In some embodiments, R1is selected from hydrogen and halogen. In some embodiments, R1is halogen. In some embodiments, R1is fluoro.

[0092] In some embodiments, R2is hydrogen.

[0093] In some embodiments, R3is selected from hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl. In some embodiments, R3is selected from hydrogen and halogen. In some embodiments, R3is selected from halogen. In some embodiments, R3is fluoro.

[0094] In some embodiments, R4is selected from hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl. In some embodiments, R4is selected from halogen and (C1-C6) alkyl. In some embodiments, R4is selected from halogen. In some embodiments, R4is chloro. In some embodiments, R4is fluoro. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is cyclopropyl.

[0095] In some embodiments, wherein Z is N. In some embodiments, Z is CRZ. In some embodiments, RZis hydrogen, (C1-C3) alkyl, or halogen. In some embodiments, RZis hydrogen or methyl. In some embodiments, RZis hydrogen.

[0096] In some embodiments, n is 0.

[0097] In some embodiments, n is 1 and R5is selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, or optionally substituted (C6-C14) aryl, or two geminal R5groups together with the atom to which they are attached form a (C3-C6) cycloalkyl, or R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached.

[0098] In some embodiments, n is 1 and R5is selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, and optionally substituted (C3-C6) cycloalkyloxy, or two geminal R5groups together with the atom to which they are attached form a (C3- C6) cycloalkyl.

[0099] In some embodiments, R5is selected from (C1-C6) alkyl, (C1-C6) alkoxy, and (C6- C14) aryl. In some embodiments, R5is selected from methyl, methoxy, and phenyl. In some embodiments, R5is selected from (C1-C6) alkyl and (C1-C6) alkoxy. In some embodiments, R5is selected from methyl and methoxy.

[0100] In some embodiments, two geminal R5groups together with the atom to which they are attached form a (C3-C6) cycloalkyl. In some embodiments, two geminal R5groups together with the atom to which they are attached form a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl. In some embodiments, two geminal R5groups together with the atom to which they are attached form a cyclopropyl or a cyclobutyl. Insome embodiments, two geminal R5groups together with the atom to which they are attached form a cyclopropyl.

[0101] In some embodiments, two geminal R5groups together with the atom to which they are attached form a cyclobutyl.

[0102] In some embodiments, two R5groups on different non-adjacent carbons can be taken together to form a C1-C2bridge.

[0103] In some embodiments, R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached.

[0104] In some embodiments, n is 2 and each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy.

[0105] In some embodiments, each R5is optionally substituted (C1-C6) alkyl. In some embodiments, each R5is methyl.

[0106] In some embodiments,wherein s is selected from 1, 2, 3, or 4 and v is selected from 1, 2, or 3.

[0107] In some embodiments,is selected fromwherein s is selected from 1, 2, 3, or 4.

[0108] In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0109] In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3.

[0110] In some embodiments,is selected from

[0111] In some embodiments,is selected from

[0112] In some embodiments,.

[0113] In some embodiments, W is selected from R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-. In some embodiments, W is R8R7N-(C3-C6) cycloalkyl-. In some embodiments, W is an optionally substituted heterocyclyl. In some embodiments, W is optionally substituted heterocyclyl- (C1-C6) alkyl-.

[0114] In some embodiments, the optionally substituted heterocyclyl is an optionally substituted nitrogen-containing containing heterocyclyl. In some embodiments, the optionally substituted heterocyclyl is an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted piperidyl.

[0115] In some embodiments, W is selected from

[0116] .

[0117] In some embodiments, W is.

[0118] In some embodiments, W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, and R8R7N-(C3-C6) cycloalkyl-. In some embodiments, W is R8R7N-. In some embodiments, W is R8R7N-(C1-C6) alkyl-. In some embodiments, W is R8R7N-(C3-C6) cycloalkyl-.

[0119] In some embodiments, R7and R8are each independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6)haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl- (C1-C6) alkyl-. In some embodiments, R7and R8are each independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, and (C1-C6) haloalkyl. In some embodiments, R7and R8are each optionally substituted (C1-C6) alkyl.

[0120] In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is hydrogen. In some embodiments, R7is optionally substituted (C3-C6) cycloalkyl and R8is hydrogen. In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is optionally substituted (C3-C6) cycloalkyl. In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is (C1-C6) haloalkyl.

[0121] In some embodiments, R7and R8are each independently selected from methyl, d3- methyl, ethyl, d5-ethyl, propyl, tert-butyl, neopentyl, 1,1-difluoromethyl, 2,2,- difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropan-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]pentan-1-yl, cyclobutyl, spiro[2.3]hexan-5-yl, 3-(difluoromethyl)cyclobutyl, and benzyl. In some embodiments, R7and R8are each methyl. In some embodiments, R7and R8are each independently selected from methyl, ethyl, propyl, tert-butyl, neopentyl, 2,2,-difluoroethyl, 2,2,2- trifluoroethyl, 1-fluoropropan-2-yl, 2-fluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, spiro[2.3]hexan-5-yl, 3-(difluoromethyl)cyclobutyl, and benzyl. In some embodiments, R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl. In some embodiments, R7and R8together with the atom to which they are attached form an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, an optionally substituted piperidyl, an optionally substituted piperazinyl, an optionally substituted morpholino, or an optionally substituted azepanyl. In some embodiments, R7and R8together with the atom to which they are attached form an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted piperidyl. In some embodiments, R7and R8together with the atom to which they are attached form an optionally substituted pyrrolidinyl. In some embodiments, R7and R8together with the atom to which they are attached form a heterocyclyl. In some embodiments, R7and R8together with the atom to which they are attached form a heterocyclyl selected from.

[0124] In some embodiments, W is.

[0125] In some embodiments, R6is selected from hydrogen, halogen, cyano, hydroxy, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In some embodiments, R6is selected from hydrogen, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, and optionally substituted (C6-C14) aryl. In some embodiments, R6is selected from hydrogen, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, and optionally substituted (C3-C6) cycloalkyloxy. In some embodiments, R6is selected from hydrogen, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, and (C6-C14) aryl. In some embodiments, R6is selected from hydrogen, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl,and (C1-C6) alkoxy. In some embodiments, R6is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, fluoro, d3-methoxy, methoxy, ethoxy, methoxymethyl, and phenyl. In some embodiments, R6is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, fluoro, methoxy, and ethoxy. In some embodiments, R6is hydrogen. In some embodiments, R6is methyl. In some embodiments, R6is methoxy. In some embodiments, R6is methyl or methoxy.

[0126] In some embodiments, R6and W are taken together with the atom to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl- , or an optionally substituted heterocyclyl. In some embodiments, R6and W are taken together with the atom to which they are attached to form an R8R7N-(C3-C7) cycloalkyl- or an optionally substituted heterocyclyl. In some embodiments, R6and W are taken together with the atom to which they are attached to form R7R8N-cyclopropyl-, R7R8N- cyclobutyl-, R7R8N-cyclopentyl-, R7R8N-methyl-cyclobutyl-, an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted morpholino. In some embodiments, R6and W are taken together with the atom(s) to which they are attached to form an optionally substituted azetidinyl or an optionally substituted pyrrolidinyl.

[0127] In some embodiments, R6is an optionally substituted (C1-C6) alkyl, wherein the optional substituents are non-cyclic substituents. In some embodiments, the optional substituents on R6are selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, hydroxyalkylamino, cycloalkylamino, aralkylamino. In some embodiments, R6is an optionally substituted (C3-C6) cycloalkyl, wherein the optional substituents non-cyclic substituents. In some embodiments, the optional substituents on R6are selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, alkylsulfonyl, carboxy, carboxyalkyl, alkyl, alkenyl, alkynyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, or mercaptoalkyl.

[0128] In some embodiments,,

[0129] In some embodiments,.

[0130] In some embodiments, A is selected from optionally substituted thiazolyl, optionally substituted benzothiazolyl, optionally substituted pyridinyl, optionally substituted isoxazolyl, optionally substituted pyridimidinyl, and optionally substituted pyridazinyl. In some embodiments, A is selected from optionally substituted thiazolyl, optionally substituted benzothiazolyl, optionally substituted pyridinyl, optionally substituted isoxazolyl, and optionally substituted pyridimidinyl. In some embodiments, A is selected from optionally substituted thiazolyl, optionally substituted benzothiazolyl, and optionally substituted pyridinyl. In some embodiments, A is optionally substitutedthiazolyl. In some embodiments, A is optionally substituted benzothiazolyl. In some embodiments, A is optionally substituted pyridinyl. In some embodiments, A is selected from ,.

[0131] In some embodiments, A is selected from

[0132] In some embodiments, A is selected from

[0133] In some embodiments, A is.

[0134] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, and XIb:

[0135] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0136] p is selected from 0, 1, 2, and 3;

[0137] q is selected from 0, 1, and 2;

[0138] t is selected from 1, 2, and 3;

[0139] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl; and

[0140] Z1is CH or O, with the proviso that when Z1is O, the sum of q + t is at least 2.

[0141] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments p is 3.

[0142] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 3.

[0143] In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0144] In some embodiments, q is 0 and t is 2. In some embodiments, q is 0 and t is 3. In some embodiments, q is 1 and t is 1. In some embodiments, q is 1 and t is 2. In some embodiments, q is 1 and t is 3. In some embodiments, q is 2 and t is 2.

[0145] In some embodiments of Formulae IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, XIa, and XIb, R6is an optionally substituted (C1-C6) alkyl, wherein the optional substituents are non-cyclic substituents. In some embodiments, the optional substituents on R6are selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, hydroxyalkylamino, cycloalkylamino, aralkylamino.

[0146] In some embodiments of Formulae IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, XIa, and XIb, R6is an optionally substituted (C3-C6) cycloalkyl, wherein the optional substituents non-cyclic substituents. In some embodiments, the optional substituents on R6are selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, alkylsulfonyl, carboxy, carboxyalkyl, alkyl, alkenyl, alkynyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, or mercaptoalkyl.

[0147] In some embodiments, R12is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In some embodiments, R12is hydrogen or methyl. In some embodiments, R12is hydrogen. In some embodiments, R12is methyl.

[0148] In some embodiments, Z1is CH. In some embodiments, Z1is O.

[0149] In some embodiments, Z1is O and q + t is 2. In some embodiments, Z1is O and q + t is 3. In some embodiments, Z1is O and q + t is 4. In some embodiments, Z1is O and q + t is 5.

[0150] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae XIIa, XIIb, XIIc, XIIIa, XIIIb, XIIIc, XIVa, XIVb, or XIVc:

[0151] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

[0152] each of R10and R11is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0153] additionally, R10and R11in Formulae XIIa, XIIb, and XIIc together with the atoms to which they are attached form an optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, or an optionally substituted cycloalkyl; and

[0154] R13and R14are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio.

[0155] In some embodiments, R10and R11in Formula XIIa, XIIb, and XIIc together with the thiazole to which they are attached form an optionally substituted benzothiazolyl.

[0156] In some embodiments, R10and R11in Formula XIIa, XIIb, and XIIc together with the thiazole to which they are attached form:.

[0157] In some embodiments, R10and R11are each independently selected from hydrogen, halogen, or optionally substituted (C1-C6) alkyl. In some embodiments, R10and R11are each independently selected from hydrogen, methyl, fluoro, chloro, and bromo.

[0158] In some embodiments, R10is hydrogen and R11is halogen. In some embodiments, R10is halogen and R11is hydrogen. In some embodiments, R10is hydrogen and R11is chloro. In some embodiments, R10is chloro and R11is hydrogen.

[0159] In some embodiments, R13and R14are each independently selected from the group consisting of hydrogen, halogen, cyano, and optionally substituted (C1-C6) alkyl. In some embodiments, R13and R14are each independently hydrogen, halogen, methyl, ethyl, propyl, or isopropyl.

[0160] In some embodiments, R13is halogen. In some embodiments, R13is fluoro, chloro, or bromo. In some embodiments, R13is fluoro.

[0161] In some embodiments, R14is hydrogen.

[0162] In some embodiments, Compounds of the Disclosure are compounds having Formula XVa, XVb, or XVc:,

[0163] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0164] In some embodiments, Compounds of the Disclosure are compounds having Formula XVa.

[0165] In some embodiments, Compounds of the Disclosure are compounds having Formula XVIa, XVIb, XVIc, XVIIa, XVIIb, or XVIIc:

[0166] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0167] p is selected from 0, 1, 2, and 3;

[0168] q is selected from 0, 1, and 2;

[0169] t is selected from 1, 2, and 3; and

[0170] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl.

[0171] In some embodiments, Compounds of the Disclosure are compounds having Formula XVIa or XVIIa.

[0172] In some embodiments, R6is selected from hydrogen, halogen, optionally substituted (C1-C6) alkyl, and optionally substituted (C1-C6) alkoxy.

[0173] In some embodiments, R6is hydrogen, methyl, or methoxy.

[0174] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0175] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0176] In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0177] In some embodiments, q is 0 and t is 2. In some embodiments, q is 0 and t is 3. In some embodiments, q is 1 and t is 1. In some embodiments, q is 1 and t is 2. In some embodiments, q is 1 and t is 3. In some embodiments, q is 2 and t is 2.

[0178] In some embodiments, R12is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl. In some embodiments, R12is hydrogen or methyl. In some embodiments, R12is hydrogen. In some embodiments, R12is methyl.

[0179] In some embodiments, R7and R8are each independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, and (C1- C6) haloalkyl. In some embodiments, R7and R8are each optionally substituted (C1-C6) alkyl. In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is hydrogen. In some embodiments, R7is optionally substituted (C3-C6) cycloalkyl and R8is hydrogen. In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is optionally substituted (C3-C6) cycloalkyl. In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is (C1-C6) haloalkyl. In some embodiments, R7and R8are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R7and R8are methyl, ethyl, or cyclobutyl.

[0180] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, or XXVI:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A, M1, M2, M3, M4, W, Z1, R5, R6, R7, R8, R12, n, p, q, and t are defined as herein.

[0181] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae XXVII, XXVIII, or XXIX:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein M1, M2, M3, M4, W, R5, R6, R10, R11, R13, R14, and n, are defined as herein.

[0182] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formula XXX:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein M1, M2, M3, M4, W, R5, R6, and n, are defined as herein.

[0183] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae XXXI and XXXII:, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein M1, M2, M3, M4, R6, R7, R8, R12, p, q, and t are defined as herein.

[0184] Compounds of the Disclosure include the compounds listed in Table A, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. Table A

[0185] In some embodiments, the Compounds of the Disclosure is a compound selected from the group consisting of:

[0186] 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(1-methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)benzenesulfonamide;

[0187] 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(6-methyl-3,6- diazabicyclo[3.2.0]heptan-3-yl)benzenesulfonamide;

[0188] 3-chloro-4-(3-((dimethylamino)methyl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)- 2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

[0189] 3-chloro-4-(6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide;

[0190] 3-chloro-4-(4-(dimethylamino)-2-azabicyclo[2.1.1]hexan-2-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide;

[0191] 3-chloro-4-(4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

[0192] 3-chloro-4-(5-(dimethylamino)-2-azabicyclo[2.1.1]hexan-2-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide;

[0193] 3-chloro-4-(1-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide;

[0194] 3-chloro-4-(4-((dimethylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

[0195] 3-chloro-4-(2-((dimethylamino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

[0196] 3-chloro-4-(6-(dimethylamino)-3-azabicyclo[3.2.0]heptan-3-yl)-2,6-difluoro-N- (6-fluoropyridin-2-yl)benzenesulfonamide; and

[0197] 3-chloro-4-(3a-((dimethylamino)methyl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)- 2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

[0198] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0199] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:

[0200] (R)-3-chloro-4-(3-((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide;

[0201] 3-chloro-4-(1,3'-dimethyl-[2,3'-bipyrrolidin]-1'-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide;

[0202] 3-chloro-4-(3-((3,3-dimethylpyrrolidin-1-yl)methyl)-3-methoxypyrrolidin-1-yl)- 2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide; and

[0203] 3-chloro-4-(1-(dimethylamino)-6-azaspiro[3.4]octan-6-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide;

[0204] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0205] In some embodiments, the Compound of the Disclosure is (R)-3-chloro-4-(3- ((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0206] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0207] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:,, , ,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0208] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0209] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0210] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0211] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0212] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0213] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:,,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0214] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:, , , , , , , , ,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0215] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0216] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0217] In some embodiments, a compound has a 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 for a sodium channel. In some embodiments, the sodium channel is NaV1.7.

[0218] In some aspects, the present disclosure relates to a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0219] In some aspects, the present disclosure relates to a method of inhibiting a sodium channel (e.g., NaV1.7) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0220] In some aspects, the present disclosure relates to a method of selectively inhibiting NaV1.7 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0221] In some aspects, the present disclosure relates to a method of treating a disease or disorder associated with inhibition of a sodium channel (e.g., NaV1.7) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0222] In some aspects, the present disclosure relates to a method of treating a disease or disordered associated with selectively inhibiting a NaV1.7 in a mammal over any other sodium channel, wherein the method comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0223] In some embodiments, a Compound of the Disclosure inhibits one or more sodium channels with an IC50 value of 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, a Compound of the Disclosure inhibits NaV1.7 channels with an IC50 value of 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” will be known to those of ordinary skill in the art and is a measure of the amount of compound required to achieve 50% inhibition of the activity of the target sodium channel over a specific time period. In some embodiments, the target sodium channel is NaV1.7. Those of ordinary skill in the art will be aware of methods for determining the IC50 of a compound, for example, by an electrophysiological assay

[0224] In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, 8, inhibition ratio of 5 or greater. In some embodiments, the Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, 8) inhibition ratio 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 NaV1.7 to Nav1.2. In some embodiments, theinhibition ratio is Nav1.7 to Nav1.5. In some embodiments, the inhibition ratio is Nav1.7 to Nav1.6.

[0225] In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, 8, inhibition ratio of from about 4 to about 7. In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, 8, inhibition ratio from about 4 to about 5, from about 4 to about 6, from from about 4 to about 8, from about 4 to about 9, from about 4 to about 10, from about 5 to about 6, from about 5 to about 7, from about 5 to about 8, from about 5 to about 9, from about 5 to about 10, from about 6 to about 7, from about 6 to about 8, from about 6 to about 9, from about 7 to about 8, from about 7 to about 9, from about 7 to about 10, from about 8 to about 9, from about 8 to about 10, or from about 9 to about 10, or from about 10 to about 15, or from about 15 to about 20, or from about 20 to about 25, or from about 25 to about 30, or from about 30 to about 35, or from about 35 to about 40, or from about 40 to about 45, or from about 45 to about 50 or greater. In some embodiments, the inhibition ratio is NaV1.7 to Nav1.2. In some embodiments, the inhibition ratio is Nav1.7 to Nav1.5. In some embodiments, the inhibition ratio is Nav1.7 to Nav1.6.

[0226] In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can inhibit about 90% of sodium channel, e.g., NaV1.7, activity. In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer 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 channel, e.g., NaV1.7, activity. In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can inhibit about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% of sodium channel, e.g., NaV1.7, activity.

[0227] In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can inhibit from about 80% to about 95% of sodium channel, e.g., NaV1.7, activity. In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can inhibit from about 50% to about 60%, from about 50% to about 70%, from about 50% toabout 80%, from about 50% to about 90%, from about 50% to about 95%, from about 50% to about 98%, from about 50% to about 99%, from about 60% to about 70%, from about 60% to about 80%, from about 60% to about 90%, from about 60% to about 95%, from about 60% to about 98%, from about 60% to about 99%, from about 70% to about 80%, from about 70% to about 90%, from about 70% to about 95%, from about 70% to about 98%, from about 70% to about 99%, from about 80% to about 90%, from about 80% to about 98%, from about 80% to about 99%, from about 90% to about 95%, from about 90% to about 98%, from about 90% to about 99%, from about 95% to about 98%, from about 95% to about 99%, or from about 98% to about 99% of sodium channel, e.g., NaV1.7, activity. In some embodiments, a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can inhibit from 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 channel, e.g., NaV1.7, activity.

[0228] In some embodiments, after administration, the ratio of the amount of a Compound of the Disclosure present in the brain compared to the blood / plasma (i.e., "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 of ordinary skill in the art will be aware of methods for determining the brain / plasma ratio, for example by measuring the concentration of the compound in the blood / plasma and measuring the concentration of the compound in the brain.

[0229] In some embodiments, the brain to plasma ratio is from about 0.01 to about 1. In some embodiments, the brain to plasma ratio is from about 0.01 to about 0.05, from about 0.01 to about 0.2, from about 0.01 to about 0.4, from about 0.01 to about 0.6, from about 0.01 to about 0.8, from about 0.01 to about 1, from about 0.01 to about 1.5, from about 0.01 to about 2, from about 0.05 to about 0.1, from about 0.05 to about 0.2, from about 0.05 to about 0.4, from about 0.05 to about 0.6, from about 0.05 to about 0.8, from about 0.05 to about 1, from about 0.05 to about 1.5, from about 0.05 to about 2, from about 0.1 to about 0.2, from about 0.1 to about 0.4, from about 0.1 to about 0.6, from about 0.1 to about 0.8, from about 0.1 to about 1, from about 0.1 to about 1.5, from about 0.1 to about 2, from about 0.2 to about 0.4, from about 0.2 to about 0.6, from about 0.2 to about 0.8,from about 0.2 to about 1, from about 0.2 to about 1.5, from about 0.2 to about 2, from about 0.4 to about 0.6, from about 0.4 to about 0.8, from about 0.4 to about 1, from about 0.4 to about 1.5, from about 0.4 to about 2, from about 0.6 to about 0.8, from about 0.6 to about 1, from about 0.6 to about 1.5, from about 0.6 to about 2, from about 0.8 to about 1, from about 0.8 to about 1.5, from about 0.8 to about 2, from about 1 to about 1.5, from about 1 to about 2, or from about 1.5 to about 2.

