Substituted ARYL sulfonamides and compositions and uses thereof

Abstract

The present disclosure provides compounds having Formula I: and stereoisomers thereof, and pharmaceutically acceptable salts or solvates of said compounds or stereoisomers thereof, wherein M1, M2, M3, M4, Z, n, R5, R6, W, A, and R9 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to inhibit sodium channels (e.g., 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

- 1 - 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] One sodium channel is NaV1.7. 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 and 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)). In addition, a single nucleotide polymorphism (R1150W) that has very subtle effects on the time- and voltage-dependence of channel gating has large effects on- 2 - pain perception (Estacion, M., et al., Ann Neurol 66:862-866 (2009); Reimann, F., et al., Proc Natl Acad Sci USA 107: 5148-5153 (2010)).

[0004] In addition, 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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, and (C1-C6) haloalkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C3-C6) cycloalkyloxy, optionally- 3 - 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] R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0016] n is 0, 1, or 2;

[0017] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-;

[0018] A is optionally substituted heteroaryl;

[0019] Z is selected from N and CRZ;

[0020] RZis selected from hydrogen and (C1-C6) alkyl;

[0021] R6is selected from 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;

[0022] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, R8R7N-(C3-C6) cycloalkyl-(C1-C6) alkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0023] 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; and

[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] In some aspects, the present disclosure relates to a pharmaceutical composition comprising a Compound of the Disclosure, or a stereoisomer thereof, or a- 4 - pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0027] In some aspects, the present disclosure relates to 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 a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0028] In some aspects, the present disclosure relates to 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 a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0029] In some embodiments, the one or more sodium channels is NaV1.7.

[0030] In some embodiments, the inhibiting or inhibition of one or more sodium channels is the selective inhibiting of or selective inhibition of NaV1.7.

[0031] In some aspects, the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

[0032] 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.

[0033] 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

[0034] In one aspect, the present disclosure relates to compounds having Formula I (also referred to herein as Compounds of the Disclosure):- 5 -

[0035] or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein:

[0036] M1is selected from N and CR1;

[0037] M2is selected from N and CR2;

[0038] M3is selected from N and CR3;

[0039] M4is selected from N and CR4;

[0040] 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;

[0041] each R5is independently selected from halogen, optionally substituted (C1-C6) alkyl, and (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

[0042] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or

[0043] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0044] R5is a C1alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0045] n is 0, 1, or 2;

[0046] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-;

[0047] A is optionally substituted heteroaryl;

[0048] Z is selected from N and CRZ;- 6 -

[0049] RZis selected from hydrogen and (C1-C6) alkyl;

[0050] R6is selected from 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;

[0051] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, R8R7N-(C3-C6) cycloalkyl-(C1-C6) alkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0052] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, R8R7N-(C3-C6) cycloalkyl-(C1-C6) alkyl-, optionally substituted nitrogen-containing heterocyclyl, and optionally substituted nitrogen-containing heterocyclyl-(C1-C6) alkyl-, or

[0053] 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

[0054] 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 nitrogen-containing heterocyclyl, or

[0055] R6is a bond between the carbon to which it is attached and R5, or

[0056] 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

[0057] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl; and

[0058] 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

[0059] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl.

[0060] 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.- 7 -

[0061] In some embodiments, one of M1, M2, M3, and M4is N.

[0062] In some embodiments, two of M1, M2, M3, and M4are N.

[0063] In some embodiments, three of M1, M2, M3, and M4are N.

[0064] In some embodiments, M1is N, and M2, M3, and M4are CR2, CR3, and CR4, respectively.

[0065] In some embodiments, M2is N, and M1, M3, and M4are CR1, CR3, and CR4, respectively.

[0066] In some embodiments, M3is N, and M1, M2, and M4are CR1, CR2, and CR4, respectively.

[0067] In some embodiments, M4is N, and M1, M2, and M3are CR1, CR2, and CR3, respectively.

[0068] In some embodiments,is

[0069] 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.

[0070] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, (C1- C6) alkyl, (C3-C6) cycloalkyl, or halogen.

[0071] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, (C1-C4) alkyl, or halogen.

[0072] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, chloro, fluoro, methyl, ethyl, or cyclopropyl.

[0073] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, chloro, or fluoro.- 8 -

[0074] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen or fluoro.

[0075] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, fluoro, or methyl.

[0076] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, fluoro, or ethyl.

[0077] In some embodiments, each of R1, R2, R3, and R4is independently hydrogen, fluoro, or cyclopropyl.