[0230] In some embodiments, after administration, the Kpu,u of the amount of a Compound of the Disclosure present 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 of ordinary skill in the art will be aware of methods for determining the brain / plasma ratio, for example 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 brain homogenate, and measuring the free fraction of the compound in the blood / plasma homogenate.

[0231] In some embodiments, Compounds of the Disclosure exhibit improved central nervous system (CNS) exposure relative to other NaV channel inhibitors, e.g., vixotrigine, PF-771, or GDC-0276. In some embodiments, Compounds of the Disclosure exhibit improved free fraction and tissue distribution relative to other NaV channel inhibitors. In some embodiments, Compounds of the Disclosure exhibit improved selectivity for NaV1.7 over other NaV channels relative to other NaV channel inhibitors. In some embodiments, Compounds of the Disclosure exhibit improved aqueous solubility relative to other NaV channel inhibitors. In some aspects, Compounds of the Disclosure exhibit i) improved central nervous system (CNS) exposure; ii) improved free fraction and tissue distribution; iii) improved selectivity for NaV1.7 over other NaV channels; iv) improved aqueous solubility relative to other NaV channel inhibitors; and combinations thereof.

[0232] In some embodiments, (R)-3-chloro-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (Example 102), 3-chloro-4-(1,3'-dimethyl-[2,3'-bipyrrolidin]-1'-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 4) (Example 436), 3-chloro-4-(3- ((3,3-dimethylpyrrolidin-1-yl)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1) (Example 588), and 3-chloro-4- (1-(dimethylamino)-6-azaspiro[3.4]octan-6-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomer 4) (Example 429a) exhibit i) improved centralnervous system (CNS) exposure; ii) improved free fraction and tissue distribution; iii) improved selectivity for NaV1.7 over other NaV channels; iv) improved aqueous solubility relative to other NaV channel inhibitors; and combinations thereof.

[0233] In some embodiments, (R)-3-chloro-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (Example 102) exhibits i) improved central nervous system (CNS) exposure; ii) improved free fraction and tissue distribution; iii) improved selectivity for NaV1.7 over other NaV channels; iv) improved aqueous solubility relative to other NaV channel inhibitors; and combinations thereof. In some embodiments, (R)-3-chloro-4-(3- ((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Example 102) has CNS exposure, free fraction and tissue distribution, selectivity, and aqueous solubility properties relative to other NaV channel inhibitors as described in Table B below. Table B:1More (+) symbols indicates greater CNS exposure 2More (+) symbols indicates greater free fraction and tissue distribution 3More (+) symbols indicates greater selectivity for NaV1.7 over other NaV channels 4More (+) symbols indicates greater aqueous solubility.

[0234] In some embodiments, the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

[0235] In some aspects, the present disclosure relates to a method of treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0236] In some aspects, the present disclosure relates to a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0237] In some aspects, the present disclosure relates to use of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0238] In some aspects, the present disclosure relates to use of a Compound of the Disclosure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0239] In some embodiments, the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof. Definitions

[0240] For the purpose of the present disclosure, the term "cyano" as used by itself or as part of another group refers to -CN.

[0241] For the purpose of the present disclosure, the term "hydroxy" as used by itself or as part of another group refers to -OH.

[0242] For the purpose of the present disclosure, the term "alkyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated (i.e., a C1 alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such aspropyl or isopropyl, etc.). The alkyl group can be suitably chosen from a straight chain C1-10 alkyl group, a branched chain C3-10 alkyl group, a straight chain C1-6 alkyl group, a branched chain C3-6 alkyl group, a straight chain C1-4 alkyl group, a branched chain C3-4 alkyl group, a straight or branched chain C3-4 alkyl group. The alkyl group can be partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting exemplary C1-10 alkyl groups include methyl (including -CD3, wherein D is Deuterium), ethyl (including -CD2CD3), propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, pentyl, and hexyl.

[0243] For the purpose of the present disclosure, the term "optionally substituted alkyl" as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, hydroxyalkylamino, cycloalkylamino, aralkylamino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. The alkyl can be an optionally substituted C1-6 alkyl. The optionally substituted alkyl can be substituted with two substituents, or one substituent. Nonlimiting exemplary optionally substituted alkyl groups include CH2C3H4, -CH2CH2-O-CH3, and CH2Ph.

[0244] For the purpose of the present disclosure, the term "alkenyl" as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds. The alkenyl group can be chosen from a C2-6 alkenyl group and a C24 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0245] For the purpose of the present disclosure, the term "optionally substituted alkenyl" as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy,carboxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.

[0246] For the purpose of the present disclosure, the term "alkynyl" as used by itself or as part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. The alkynyl can have one carbon-to-carbon triple bond. The alkynyl group can be chosen from a C2-6 alkynyl group and a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0247] For the purpose of the present disclosure, the term "optionally substituted alkynyl" as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo.

[0248] For the purpose of the present disclosure, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and / or iodine atoms. The alkyl group can be substituted by one, two, or three fluorine and / or chlorine atoms. The alkyl group can be substituted by one, two, or three fluorine atoms. The haloalkyl group can be chosen from a C1-6 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropan-2-yl, 2-fluoropropyl, 3,3,3-trifluoropropyl, 4,4,4- trifluorobutyl, and trichloromethyl groups.

[0249] For the purpose of the present disclosure, the term "hydroxyalkyl" as used by itself or as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. The hydroxyalkyl group can be chosen from a monohydroxyalkyl group, i.e., substituted with one hydroxy group, a dihydroxyalkyl group, i.e., substituted with two hydroxy groups, and a C14hydroxyalkyl group. Non- limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1hydroxyethyl, 2-hydroxyethyl, 1,2- dihydroxyethyl, 2hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4hydroxybutyl, 2- hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

[0250] For the purpose of the present disclosure, the term "alkoxy" or "optionally substituted alkoxy" as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. The alkoxy group can be chosen from a C1-6 alkoxy group and a C1-6 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.

[0251] For the purpose of the present disclosure, the term "alkoxyalkyl" as used by itself or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tertbutoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0252] For the purpose of the present disclosure, the term "haloalkoxy" as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Nonlimiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0253] For the purpose of the present disclosure, the term "alkylthio" or "optionally substituted alkylthio" as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. The alkylthio group can be chosen from a C1-4 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH3 (i.e., methylthio), and -SCH2CH3.

[0254] For the purpose of the present disclosure, the term "cycloalkyl" as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl) or the number of carbons designated. The cycloalkyl group can have two rings, or one ring. The cycloalkyl group can be chosen from a C3-8 cycloalkyl group and a C3-6 cycloalkyl group. The cycloalkyl group can contain one or more carbon-to-carbon double bonds or one carbon-to-carbon double bond. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, 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.

[0255] For the purpose of the present disclosure, the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. The optionally substituted cycloalkyl can be substituted with two substituents or one substituent.

[0256] For the purpose of the present disclosure, the term "cycloalkyloxy" or "optionally substituted cycloalkyoxy" as used by itself or as part of another group refers to an optionally substituted cycloalkyl attached to a terminal oxygen atom. Exemplary cycloalkyloxy groups include cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0257] For the purpose of the present disclosure, the term "cycloalkylthio" or "optionally substituted cycloalkythio" as used by itself or as part of another group refers to an optionally substituted cycloalkyl attached to a terminal sulfur atom. Exemplary cycloalkylthio groups include cyclobutylthio, cyclopentylthio, and cyclohexylthio.

[0258] For the purpose of the present disclosure, the term "heterocycle" or "heterocyclo" as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom. The heterocyclo group can be chosen from a C3-14 heterocyclo group and a C3-8 heterocyclo group. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and / or nitrogen atoms, which can be quaternized. The term "heterocyclo" is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as βlactam, γ-lactam, δ-lactam and ε-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. The term "heterocyclo" is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl- 2(3H)-one. The heterocyclo group can be chosen from a 4-, 5-, 6-, 7- or 8-memberedcyclic group containing one ring and one or two oxygen and / or nitrogen atoms, a 5- or 6- membered cyclic group containing one ring and one or two nitrogen atoms, an 8-, 9-, 10-, 11-, or 12membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Nonlimiting exemplary heterocyclo groups include 2oxopyrrolidin-3-yl, 2imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, azetidinyl, 8- azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, 1,6- diazaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, indolinyl, indolinyl-2-one, 1,3-dihydro- 2H-benzo[d]imidazol-2-one.

[0259] For the purpose of the present disclosure, the term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle.

[0260] For the purpose of the present disclosure, the term "aryl" as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C6-14 aryl). The aryl group can be chosen from a C6-14 aryl group and a C6-10 aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. The aryl group can be chosen from phenyl or naphthyl. The aryl group can be phenyl.

[0261] For the purpose of the present disclosure, the term "optionally substituted aryl" as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C14haloalkoxy)alkyl, (heteroaryl)alkyl. The optionally substituted aryl can be an optionally substituted phenyl. The optionally substituted phenyl can have four substituents, three substituents, two substituents, or one substituent. The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include.

[0262] For the purpose of the present disclosure, the term "heteroaryl" or "heteroaromatic" refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., C5-14 heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur. The heteroaryl group can be chosen from a C5-14 heteroaryl group and a C3-6 heteroaryl group. The heteroaryl can have three heteroatoms, two heteroatoms, or one heteroatom. The heteroaryl can be a C5heteroaryl, or a C6heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH- carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, triazolyl, tetrazolyl, and phenoxazinyl. The heteroaryl can be chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (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), pyridyl (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., thiazol-2-yl, thiazol-4-yl, and thiazol-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 "heteroaryl" is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxide.

[0263] For the purpose of the present disclosure, the term "optionally substituted heteroaryl" as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R14a)(R14b), or -N(H)C(=O)-R15, wherein R14ais hydrogen or C1-6 alkyl; R14bis alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R15is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. The optionally substituted heteroaryl can have one substituent. The substituent can be amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, -N(R14a)(R14b), or -N(H)C(=O)-R15. The optionally substituted heteroaryl can be an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted.

[0264] For the purpose of the present disclosure, the term "aryloxy" as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A nonlimiting exemplary aryloxy group is PhO-.

[0265] For the purpose of the present disclosure, the term "heteroaryloxy" as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.

[0266] For the purpose of the present disclosure, the term "aralkyloxy" or "arylalkyloxy" as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.

[0267] For the purpose of the present disclosure, the term "aralkyl" or "arylalkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, orthree optionally substituted aryl groups. The aralkyl group can be a C1-4alkyl substituted with one optionally substituted aryl group. The aralkyl group can be an optionally substituted (C6-C14) aryl-(C1-C6) alkyl. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh2, -CH2(4-OH-Ph), and -CH(4-F-Ph)2.

[0268] For the purpose of the present disclosure, the term "amino" as used by itself or as part of another group refers to NH2.

[0269] For the purpose of the present disclosure, the term "alkylamino" as used by itself or as part of another group refers to -NHR14c, wherein R14cis C1-6 alkyl. R14ccan be C14alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and N(H)CH2CH3.

[0270] For the purpose of the present disclosure, the term "dialkylamino" as used by itself or as part of another group refers to –NR16aR17, wherein R16and R17are each independently C1-6 alkyl. R16and R17can each independently be C1-4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0271] For the purpose of the present disclosure, the term "hydroxyalkylamino" as used by itself or as part of another group refers to –NHR18, wherein R18is hydroxyalkyl.

[0272] For the purpose of the present disclosure, the term "cycloalkylamino" as used by itself or as part of another group refers to –NR19R20, wherein R20is optionally substituted cycloalkyl and R21is hydrogen or C14alkyl.

[0273] For the purpose of the present disclosure, the term "aralkylamino" as used by itself or as part of another group refers to –NR22R23, wherein R22is aralkyl and R23is hydrogen or C14alkyl. Non-limiting exemplary aralkylamino groups include N(H)CH2Ph and N(CH3)CH2Ph.

[0274] For the purpose of the present disclosure, the term "(amino)alkyl" as used by itself or as part of another group refers to an amino group, e.g., R24R25N-, attached to a terminal alkyl group, i.e., R24R25N-alkyl, wherein R24and R25are each independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1- C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl, and (C3-C6) cycloalkyl-(C1-C6) alkyl, or R24and R25together with the atom to which they are attached form an optionally substituted heterocyclyl. Non-limiting examples of (amino)alkyl groups include:

[0275] For the purpose of the present disclosure, the term "(amino)cycloalkyl" as used by itself or as part of another group refers to an amino group, e.g., R24R25N-, attached to a terminal cycloalkyl group, i.e., R24R25N-cycloalkyl, wherein R24and R25are each independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1- C6) alkyl, and (C3-C6) cycloalkyl-(C1-C6) alkyl, or R24and R25together with the atom to which they are attached form an optionally substituted heterocyclyl. Non-limiting examples of (amino)cycloalkyl groups include:

[0276] For the purpose of the present disclosure, the term "carboxamido" as used by itself or as part of another group refers to a radical of formula C(=O)NR26R27, wherein R26and R27are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R26and R27taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclyl group. R26and R27can each independently be hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include CONH2, CON(H)CH3, -CON(CH3)2, and -CON(H)Ph.

[0277] For the purpose of the present disclosure, the term "sulfonamido" as used by itself or as part of another group refers to a radical of the formula SO2NR28R29, wherein R28and R29are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R28and R29taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. Nonlimiting exemplary sulfonamido groups include SO2NH2, SO2N(H)CH3, and -SO2N(H)Ph.

[0278] For the purpose of the present disclosure, the term "alkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an alkyl group. A nonlimiting exemplary alkylcarbonyl group is -COCH3.

[0279] For the purpose of the present disclosure, the term "arylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an optionally substituted aryl group. A nonlimiting exemplary arylcarbonyl group is COPh.

[0280] For the purpose of the present disclosure, the term "alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by any of the abovementioned optionally substituted alkyl groups. Nonlimiting exemplary alkylsulfonyl groups are -SO2CH3 (i.e., methylsulfonyl) and -SO2CH2CH3 (i.e., ethylsulfonyl).

[0281] For the purpose of the present disclosure, the term "arylsulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by any of the abovementioned optionally substituted aryl groups. A nonlimiting exemplary arylsulfonyl group is -SO2Ph.

[0282] For the purpose of the present disclosure, the term "carboxy" as used by itself or as part of another group refers to a radical of the formula -COOH.

[0283] For the purpose of the present disclosure, the term "carboxyalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a -COOH. A nonlimiting exemplary carboxyalkyl group is CH2CO2H.

[0284] For the purpose of the present disclosure, the term "mercaptoalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a –SH group.

[0285] For the purpose of the present disclosure, the term "(heterocyclyl)(alkyl)" refers to a heterocyclyl or optionally substituted heterocyclyl that is attached to a terminal alkyl group. The (heterocyclyl)(alkyl) may be an optionally substituted heterocyclyl-(C1-C6) alkyl. The heterocyclyl group may be, e.g., azetidinyl, pyrrolidinyl, or piperidyl, or N- methylated derivatives thereof. The alkyl group may be a C1-6 alkyl group, e.g., methyl. Non-limiting examples of (heterocyclyl)(alkyl) groups include:.

[0286] For the purpose of the present disclosure, the term "(alkyl)-O-(alkyl)" refers to an optionally substituted alkoxy group that is attached to a terminal alkyl group. The (alkyl)-O-(alkyl) may be an optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl. Non-limiting examples of (alkyl)-O-(alkyl) groups include CH3-O-CH2CH2-.

[0287] For the purpose of the present disclosure, the term "(cycloalkyl)(alkyl)" refers to a cycloalkyl or optionally substituted cycloalkyl that is attached to a terminal alkyl group. The (cycloalkyl)(alkyl) may be (C3-C6) cycloalkyl-(C1-C6) alkyl. The cycloalkyl group may be, e.g., cyclopropyl. The alkyl group may be a C1-6 alkyl group. Non-limiting examples of (cycloalkyl)(alkyl) groups include:.

[0288] The term "geminal" as used herein indicates that two atoms or groups are attached to the same atom. For example, a cyclopropyl group substituted with two geminal methyl groups may have the following structure:.

[0289] The term "non-cyclic" or "non-cyclic substituents" refers to groups or substituents that do not have a cyclic structure. Examples of such non-cyclic groups and substituents include, but are not limited to, (C1-C6) alkyl, (C1-C6) alkenyl, and (C1-C6) alkynyl. Examples of groups and substituents that are not "non-cyclic substituents" include, but are not limited to, aryl, cycloalkyl, heteroaryl, and heterocyclo.

[0290] The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H, 11C,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively, e.g.,3H,11C, and14C. The present disclosure also provides a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. The present disclosure also provides a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number. In one embodiment, the present disclosure provides a composition wherein a Compound of the Disclosure hasfrom 1 to 8 hydrogens replaced with deuterium. In another embodiment, the hydrogen atoms of a methyl group are replaced with deuterium atoms. In another embodiment, the hydrogen atoms of an ethyl group are replaced with deuterium atoms. Isotopically- labelled Compounds of the Disclosure can be prepared by methods known in the art.

[0291] Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. It is to be understood that, when a disclosed chemical entity or Compound of the Disclosure (i.e., "compound") has at least one chiral center, the present disclosure encompasses one enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, and mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a mixture is enriched in one enantiomer relative to its optical isomers, the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95%, 99%, or 99.5%. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.

[0292] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0293] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0294] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0295] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.

[0296] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0297] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0298] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]obs / [ α]max)*100, where [α]obs is the optical rotation of the mixture of enantiomers and [α]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

[0299] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.

[0300] The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure.

[0301] It is understood that embodiments of the invention described herein include "consisting" and / or "consisting essentially of" embodiments. As used herein, the singular form "a," "an," and "the" includes plural references unless indicated otherwise. Use of the term "or" herein is not meant to imply that alternatives are mutually exclusive.

[0302] In this application, the use of "or" means "and / or" unless expressly stated or understood by one skilled in the art. In the context of a multiple dependent claim, the use of "or" refers back to more than one preceding independent or dependent claim.

[0303] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11. As is understood by one skilled in the art, reference to "about" a value or parameter herein includes (and describes) instances that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X."

[0304] The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organicacid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate and the like. The term "pharmaceutically acceptable salt" as used herein, refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).

[0305] Acid addition salts can be formed by mixing a solution of the particular Compound of the 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 the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.

[0306] The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended thatthe disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L. Bingham et al., Chem. Commun.603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.

[0307] In some aspects, Compounds of the Disclosure are inhibitors of NaV1.7 and the present disclosure provides a method for inhibiting NaV1.7 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more Compounds of the Disclosure.

[0308] In embodiments where the Compounds of the Disclosure are inhibitors of NaV1.7, a number of diseases, conditions, or disorders mediated by NaV1.7 can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of NaV1.7 in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.

[0309] The present disclosure is further directed to a method of inhibiting NaV1.7 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.

[0310] As used herein, "treatment" is an approach for obtaining beneficial or desired clinical results. "Treatment" as used herein, covers any administration or application of a therapeutic for disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing ordelaying spread (for example, metastasis) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by "treatment" is a reduction of pathological consequence of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. In-line with the above, the term treatment does not require one-hundred percent removal of all aspects of the disorder.

[0311] A "therapeutically effective amount" of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the substance are outweighed by the therapeutically beneficial effects. A therapeutically effective amount can be delivered in one or more administrations. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect.

[0312] The terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of the therapeutic agent to the desired site of biological action. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0313] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.

[0314] A "pharmaceutically acceptable excipient" refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or excipient conventional in the art for use with a therapeutic agent that together comprise a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable excipient is non-toxic to recipients at the dosages and concentrationsemployed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable excipient is appropriate for the formulation employed.

[0315] A "sterile" formulation is aseptic or essentially free from living microorganisms and their spores.

[0316] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0317] The term "insert" or "package insert" means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product.

[0318] The term "disease" or "condition" or "disorder" as used herein refers to a condition where treatment is needed and / or desired and denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions. As demonstrated below, in some embodiments, Compounds of the Disclosure inhibit a sodium channel (e.g., NaV1.7) and can be used in treating diseases and conditions such as pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, and combinations thereof, wherein inhibition of a sodium channel (e.g., NaV1.7) provides a benefit.

[0319] The terms "reduction" or "reduce" or "inhibition" or "inhibit" refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To "reduce" or "inhibit" is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 20% or greater. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 50% or greater. In some embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. In some embodiments, the amount noted above is inhibited or decreased over a period of time, relative to a control over the same period of time.

[0320] The terms "individual" or "subject" are used interchangeably herein to refer to an animal; for example, a mammal, such as a human. In some instances, methods of treating mammals, including, but not limited to, humans, rodents, simians, felines, canines,equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are provided. In some examples, an "individual" or "subject" refers to an individual or subject in need of treatment for a disease or disorder. In some instances, the subject to receive the treatment can be a patient, designating the fact that the subject has been identified as having a disorder of relevance to the treatment, or being at particular risk of contracting the disorder. Methods of Use

[0321] Compounds of the Disclosure can be used to inhibit the activity of sodium channels. In some embodiments, Compounds of the Disclosure can be used to inhibit the activity of NaV1.7. The present disclosure provides a method of inhibiting sodium channels (e.g., NaV1.7) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure.

[0322] The present disclosure also provides a method of inhibiting one or more sodium channels comprising contacting the one or more sodium channels with a Compound of the Disclosure.

[0323] In some aspects, the present disclosure provides a method of inhibiting NaV1.7 comprising contacting NaV1.7 with a Compound of the Disclosure. In some aspects, the present disclosure provides a method of selectively inhibiting NaV1.7 comprising contacting NaV1.7 with a Compound of the Disclosure.

[0324] The present disclosure also provides a method of treating a disease or disorder associated with inhibition of one or more sodium channels (e.g., NaV1.7) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure. In some aspects, the present disclosure provides a method of treating a disease or disorder associated with the selective inhibition of NaV1.7 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure.

[0325] The present disclosure also provides a method of treating a disease or disorder associated with inhibition of one or more sodium channels (e.g., NaV1.7) in a subject in need thereof, comprising contacting the one or more sodium channels with a Compound of the Disclosure.

[0326] In some aspects, the present disclosure also provides a method of treating a disease or disorder associated with selective inhibition of NaV1.7 in a subject in need thereof, comprising contacting NaV1.7 with a Compound of the Disclosure.

[0327] In some embodiments, the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, 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, the pain is nociceptive pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain in inflammatory pain. In some embodiments, the pain is neuralgic pain. In some embodiments, the pain in chronic pain. In some embodiments, the pain is acute pain.

[0328] The term "pain" refers to all categories of pain and is recognized to include, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain, orofacial pain, burn pain, burning mouth syndrome, somatic pain, visceral pain, myofacial pain, dental pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, chronic regional pain syndrome (CRPS),reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and post-operative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, familial hemiplegic migraine, conditions associated with cephalic pain, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, pain following stroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia, and combinations thereof.

[0329] In some embodiments, the pain is a pain associated with disease or disorder, for example, pain associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation, or ventricular fibrillation.

[0330] In some embodiments, the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof. In some embodiments, the disease or disorder is pain.

[0331] In some embodiments, the disease or disorder is a central nervous condition such as epilepsy, anxiety, depression and bipolar disease; a cardiovascular condition such as arrhythmias, atrial fibrillation and ventricular fibrillation; a neuromuscular condition such as restless leg syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neural trauma and multiple sclerosis; or channelopathies such as erythromyalgia and familial rectal pain syndrome. In some embodiments, the disease or disorder is pain associated with HTV, HIV treatment induced neuropathy, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathy secondary to metastatic infiltration, adiposis dolorosa, thalamic lesions, hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate, benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation), Alzheimer's disease, dementia, age-related memory impairment, Korsakoff syndrome, restenosis, urinary dysfunction, incontinence, Parkinson's disease, cerebrovascular ischemia, neurosis, gastrointestinal disease, sickle cell anemia, transplant rejection, heart failure, myocardial infarction, reperfusion injury, intermittant claudication, angina, convulsion, respiratory disorders, cerebral or myocardial ischemias, long-QT syndrome, Catecholeminergic polymorphic ventricular tachycardia, ophthalmic diseases, spasticity, spastic paraplegia, myopathies, myasthenia gravis, paramyotonia congentia, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, alopecia, anxiety disorders, psychotic disorders, mania, paranoia, seasonal affective disorder, panic disorder, obsessive compulsive disorder (OCD), phobias, autism, Aspergers Syndrome, Retts syndrome, disintegrative disorder, attention deficit disorder, aggressivity, impulse control disorders, thrombosis, pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich's ataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemic lupus erythamatosis,granulomatous disease, olivo-ponto-cerebellar atrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressive pallidal atrophy, progressive supranuclear palsy and spasticity, traumatic brain injury, cerebral oedema, hydrocephalus injury, spinal cord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity, optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy, retinitis pigmentosa, acute and chronic glaucoma, macular degeneration, retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema, proctitis, post-herpetic neuralgia, eudynia, heat sensitivity, sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-Nyhan Syndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiple sclerosis and the pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabetic neuropathy, peripheral neuropathy, Charcot marie tooth syndrome, arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin related illnesses, familial erythromelalgia, primary erythromelalgia, rectal pain, cancer, epilepsy, partial and general tonic seizures, febrile seizures, absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures, seizure prophylaxis (anti- epileptogenic), familial Mediterranean fever syndrome, gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions caused by stroke or neural trauma, tachy-arrhythmias, atrial fibrillation and ventricular fibrillation and as a general or local anesthetic.

[0332] The present disclosure also provides a method of treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure.

[0333] The present disclosure also provides a Compound of the Disclosure for use in treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0334] The present disclosure also provides use of a Compound of the Disclosure for treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0335] The present disclosure also provides use of a Compound of the Disclosure in the manufacture of a medicament for the treatment of a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof. Pharmaceutical Compositions

[0336] Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present, or Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined 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 ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Such an excipient can be selected from pharmaceutically acceptable excipients and auxiliaries. The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient,"or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, excipients, solvents, surfactants, or vehicles. Standard pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed.1995.

[0337] A pharmaceutical composition of the present disclosure may be prepared as a solid dosage form, e.g., as a tablet, a capsule, a pill, a powder, a lozenge, or a sachet.

[0338] A pharmaceutical composition of the present disclosure may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these.

[0339] A pharmaceutical composition of the present disclosure may be prepared as a sterile injectable, which may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art.

[0340] A pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.

[0341] A pharmaceutical composition of the present disclosure may be administered in the form of suppositories for rectal administration.

[0342] A pharmaceutical composition of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment, lotion, or cream containing the active component suspended or dissolved in one or more excipients.

[0343] A pharmaceutical composition of the present disclosure may also be administered ophthalmically and formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0344] A pharmaceutical composition of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0345] The pharmaceutical compositions to be used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes.

[0346] Pharmaceutical compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable excipients. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose.

[0347] A pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure. Foremost among such patients are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient is a human.

[0348] In another aspect, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. In some embodiments, the present disclosure provides a kit which comprise a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a patient having a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof. In some embodiments, the disease or disorder is pain.

[0349] In some aspects, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0350] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0351] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0352] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula IIa, IIb, or IIc or apharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0353] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0354] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula IVa, IVb, or IVc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0355] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula Va, Vb, or Vc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0356] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula VIa, VIb, or VIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0357] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0358] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula VIIIa, VIIIb, or VIIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0359] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula IXa, IXb, or IXc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0360] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula Xa, Xb, or Xc, or apharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0361] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XIa or XIb, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0362] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XIIa, XIIb, or XIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0363] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XIIIa, XIIIb, or XIIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0364] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XIVa, XIVb, or XIVc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0365] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XVa, XVb, or XVc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0366] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XVIa, XVIb, or XVIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0367] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula XVIIa, XVIIb, or XVIIc, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0368] In some aspects, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for use in treating a disease or disorder selected from pain, depression, acardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof. In some embodiments, the disease or disorder is pain.

[0369] In some aspects, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for the manufacture of a medicament for treatment of a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof. In some embodiments, the disease or disorder is pain.

[0370] The present disclosure also provides the following numbered embodiments.

[0371] Embodiment 1. A compound having Formula I:

[0372] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0373] M1is selected from N and CR1;

[0374] M2is selected from N and CR2;

[0375] M3is selected from N and CR3;

[0376] M4is selected from N and CR4;

[0377] each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0378] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6- C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or

[0379] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or

[0380] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0381] R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0382] n is 0, 1 or 2;

[0383] R6is selected from hydrogen, halogen, cyano, hydroxy, optionally substituted (C1- C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

[0384] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0385] R6and W are taken together with the atom(s) to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl;

[0386] R6is a bond between the carbon to which it is attached and R5, or

[0387] R5and W are taken together with the atoms to which they are attached to form an amine substituted (C3-C6) cycloalkyl or optionally substituted heterocyclyl, or

[0388] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl;

[0389] each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or

[0390] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl;

[0391] A is optionally substituted heteroaryl;

[0392] Z is selected from N and CRZ;

[0393] RZis selected from hydrogen and (C1-C6) alkyl; and

[0394] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-.

[0395] Embodiment 2. A compound having Formula Ia:Ia;

[0396] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0397] M1is selected from N and CR1;

[0398] M2is selected from N and CR2;

[0399] M3is selected from N and CR3;

[0400] M4is selected from N and CR4;

[0401] each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0402] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6- C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or

[0403] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or

[0404] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0405] R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0406] n is 0, 1 or 2;

[0407] R6is selected from hydrogen, halogen, optionally substituted (C1-C6) alkyl, (C1- C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

[0408] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0409] R6and W are taken together with the atom(s) to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl;

[0410] R6is a bond between the carbon to which it is attached and R5, or

[0411] R5and W are taken together with the atoms to which they are attached to form an amine substituted (C3-C6) cycloalkyl or optionally substituted heterocyclyl, or

[0412] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl;

[0413] each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or

[0414] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl;

[0415] A is optionally substituted heteroaryl;

[0416] Z is selected from N and CRZ;

[0417] RZis selected from hydrogen and (C1-C6) alkyl; and

[0418] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-.

[0419] Embodiment 3. The compound of Embodiment 1 or 2, having Formula Ib:,

[0420] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0421] M1is selected from N and CR1;

[0422] M2is selected from N and CR2;

[0423] M3is selected from N and CR3;

[0424] M4is selected from N and CR4;

[0425] each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio;

[0426] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6- C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or

[0427] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl;

[0428] n is 0, 1 or 2;

[0429] R6is selected from hydrogen, halogen, optionally substituted (C1-C6) alkyl, (C1- C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

[0430] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0431] R6and W are taken together with the atom to which they are attached to form R8R7N-(C3-C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl;

[0432] each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O-(C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or

[0433] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl;

[0434] A is optionally substituted heteroaryl;

[0435] Z is selected from N and CRZ;

[0436] RZis selected from hydrogen and (C1-C6) alkyl; and

[0437] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-.

[0438] Embodiment 4. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis.

[0439] Embodiment 5. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R1, R2, R3, and R4is independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, or halogen.

[0440] Embodiment 6. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R1, R2, R3, and R4is independently hydrogen, (C1-C6) alkyl, or halogen.

[0441] Embodiment 7. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis selected from, , , , ,.

[0442] Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis selected from.

[0443] Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis selected from

[0444] Embodiment 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein.

[0445] Embodiment 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. hydrogen and halogen; or iii. halogen.

[0446] Embodiment 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is hydrogen.

[0447] Embodiment 13. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. hydrogen and halogen; or iii. halogen.

[0448] Embodiment 14. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. halogen and (C1-C6) alkyl; or iii. halogen.

[0449] Embodiment 15. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1is halogen.

[0450] Embodiment 16. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is hydrogen.

[0451] Embodiment 17. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is selected from hydrogen and halogen.

[0452] Embodiment 18. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is selected from halogen and (C1-C6) alkyl.

[0453] Embodiment 19. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.

[0454] Embodiment 20. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R5is selected from (C1-C6) alkyl, (C1-C6) alkoxy, and (C6-C14) aryl, or two geminal R5groups together with the atom to which they are attached form a (C3-C6) cycloalkyl.

[0455] Embodiment 21. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R5is selected from (C1-C6) alkyl and (C1-C6) alkoxy, or two geminal R5groups together with the atom to which they are attached form a (C3-C6) cycloalkyl.

[0456] Embodiment 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5is selected from methyl, methoxy, and phenyl, or two geminal R5groups together with the atom to which they are attached form a cyclopropyl.

[0457] Embodiment 23. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5is selected from methyl and methoxy, or two geminal R5groups together with the atom to which they are attached form a cyclopropyl.

[0458] Embodiment 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2 and each R5is independently (C1-C6) alkyl.

[0459] Embodiment 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5is methyl.

[0460] Embodiment 26. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis selected from

[0461] Embodiment 27. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis selected from

[0462] Embodiment 27. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein.

[0463] Embodiment 28. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-.

[0464] Embodiment 29. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from

[0465] Embodiment 30. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from.

[0466] Embodiment 31. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from.

[0467] Embodiment 32. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is.

[0468] Embodiment 33. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, and R8R7N-(C3-C6) cycloalkyl-.

[0469] Embodiment 34. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is R8R7N- or R8R7N-(C1-C6) alkyl-.

[0470] Embodiment 35. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are each independently selected from hydrogen, methyl, d3-methyl, ethyl, d5-ethyl, propyl, tert-butyl, neopentyl, 1,1-difluoromethyl, 2,2,-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropan-2-yl, 2-fluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3- trifluoropropyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, 3-fluorocyclobutyl, 3,3- difluorocyclobutyl, bicyclo[1.1.1]pentan-1-yl, spiro[2.3]hexan-5-yl, 3- (difluoromethyl)cyclobutyl, and benzyl.

[0471] Embodiment 36. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are each independently selected from hydrogen, methyl, ethyl, propyl, tert-butyl, neopentyl, 2,2,-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropan-2-yl, 2-fluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, spiro[2.3]hexan-5-yl, 3- (difluoromethyl)cyclobutyl, and benzyl.

[0472] Embodiment 37. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are each methyl.

[0473] Embodiment 38. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8together with the atom to which they are attached form a heterocyclyl.

[0474] Embodiment 39. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8together with the atom to which they are attached form a heterocyclyl selected from

[0475] Embodiment 40. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from

[0476] Embodiment 41. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from ,, , , , , , , ,, ,.

[0477] Embodiment 42. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from.

[0478] Embodiment 43. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is.

[0479] Embodiment 44. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is selected from hydrogen, cyano, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, fluoro, methoxy, d3- methoxy, ethoxy, methoxymethyl, and phenyl.

[0480] Embodiment 45. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, fluoro, methoxy, d3-methoxy, ethoxy, methoxymethyl, and phenyl.

[0481] Embodiment 46. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, fluoro, methoxy, and ethoxy.

[0482] Embodiment 47. compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is methyl or methoxy.

[0483] Embodiment 48. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6and W are taken together with the atom(s) to which they are attached to form an R8R7N-(C3-C7) cycloalkyl-, an R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl.

[0484] Embodiment 49. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6and W are taken together with the atom(s) to which they are attached to form an R8R7N-(C3-C7) cycloalkyl- or an optionally substituted heterocyclyl.

[0485] Embodiment 50. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6and W are taken together with the atom to which they are attached to form R7R8N-cyclopropyl-, R7R8N-cyclobutyl-, R7R8N-cyclopentyl-, R7R8N-methyl-cyclobutyl-, an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted morpholino.

[0486] Embodiment 51. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6and W are taken together with the atom to which they are attached to form an optionally substituted azetidinyl or an optionally substituted pyrrolidinyl.

[0487] Embodiment 52. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis,

[0488] Embodiment 53. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

[0489] Embodiment 54. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis.

[0490] Embodiment 55. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted benzothiazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, and optionally substituted pyridazinyl.

[0491] Embodiment 56. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from optionally substituted thiazolyl, optionally substituted benzothiazolyl, and optionally substituted pyridinyl.

[0492] Embodiment 57. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from.

[0493] Embodiment 58. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from ,

[0494] Embodiment 59. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from

[0495] Embodiment 60. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is.

[0496] Embodiment 61. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having any one or more of Formulae IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, and XIb;

[0497] wherein:

[0498] p is selected from 0, 1, 2, and 3;

[0499] q is selected from 0, 1, and 2;

[0500] t is selected from 1, 2, and 3;

[0501] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl; and

[0502] Z1is CH or O, with the proviso that when Z1is O, the sum of q + t is at least 2.

[0503] Embodiment 62. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having any one or more of Formulae IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, and VIIIb;

[0504] wherein:

[0505] p is selected from 0, 1, 2, and 3;

[0506] q is selected from 0, 1, and 2;

[0507] t is selected from 1, 2, and 3; and

[0508] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl.

[0509] Embodiment 63. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having any one or more of Formulae XIIa, XIIb, XIIc, XIIIa, XIIIb, XIIIc, XIVa, XIVb, or XIVc;

[0510] wherein

[0511] each of R10and R11is independently selected from hydrogen, halogen, and (C1- C4) alkyl, or

[0512] R10and R11in Formulae XIIa, XIIb, and XIIc together with the atoms to which they are attached form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an optionally substituted cycloalkyl; and

[0513] R13and R14are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio.

[0514] Embodiment 64. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having any one or more of Formulae XIIa, XIIb, XIIIa, XIIIb,,

[0515] wherein

[0516] each of R10and R11is independently selected from hydrogen, halogen, and (C1- C4) alkyl, or

[0517] R10and R11in Formulae XIIa and XIIb together with the atoms to which they are attached form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an optionally substituted cycloalkyl; and

[0518] R13is selected from the group consisting of hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio.

[0519] Embodiment 65. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R10is hydrogen and R11is halogen.

[0520] Embodiment 66. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13and R14are each independently hydrogen, halogen, or (C1-C6) alkyl.

[0521] Embodiment 67. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13is halogen.

[0522] Embodiment 68. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R14is hydrogen.

[0523] Embodiment 69. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVa, XVb, or XVc.

[0524] Embodiment 70. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVa or XVb.

[0525] Embodiment 71. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVa.

[0526] Embodiment 72. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVIa, XVIb, XVIc, XVIIa, XVIIb, or XVIIc;,

[0527] wherein:

[0528] p is selected from 0, 1, 2, and 3;

[0529] q is selected from 0, 1, and 2;

[0530] t is selected from 1, 2, and 3; and

[0531] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl.

[0532] Embodiment 73. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVIa, XVIb, XVIIa, or XVIIb;

[0533] wherein:

[0534] p is selected from 0, 1, 2, and 3;

[0535] q is selected from 0, 1, and 2;

[0536] t is selected from 1, 2, and 3; and

[0537] R12is selected hydrogen and optionally substituted (C1-C6) alkyl.

[0538] Embodiment 74. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVIa or XVIIa.

[0539] Embodiment 75. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is hydrogen, methyl, or methoxy.

[0540] Embodiment 76. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0 or 1.

[0541] Embodiment 77. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 and t is 3.

[0542] Embodiment 78. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2 and t is 2.

[0543] Embodiment 79. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12is methyl.

[0544] Embodiment 80. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are methyl, ethyl, or cyclobutyl.

[0545] Embodiment 81. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0546] Embodiment 82. A pharmaceutical composition comprising the compound of any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0547] Embodiment 83. A method of inhibiting one or more sodium channels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding embodiments.

[0548] Embodiment 84. A method of treating a disease or disorder associated with inhibition of one or more sodium channels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding embodiments.

[0549] Embodiment 85. The method of any one of the preceding embodiments, wherein the one or more sodium channels is NaV1.7.

[0550] Embodiment 86. The method of any one of the preceding embodiments, wherein the inhibiting or inhibition of one or more sodium channels is the selective inhibiting of or selective inhibition of NaV1.7.

[0551] Embodiment 87. The method of any one of the preceding embodiments, wherein the disease or disorder is selected from pain, depression, a cardiovasculardisease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

[0552] Embodiment 88. The method of any one of the preceding embodiments, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post- surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

[0553] Embodiment 89. A method of treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding embodiments.

[0554] Embodiment 90. The method of any one of the preceding embodiments, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post- surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

[0555] Embodiment 91. The compound of any one of the preceding embodiments for use in treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0556] Embodiment 92. The compound of any one of the preceding embodiments, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post- surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain,chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

[0557] Embodiment 93. Use of the compound of any one of the preceding embodiments for treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0558] Embodiment 94. The use of any one of the preceding embodiments, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

[0559] Embodiment 95. Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for the treatment of a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

[0560] Embodiment 96. The use of any one of the preceding embodiments, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

[0561] Embodiment 97. The compound, use, or method of any one of the preceding embodiments, wherein the pain is associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation, or ventricular fibrillation. EXAMPLES General Synthetic Methods

[0562] Compounds of the Disclosure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative methods shown in the General Schemes below. In any of the General Schemes, suitable protecting groups can be employed 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).