[0078] In some embodiments, , , ,

[0079] some embodiments,- 9 -is selected from

[0080] In some embodiments,is selected from

[0081] 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.

[0082] In some embodiments, R2is hydrogen.

[0083] 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.

[0084] In some embodiments, R4is selected from hydrogen, halogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl. 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.

[0085] In some embodiments, 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.- 10 -

[0086] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0087] In some embodiments, each R5is independently selected from hydrogen, optionally substituted (C1-C6) alkyl, and (C1-C6) haloalkyl. In some emobodiments, each R5is independently selected from hydrogen, (C1-C6) alkyl, and (C1-C6) haloalkyl. In some emobodiments, each R5is independently selected from hydrogen, methyl, ethyl, difluoromethyl, and trifluoromethyl.

[0088] In some embodiments, two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl. In some embodiments, two geminal R5, together with the atom to which they are attached, form a cyclopropyl. In some embodiments, two geminal R5, together with the atom to which they are attached, form a cyclobutyl. In some embodiments, two geminal R5, together with the atom to which they are attached, form a cyclopentyl. In some embodiments, two geminal R5, together with the atom to which they are attached, form a cyclohexyl.

[0089] In some embodiments, W is selected from R8R7N-(C1-C6) alkyl-, optionally substituted nitrogen-containing heterocyclyl, and optionally substituted nitrogen- containing heterocyclyl-(C1-C6) alkyl-.

[0090] In some embodiments, W is R8R7N-(C3-C6) cycloalkyl-. In some embodiments, W is R8R7N-(C3-C6) cycloalkyl-(C1-C6) alkyl-. In some embodiments, W is an optionally substituted nitrogen-containing heterocyclyl. In some embodiments, W is optionally substituted nitrogen-containing heterocyclyl-(C1-C6) alkyl-.

[0091] In some embodiments, W is selected from- 11 -

[0092] In some embodiments, W is selected from

[0093] In some embodiments, R7and R8are each independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, and (C1- C6) haloalkyl.

[0094] In some embodiments, R7and R8are each optionally substituted (C1-C6) alkyl.

[0095] In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is hydrogen.

[0096] In some embodiments, R7is optionally substituted (C3-C6) cycloalkyl and R8is hydrogen.

[0097] In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is optionally substituted (C3-C6) cycloalkyl.

[0098] In some embodiments, R7is optionally substituted (C1-C6) alkyl and R8is (C1-C6) haloalkyl.

[0099] 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-- 12 - fluorocyclobutyl, 3,3-difluorocyclobutyl, bicyclo[1.1.1]pentan-1-yl, cyclobutyl, spiro[2.3]hexan-5-yl, 3-(difluoromethyl)cyclobutyl, and benzyl.

[0100] In some embodiments, R7and R8are (C1-C6) alkyl.

[0101] In some embodiments, R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl.

[0102] 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.

[0103] In some embodiments, W is selected from- 13 -- 14 -

[0104] In some embodiments, 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.

[0105] In some embodiments, R6is selected from hydrogen, halogen, (C1-C6) alkyl, (C3- C6) cycloalkyl, (C1-C6) alkoxy, and optionally substituted (C6-C14) aryl.

[0106] 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, cyclopropyl, methoxy, and phenyl. In some embodiments, R6is hydrogen. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is cyclopropyl. In some embodiments, R6is methoxy. In some embodiments, R6is phenyl.

[0107] 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 nitrogen- containing heterocyclyl.

[0108] 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.

[0109] In some embodiments, R6and W are taken together with the atom to which they are attached to form an optionally substituted cyclobutyl or an optionally substituted pyrrolidinyl.

[0110] In some embodiments,- 15 -- 16 -

[0111] In some embodiments, R9is hydrogen.

[0112] 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.

[0113] In some embodiments, A is selected from optionally substituted thiazolyl and optionally substituted pyridinyl.

[0114] In some embodiments, A is optionally substituted thiazolyl.

[0115] In some embodiments, A is optionally substituted benzothiazolyl.

[0116] In some embodiments, A is optionally substituted pyridinyl.

[0117] In some embodiments, A is optionally substituted isoxazolyl.

[0118] In some embodiments, A is optionally substituted pyridimidinyl.

[0119] In some embodiments, A is optionally substituted pyridazinyl.

[0120] In some embodiments, A is selected from.