[0563] Unless otherwise noted, all reagents were used without further purification. Example 1 5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide (Stereoisomer 1)Step 1. Preparation of 5-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2- yl)benzenesulfonamide

[0564] To a solution of N-[(4-methoxyphenyl)methyl]thiazol-2-amine (1.00 g, 4.54 mmol) in tetrahydrofuran (20 mL) was added lithium bis(trimethylsilyl)amide (1 M, 5.45 mL) by dropwise at -78 °C. After stirred at 25 °C for 0.5 h. After that a solution of 5- chloro-2,4-difluoro-benzenesulfonyl chloride (1.35 g, 5.45 mmol ) in tetrahydrofuran (5 mL) was added at -78 °C. The reaction mixture was then warmed to 25 °C and stirred for additional 12 h. The reaction was quenched with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 × 30 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 flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0–25% ethyl acetate / petroleum ether gradient at 36 mL / min) to give 5-chloro- 2,4-difluoro-N-[(4-methoxyphenyl)methyl]-N-thiazol-2-yl-benzenesulfonamide (0.830 g, 1.93 mmol, 42% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 7.89 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.03–6.97 (m, 2H), 6.78 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 3.76 (s, 3H). Step 2. Preparation of (R)-5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0565] A solution of 5-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2- yl)benzenesulfonamide (0.100 g, 0.232 mmol), (R)-N,N-dimethylpyrrolidin-3-amine (0.0265 g, 0.232 mmol) and cesium carbonate (0.226 g, 0.696 mmol) in N,N- dimethylformamide (1 mL) was stirred at 25 °C for 16 h. The mixture was extracted with ethyl acetate (3 × 20 mL). Combined extracts were washed with brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (R)-5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide (0.133 g) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.41–7.37 (m, 1H), 7.37–7.30 (m, 3H), 6.94 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 13.2 Hz, 1H), 5.21–5.15 (m, 2H), 3.76 (s, 3H), 3.68–3.51 (m, 4H), 2.79–2.68 (m, 1H), 2.23–2.12 (m, 1H), 1.92–1.77 (m, 1H).Step 3.5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide

[0566] A solution of (R)-5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.133 g, 0.253 mmol) in trifluoroacetic acid (4.62 g, 40.5 mmol, 3 mL) was stirred at 50 °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 adjusted to pH= ~8 with ammonium hydroxide (10 wt%). The mixture was purified by prep-HPLC (column: Waters Xbridge 150 mm × 25mmmobile phase: [water (ammonia hydroxide v / v)–acetonitrile]; B%: 12–42%, 9 min) to give 5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide (Stereoisomer 1) (0.0314 g, 0.0674 mmol, 29% yield, 96% purity) as a white solid. MS (ES+) m / z 405.2, 407.2 (M +1).1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 4.4 Hz, 1H), 6.50 (d, J = 4.4 Hz, 1H), 6.37 (d, J = 13.2 Hz, 1H), 3.68–3.44 (m, 4H), 2.81–2.63 (m, 1H), 2.30 (s, 6H), 2.20–2.10 (m, 1H), 1.92–1.73 (m, 1H). Example 209 3-chloro-4-(3-(cyclobutyl(methyl)amino)-3-methylpyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1)Step 1. Preparation tert-butyl (R)-3-(cyclobutylamino)-3-methylpyrrolidine-1-carboxylate

[0567] To a solution of tert-butyl (R)-3-amino-3-methylpyrrolidine-1-carboxylate (0.200 g, 0.998 mmol) and cyclobutanone (0.210 g, 3.00 mmol) in 1,2-dichloroethane (2.0 mL) were added sodium triacetoxy borohydride (0.635 g, 3.00 mmol) and acetic acid (0.180 g, 3.00 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature. Dichloromethane (15 mL) and saturated sodium bicarbonate (10 mL) were added and layers were separated. The aqueous phase was extracted with dichloromethane (2 ×15 mL). Combined extracts were washed with brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (R)-3-(cyclobutylamino) -3-methylpyrrolidine-1-carboxylate (0.210 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 3.49–3.31 (m, 3H), 3.21–3.17 (m, 1H), 2.29–2.18 (m, 2H), 1.85–1.78 (m, 2H), 1.76–1.67 (m, 3H), 1.66–1.59 (m, 2H), 1.44 (s, 9H), 1.20 (s, 3H). Step 2. Preparation of tert-butyl (R)-3-(cyclobutyl(methyl)amino)-3-methylpyrrolidine-1- carboxylate

[0568] To a solution of tert-butyl (R)-3-(cyclobutylamino)-3-methylpyrrolidine-1- carboxylate (0.210 g, 0.826 mmol) (crude) and formaldehyde (0.201 g, 2.48 mmol) in methanol (2.0 mL) were added acetic acid (0.149 g, 2.48 mmol) and sodium cyanoborohydride (0.156 mg, 2.48 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated. Dichloromethane (15 mL) and saturated sodium bicarbonate (10 mL) were added and layers were separated. The aqueous phase was extracted with dichloromethane (2 ×15 mL). Combined extracts were washed with brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (R)-3-(cyclobutyl (methyl) amino)-3- methylpyrrolidine-1-carboxylate (180 mg, crude) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 3.60–3.39 (m, 2H), 3.37–3.26 (m, 3H), 2.32–2.27 (m, 3H), 2.26–1.93 (m, 5H), 1.85–1.78 (m, 1H), 1.75–1.55 (m, 2H), 1.45 (s, 9H), 1.13–1.06 (m, 3H). Step 3. Preparation of (R)-N-cyclobutyl-N,3-dimethylpyrrolidin-3-amine

[0569] To a solution of tert-butyl (R)-3-(cyclobutyl(methyl)amino)-3-methylpyrrolidine- 1-carboxylate (0.180 g, 0.671 mmol) (crude) in methanol (4.0 mL) was added acetyl chloride (0.264 g, 3.36 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give (R)-N-cyclobutyl-N,3- dimethylpyrrolidin-3-amine (0.140 g, crude, 2hydrochloride) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.4 (s, 1H), 9.81 (s, 1H), 3.98–3.86 (m, 1H),3.61–3.53 (m, 1H), 3.50–3.34 (m, 2H), 3.27 (dd, J = 5.2, 10.4 Hz, 1H), 2.63–2.56 (m, 3H), 2.55–2.51 (m, 2H), 2.46–2.33 (m, 1H), 2.24–2.02 (m, 3H), 1.76–1.56 (m, 2H), 1.49– 1.38 (m, 3H). Step 4. (R)-3-chloro-4-(3-(cyclobutyl(methyl)amino)-3-methylpyrrolidin-1-yl)-N-(2,4- dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0570] A solution of (R)-N-cyclobutyl-N,3-dimethylpyrrolidin-3-amine (0.0700 g, 0.290 mmol, 2hydrochloride) (crude), 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (0.130 mg, 0.265 mmol) and cesium carbonate (0.473 g, 1.45 mmol) in N,N-dimethylformamide (1.0 mL) was stirred at 25 °C for 2 h. Ethyl acetate (5 mL) and water (5 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (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 (R)-3-chloro-4-(3- (cyclobutyl(methyl)amino)-3-methylpyrrolidin-1-yl)-N-(2,4-dimeth oxybenzyl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.180 mg, crude) as a yellow oil. 1H NMR (400 MHz, CDCl3) 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), 6.44–6.34 (m, 2H), 6.22–6.11 (m, 1H), 5.15–5.06 (m, 2H), 3.79–3.71 (m, 7H), 3.67 (d, J = 9.6 Hz, 1H), 3.55 (t, J = 9.2 Hz, 1H), 3.39 (d, J = 9.2 Hz, 1H), 3.26 (t, J = 8.0 Hz, 1H), 2.02–1.85 (m, 4H), 1.66–1.54 (m, 4H), 1.11–1.02 (m, 3H) Step 5.3-chloro-4-(3-(cyclobutyl(methyl)amino)-3-methylpyrrolidin-1-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1)

[0571] To a solution of (R)-3-chloro-4-(3-(cyclobutyl(methyl)amino)-3-methylpyrrolidin- 1-yl)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.180 g, 0.282 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.0 mL). The mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with N,N-dimethylformamide (1.0 mL). The mixture was adjusted to pH= ~8 with ammonium hydroxide (10 wt%). The mixture was purified by prep-HPLC (column: Waters xbridge 150 mm × 25 mm × 10 µm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 23%–53% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-4-(3- (cyclobutyl(methyl)amino)-3-methylpyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomer 1) (0.0522 g, 0.105 mmol, 37% yield, 98% purity) as a white solid. MS (ES+) m / z 489.1, 491.1 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.72(q, J = 8.0 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 6.61 (dd, J = 2.4, 8.0 Hz, 1H), 6.16 (d, J = 13.2 Hz, 1H), 3.81–3.64 (m, 2H), 3.55 (t, J = 9.6 Hz, 1H), 3.39 (d, J = 9.2 Hz, 1H), 3.31– 3.20 (m, 1H), 2.21 (s, 3H), 2.10–1.85 (m, 6H), 1.71–1.54 (m, 2H), 1.05 (s, 3H). MS (ES+) m / z 489.1, 491.1 (M + 1).

[0572] The following further Examples listed in Table 1 were prepared analogously to Example 1 (as described above) or Example 209, substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC).4(8 2.—H1 + 4(= JH0 6)6 4( H0.( (7+4(= JH (9 1 4(= J2 50 15.R 79 5. ,M m[R,d2. .d7 2 - R47 6.9.M(R,7 d2.7.;)R, . .9 d 320 M N—3 (S M(,—OM=21 M(7,2H M(1 9,12)0 7 11M 8 8 SJ,2 CNL 15 1.7 16MN, )–80.5N80.,)1,2 D 1Hd(1 241H 71 2m(. N9 —2 —6-,)H.H.H.0.H0.32.0 H)11H8.66.31.2 F 1 id i i ild oil- d i i di-2 rr- oni ly 2 p-)lrr- d y 4-lilol- or- orlo lo r-r2r z2 y -lyaiyzp)loz r-lp)lozp)lhthaie yaiy e p) oze yaie y(- eeteht(m-diht htdi la dihhtdihdiam)me(- yitm htht e(-teN- o N oN- anm)oN- an -2e)(-man -3m-3niorofl-niorofl(- o n(iN- ofl()m- oN- anm) ro omau n)-mo4 niorofl-ni lfiofl1ra ulus3(- mo ulus3(- moro us- ormo ulus3(- md- use4- lo yf- en4-alyf- en4-al ealyulnolyf- en4-aly6, em n os1rh elolte2-)lezorhte2-) ezorhf-ezh hte2-) ezorht 2-ez io hmy-neol lmy-neolte2-)lnec-5lmy-neol e)ly-neerbac- id1- b)lhc- id1- b)lhc miyb) -) id1b)hc mid1b) etT 5((n y 5((n y - 5d( -1lyS((( -nly - 3(( -nlyS(.x E 2 3 4 5 64(==0.87.S 4(=,z(1 S 4( 7.,3H1 4(z2.2.3 47(==S 4( 1,z9..)H RJ, J, ,1Md1.,)MJ;)R,H6.2 M DR,) ,RH 26.,)54 RJ,JM2,tDRH,)1,N (d 0 H Md2.3(17711 F(76=,1,N05 6J ( (10,—9;zMHm HN 1 (M3 H,,z5N 142.Md( ( ;zM6.Hz31 =,1N56 HN7 8 2 M 1 H 1 1J (4 1 73 M 11,HH. .msH.0.6.H8.Hm5 H0.2.H =m(2.5 id - -i3l4 - , o -l)l- e -)y 2-)-di l3-rryoz - lma 1-y-N- ay- n1- -)lpipy)lhtni-21- -)lof(lni-4 -n1ey(- edil-l eni7,y- u dil-l e(- h h peteN-diorrozdidile di22-seoo di4)-lldimormayaimaorr-(2m-a4-nanrr znezyaimayy-m)o a oulno)p1)oht(- no)1 y -plo nooro n]nep)oht(- no)h3t-enina- t 3nif(iflre-3niN-flre-) z3 oaiflo ul4.b)-3niN-fl1rem - md- u(- m u( niufl(m u idid-tualsemorsem -htse -4[y-orsem ebl4- y6,2 n osi4-aly o n osi4- ma (- n2- or-i24-aly o n osi6,zayhorhte -)lezoorht ulf ezoor lyN-ezorps-lorht ulf ezo 2)(lteol-ylmihc-miyd -neerol1- b)lethe ic-mid-neerolhtorneola ozol e id6-neer,b) ethc eiou b)hczaaih hc mi6b) etNotd 3((n yS(3d(2lyS( -5d(lf ly - 5idt( -3d( ,2lyS(7 8 9 01 11 214( (4 56 ( (4 ,(96+ (J,H,s2( 44 1z / ( ( H0. .46.H 16.15( 1, 31J46.,( 3H1 R5. zR4.0.M Rd,R,)15 Rz,) ,d R,) ,M6HM62(Mdm5.m)M2.9= H,MHHmd MHm N–706.––0.( ( 24 .)N6,56 1 1N96)+6SN,) J,1,2.3N0.1 ( ( 1 (7 ,z36N,z3 1H.6 = 1 + 1H.6.254 1H4.65.3 H 2E(1HH 1q(m(15 1H = H3.36.11H H9.1 -)l- - i e y -)y ni ld yilrrp - o ydi)l-)l edi1- di-r1-rrp y -)l-mayh 2-ly- 1-mniy ieni- p-2,y n hN- ote- 6,ozni an dp loordd 2- )ly 6( 2,teo flm)2-aid oflrroiilm ol erozdiht- e2reN-di(lm)o useo nior- e 2dihtilo orus- yul3(-p)f- anro yapihtmam)oromay h o tunlifin ezmaolh -loma rorlyep ne4o 6(-fl )n)-noirmN- u o(s- o e -2o 3niN-fl-n ul- no)1e(d( ma -6ne)lyc- zaino hc)-ozn)2 ure3ifi2-flure -3)l ,2 b)lh3-)lhtflu 4ni ebreolalorn oe (- m z4-alorsoem(- m n o4-ald-niy6,dirsem(- yh - 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- y)ly)ly)ly - -eh -l '-1'-'-'-3-]l6,dy2i-te-3y- '- -h] m [-m] '- 1 ] 2 5(- -n5] '- 1 i(- -n5] '- 1 i(- -n5(- ]ntl-aey-2- n 1 o4- o -l4-orflornioz -dil edi4- dil edi4- idil edi4- idil edioaieoro om oro om oro ooro o m)o u on u mahdiu rryau rryau rrmau rrma-3niiduilslfe lfi)lty -ma lfipino)1lfipino)2lfiy pino)3lfiy pino)4[- mo - n 6ezd- pN-]nod- b'-flured- b'-flured- b'-flured- b'-flure4-alroyr(y -n 6,or ly-fl6,-3,2- sem6,-3,2- sem6,-3,2- sem6,-3,2sem r h pN- eb2- p(l1- us 2-1[ lo n osi2-1[ lo n osi2-1[ lo n osi2-1[-lo n osiolte-lyor)loo yryni enor-l zaiezoor-l zaiezoor-l zaiezoor-l zaiezo hmh dolh htedi ezolyhhtneerolyhhtneerolyhhtneerolyhhtneerc- idteulfiirc- mlonehc te(- b) ethc te(- b) ethc te(- b) ethc te(- b) et3([m dy p 3[[rrb - 3 m NlyS( -3 m NlyS( -3 m NlyS( -3 m NlyS(7 8 0 1ab 4 4 5 5 15 15H,z2M H.3 H3 OH,6.R.)H,z4,z( .)6,)1 , S6.2 M1 H 6,s ,H 06.— MM2 1 —+ M4.( 0.H5 5M4.3.H H 68.,M3 H3.–1,10440 m( D00 =9NM00456 004 2,m 002 m,)( = RJ3.,32;d,)8. z4(J1 HR,7.d29F(4 =3.44 =)(49.(H ,)1;)0.(1J2 z / (JH 5 R,,)m R,33( 381 ,,s3.R,)3.M N(H 84,—2MMd 6(HH 4 Md(H)Md( (1– MH2–m(7N31,6, z N63,+SN622N1,23 1H2.7m(9.13(1H2.7m( z / H m 1H5.6m(E(1H5.65.24.1 1Hm(4.27.1 - - ni-)6dilo,ni2- - )l2,- - 62,- - 62,- - o my 2- ,2- ,2-6,1(-rr -ya )l2-) 2-) 2- 3(p ely1- e y)l l)l l)l-)ldhyeyyeyye4-yih - -tenid -diil2-lte -1 - - 2d-ih lte -1 - - 2d-ih lte -1 - - 2d-ilor4- 2manmiomr oz anm)onimdoz an)m)onimdoz an)m)nimdoz an)o ulni-lofzofld(- ryaiofl-niiloaiofl1-niiloaiofl2o -niiloaiofl1-dir aiu 4(-plyht(- u 4(- mrrht(- ure4(- mrrht(ure3(mrrht(ure2- ephtsen4- hst Nen4-alysyp Nem n o4-aly -syp Nem- n o4-aly -syem n o or ipl(-ezor e -orezorhtly - orezsiorhtly - orezsiorhptlyN- oezsioly h hN-)clneolmi-tey- bd)- oneol eh l hc-2 ulfb)hc miteoneoerol ehteoneoerol ehtreoneoerdmulfb) ethc midmulfb) ethc midmulfb) et5 m 1 y 3,2idly - 3(( ididlyS( -3(( ididlyS( -3(( ididlyS(48 58 88 09 69M040.HHM.4,s( MHHM 14 6 300,)6 001 600,3 z –)M 61 +S 00,)6 9..)4 =,s( ,s(4 H3.4,z,s4H3.E 4 H11(J94(1,2, . ( H (5( 4.3, ( ( 1,z–8+R,Md2N (.372.Rm) )R4.3.R6)S R H0.M(, 1,M(H21M22, .M= 5) )N0,+ N 1=) )6 2 1 6 21 NJH , 2,M.)M N0.2 1.+ 1 18 ,)9 1H.HH 1H2.m(M(1HJH 1Hd(m(H H = H 544 - - - 2,-1- -1n6(- -6(2-6,- )l2-3-i-)l- 6,3-)- d -ni6ilN- d- ilN- y)lhtey- 1 -eylh2- y,ooroor) -eh2-)-erry oerry oem- 2d) -iltme l2dite l2dipuldiuldionidoay- -lm y- -lm )lfimp)lfimizm)1ano)o -oz anm)1o)o -oz ano)y-d- a- no)y-d- a- no)-ni loifl2r-ninidaifl1r-ninidaifl2r 1-6,2-fl1 1-6,2-fl23(- mrrht(- ue3(- milht(- ue3(- milht(ueni2-niureni2-niure4-alysemo4 aloroy r hplyN- ne si -o yhrsemo yN- ne si4-alor- o yhrsemodiyN- ne siteoro d lirsem n odit ordirsemo h ye si eoln h ye siolteht orozn orolteporozn orolteporozn ozac- pzn ozac- pzn o hmi eul eberhmioroul eberhmioroul eer(-33-or eer(-33-or eerc- dmifi)letc- dufi)letc- d ufib)let(-)lou b)let(-)lou b) et3((d d yS(3((lfd yS(3((lfd yS(4 ylfyS(4 ylf lyS(7 8 9 0 1 9 9 9 02 02, ,MH N2 Hm , 3)M.,zH,,, + = SNJ2,,)H 3M2.H,,N 1 0.1m, , .. M( H5 d m 1N60.4M N(H 1 1,( 1Md.7+ N (3.1 –72,,)1.7 1Hm(m(E(H 1d(H 10. z8 H 1H= J01 54 1H1.60z / 1 m 1H5.6m(9.1M(1H5.66.3 H 674 -ly -l- h y -)o6,- 2 - -)6,- - -oror-teh - -te --ni)l2- o ni2-)l2- o u o 6(-m-6- 6m6- my-nid my-nid -lfi-ulfiN- 1(-na e(- -N- 1(-na ealy1-inraliyey1-inr2-iyenad- e2- nad- eor4-tcdoior4-tcdoihted pdi oih p rteddi oirp6,- 2-2-dip6,- 2-2-dio ul)l ]4.mao )ul)l ]4.ma l)mio omami lo omao-rp))lnimao-rp))lnimafiy- d-2-3[no ofl1 friy-3[no ed-2- ofl2drrre(- yulno)1 drrulno)22 oy- dirno)1 2 oy- dirno)2 4plf-flr (- y plf-flr (-ni1- yflr (-ni1- yflr6,nidriusm6,nidrius (- y 6(- use4(- y 6(- use3(- mnip use3(- mnip use2-irps en o2-irps em n o4- ht Nem n o4- htem n o4-aldor em n o4-aldor em n o oryazezsioryazezsior e -ezsior eN-ezsioryihlo o uezsioryihlo oe siolpainoe olpainoe olmioronoolmioronoolterr lf-noolterrulf- zn o horc- odu- ebroehrod- ebre hd-ul ebere hd-ul ebere h yp6ebere h yp6eberel 6,)l tSc- u6,)l tc-3,fi)l tc-3,fi)l tc-mi)l(-)l tc-mi)l(-)l t3f1 y(3lf1 yS(33 d yS(33 d yS(3d(y N yS(3d(y N yS(2a0 20 30 40 7 8 2 2 2 2 02 02=,H0.m)4.,z .,1 H.1 m.,2HHS M NJ,d3 2,z,)+ M6SN,)H0.– M 1 2 – M(–MM6.1 E(H 1 1 1 16 N,5N52.)N3 1 1 2 1 6 2 3 11,S 1Hd(HE(HH0.Hm(0.H4.9.H H =m(M - 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orezsiolhcioneoerc-baulfb) et3za idlyS(969Example 24 5-chloro-4-(3-((diethylamino)methyl)pyrrolidin-1-yl)-2-fluoro-N-(4-methoxybenzyl)-N- (thiazol-2-yl)benzenesulfonamide (Stereoisomer 1)Step 1. Preparation of tert-butyl (S)-((1-(2-chloro-5-fluoro-4-(N-(4-methoxybenzyl)-N- (thiazol-2-yl)sulfamoyl)phenyl)pyrrolidin-3-yl)methyl)carbamate