[0121] In some embodiments, A is selected from- 17 -

[0122] In some embodiments, the compound can have any one or more of Formulae IIa, IIb, IIc, IId- 18 -- 19 -

[0123] or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein:

[0124] p is selected from 0, 1, 2, and 3;

[0125] t is selected from 0, 1, and 2;

[0126] q is selected from 1, 2, and 3, with the proviso that if t is 0, q is selected from 2 and 3;

[0127] Z1is selected from CR15and N;

[0128] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl; and

[0129] R15is selected from hydrogen, optionally substituted (C1-C6) alkyl, and -NR8R9.

[0130] In some embodiments, p is 0. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0131] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0132] In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0133] In some embodiments, t is 1 and q is 1.

[0134] In some embodiments, t is 1 and q is 2.

[0135] In some embodiments, t is 0 and q is 3.

[0136] In some embodiments, Z1is CR15.

[0137] In some embodiments, R15is hydrogen.

[0138] In some embodiments, Z1is N.

[0139] In some embodiments, R12is (C1-C6) alkyl. In some embodiments, R12is methyl.

[0140] In some embodiments, the compound can have any one or more of Formulae IIg, IIh, IIi, IIj, IIk, IIm, IIt, IIu, and IIv:- 20 -- 21 -- 22 -

[0141] or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein:

[0142] R10and R11are each independently selected from hydrogen, halogen, and (C1-C4) alkyl, or

[0143] R10and R11in Formulae IIg, IIh, and IIt 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

[0144] 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.

[0145] In some embodiments, R10and R11in Formulae IIg, IIh, and IIt together with the atoms to which they are attached form an optionally substituted benzothiazolyl.

[0146] In some embodiments, R10and R11in Formulae IIg, IIh, and IIt together with the atoms to which they are attached form:- 23 -.

[0147] 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. In some embodiments, R10and R11are hydrogen. 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.

[0148] 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.

[0149] In some embodiments, R13is halogen. In some embodiments, R13is fluoro, chloro, or bromo. In some embodiments, R13is fluoro.

[0150] In some embodiments, R14is hydrogen.

[0151] In some embodiments, the compound can have any one or more of Formulae IIn,- 24 -

[0152] or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.- 25 -

[0153] Compounds of the Disclosure include the compounds listed in Table A, or pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

[0154] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae III, IV, or V:or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein A, M1, M2, M3, M4, Z1, R6, R7, R8, R12, p, q, and t are defined as herein.

[0155] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formulae VI, VII, or VIII:- 26 -or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein M1, M2, M3, M4, W, Z, R6, R10, R11, R13, R14, and n, are defined as herein.

[0156] In some embodiments, Compounds of the Disclosure are compounds having any one or more of Formula IX, X, and XI:- 27 -or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein M1, M2, M3, M4, R6, and W are defined as herein.

[0157] Compounds of the Disclosure include the compounds listed in Table A, or stereoisomers thereof, or pharmaceutically acceptable salts or solvates of said compounds or stereoisomers thereof. Table A- 28 -- 29 -- 30 -- 31 -- 32 -- 33 -- 34 -- 35 -

[0158] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:,- 36 - or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0159] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0160] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:- 37 -or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0161] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0162] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:- 38 -- 39 - or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0163] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:- 40 - , , ,, ,- 41 -or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0164] In some embodiments, the Compound of the Disclosure is a compound selected from the group consisting of:- 42 - ,or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0165] 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.- 43 -

[0166] In some aspects, the present disclosure relates to a pharmaceutical composition comprising a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0167] In some aspects, the present disclosure relates to a method of inhibiting 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, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0168] 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0169] In some aspects, the present disclosure relates to 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, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0170] In some embodiments, the one or more sodium channels is NaV1.7.

[0171] In some embodiments, the inhibiting or inhibition of one or more sodium channels is the selective inhibiting of or selective inhibition of NaV1.7.

[0172] 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0173] 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- 44 - 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.

[0174] In some embodiments, a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, or 8) inhibition ratio of 5 or greater. In some embodiments, the Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, or 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, the inhibition ratio is NaV1.7 to NaV1.5. In some embodiments, the inhibition ratio is NaV1.7 to NaV1.6.

[0175] In some embodiments, a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, or 8) inhibition ratio of from about 4 to about 7. In some embodiments, a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, has a NaV1.7 to NaV1.x (wherein x is 1, 2, 3, 4, 5, 6, or 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- 45 - 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.

[0176] In some embodiments, a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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.