[0573] To a solution of tert-butyl (R)-(pyrrolidin-3-ylmethyl)carbamate hydrochloride (0.100 g, 0.422 mmol hydrochloride) and 5-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N- (thiazol-2-yl)benzenesulfonamide (0.182 g, 0.422 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (0.412 g, 1.27 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate (15 mL) and water (5 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 flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0–20% ethyl acetate / petroleum ether gradient at 40 mL / min) to give tert-butyl N-[[(3S)-1-[2- chloro-5-fluoro-4-[(4-methoxyphenyl)methyl-thiazol-2-yl-sulfamoyl]phenyl]pyrrolidin-3- yl]methyl]carbamate (0.150 g, 0.245 mmol, 58% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 13.2 Hz, 1H), 5.18 (s, 2H), 4.70 (s, 1H), 3.76 (s, 3H), 3.67–3.53 (m, 3H), 3.35 (dd, J = 7.6, 9.6 Hz, 1H), 3.30– 3.21 (m, 1H), 3.20–3.11 (m, 1H), 2.51–2.37 (m, 1H), 1.78–1.65 (m, 1H), 1.45 (s, 9H). Step 2. Preparation of (S)-4-(3-(aminomethyl)pyrrolidin-1-yl)-5-chloro-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide

[0574] To a solution of tert-butyl (S)-((1-(2-chloro-5-fluoro-4-(N-(4-methoxybenzyl)-N- (thiazol-2-yl) sulfamoyl) phenyl)pyrrolidin-3-yl)methyl)carbamate (0.150 g, 0.245 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at 30 °C for 2 h. The reaction mixture was concentrated under reduced pressure togive (S)-4-(3-(aminomethyl) pyrrolidin-1-yl)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide (0.110 g, crude, trifluoroacetate) a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 7.86 (s, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 4.4Hz, 1H), 6.67 (d, J = 13.2 Hz, 1H), 3.80–.58 (m, 6H), 2.98–86 (m, 2H), 2.09 (dd, J = 6.412.4Hz, 1H), 1.71 (qd, J = 8.0, 12.4 Hz, 1H). Step 3. Preparation of 5-chloro-4-(3-((diethylamino)methyl)pyrrolidin-1-yl)-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide

[0575] A solution of (S)-4-(3-(aminomethyl) pyrrolidin-1-yl)-5-chloro-2-fluoro-N- (thiazol-2-yl) benzenesulfonamide (0.110 g, 0.217.mmol, trifluoroacetate) and acetaldehyde (0.119 g, 1.09 mmol, 40% purity) in methanol (5 mL) at 25 °C was stirred for 0.5 h. Then the mixture was added sodium cyanoborohydride (0.0411 g, 0.653.mmol). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150 mm × 25 mm× 5 µm; mobile phase: [water (ammonia hydroxide v / v)- acetonitrile]; gradient: 14–44% B over 9 min). The desired fraction was collected and lyophilized to give 5-chloro-4-(3-((diethylamino)methyl)pyrrolidin-1-yl)-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide (Stereoisomer 1) (0.0500 g, 0.107 mmol, 49% yield, 96% purity) as a white solid. MS (ES+) m / z 447.2, 449.2 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 4.4 Hz, 1H), 6.49 (d, J = 4.4 Hz, 1H), 6.32 (d, J = 13.2 Hz, 1H), 3.67–3.44 (m, 3H), 3.35–3.20 (m, 1H), 2.68–2.54 (m, 4H), 2.52– 2.37 (m, 3H), 2.12–2.03 (m, 1H), 1.68 (dd, J = 8.1, 12.4 Hz, 1H), 1.04 (t, J = 7.2 Hz, 6H).

[0576] The following further Examples listed in Table 2 were prepared analogously to Example 24 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. 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-6 - i)l-(- 6 re '- 13- -rdied y'- 3-N- e(- deiN-d6e ry'-i1-])lyoror imo)sl ,m i y2- o p3s or ,m2a[nni -2- - om6ul an - om6ul an o h)l io - o di ni-)fio -)fio ertey etm'- o -2-erul )f d3flulordiro nid-flu o nid-flu Sl(y 1-]niedt -- se pS6lye rn y ye6,spdim2en m6,s2en diornipdir ((- h yeNteezpibormaal -y)lezal -y)lezm oilalco p rrordi -ormne '- o hyb3,ulnte -n6ehybte -n6eb y omao(u-l1)lfy)2[ -o 6fl -umina)lm-ina)l- n 2- oynifcl( piuln f ofi-ly'- 1 -ly(-se )1 d( tcy- )1 d( tcy- u -1 b - d'- 6flud- h 1-]reht N- nre -2o]2-re -2o]2-r(i se -3,(-se6,te eemnimor zm(-4.nid(y n4-2pe[N- n2- '- dilosimioneosi4-3[irm -4.nid y osi4-3[iry ozor-lrnoeolyoreozor3 d ( h h u bu- oulneolh4-rro'-lfibly oororip oororip yer3,1d- herolh porerolh porlf)lyc-te3 mfib d)lyc- 3)lypietbS((- 46,teet2 mS(c-sao 3zaueltfS(c-sao 3zaulf59 69 79 89 9 4 4 4 4 94= Jm ,(,m3=,m , q 1(s JH(93,s(5.7(,1 0 q(,m1.3(2 2 637..— 33..)1 8 574 ,)5.—21,)+.(1 —9..)20HM7,)3.62.,)1H+H6 4.1(H37 M 1,,) ,0.—,) ,(s H3,(1)m741,s7 H2, H( 4 ( 3.61 m.,(9 6 1 9 6.z / 3,)82 m,5.1( 4.m3.5,1^4 m(2 m)2 H(1 1 1,6z / δ6.—+2) 66 52 S δ m.3 —4 m)d6.-— 36.82E()6(3 —6.+ 91S O6.—2,)Sd-4.62.,)E(S6, 6.H3MO ;)S —3,H ) 5 S M)DH3,,)mHM9 ; 14.H,M2 m.tz1,zH(17,D;z6,,(5neH MH,z6.m)m 2(H7.ra0 H(1 p 01.2H—8.M01,1 z4.—pa0,1.01 0 32t4( 0.2,8.4H 9.o R8 4.2— , 5(R8.—91, n / d M= NJ4), ,H8.61M=4. )3 Heru d5.1 8,,) J,)2 HN, ,cs1Hd(=m(11Hd(H 1m(b o -lyh - t 6 e(- mNe'- -d3or i- oma1 -l-lytulno o ubfid-fl-arro yl 66,p,use6] cy2- n ,4b,-a4ec,d-)lezi1 y'ne3,3[-)-1 b 3,olman'R3 -])l2 o,n-lriy-roflSd2- y y u2(ilhtp eorse(- o n4-rrnid yirm- dyezorpiyp 5-haneolb i h'- os xb3r,o Ceh]lyc- 32[ulf20 3 5 05Example 40 3-chloro-4-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-2,6-difluoro-N- (thiazol-2-yl)benzenesulfonamideStep 1: Preparation of methyl 1-(2-chloro-3,5-difluoro-4-(N-(4-methoxybenzyl)-N- (thiazol-2-yl)sulfamoyl)phenyl)pyrrolidine-3-carboxylate

[0577] A mixture of methyl pyrrolidine-3-carboxylate (0.200 g, 1.21 mmol, hydrochloride), 3-chloro-2,4,6-trifluoro-N-[(4-methoxyphenyl)methyl]-N-thiazol-2-yl- benzenesulfonamide (0.540 g, 1.20 mmol) and cesium carbonate (1.57 g, 4.83 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 12 h. Ethyl acetate (20 mL) and water (20 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). Combined extracts were washed with brine (2 × 20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give methyl 1-(2-chloro-3,5-difluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-2- yl)sulfamoyl)phenyl)pyrrolidine-3-carboxylate (0.650 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.23–6.15 (m, 1H), 5.21 (s, 2H), 3.90–3.79 (m, 2H), 3.75 (d, J = 3.5 Hz, 6H), 3.69–3.62 (m, 2H), 3.16 (s, 1H), 2.25 (q, J = 7.2 Hz, 2H). Step 2: Preparation of 3-chloro-2,6-difluoro-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0578] To a solution of methyl 1-(2-chloro-3,5-difluoro-4-(N-(4-methoxybenzyl)-N- (thiazol-2-yl)sulfamoyl)phenyl)pyrrolidine-3-carboxylate (0.650 g, 1.16 mmol) in tetrahydrofuran (10 mL) was added lithium aluminium hydride (1 M, 2.40 mL) at 0 °C. The mixture was heated to 25 °C for 2 h. The reaction mixture was quenched with sodium sulfafe decahydrate (1 g) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was filtered over Celite. The filter cake was washed with tetrahydrofuran (50 mL). The filtrate was concentrated under reduced pressure to give 3-chloro-2,6-difluoro-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-methoxybenzyl)-N-(thiazol-2- yl)benzenesulfonamide (0.620 g, crude) as a yellow oil. MS (ES+) m / z 530.2, 532.2 (M+1). Step 3: Preparation of 3-chloro-2,6-difluoro-4-(3-formylpyrrolidin-1-yl)-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0579] To a solution of 3-chloro-2,6-difluoro-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.620 g, 1.17 mmol) in dichloromethane (20 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol- 3(1H)-one (0.990 g, 2.33 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with saturated sodium bicarbonate (10 mL) and dichloromethane (10 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (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 flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0–45% ethyl acetate / petroleum ether gradient at 36 mL / min) to give 3-chloro-2,6-difluoro-4-(3-formylpyrrolidin-1-yl)-N-(4-methoxybenzyl)-N-(thiazol- 2-yl)benzenesulfonamide (0.120 g, 0.227 mmol, 19% yield) as a yellow oil. MS (ES+) m / z 528.2, 530.2 (M+1).1H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 3.6 Hz, 1H), 6.81–6.74 (m, 2H), 6.21 (dd, J = 1.6, 13.6 Hz, 1H), 5.21 (s, 2H), 3.97 (dd, J = 4.8, 10.4 Hz, 1H), 3.80–3.76 (m, 1H), 3.75 (s, 3H), 3.61–3.53 (m, 2H), 3.17 (quin, J = 6.4 Hz, 1H), 2.35–2.27 (m, 1H), 2.25 (d, J = 7.2 Hz, 1H). Step 4: Preparation of 3-chloro-4-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1- yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0580] To a solution of 3-chloro-2,6-difluoro-4-(3-formylpyrrolidin-1-yl)-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.120 g, 0.227 mmol) and N- methylcyclopropanamine (0.0330 g, 0.464 mmol) in dichloromethane (5 mL) was added sodium triacetoxy borohydride (0.145 g, 0.684 mmol). The resulting mixture was stirred at 25 °C for 2 h. The mixture was diluted with saturated sodium bicarbonate (10 mL) and dichloromethane (10 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (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 to give 3-chloro-4-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-2,6-difluoro-N-(4-methoxybenzyl)- N-(thiazol-2-yl)benzenesulfonamide (0.120 g, crude) as a yellow oil. MS (ES+) m / z 583.3, 585.3 (M+1). Step 5: Preparation of ((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-2,6-difluoro- N-(thiazol-2-yl)benzenesulfonamide

[0581] To a solution of 3-chloro-4-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1- yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.120 g, 0.206 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 10 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dimethylsulfoxide (2 mL) and the pH was adjusted to 8 with ammonium hydroxide (10% purity). The residue was purified by prep- HPLC (column: Waters Xbridge 150 mm × 25 mmmobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 8–38% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-4-(3- ((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-2,6-difluoro-N-(thiazol-2- yl)benzenesulfonamide (0.0464 g, 0.0982 mmol, 48% yield, 98% purity) as a white solid. MS (ES+) m / z 463.2, 465.2 (M+1).1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 4.4 Hz, 1H), 6.53 (d, J = 4.4 Hz, 1H), 6.20 (d, J = 14.0 Hz, 1H), 3.67–3.52 (m, 3H), 3.26 (dd, J = 6.4, 10.3 Hz, 1H), 2.58–2.44 (m, 3H), 2.32 (s, 3H), 2.09–2.01 (m, 1H), 1.70–1.54 (m, 2H), 0.50–0.40 (m, 2H), 0.39–0.28 (m, 2H). Example 43 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- ((methyl(neopentyl)amino)methyl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 1)Preparation of 3-chloro-N-(3,4-dimethylbenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamideStep 1. Preparation of N-(3,4-dimethylbenzyl)-6-fluoropyridin-2-amine

[0582] To a mixture of 2,6-difluoropyridine (10.0 g, 86.9 mmol) and N-ethyl-N- isopropylpropan-2-amine (14.6 g, 113 mmol) in dimethylsulfoxide (70 mL) was added (2,4-dimethoxyphenyl)methanamine (17.4 g, 104 mmol). 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 layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). Combined extracts were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0–15% ethyl acetate / petroleum ether gradient at 50 mL / min) to give N-(2,4-dimethoxybenzyl)-6- fluoropyridin-2-amine (22.0 g, 83.9 mmol, 96% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) 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

[0583] To a solution of N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (10.0 g, 38.1 mmol) in tetrahydrofuran (100 mL) was added lithium methide (1.6 M, 34 mL) by dropwise at -78 °C. After stirred at 0 °C for 0.5 h. The reaction mixture was cooled to - 78 °C and a solution of 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 warmed to 25 °C and stirred for additional 12 h under nitrogen. The reaction was 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 flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0–20% ethyl acetate / petroleum ether gradient at 50 mL / min) to give 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) as a yellow solid. MS (ES+) m / z 513.1, 515.1 (M +23).Preparation of (S)-3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- ((methyl(neopentyl)amino)methyl)pyrrolidin-1-yl)benzenesulfonamideStep 1. Preparation of tert-butyl (S)-3-((methyl(neopentyl)amino)methyl)pyrrolidine-1- carboxylate

[0584] To a solution of tert-butyl (R)-3-formylpyrrolidine-1-carboxylate (0.100 g, 0.502 mmol) and N,2,2-trimethylpropan-1-amine (0.0830 g, 0.603 mmol, hydrochloric acid) in dichloromethane (2 mL) and methanol (0.2 mL) was added sodium triacetoxy borohydride (0.320 g, 1.51 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with saturated sodium bicarbonate (10 mL) and dichloromethane (10 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (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 to give tert-butyl (S)-3-((methyl(neopentyl)amino) methyl)pyrrolidine- 1-carboxylate (0.0800 g, 0.281 mmol, 56% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 3.68–3.20 (m, 4H), 3.17–2.99 (m, 1H), 2.43–2.28 (m, 3H), 2.25 (s, 3H), 2.08 (s, 2H), 1.96 (td, J = 6.4, 12.8 Hz, 1H), 1.66–1.57 (m, 1H), 1.46 (s, 10H), 0.86 (s, 9H). Step 2. Preparation of (R)-N,2,2-trimethyl-N-(pyrrolidin-3-ylmethyl)propan-1-amine

[0585] A mixture of tert-butyl (S)-3-((methyl(neopentyl)amino)methyl)pyrrolidine-1- carboxylate (0.0800 g, 0.281 mmol) in hydrogen chloride / dioxane (4 M, 4.00 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give (R)-N,2,2-trimethyl-N-(pyrrolidin-3-ylmethyl)propan-1-amine (0.0700 g, crude, dihydrochloride) as a colorless oil.1H NMR (400 MHz, MeOD-d4) δ 3.72–3.55 (m, 2H), 3.52–3.43 (m, 2H), 3.41–3.33 (m, 2H), 3.28–3.15 (m, 2H), 3.14–3.07 (m, 1H), 3.02 (d, J = 2.0 Hz, 3H), 2.98–2.85 (m, 1H), 2.48–2.32 (m, 1H), 2.23–1.77 (m, 2H), 1.17 (s, 9H).Step 3. Preparation of ((S)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-((methyl(neopentyl)amino)methyl)pyrrolidin-1- yl)benzenesulfonamide

[0586] To a solution of (RN,2,2-trimethyl-N-(pyrrolidin-3-ylmethyl)propan-1-amine (0.0700 g, 0.272 mmol, dihydrochloride) and cesium carbonate (0.440 g, 1.35 mmol) in dimethyl formamide (2 mL) was added 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6- trifluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.130 g, 0.265 mmol). The resulting mixture was stirred at 25 °C for 12 h. Ethyl acetate (4 mL) and water (3 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 5 mL). Combined extracts were washed with brine (15 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (S)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- ((methyl(neopentyl)amino)methyl)pyrrolidin-1-yl)benzenesulfonamide (0.150 g, crude) as a yellow solid. MS (ES+) m / z 655.1, 657.1 (M + 1). Step 4. Preparation of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- ((methyl(neopentyl)amino)methyl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 1)

[0587] To a solution of (S)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-((methyl(neopentyl)amino)methyl)pyrrolidin-1- yl)benzenesulfonamide (0.150 g, 0.229 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dimethyl formamide (2 mL). The mixture was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 16–46% B over 10 min). The desired fraction was collected. To the mixture was added one drop of concentrated hydrochloric acid and lyophilized to give 3-chloro- 2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-((methyl(neopentyl)amino)methyl) pyrrolidin- 1-yl)benzenesulfonamide (Stereoisomer 1) (0.0414 g, 0.0749 mmol, 33% yield, 98% purity, hydrochloride) as a white solid. MS (ES+) m / z 505.1, 507.1 (M + 1).

[0588] The following further Examples listed in Table 3 were prepared analogously to Example 43 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gelchromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC).(.R42,)8(.2.R381(2.8 R8 – 3.91(0R,–H9(d03,RJH),23+(R72 2,M.)M1= NJH0124 , 3,–M= 9NJ–,20.M61. .–32–Md6(.3,s(m(Md3(.3,sS.( E 9N1,)1N2,)21N7,)6(M6 N–m 5(H 21,1Hd(m(3. ,0 1Hd(6.2741H5.6 H 21.21H6.6 H 20.31.11H7.6 H 21.S 2 M 1H4.68.2m(ryp- )l2 - - --lorrrrlN-niozy yep pdi- 1e-diyho )ld tzi ai)lm nimeaiy- el)ld yaiohty h n daoilno m)ht1-ro(-nriy(- - h 6teete-florr-6flniN- - dmap 3ilno(-N-(- 3)lN-m)dim)6(- u omaoseyp(- u )lN-seemaor(o e - o 4-rrfl(-y- eoy u4-1-di r- o 3na(inniN- n y - omorezyhorn oezm)luldipsenim ulmafl aoneteulneefior)dlnorda-fi4-)lu)lulbfib N ht mao nuyezoilno)lytseyfi)lml)l- m6,olfihteneulfiorrfld- u6,y-nen h eted-y- )y1-d1- 6,y- )1 3((l-y2-fl-p)luds- 6,mb o)ld- y y6,ps)l e2n -2- ornipzn doe e-3 m6b(-(,l2-2- )lnire -ni2d-2- ornire4o y- e2ni-2ye irn)l4 ytdimoidimo 3orn- l2 -rp1ool-eni zonro -loohoz rhtznoe eolh y(l -u yy-obc- ph1- rby- ro1- ypsiteoz ol rah ysci-po el lbc e lpr l3ort ollcniorer(-orerahc-ycdilb)lhc- oaihml)lhc-y-y -)oeu mnihc ycdiouet3( 3-)ouetT 3((ory 3m(t(31 - 2S(lf((dil -3(( lolfS( -4lylfS(.x E 04 14 24 34 44 54,M0.,s6(m M.,),)4 6 HH,M6.67. ,7, ,3 m M= dm M6.67. , .3 m1,95.,)Mm3 H8.0N8,( .01 52 2)1N,)1,2 z,1.5N,),)(9 7NJ( (, 3,24 6N),)(34 (–2,3 z / N6 23, )1H.2.3.2 + 1HH 1 Hm(741HH 1 H 1.1 1Hd( .3.1 1HH 1 H 2.3 m 1H.76.3m(H 3 -) ) )-)o ni eddi-1il1 rom- e-1re1 3- -1 r-re)lN re ry ranim1-r- onimo6,m y - p o hormo -)ly 6 no dilsidisi2-siteosi3-lyh p(-floroe reooe-r- om)ulfio yhte e)lN- us-ryrpi r3 ol2-erod-ertemdiyhotr e6 pet-6 pet -eo n( )lhc nietniet-6)omm)u-(-S((-(-S(lezofineN- 3 y - dS(m6,S((-m- a(- -eN3 -eh3-ir eal2- eN3nino bor4n-1-di -or(- 4-1-dite)ly y- p id-o diy)hlty-di -or(- 4-maf)lu 6m,)lo )ul)lnidmao nul)lnidmamly1- romaei1- - 2-mao ul)l lytsen)a2)-y-l2-1 fiy- 2ilo ofiy- 2iln o o - 1-niduln f- od((-nin dniofiy- 2neez1yornired- -nirrfldy u- -nirrfluniilflo 6(u 3ildfloirud- -nip onere-trh et olh dirm6o,2 dirpse6,2 d y irpsedit rr -se(- 4rrypse6,2 diern b)lmo te(c- ysi -o(ry)ln ye-zory)ln yez e-m 3(l3- pzyNpol -n r oo e- ezory plorn e -zory(lyy-sirolp orhteneolp orht ne a(- yroneoly o uneolp orht 1- oer(-yt)ly- ouethc- oumlb)lhcoeumb)3 h (teulfb)h h cte lf- b)hcoeu mniet4 u b 1lfS(3lfy y - 3lf lyly - 4 midly - 3 m6( ly - 3lf((dilS(6 07 9 50 6 3 4 4 8 2 02 22N2=,)2 1HJ25 N2 1 1H68.)N,) ,SN,),z,) .1N,) ,7N,),),)niuN,),)31 H. .65.3 H 51HH 1m(E(1HH 1 HH 4941HH 12.13.21HH 1 H 2 H 1q(1HH 1 H 27.25.1 -))y1) ) ) ) ) )l-1 2-1 2 1 2h6t,r2e- -re- -re6,re- 6,re-r r-e- -ee -m m)oro3s-1- mo3-1- mo2- mo2- mo3-1mo3-1mo ool-iy o xnoidsiiyxnisiorsiorsiyx -siy -silo o diool- ool- o onix d o onido nihc-2-erhee-teorhlee-teor- h e3-c-2-er- h e3-c-2-erh e -teiloerh -teiloerma)l3-ni)ldtirS(6r(r t-m- y 3 pS(6r(r t-m- y 3 pS()ly3-ni)ldtirS()ly3-ni)ldtirS(6(-m-rret3 yS6(p( -m-rret3 ySp(yhyt- yeN-(-)l eN-(-)l ehtyeh yeN-(eN-(ee1- p ordior4- yhdior4- yhdi ey- 1- p orditey- 1- p ordio-r4-)lydi -)ldihor4- y m(lnidomao iulnoul)ltemao fy-mlnoul)ltemamlmf y-mlnoy-nio duamlmo l noy-nio dualnul)ltf y- emao nul)lhtf y- eman yt lf-fi2- i2 1-ilf-1-ilf- oi2 mloi2 mlo u o br-r6lud-ty( niy-f1lud- -niy-f1luniorr6f(luniorr6flud- -niy-flud- -niy-flu rep-lsN- e6,n2- di-rnise6,2 di-rnisedity - psedi(ty - pse6,2 dir1-se6,2 dir1-se(y dn - y dneyN- neyN- n - ynin -nin t y (- h 3t orezorilezorilezze oneolpo eozzr oo ezorezoryezrneolp oror ne a(x - orone a(x - oroneolp ordirp eneolordirene(- 4m-ul3fib d)lh yc- or3 uly b fp()lh yc- or3 uly b fp()l3 h y(-teul4 mfib d)l3 h y(-teul4 mfib d)lh yc- o 3 uplib fp()lh yc- o 3 uplib fp()ly 42 5 6 7 8 2 62 62 62 6 9 2 6 0 2 72( (R1,z25( (6 H,)94 R1 6J,H + ( (6.MR921 ( (5 5.,zR03.(.– 5.6R7,12 (,)7(R,z3 4.H (S M.6N,)6.H,M.11 21 ,.6d3(z 3N,)(51,2.M.63 , –H.)M6.63 = , –J,M0.6.H7.23, 1 1,MH36.0.–3 1 M.17345N)7 6 4 16 4.3 11 N)7 + 16dN=),z )N3 2 H 182 =6=)1HH 1 = H941HH. .91HH.4 1HH.d(1HJH H 1H.3JH 1 - N)-1-)orreN-2-)orre1- - ni)l1-)ry- e1- - ni)l2r- -)y- e)lor1-)y or- ue)lor2y oreo m o mdi- md- m hlm hulm -ulos-ulos r 1-2- osir 1-2- os tefiotefio 3-fi io3-fi ioenini ioenini imd-simd-si)lyd-er)ld-erpidde pidd oe )l6,oe )l6,oeht 6,2-etyht 6,2-etp oriloir rorryetp oriloir rorryety-21- r-)lety-21- r-)letem))lS( e)ylS(- em)y- euly p fipo S(uly p oS(nyroefipyroe iyd-S(1-n y-S(-e id1- -eo ni1-dio -mani1-di-mad- xu4ldi,of-mad- xu4ldi i,of-matenid2-di imtenid2-dimmni2- nmni2- n ht6 n ht6 -zailni a-zailni aad -)lilniofad -)lilnio4f((e-(- o4f((e-(- no3f((-)ly o dn rriro3((-)ly o d n riro 3 y o dl3 y o dl3m-N- l3m-N- l3 h y yfl3 hry yfl(- h 4-terriyru y p pse(- hterriyru yse(-3-oruse(-3-oruse(-tep pu yorse(-tepp u yorseo n4- pp n4-)lrmyorezomyore oy o uln e4-)lo y o uln e4- m oorxo o n4u e- m oorxo o n ueol(ly xo o hnreol(ly xo oznrh eoltefi znrh eoltefi znreolo htlef- znreolo htlef- znec h -th 3et(eulf- b ( m6()lh ych -th 3et(eulf- b ( m6()lh yc- md3)l -y6,b 2)lh yc- md3)l -y6,b 2)lhuycl-fi3d(m6 -(- b 3 N)lhuycl-fi3d(m6 -(- b 3 N)ly 17 27 37 4 5 6 2 2 2 72 72 72N,),)6 1 1 77.N,),) ,dN1 1 1 1 7t(12. ,.)N4 6m(212.8 64.8 37 N,d 6,11d(7) .7N,) ,7,2 1 51 1m(0 N) , ,HHH HHH H HH.H.H3 HH.2 1HH 1m(m() ) ) )- 1 - -)l1r- -) 2r- -)yl-1r-1l r yhel d yhedd- e1- ly- e3- 4 yy- e-l e- 3- 4-l ete ite iniit 1- - moni1- mo x1-diozmo)lozmom-mam-maenzi2-adnisidi -2- oteninisio o ht nima- -aisiy o haisi )o -3 o 6(- no)fl-3 o 6(- noforild oirerzadildirer ed milno3(h( 3- t(-erteht(-er((ni(mN-)lus ((nimN- l)lusoruryel y ptoSro ( orryeptS - o 3rrflu -3)lyN-et-mS3)oN-etS -3a)ly- e(n -3a)ly- en fipor euly((f- ysi por e4- p)e(n - 4 h -te)l (e(- 4-ni)l (e(- 4- yh1-ez(- 4- yh1-ezd- yx odiy 3,ould- x odi louloryhezormy-d)il1-ormay-d)itenineteninel1-ord bordb 3 hf(t-6man3,hft-6mao u(e lteneo )uly-nimao ulynimao ulm(i)llo)lo )ulm(i)llo)l)-(- o3f((e-(- nof fimlb)l1 fi1- dilnof fihtedilnof fiytrryy - 21 fiytrryy - 223m(--3 N- lu 3m(- 3N- lud- 4 --)lors 6 y-y-4red- 6niorlrud- old6mrru - u 6 bp - ynired- ub p- ynireoe -4 -)lorsoe ,21- -lmo,2ditypse ,2(ly ypse ,2 olxo dirm6o,2 olxo dirmo ory n hule-zory n hule-zornidozsi -oerzay ne-zorp o y n e- czorychtysi -ocrychtysiolthefidneoltefidneol ireaio hcterolox r ohneol rx pohneolor ep oroerolor ep oroer-m)l -6,b)lhc- m)l -6,b)hc pi(-ethcouteb)hcositeb)hcoum-3 ouethcoum-3 ouet3 y 2 y 3 y 2ly - 3p(NS( -3lfmly - 3((mly - 3lf-)lfS( -3lf-)lfS(77 87 97 08 18 2 3 2 2 2 2 2 82 82N,),)3 1HH 1 H 12.N,)8 2 1HH 17.1.34,.7Nd 8 235 1Hd(7.H.138.7N=3, ,N2 4841HJs(m(1H1.0 78.,z1.3 H2.7N,d2 284 1Hd(8.3,,)M3s(H 1.)1 ly l -)-)-) )hed yhed2-1r 2-2r 2- - ni1- r2- - ni2te im)-6mate im)-6mani edir- mni eo dir- mnid o dirit ee mnidro dirit ee mo -3 o(- no - o(- no y1-siy1-siyzasiyzsi((ni(-3mN-fl3nia)lus ((N-flpnio pnio ply o paly o ) uorderorderorherorher(-)lyy- e(n -3ma)l1e (- lyy-seoin eul lf oetoile-rrStot etot et(ulfo -rrS(ul ef-m- - 1S(ul ef-m- - 1S(4- h- z4- h1- z6 yp-e6 yp-e63( - e63( - eortenio dnietenine(-di(-di( nidi( nidiulbord lm(ib(-1-(-1- -(- di- )l(- d l o)loil)ulm()llo)l)N-3-nyidmaNn -3-nyidmaN-3-y omaN-3-y omafid-ytrryu y - 23 fiytrryy -o2 4ro xoiloo oro xoilnoo oro xrornoy oro xrorn y o 6,bp - ynired- ubp- ynireulfht rrfluulht rrfluulhtpf)lluulhtpf)llu 2- olcxo dirm6o,2- olcxo dirmo - 2ey - psef- eysn2- pef- esn2yef- 2eyseoryol chtysiohoryh repotysiorm-)3lyezorm-)3lye-zorm- h 3ten e -zorm- h 3ten ezc- omorerol cor ep o morerol(- hteneol(- hteneol(- m)lneol(- m)lne3 u - lf3 o -)uelth fS(c- o 3 u - lf3 o -)uelth fS(c-4- 5)lymlb y)lh yc-4- 5)lymlb y)lh yc-4- 5)lyy- b 1)lh yc-4- 5)lyy- b 1)ly 48 58 68 78 8 9 2 2 2 2 82 82N2,1H8. )7 6 H 12.8.N8,321 1H8. )H6 H 12.7 93.9 24.N1,11H8. )756 H 12.2.z / N3,331 m 1H8. ),)2(6 H 1 H 30.SN,d4 2 M Hd(7.2 31.N,d3 2 1Hd(7.9 30.2 - 5)- - - - -)l-1r 5)--2r 5)--3r 5)--4)r1)r2ry 2- e-)ly2- e-)ly2- e-)ly2- e-e-e2- -nimo2- -nim2- -nim2- -nim2- m2- m n1- d atnisn1- d osn1- dosn1- dos oros orospedir iihly o pe] ooratnidir iy oeratnidir iy oeratnidir iy oe-ol ih oe-ol ih oeretpeilp ooretpeilp ooretpeilp oorret3-c- - 2r-et3-c- - 2r-et1.rry oS(h]1.rry oS(h]1.rry oS(h]1.rry oS()ly5-))llniS(y5-) niS(2.pu2[ylxf- edi2.puylf- ed2.puylf- ed2.puylf- ed htd ey-ir ed htld ey-ir edlo 62[x 6i2[x 6i2[x 6i1- ypi1- ypio c h(-mao o(-mao o(-mao o(-mamlmamlmaytceN- nli och yteN- nloch yteN- nloch yteN- noy-nidoiro noy-nidoro no bm-oroflcibm-oroflcibm-oroflcibm-orofl1- nloul1f fl -inloulf fla3- us a 3- us a 3- us a 3- usirr -usirr -u z a-)lul e z) ul e z) ul e z) ul ediy 6ediy 6se2(yf- n h2(-eza- lyf- n h2-e a- lyf- 2 n -e a- lyf- 2 n -e tepy(- ntp(- n -te3orn 2(NeeyNe(-teozrn 2(h (-teozrn 2(h (-teozrn za(x - o - oznza(x - o - ozn(- m 4)lol eb yhc)l3 y(- m 4)lol eb yhc)l3 y(- me4)lolb yhc)l3 y(- me4)lolb yhc)l3 hry(-teoe4 mu b lf)l3 hry(-teoe4 mu b lf)ly 09 19 29 29a3 4 2 2 2 2 92 92N,d5 1Hd(1.7 48.,zN,d7 2 H 1Hd(1.4 48J. ,N,z8.,)4.2d(1H H41 H 18.1NJ,,)8 1 051Hd(H 39.H ,28.N) ,H61HH 1m(6. ,N,)5 7m(1HH 12,.z / 3 m - 5)-)--)- - - - )l-1r 5- -2r 2-1r 3(-re3(-re)ly6,-y 2- e)ly2- eni e(-nidmo(-nid mo h2- 2 --1n-nim d o - -naniirsim d i2-1- dosiirmo3-ilsi3-ilsite)lysiy oro y oromy- xed oniyaniiro p o xorerxorer )o1- perxd yerorerh ypeth ypetni -2hl]o 1.rroreot eihlp ] orroreoto ulet-6te)lS-te)lS ni -my(6my(mdilnid 1.ySpul (e1.1 ySpul (ef-6 - -S(e(- -he(- -healN3tediN3tediy orriry e 2[yxf-6di .2[yxf-6di(-2((-1-di -or(- 4- m)-(-lmaor4- m h )lmateyp pdiolo c h(t-maolo c h(-maN-3- - 1-nidi mao ul)ly- no o ul)ly- nomi)lory omayceN- ntibmoo yceN- nooory o xni lnyd o ofi -21-flufiy- 21-flud((hteuln f- o a- rfl imz3- o u b- roflo uulht ilrrfla-)o y ud- -ninidsed- -nini -dse3 m6flul(lu fseaz3-)lulf sef- 2errp)lse6,2 diritn6e e,2 diritne (- 4 yx -se2(y - na- y - n -m- y y n - yz z -yez z -oN- n h2(-ezh2-ezor3 -te3orn phezora n ora n orh e2((-teorneol(- lyo ezhtenpleoloryeh b pl)oloryeh bt) ol e rone(- m 4)lolb yhc)l3 y(- m 4)lolb yhc)lh yc-4- 5)ltem y m)lb y)lh yc- o 3 utle lfmy- h 1)1c- o 3 utle lfmy- h 1)2c- m 3(-ul3fib d)ly 59 59a69 79 8 5 2 2 2 2 92 05,zH H1 0.,)5.39.1 –.343,z0.,z2H1,)–8 1H,) ,H9.7 =H8H = J2.3 .)m( 1, 0.2 δJ) ,4.2 , 4 q1 ,z1+1z7.H,)d6 d -(= 5J( = 7JH4.M(7–2.H 43OS3. ,d 7. ,d2 2.3 78.1 ,z6 (=HM,)3 7(= δ 5J)3. ,974δJ) ,4.Dd2 ,H z1 1.,2d6 -6d ,( z / 6(=Hz,)H O)3 md- 5JHS H)M1 1.+ O3. ,M0.2,,2S d0 , S6, (0.46m()H Dz )E M)3 ,zHH( DH1.(= H0.2 6,S,z1RJ34,mM. ,z2,,7. s)Md2(M)H(–39 =( HH2N9 0J9.4.0,4 HM47.400. ,1H5.62 0,)( d(2,–s06(4 =m( .), ,)H)H R9 5.3 99(4RJ,3 HH1 7.4 1 3,M6. .d2,s,N,)2,)0,)M N(9 –(z,s(m(1HH 1 H 3 H 1 1H5.3 69.9 24.H06.4 71.2 37.1 - - -)l3- - y-)l)yl3- y-)l1- -1 y- -n5i2- -2- dnind - 5i -dnid nilaoirrrye -nilaoirrryexey pdixy pdih]porm3a eporma.yx o nh]y o n 2[oulo3.xulo o hfrit-e6fl( u)2[ohft-6flu psm- a -seoe(-s)n1 rime2z3-N-ezreps -3-N- nezrea-)loron5emoazoa )l ronmo ( yhulblsi -5 yhul eblsi(-tefiy o(3 her(-tefiy o her(- md)- 6teet3(md)- 6teet4ly,2 mS( -4ly,2 mS(60 7 5 05Example 80 (R)-4-(3-(dimethylamino)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3- methylbenzenesulfonamideStep 1. (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0589] A solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (0.107 g, 0.217 mmol), (R)-N,N- dimethylpyrrolidin-3-amine (0.0250 g, 0.218 mmol) and cesium carbonate (0.214 g, 0.656 mmol) in dimethyl formamide (1 mL) was stirred at 30°C for 4 h. Ethyl acetate (5 mL) and water (5 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (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. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 21–51% B over 10 min). The desired fraction was collected and lyophilized to afford (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0600 g, 0.100 mmol, 46% yield, 98% purity) as a white solid. MS (ES+) m / z 585.4, 587.4 (M + 1). Step 2. (R)-N-(2,4-dimethoxybenzyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide

[0590] To a mixture of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- (dimethylamino)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.0330 g, 0.0564 mmol), methylboronic acid (0.0337 g, 0.564 mmol) and cesium carbonate (0.0551 g, 0.169 mmol) in 2-methylbutan-2-ol (1.5 mL) was added (2'-amino-[1,1'-biphenyl]-2-yl)palladium(II) adamantan-1-yl(adamantan-1- yl(butyl)phosphaneyl)methanesulfonate (0.00822 g, 0.0112 mmol) under nitrogenatmosphere. The mixture was stirred at 90 °C for 16 h under nitrogen. After being cooled to room temperature. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 18%-48% B over 10 min). The desired fraction was collected and lyophilized to afford (R)-N-(2,4-dimethoxybenzyl)-4- (3-(dimethylamino)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3- methylbenzenesulfonamide (0.0220 g, 0.0389 mmol, 69% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.94 (q, J = 8.0 Hz, 1H), 7.23 (dd, J = 1.6, 7.6 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 2.4, 8.0 Hz, 1H), 6.52 (d, J = 2.0 Hz, 1H), 6.45– 6.40 (m, 2H), 4.98 (s, 2H), 3.72 (d, J = 10.0 Hz, 6H), 3.58–3.46 (m, 3H), 3.32 (s, 1H), 2.76–2.65 (m, 1H), 2.21 (s, 6H), 2.15 (d, J = 2.0 Hz, 3H), 2.10–2.03 (m, 1H), 1.78–1.64 (m, 1H). Step 3. (R)-4-(3-(dimethylamino)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3- methylbenzenesulfonamide

[0591] To a mixture of (R)-N-(2,4-dimethoxybenzyl)-4-(3-(dimethylamino)pyrrolidin-1- yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide (0.0220 g, 0.0389 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.767 g, 6.73 mmol). The mixture was stirred at 30 °C for 12 h. The reaction mixture was concentrated. The residue was diluted with N,N-dimethylformamide (2 mL). The pH was adjusted to 7-8 with N,N-diisopropylethylamine. The mixture was purified by prep- HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient:6–36% B over 10 min). The desired fraction was collected and lyophilized to afford (R)-4-(3-(dimethylamino)pyrrolidin-1-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide (0.0113 g, 0.0233 mmol, 60% yield, 95% purity, formate) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.2 (s, 1H), 7.78 (q, J = 8.0 Hz, 1H), 6.83 (dd, J = 2.0, 8.0 Hz, 1H), 6.61 (dd, J = 2.4, 8.0 Hz, 1H), 6.39 (d, J = 14.4 Hz, 1H), 3.56–3.42 (m, 3H), 3.29 (t, J = 8.8 Hz, 1H), 2.81–2.68 (m, 1H), 2.21 (s, 6H), 2.13 (d, J = 2.4 Hz, 3H), 2.10–2.03 (m, 1H), 1.72 (td, J = 9.7, 19.9 Hz, 1H). MS (ES+) m / z 415.1 (M + 1).Example 82 4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-2,6-difluoro-3-methyl-N-(thiazol-2- yl)benzenesulfonamide (Stereoisomer 1)Step 1.2,4,6-trifluoro-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2- yl)benzenesulfonamide

[0592] To a vial containing a solution of 3-chloro-2,4,6-trifluoro-N-(4-methoxybenzyl)- N-(thiazol-2-yl)benzenesulfonamide (1.00 eq, 430 mg, 0.958 mmol) in 1,4-dioxane (9.58 mL) was added methylboronic acid (3.00 eq, 172 mg, 2.87 mmol), tricyclohexylphosphine tetrafluoroborate (0.2 eq, 71 mg, 0.192 mmol), and potassium phosphate tribasic (3.3 eq, 671 mg, 3.16 mmol). The solution was sparged with nitrogen for 15 minutes followed by the addition of palladium (II) acetate (0.1 eq, 22 mg, 0.0958 mmol). The headspace was replaced with nitrogen and the reaction mixture was then heated at 100°C for 4 hours. Upon completion the reaction mixture was filtered over Celite. The Celite pad was rinsed with EtOAc (10 ml), and combined organics concentrated to afford 2,4,6-trifluoro-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2- yl)benzenesulfonamide (235.6 mg, 0.550 mmol, 57% yield) as a yellow residue. Material was progressed to the next reaction without further purification. LCMS [M+H]+: 429.6. Step 2. (S)-4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-2,6-difluoro-N-(4- methoxybenzyl)-3-methyl-N-(thiazol-2-yl)benzenesulfonamide

[0593] To a vial containing a solution of 2,4,6-trifluoro-N-(4-methoxybenzyl)-3-methyl- N-(thiazol-2-yl)benzenesulfonamide (1.20 eq, 412 mg, 0.961 mmol) in N,N- dimethylformamide (2.67 mL) was added dimethyl({[(3R)-pyrrolidin-3-yl]methyl})amine dihydrochloride (1.00 eq, 161 mg, 0.800 mmol) followed by DIPEA (4.00 eq, 0.56 mL, 3.20 mmol). The reaction mixture was left to stir at RT for 2.5 hours. Upon completion, the reaction mixture was diluted with EtOAc (5 ml) and poured into a half-saturated solution of brine (10 ml). Upon separation of phases the aqueous phase was extractedwith EtOAc (10 ml x 3), washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated to afford (S)-4-(3-((dimethylamino)methyl)pyrrolidin-1- yl)-2,6-difluoro-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)benzenesulfonamide (302.8 mg, 0.564 mmol, 71% yield) as a yellow foam. The crude material was carried forward to the next reaction without further purification. LCMS [M+H]+: 537.8. Step 3.4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-2,6-difluoro-3-methyl-N-(thiazol-2- yl)benzenesulfonamide; hydrochloride (Stereoisomer 1)

[0594] To a vial containing a solution of (S)-4-(3-((dimethylamino)methyl)pyrrolidin-1- yl)-2,6-difluoro-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)benzenesulfonamide (1.00 eq, 429 mg, 0.800 mmol) in DCM (8 mL) was added trifluoroacetic acid (8.64 eq, 0.53 mL, 6.91 mmol). The reaction mixture was left to stir at RT overnight. Upon completion, the reaction mixture was concentrated. A minimum amount to EtOAc and H2O (5 ml) was added, and the crude material was basified to pH 7.5 with saturated sodium bicarbonate, extracted with ethyl acetate (5 ml x 3), washed with water, (10 ml), brine (10 ml), and concentrated. The crude material was purified by reverse phase chromatography on the Biotage (25 g column, ACN / H2O, 5 mM HCl) to afford 4-(3- ((dimethylamino)methyl)pyrrolidin-1-yl)-2,6-difluoro-3-methyl-N-(thiazol-2- yl)benzenesulfonamide; hydrochloride (Stereoisomer 1) (8.8 mg, 0.0192 mmol, 2.4% yield over 3 steps) as a white solid.1H NMR (400 MHz; DMSO-d6) δ 12.82 (s, 1H), 10.48 (s, 1H), 7.28 (d, J = 4.6 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 6.36 (d, J = 14.2 Hz, 1H), 3.58—3.54 (m, 1H), 3.45—3.34 (m, 2H), 3.29—3.25 (m, 1H), 3.22—3.11 (m, 2H), 2.75 (d, J = 4.8 Hz, 6H), 2.67—2.60 (m, 1H), 2.14—2.07 (m, 4H), 1.74—1.65 (m, 1H); 19F NMR (376 MHz; DMSO-d6) δ -108.82 (s, 1F), -112.11 (s, 1F); MS (ES+) m / z 417.0 (M + 1).

[0595] The following further Examples listed in Table 4 were prepared analogously to Example 80 or 82 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC).Table 4Examples 300 and 301 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin- 1-yl)benzenesulfonamide (Stereoisomers 1 and 2)Step 1. tert-butyl 3-methyl-3-(piperidin-1-yl)pyrrolidine-1-carboxylate

[0596] To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.00 g, 5.40 mmol) in toluene (10.0 mL) were added piperidine (0.506 g, 5.94 mmol) and 1,2,3-triazole (0.448 g, 6.49 mmol). The mixture was stirred at 140 °C for 6 h while collecting water via a Dean-Stark trap. Methylmagnesium bromide (3 M, 9.0 mL) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 12 h. Ethyl acetate (10 mL) and water (10 mL) were added and 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 to give tert-butyl 3-methyl-3-(piperidin-1-yl)pyrrolidine-1-carboxylate (0.780 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 3.74 (d, J = 8.0 Hz, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 3.31–3.26 (m, 1H), 3.15 (dd, J = 4.8, 10.0 Hz, 1H), 2.56 (s, 1H), 2.51–2.46 (m, 2H), 2.39–2.34 (m, 2H), 1.88–1.75 (m, 2H), 1.58–1.53 (m, 4H), 1.42 (s, 9H), 1.02 (d, J = 4.4 Hz, 3H). Step 2.1-(3-methylpyrrolidin-3-yl)piperidine

[0597] A solution of tert-butyl 3-methyl-3-(piperidin-1-yl)pyrrolidine-1-carboxylate (0.300 g, 1.12 mmol) (crude) in hydrogen chloride / dioxane (4 M, 5.0 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 1- (3-methylpyrrolidin-3-yl)piperidine (0.230 g, crude, 2 hydrochloride) as a yellow oil.1HNMR (400 MHz, MeOD-d4) δ 8.55 (s, 1H), 3.56 (d, J = 12.0 Hz, 1H), 3.53–3.47 (m, 2H), 3.45–3.36 (m, 2H), 3.28–3.21 (m, 2H), 3.20–3.12 (m, 2H), 2.67 (dd, J = 3.2, 13.2 Hz, 1H), 2.34 (ddd, J = 2.8, 7.2, 13.2 Hz, 1H), 2.15–2.05 (m, 2H), 1.89–1.84 (m, 1H), 1.80 (d, J = 5.6 Hz, 1H), 1.74–1.67 (m, 1H), 1.62–1.58 (m, 3H). Step 3.3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide

[0598] A mixture of 1-(3-methylpyrrolidin-3-yl)piperidine (0.210 g, 0.871 mmol, 2 hydrochloride) (crude), 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (0.342 g, 0.697 mmol) and cesium carbonate (1.42 g, 4.35 mmol) in N,N-dimethylformamide (4.0 mL) was stirred at 25 °C for 2 h. Ethyl acetate (15 mL) and water (15 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Phenomenex Luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 25%–55% B over 9 min). The desired fraction was collected and lyophilized to give 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (0.110 g, 0.170 mmol, 20% yield, 99% purity) as a yellow solid. MS (ES+) m / z 639.1, 641.1 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.66 (q, J = 8.0 Hz, 1H), 7.25 (s, 2H), 6.64 (dd, J = 2.8, 8.0 Hz, 1H), 6.42–6.33 (m, 2H), 6.20 (d, J = 12.8 Hz, 1H), 5.11 (s, 2H), 3.83 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 6.0 Hz, 6H), 3.66–3.58 (m, 1H), 3.42 (d, J = 8.8 Hz, 1H), 2.76–2.42 (m, 3H), 1.99–1.65 (m, 8H), 1.57–1.44 (m, 2H), 1.25–1.04 (m, 3H). MS (ES+) m / z 639.1, 641.1 (M + 1). Step 4. (R)- and (S)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin- 2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide

[0599] The residue (0.120 g) was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 µm); mobile phase: [carbon dioxide-isopropyl alcohol (0.1% ammonium hydroxide)]; B%:50%, isocratic elution mode). Two desired fractions were collected and concentrated under reduced pressure to give two compounds.

[0600] Peak 1 (Rt = 2.305 min): 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 1) (0.0600 g, 0.0929 mmol, 49 % yield, 99% purity) as a yellow oil.

[0601] Peak 2 (Rt = 2.554 min): 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 2) (0.0520 g, 0.0789 mmol, 42% yield, 97% purity) as a yellow oil. Step 5. (R)- and (S)-3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methyl-3- (piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide Example 300 (Peak 1 from Step 4)

[0602] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 1) (0.0600 g, 0.0929 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.0 mL). 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 (4 mL) and a drop of concentrated hydrochloric acid. The mixture was purified by prep-HPLC (column: YMC Triart C18150 mm × 25 mmmobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: 23%–53% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 1) (0.0185 g, 0.0349 mmol, 38% yield, 99% purity, hydrochloride) as a white solid. MS (ES+) m / z 489.1, 491.1 (M + 1).1H NMR (400 MHz, MeOD-d4) δ 7.78 (q, J = 8.0 Hz, 1H), 6.92 (dd, J = 2.0, 8.0 Hz, 1H), 6.69–6.58 (m, 2H), 4.03–3.87 (m, 2H), 3.81–3.66 (m, 2H), 3.56–3.46 (m, 1H), 3.43–3.35 (m, 1H), 3.27–3.12 (m, 2H), 2.29 (dd, J = 5.4, 8.4 Hz, 2H), 2.09–1.95 (m, 2H), 1.95–1.80 (m, 3H), 1.61–1.53 (m, 1H), 1.50 (s, 3H). MS (ES+) m / z 489.1, 491.1 (M + 1). Example 301 (Peak 2 from Step 4)

[0603] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 2) (0.0520 g, 0.0789 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.0 mL). 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 (4 mL) and a drop of concentrated hydrochloric acid. The mixture was purified by prep-HPLC (column: YMC Triart C18150 mm × 25 mmmobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: 23%–53% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methyl-3-(piperidin-1-yl)pyrrolidin-1-yl)benzenesulfonamide (Stereoisomer 2) (0.0175 g, 0.0326 mmol, 41% yield, 98% purity, hydrochloride) as a white solid. MS (ES+) m / z 489.1, 491.1 (M + 1).1H NMR (400 MHz, MeOD-d4) δ 7.78 (q, J = 8.0 Hz, 1H), 6.92 (dd, J = 1.6, 8.0 Hz, 1H), 6.68–6.53 (m, 2H), 4.04–3.89 (m, 2H), 3.79–3.68 (m, 2H), 3.51 (d, J = 12.0 Hz, 1H), 3.44–3.36 (m, 1H), 3.28–3.13 (m, 2H), 2.37–2.25 (m, 2H), 2.06–1.98 (m, 2H), 1.95–1.82 (m, 3H), 1.63–1.53 (m, 1H), 1.50 (s, 3H). MS (ES+) m / z 489.1, 491.1 (M + 1).

[0604] The following further Examples listed in Table 5 were prepared analogously to Example 300 / 301 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC).- 2- e- d2- e- d2- -2- -2- - - 62- - ni idni ini- ir-m 1eni- 1eni -neni6- n yp3ad - nir-m3ad - nir -d ynidiir -d ynidiir atd cdiir atecdior)loflyp oy- uo )loflpzor ar mapzor ar my a poo]yp ro4].maor4.maul1-sreoy- u 1-seoen f-ninuln u piofloen upioflo n u3[oflo n u3[ofle6(m-dierzf- inlene6diezf-pln 6 y ulsef-ply ulsf- oriulo sf-riusaN-pb(-re e(- hten 6 e(- hteen 6 e(-ps e6 a n e(-ps ea n e Noirp)lN-po yoib p)lN- zNo m-ne - zNo m-ne - z zNo a-ne - za- zneulxy- ryy- r4 fio1h - o x ni )ulfio1h - o(- bro 4 ni )ulfi3)-l(- b l)r6 ylo(- bo-)ul)r6 l o(- b)lf 3-ly- )ulf3-ly- )ulf3-ly- )d-tedil1r d-tedil2r d- yh1-1rid- yh1-2rid- yh1-1rid- yh1-2r6,m2- oe-4(5 or -rrm6,m- oey or3srm6,teni ed m6,teni edm6,teni em6,teni em (i2- 4(- y osi2-m-ilosi2-m-ilos 2-m- dilos 2-m- dilos-ploor3(-ploor3(orroor3(oriroor3(oriroor3(oriro eloly bahc-4- heroly )lteethc-4- herol)lteeth - c-4- yerol)lp)leth - c-4- yerol)lp)leth - c-4- yerol)lp) eth - c4- yer) p) etT 3 y mS(3 y mS(3 y yS(3 y yS(3 ylyS( -3lylyS(.x 20 30 7a7 8 9 E 3 3 5 5 5 5,)H7,m(5 7.1–8 9.1,)H2,m(a 8.ta9).1D1 l –+a0 c1i.M t(y2 1la,) .7 H1 n 1 5 A, ,m1(.5 01 3.52z / –3 m 4. )2 + , S ) E H(4,S mM( .)7 H 9.32,–s7(0.4 32.1 e maN .x EExample 100 5-chloro-4-(3-(3-(dimethylamino)propyl)pyrrolidin-1-yl)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamideStep 1. Preparation of methyl 3-(1-(2-chloro-4-(N-(3,4-dimethylbenzyl)-N-(thiazol-2- yl)sulfamoyl)-5-fluorophenyl)pyrrolidin-3-yl)propanoate

[0605] To mixture of methyl 3-(pyrrolidin-3-yl)propanoate hydrochloride (0.300 g, 1.55 mmol hydrochloric acid), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2- yl)benzenesulfonamide (0.714 g, 1.55 mmol), cesium carbonate (1.01 g, 3.10 mmol) in N,N-dimethylformamide (6 mL). The mixture was stirred at 25 °C for 12 h. Ethyl acetate (40 mL) and water (40 mL) were added and layers were separated. The aqueous was extracted with ethyl acetate (2 × 30 mL). Combined extracts were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) to afford methyl 3-(1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2- yl)sulfamoyl)-5-fluorophenyl)pyrrolidin-3-yl)propanoate (0.586 g, 0.980 mmol, 63% yield) as a brown solid.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 3.6 Hz, 1H), 6.43–6.30 (m, 3H), 3.78 (d, J = 2.0 Hz, 6H), 3.72 (s, 3H), 3.69–3.53 (m, 3H), 3.29 (t, J = 9.2 Hz, 1H), 2.42 (t, J = 7.6 Hz, 2H), 2.30–2.20 (m, 1H), 2.15 (tdd, J = 3.2, 6.0, 12.0 Hz, 1H), 1.92–1.74 (m, 2H), 1.67–1.62 (m, 1H). Step 2. Preparation of 3-(1-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenyl)pyrrolidin-3-yl)propanoic acid

[0606] To a solution of methyl 3-(1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2- yl)sulfamoyl)-5-fluorophenyl)pyrrolidin-3-yl)propanoate (0.586 g, 0.980 mmol) in tetrahydrofuran (15 mL), methanol (10 mL) and water (15 mL) was added lithiumhydroxide monohydrate (1.05 g, 25.07 mmol). The mixture was stirred at 25°C for 1 h. The mixture was adjusted to ~3 with 4N hydrochloric acid. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column (0.1% formic acid condition) and concentrated. The desired fraction was collected and lyophilized to afford 3-(1-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenyl)pyrrolidin-3-yl)propanoic acid (0.150 g, 0.311 mmol, 32% yield, 90% purity) as an white solid.1H NMR (400 MHz, MeOD-d4) δ 7.70 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 4.4 Hz, 1H), 6.75 (d, J = 4.8 Hz, 1H), 6.60 (d, J = 13.6 Hz, 1H), 3.71–3.48 (m, 3H), 3.30–3.26 (m, 1H), 2.45–2.33 (m, 2H), 2.32–2.21 (m, 1H), 2.20–2.09 (m, 1H), 1.88–1.71 (m, 2H), 1.69–1.56 (m, 1H). Step 3. Preparation of 3-(1-(2-chloro-4-(N-(3,4-dimethylbenzyl)-N-(thiazol-2- yl)sulfamoyl)-5-fluorophenyl)pyrrolidin-3-yl)-N,N-dimethylpropanamide

[0607] To mixture of 3-(1-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenyl)pyrrolidin-3-yl)propanoic acid (0.150 g, 0.346 mmol), diisopropylethylamine (0.223 g, 1.73 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (0.197 g, 0.519 mmol) in N,N- dimethylformamide (6 mL) was added N-methylmethanamine (0.0564 g, 0.691 mmol, hydrochloric acid). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse prep-HPLC (0.1% formic acid). The desired fraction was collected and lyophilized to afford 3-(1-(2- chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl)pyrrolidin-3-yl)-N,N- dimethylpropanamide (0.140 g, 0.304 mmol, 88% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) δ 7.69 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.75 (d, J = 4.8 Hz, 1H), 6.59 (d, J = 13.2 Hz, 1H), 3.69–3.51 (m, 3H), 3.30–3.26 (m, 1H), 3.09 (s, 3H), 2.95 (s, 3H), 2.52–2.45 (m, 2H), 2.31–2.20 (m, 1H), 2.19–2.10 (m, 1H), 1.83–1.74 (m, 2H), 1.72–1.60 (m, 2H). Step 4. Preparation of 5-chloro-4-(3-(3-(dimethylamino)propyl)pyrrolidin-1-yl)-N-(3,4- dimethylbenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0608] To a mixture of 3-(1-(2-chloro-5-fluoro-4-(N-(thiazol-2- yl)sulfamoyl)phenyl)pyrrolidin-3-yl)-N,N-dimethylpropanamide (0.070 g, 0.152 mmol) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (1 M, 0.304 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 50 °C for 12 h. After being cooled to room temperature. The reaction mixture was poured into water (20 mL) andextracted with ethyl acetate (3 × 15 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; B%: 5–35%, 10 min). The desired fraction was collected and lyophilized 5-chloro-4-(3-(3- (dimethylamino)propyl)pyrrolidin-1-yl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.005 g, 0.0112 mmol, 5% yield, formate) as a white solid. MS (ES+) m / z 447.0, 449.0 (M+1).1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 4.4 Hz, 1H), 6.52 (d, J = 4.4 Hz, 1H), 6.33 (d, J = 13.2 Hz, 1H), 3.65–3.57 (m, 1H), 3.55– 3.44 (m, 2H), 3.16 (t, J = 9.2 Hz, 1H), 2.87–2.72 (m, 2H), 2.62 (s, 6H), 2.23–2.04 (m, 2H), 1.75 (t, J = 7.6 Hz, 2H), 1.61–1.42 (m, 3H). Examples 112 and 112a (Stereochemistry assigned arbitrarily) 3-chloro-4-(3-((dimethylamino)methyl)-3-ethylpyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1) (Compound 112)3-chloro-4-(3- ((dimethylamino)methyl)-3-ethylpyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomer 2) (Compound 112a)

[0609] This compound was prepared analogously to Example 100. Purification was performed by supercritical fluid chromatography (SFC). The stereocenter was assigned arbitrarily. Peak 1 (Example 112, Stereoisomer 1):1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.61–6.56 (m, 1H), 6.54 (d, J = 14.4 Hz, 1H), 3.67–3.60 (m, 1H), 3.60–3.54 (m, 1H), 3.41–3.36 (m, 2H), 2.41–2.32 (m, 2H), 2.25 (s, 6H), 1.80–1.67 (m, 2H), 1.44 (dt, J = 6.8, 13.6 Hz, 2H), 0.83 (t, J = 7.6 Hz, 3H). MS (ES+) m / z 477.1, 479.1 (M + 1); Peak 2 (Example 112a, Stereoisomer 2):1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.61–6.56 (m, 1H), 6.54 (d, J = 14.4 Hz, 1H), 3.67–3.60 (m, 1H), 3.60–3.54 (m, 1H), 3.41–3.36 (m, 2H), 2.41–2.32 (m, 2H), 2.25 (s, 6H), 1.80–1.67 (m, 2H), 1.44 (dt, J = 6.8, 13.6 Hz, 2H), 0.83 (t, J = 7.6 Hz, 3H). MS (ES+) m / z 477.1, 479.1 (M + 1). Example 101 3-chloro-4-(3-((dimethylamino)methyl)-3-methylpyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1)Step 1. Preparation of methyl (R)-3-methylpyrrolidine-3-carboxylate

[0610] To a solution of (R)-3-methylpyrrolidine-3-carboxylic acid (0.500 g, 3.87 mmol) in methanol (20 mL) was added sulfurous dichloride (1.0 mL) by dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give methyl (R)-3-methylpyrrolidine-3-carboxylate (0.680 g, crude, hydrochloride) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 10.15–9.72 (m, 2H), 9.84 (s, 1H), 3.74 (s, 4H), 3.54–3.37 (m, 2H), 3.21–3.11 (m, 1H), 2.46 (ddd, J = 5.6, 7.6, 13.2 Hz, 1H), 1.97–1.92(m, 1H), 1.44 (s, 3H). Step 2. Preparation methyl (R)-1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-3-methylpyrrolidine-3-carboxylate

[0611] A solution of methyl (R)-3-methylpyrrolidine-3-carboxylate (0.600 g, 3.34 mmol, hydrochloride) (crude), 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (2.06 g, 4.20 mmol) and cesium carbonate (4.10 g, 12.6 mmol) indimethylformamide (10.0 mL) was stirred at 25 °C for 12 h. Ethyl acetate (30 mL) and water (30 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0–25% ethyl acetate / petroleum ether gradient at 100 mL / min) to give methyl (R)-1-(2-chloro-4-(N- (2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-3-methylpyrrolidine-3-carboxylate (1.66 g, 2.70 mmol, 81% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.67 (q, J = 8.0 Hz, 1H), 7.26–7.21 (m, 2H), 6.64 (dd, J = 2.8, 8.0 Hz, 1H), 6.40–6.35 (m, 2H), 6.19 (dd, J = 1.6, 13.6 Hz, 1H), 5.11 (s, 2H), 4.03 (d, J = 10.4 Hz, 1H), 3.78–3.72 (m, 9H), 3.67 (t, J = 7.2 Hz, 2H), 3.46 (d, J = 10.4 Hz, 1H), 2.50–2.42 (m, 1H), 1.88 (d, J = 12.4 Hz, 1H), 1.41 (s, 3H). Step 3. Preparation of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)benzenesulfonamide

[0612] To a solution of methyl (R)-1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-3-methylpyrrolidine-3-carboxylate (1.33 g, 2.17 mmol) in tetrahydrofuran (15.0 mL) was added lithium aluminium hydride (2.5 M, 1.3 mL) at 0 °C. The mixture was heated to 0 °C for 1 h. The reaction mixture was quenched with sodium sulfafe decahydrate (10.0 g) at 0 °C. The mixture was stirred at 25 °C for 2 h. Then the mixture was filtered over Celite. The filter cake was washed with tetrahydrofuran (100 mL). The filtrate was concentrated under reduced pressure to give (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- (hydroxymethyl)-3-methylpyrrolidin-1-yl)benzenesulfonamide (1.26 g, crude) as a colorless oil. MS (ES+) m / z 586.1, 588.1 (M +1). Step 4. Preparation of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-formyl-3-methylpyrrolidin-1-yl)benzenesulfonamide

[0613] To a solution of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)benzenesulfonamide (1.26 g, 2.15 mmol) (crude) in dichloromethane (30.0 mL) was added (1,1,1-triacetoxy)- 1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.83 g, 4.31 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with saturated sodium bicarbonate (20 mL) and dichloromethane (20 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0–35% ethyl acetate / petroleum ether gradient at 50 mL / min) to give (R)-3-chloro-N-(2,4- dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-formyl-3-methylpyrrolidin- 1-yl)benzenesulfonamide (0.830 g, 1.42 mmol, 66 % yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.77–7.63 (m, 1H), 7.26–7.18 (m, 2H), 6.64 (dd, J =2.8, 8.0 Hz, 1H), 6.46–6.34 (m, 2H), 6.26–6.15 (m, 1H), 5.11 (s, 2H), 3.98 (d, J = 10.4 Hz, 1H), 3.74 (d, J = 6.4 Hz, 6H), 3.61 (t, J = 6.8 Hz, 2H), 3.44 (d, J = 10.4 Hz, 1H), 2.39–2.33 (m, 1H), 1.88–1.80 (m, 1H), 1.32 (s, 3H). Step 5. Preparation of (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-methylpyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide

[0614] To a solution of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-formyl-3-methylpyrrolidin-1-yl)benzenesulfonamide (0.200 mg, 0.342 mmol) and dimethylamine (2 M, 1.0 mL) in dichloromethane (10.0 mL) was added sodium triacetoxy borohydride (0.220 g, 1.04 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with N,N-dimethylformamide (2.0 mL). The mixture was purified by prep- HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 22%–52% B over 10 min). The desired fraction was collected and lyophilized to give (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-methylpyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.0800 g, 0.123 mmol, 36% yield, 94% purity) as a white solid. MS (ES+) m / z 613.2, 615.2 (M +1). Step 6. Preparation of 3-chloro-4-(3-((dimethylamino)methyl)-3-methylpyrrolidin-1-yl)- 2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1)

[0615] To a solution of (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-methylpyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.100 g, 0.153 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.0 mL). 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 (2.0 mL). The mixture was purified by prep-HPLC (column: YMC Triart C18150 mm × 25 mm × 5mobile phase: [water (hydrochloric acid)- acetonitrile]; gradient: 22%–52% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-4-(3-((dimethylamino)methyl)-3-methylpyrrolidin-1-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 1) (0.0609 g, 0.118 mmol, 77% yield, 97% purity, hydrochloride) as a white solid. MS (ES+) m / z 463.1, 465.1 (M +1).Examples 102 and 103 (R)-3-chloro-4-(3-((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N- (6-fluoropyridin-2-yl)benzenesulfonamide (Compound 102) (S)-3-chloro-4-(3-((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Compound 103)Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3-methoxypyrrolidin-1-yl)benzenesulfonamide

[0616] To a solution of (3-methoxypyrrolidin-3-yl)methanol hydrochloride (0.186 g, 1.11 mmol) and triethylamine (0.455 g, 4.50 mmol) in dimethyl sulfoxide (5.0 mL) was added 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.550 g, 1.12 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate waspurified by prep-HPLC (column: Waters Xbridge 150 mm × 25 mm × 5mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 30%–50%, 10min). The desired fraction was collected and lyophilized to give 3-chloro-N-(2,4-dimethoxybenzyl)- 2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3-methoxypyrrolidin-1- yl)benzenesulfonamide (0.420 g, 0.690 mmol, 62% yield, 99% purity) as a white solid. MS (ES+) m / z 602.1, 604.1 (M + 1). Step 2. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-formyl-3-methoxypyrrolidin-1-yl)benzenesulfonamide

[0617] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3-methoxypyrrolidin-1-yl)benzenesulfonamide (0.420 g, 0.691 mmol) in dichloromethane (15.0 mL) was added (1,1,1-triacetoxy)-1,1- dihydro-1,2-benziodoxol-3(1H)-one (0.582 g, 1.37 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The combined mixture was diluted with saturated sodium bicarbonate (20 mL) and dichloromethane (20 mL). The mixture was extracted with dichloromethane (3 × 20 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 a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0–60% petroleum ether / Ethyl acetate gradient at 40 mL / min) to give 3-chloro-N-(2,4- dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-formyl-3- methoxypyrrolidin-1-yl)benzenesulfonamide (0.0900 g, 0.150 mmol, 22% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.65 (q, J = 8.0 Hz, 1H), 7.26 (s, 2H), 6.62 (dd, J = 2.8, 7.6 Hz, 1H), 6.41–6.30 (m, 2H), 6.22 (d, J = 13.6 Hz, 1H), 5.09 (s, 2H), 3.96 (d, J = 11.6 Hz, 1H), 3.77 (s, 1H), 3.72 (d, J = 5.0 Hz, 6H), 3.57 (td, J = 6.0, 9.6 Hz, 1H), 3.43 (dd, J = 6.4, 7.6 Hz, 1H), 3.38 (s, 3H), 2.25–2.18 (m, 2H). Step 3. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)- 3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0618] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-formyl-3-methoxypyrrolidin-1-yl)benzenesulfonamide (0.0700 g, 0.117 mmol) and dimethylamine in tetrahydrofuran (2 M, 0.35 mL) in dichloromethane (2.5 mL) was stirred at 25 °C for 0.5 h. Then the mixture was added sodium triacetoxy borohydride (0.0700 g, 0.330 mmol) and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC(column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 20%–50% B over 10 min. The desired fraction was collected and lyophilized to give 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.0400 g, 0.0629 mmol, 54% yield, 99% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.66 (q, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.25–7.23 (m, 1H), 6.63 (dd, J = 2.8, 8.0 Hz, 1H), 6.40–6.35 (m, 2H), 6.20 (d, J = 13.2 Hz, 1H), 5.12 (s, 2H), 3.75 (d, J = 5.6 Hz, 7H), 3.71–3.64 (m, 2H), 3.60–3.52 (m, 1H), 3.26 (s, 3H), 2.70–2.62 (m, 1H), 2.56–2.48 (m, 1H), 2.39 (s, 6H), 2.25–2.19 (m, 1H), 1.95–1.86 (m, 1H). MS (ES+) m / z 629.2, 631.2 (M + 1). Step 4. (R)- and (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0619] 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide was purified by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); mobile phase: [carbon dioxide-ethyl alcohol (0.1%ammonium hydrogen)];B%: 30%, isocratic elution mode). Two peaks were isolated and collected.

[0620] Peak 1 (Rt = 1.741 min) The first fraction was concentrated under reduced pressure to give (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0250 g, 0.0393 mmol, 49% yield, 99% purity) as a white solid.

[0621] Peak 2 (Rt = 1.857 min) The second fraction was concentrated under reduced pressure to give (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0200 g, 0.0318 mmol, 39% yield, 99% purity) as a white solid. Step 4. (R)- and (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0622] To a solution of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.0250 g, 0.0398 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dimethyl sulfoxide (2 mL). The pH was adjusted to 7-8 with ammonium hydroxide (10% purity).The mixture was purified by prep-HPLC (column: YMC Triart C18150 mm ×25 mm ×5 µm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 20%–54% B over 10 min). The desired fraction was collected and lyophilized to give (R)-3-chloro-4- (3-((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin- 2-yl)benzenesulfonamide (0.00920 g, 0.0184 mmol, 46% yield, 96% purity) as a white solid. (Example 102)1H NMR (400 MHz, DMSO-d6) δ 11.54–11.12 (m, 1H), 7.75 (q, J = 8.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 14.4 Hz, 1H), 3.71–3.45 (m, 4H), 3.16 (s, 3H), 2.77–2.66 (m, 1H), 2.57–2.53 (m, 1H), 2.33 (s, 6H), 2.15 (dd, J = 5.6, 12.8 Hz, 1H), 1.87–1.76 (m, 1H). MS (ES+) m / z 479.1, 481.1 (M + 1).

[0623] To a solution of (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.0200 g, 0.0318 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dimethylsulfoxide (2 mL). The pH was adjusted to 7-8 with ammonium hydroxide (10% purity). The mixture was purified by prep-HPLC (column: YMC Triart C18150 mm ×25 mm ×5 µm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 20%– 50% B over 10 min). The desired fraction was collected and lyophilized to give (S)-3- chloro-4-(3-((dimethylamino)methyl)-3-methoxypyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (0.0100 g, 0.0206 mmol, 65% yield, 99% purity) as a white solid. (Example 103)1H NMR (400 MHz, DMSO-d6) δ 11.57–11.07 (m, 1H), 7.82–7.72 (m, 1H), 6.78 (dd, J = 1.6, 7.6 Hz, 1H), 6.64–6.57 (m, 1H), 6.54 (d, J = 14.4 Hz, 1H), 3.72–3.47 (m, 4H), 3.16 (s, 3H), 2.80–2.69 (m, 1H), 2.56 (d, J = 11.2 Hz, 1H), 2.34 (s, 6H), 2.16 (dd, J = 4.4, 11.6 Hz, 1H), 1.88–1.76 (m, 1H). MS (ES+) m / z 479.1, 481.1 (M + 1). Examples 104 and 105 3-chloro-4-(3-((dimethylamino)methyl)-3-(trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide (Stereoisomers 1 and 2)Step 1. (3-(trifluoromethyl)pyrrolidin-3-yl)methanol

[0624] A mixture of tert-butyl 3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidine-1- carboxylatelate (1.00 g, 3.71 mmol) in hydrogen chloride / dioxane (4 M, 10.0 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressuret to give (3-(trifluoromethyl)pyrrolidin-3-yl)methanol (0.800 g, crude, hydrochloride) as a white solid.1H NMR (400 MHz, MeOD-d4) δ 3.76 (d, J = 12.8 Hz, 2H), 3.59–3.52 (m, 2H), 3.51–3.39 (m, 2H), 2.37–2.23 (m, 2H). Step 2.3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- (hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1-yl)benzenesulfonamide

[0625] To a solution of (3-(trifluoromethyl)pyrrolidin-3-yl)methanol (0.500 g, 2.43 mmol, hydrochloride) (crude) and 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N- (6-fluoropyridin-2-yl)benzenesulfonamide (1.07 g, 2.19 mmol) in dimethylsulfoxide (10.0 mL) was added triethylamine (0.984 g, 9.73 mmol). The mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 80%–100% B over 10 min). The desired fraction was concentrated under reduced pressure to give 3-chloro-N- (2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3- (trifluoromethyl)pyrrolidin-1-yl)benzenesulfonamide (1.25 g, 1.95 mmol, 80% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.68 (q, J = 8.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 1.6, 8.0 Hz, 1H), 6.93–6.83 (m, 1H), 6.69 (dd, J = 2.8, 8.0 Hz, 1H), 6.43–6.36 (m, 2H), 5.09 (s, 2H), 3.75 (d, J = 10.0 Hz, 6H).Step 3.3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- formyl-3-(trifluoromethyl)pyrrolidin-1-yl)benzenesulfonamide

[0626] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(hydroxymethyl)-3-(trifluoromethyl)pyrrolidin-1- yl)benzenesulfonamide (1.25 g, 1.95 mmol) in dichloromethane (10.0 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.68 g, 3.96 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. 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 extracts were washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0–40% ethyl acetate / petroleum ether gradient at 30 mL / min) to give 3- chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-formyl-3- (trifluoromethyl)pyrrolidin-1-yl)benzenesulfonamide (0.0550 g, 0.862 mmol, 44% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.26–7.17 (m, 2H), 6.66 (dd, J = 2.8, 8.0 Hz, 1H), 6.40–6.36 (m, 2H), 6.34–6.28 (m, 1H), 5.10 (s, 2H), 4.07–3.91 (m, 2H), 3.75 (d, J = 8.4 Hz, 6H), 3.60 (m, 2H), 2.53–2.34 (m, 2H). Step 4.3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- (trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide

[0627] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-formyl-3-(trifluoromethyl)pyrrolidin-1-yl)benzenesulfonamide (0.200 g, 0.313 mmol), acetic acid (0.0600 g, 0.999 mmol) and dimethylamine (2 M, 0.776 mL) (in tetrahydrofuran) in 1, 2-dichloroethane (2.0 mL) was added sodium triacetoxy borohydride (0.200 g, 0.944 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 prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 70%–100% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-N-(2,4- dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3-(trifluoromethyl)pyrrolidin-1-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0200 g, 0.0300 mmol, 10%yield) as a white solid. MS (ES+) m / z 667.1, 669.1 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.67 (q, J = 8.0 Hz, 1H), 7.26–7.18 (m, 2H), 6.65 (dd, J = 2.8, 8.0 Hz, 1H), 6.42–6.36 (m, 2H), 6.24 (d, J = 14.0 Hz, 1H), 5.11 (s, 2H), 3.81–3.67 (m, 10H), 2.60 (d, J = 8.8 Hz, 2H), 2.35 (s, 6H), 2.26–2.16 (m, 2H). MS (ES+) m / z 667.1, 669.1 (M + 1). Step 5.3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- (trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomers 1 and 2)

[0628] 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- (trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide was purified by chiral SFC (column: DAICEL CHIRALCEL OJ- H (250 mm × 30 mm, 5 µm); mobile phase: [carbon dioxide - methanol (0.1% ammonium hydroxide)]; B%:20%, isocratic elution mode). Two peaks were isolated and collected.

[0629] Peak 1 (Rt = 2.153 min): The first fraction was concentrated under reduce pressure to 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- (trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomer 1) (0.0210 g, 0.0312 mmol, 33 % yield, 99% purity) as a yellow oil. MS (ES+) m / z 667.1, 669.1 (M + 1).

[0630] Peak 2 (Rt = 2.328 min): The second fraction was concentrated under reduce pressure to 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-((dimethylamino)methyl)-3- (trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomer 2) (0.0200 g, 0.0297 mmol, 31% yield, 99% purity) as a yellow oil. MS (ES+) m / z 667.1, 669.1 (M + 1). Step 6.3-chloro-4-(3-((dimethylamino)methyl)-3-(trifluoromethyl)pyrrolidin-1-yl)-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0631] (Example 104): To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-(3- ((dimethylamino)methyl)-3-(trifluoromethyl)pyrrolidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (0.02...

Claims

WHAT IS CLAIMED IS:

1. A compound having Formula I:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: M1is selected from N and CR1; M2is selected from N and CR2; M3is selected from N and CR3; M4is selected from N and CR4; each of R1, R2, R3, and R4is independently selected from hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio; each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, (C1- C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or R5is a C1alkyl group that forms a bond with each of two carbons of the ring to which it is attached; n is 0, 1 or 2; R6is selected from hydrogen, halogen, cyano, hydroxy, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C6-C14) aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or R6and W are taken together with the atom to which they are attached to form R8R7N-(C3- C7) cycloalkyl-, R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl, or R6is a bond between the carbon to which it is attached and R5, or R5and W are taken together with the atoms to which they are attached to form an amine substituted (C3-C6) cycloalkyl or optionally substituted heterocyclyl, or R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl; each of R7and R8is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C6-C14) aryl-(C1-C6) alkyl-, (C1-C6) haloalkyl, optionally substituted (C1-C6) alkyl-O- (C1-C6) alkyl-, and (C3-C6) cycloalkyl-(C1-C6) alkyl-, or R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl; A is optionally substituted heteroaryl; Z is selected from N and CRZ; RZis selected from hydrogen and (C1-C6) alkyl; and R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1- C6) alkyl-.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis.

3. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R1, R2, R3, and R4is independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, or halogen.

4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein,5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. hydrogen and halogen; or iii. halogen.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is hydrogen.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is selected from i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; ii. hydrogen and halogen; or iii. halogen.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is selected from: i. hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl;ii. halogen and (C1-C6) alkyl; or iii. halogen.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R5is selected from (C1-C6) alkyl, (C1-C6) alkoxy, and (C6-C14) aryl, or two geminal R5groups together with the atom to which they are attached form a (C3-C6) cycloalkyl.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5is selected from methyl, methoxy, and phenyl, or two geminal R5groups together with the atom to which they are attached form a cyclopropyl.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2 and each R5is independently (C1-C6) alkyl.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5is methyl.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis selected from16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, and R8R7N-(C3-C6) cycloalkyl-.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is R8R7N- or R8R7N-(C1-C6) alkyl-.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are each independently selected from hydrogen, methyl, d3-methyl, ethyl, d5-ethyl, propyl, tert-butyl, neopentyl, 1,1-difluoromethyl, 2,2,-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropan-2-yl, 2-fluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, bicyclo[1.1.1]pentan-1-yl, spiro[2.3]hexan-5-yl, 3- (difluoromethyl)cyclobutyl, and benzyl.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are each methyl.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8together with the atom to which they are attached form a heterocyclyl.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from,26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is selected from hydrogen, cyano, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1- difluoroethyl, fluoro, methoxy, d3-methoxy, ethoxy, methoxymethyl, and phenyl.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is methyl or methoxy.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6and W are taken together with the atom to which they are attached to form an R8R7N-(C3-C7) cycloalkyl-, an R8R7N-(C1-C6) alkyl-(C3-C7) cycloalkyl-, or an optionally substituted heterocyclyl.

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6and W are taken together with the atom to which they are attached to form R7R8N-cyclopropyl-, R7R8N-cyclobutyl-, R7R8N-cyclopentyl-, R7R8N- methyl-cyclobutyl-, an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, or an optionally substituted morpholino.

31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted benzothiazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, and optionally substituted pyridazinyl.

33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is.

35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having any one or more of Formulae IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, IXa, IXb, IXc, Xa, Xb, Xc, XIa, and XIb:wherein: p is selected from 0, 1, 2, and 3; q is selected from 0, 1, and 2; t is selected from 1, 2, and 3; R12is selected from hydrogen and optionally substituted (C1-C6) alkyl; and Z1is CH or O, with the proviso that when Z1is O, the sum of q + t is at least 2.

36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having any one or more of Formulae XIIa, XIIb, XIIc, XIIIa, XIIIb, XIIIc, XIVa, XIVb, or XIVc:wherein each of R10and R11is independently selected from hydrogen, halogen, and (C1-C4) alkyl, or R10and R11in Formulae XIIa, XIIb, and XIIc together with the atoms to which they are attached form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an optionally substituted cycloalkyl; andR13and R14are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted (C1-C6) alkyl, (C1-C6) haloalkyl, optionally substituted (C3- C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally substituted (C1-C6) alkylthio, and optionally substituted (C3-C6) cycloalkylthio.

37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R10is hydrogen and R11is halogen.

38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13and R14are each independently hydrogen, halogen, or (C1-C6) alkyl.

39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13is halogen.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R14is hydrogen.

41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVa, XVb, or XVc:

42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVa.

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVIa, XVIb, XVIc, XVIIa, XVIIb, orwherein: p is selected from 0, 1, 2, and 3; q is selected from 0, 1, and 2; t is selected from 1, 2, and 3; and R12is selected from hydrogen and optionally substituted (C1-C6) alkyl.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having Formula XVIa or XVIIa.

45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is hydrogen, methyl, or methoxy.

46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0 or 1.

47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 and t is 3.

48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2 and t is 2.

49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12is methyl.

50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are methyl, ethyl, or cyclobutyl.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

52. A pharmaceutical composition comprising the compound of any one of the preceding claims and a pharmaceutically acceptable excipient.

53. A method of inhibiting one or more sodium channels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding claims.

54. A method of treating a disease or disorder associated with inhibition of one or more sodium channels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding claims.

55. The method of any one of the preceding claims, wherein the one or more sodium channels is NaV1.

7.

56. The method of any one of the preceding claims, wherein the inhibiting or inhibition of one or more sodium channels is the selective inhibiting of or selective inhibition of NaV1.

7.

57. The method of any one of the preceding claims, wherein the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

58. A method of treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding claims.

59. The compound of any one of the preceding claims for use in treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

60. Use of the compound of any one of the preceding claims for treating a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

61. Use of the compound of any one of the preceding claims in the manufacture of a medicament for the treatment of a disease or disorder selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

62. The compound, use, or method of any one of the preceding claims, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, diabetic painful neuropathy, fibromyalgia, trigeminal neuralgia, postherpetic neuralgia, bone pain, musculoskeletal pain, soft tissue pain, idiopathic pain, and combinations thereof.

63. The compound, use, or method of any one of the preceding claims, wherein the pain is associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation, or ventricular fibrillation.

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