[0177] In some embodiments, a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, can inhibit from about 50% to about 60%, from about 50% to about 70%, from about 50% to about 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- 46 - stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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.

[0178] 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.

[0179] 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.

[0180] In some embodiments, after administration, the Kpu,uof 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- 47 - 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.

[0181] 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.

[0182] 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

[0183] In some aspects, the present disclosure relates to a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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.

[0184] In some aspects, the present disclosure relates to use of a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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.

[0185] In some aspects, the present disclosure relates to use of a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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.

[0186] 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- 48 - 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

[0187] 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., C1-12alkyl) 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 as propyl or isopropyl, etc.). The alkyl group can be suitably chosen from a straight chain C1-10alkyl group, a branched chain C3-10alkyl group, a straight chain C1-6alkyl 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 C1-10alkyl 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 C1-6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, pentyl, and hexyl.

[0188] 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 C1-6alkyl. 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.

[0189] 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- 49 - three carbon-to-carbon double bonds. The alkenyl group can be chosen from a C2-6alkenyl group and a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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.- 50 -

[0194] 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 C1-4 hydroxyalkyl group. Non- limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2- dihydroxyethyl, 2hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4hydroxybutyl, 2- hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

[0195] 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 C1-6alkoxy group and a C1-6alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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- 51 - from three to twelve carbon atoms (i.e., C3-12cycloalkyl) 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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)- 52 - and at least one heteroatom. The heterocyclo group can be chosen from a C3-14heterocyclo 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 β- lactam, 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-membered cyclic 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 12-membered 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.

[0204] 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.

[0205] 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 C6-10aryl group. Non-limiting exemplary aryl groups include phenyl- 53 - (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.

[0206] 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.

[0207] 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., C5-14heteroaryl) 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-- 54 - 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.

[0208] 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(R16a)(R16b), or -N(H)C(=O)-R17, wherein R16ais hydrogen or C1-6alkyl; R16bis alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R17is 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(R16a)(R16b), or -N(H)C(=O)-R17. 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.- 55 -

[0209] 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-.

[0210] 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.

[0211] 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-.

[0212] 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, or three optionally substituted aryl groups. The aralkyl group can be a C1-4 alkyl 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.

[0213] For the purpose of the present disclosure, the term "amino" as used by itself or as part of another group refers to NH2.

[0214] For the purpose of the present disclosure, the term "alkylamino" as used by itself or as part of another group refers to -NHR16c, wherein R16cis C1-6 alkyl. R16ccan be C1- 4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3and N(H)CH2CH3.

[0215] For the purpose of the present disclosure, the term "dialkylamino" as used by itself or as part of another group refers to -NR18aR19, wherein R18and R19are each independently C1-6alkyl. R18and R19can each independently be C1-4alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2and -N(CH3)CH2CH(CH3)2.

[0216] For the purpose of the present disclosure, the term "hydroxyalkylamino" as used by itself or as part of another group refers to –NHR20, wherein R20is hydroxyalkyl.

[0217] For the purpose of the present disclosure, the term "cycloalkylamino" as used by itself or as part of another group refers to -NR21R22, wherein R21is optionally substituted cycloalkyl and R22is hydrogen or C14 alkyl.

[0218] For the purpose of the present disclosure, the term "aralkylamino" as used by itself or as part of another group refers to –NR23R24, wherein R23is aralkyl and R24is hydrogen or C14 alkyl. Non-limiting exemplary aralkylamino groups include N(H)CH2Ph and N(CH3)CH2Ph.- 56 -

[0219] 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., R25R26N-, attached to a terminal alkyl group, i.e., R25R26N-alkyl, wherein R25and R26are 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 R25and R26together with the atom to which they are attached form an optionally substituted heterocyclyl. Non-limiting examples of (amino)alkyl groups include:

[0220] 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., R27R28N-, attached to a terminal cycloalkyl group, i.e., R27R28N-cycloalkyl, wherein R27and R28are 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 R27and R28together with the atom to which they are attached form an optionally substituted heterocyclyl. Non-limiting examples of (amino)cycloalkyl groups include:

[0221] 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)NR29R30, wherein R29and R30are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R29and R30taken together with the nitrogen- 57 - to which they are attached from a 3- to 8-membered heterocyclyl group. R29and R30can 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.

[0222] 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 SO2NR31R32, wherein R31and R32are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R31and R32taken 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.

[0223] 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.

[0224] 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.

[0225] 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).

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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- 58 - 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:.

[0231] 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-.

[0232] 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 C1-6alkyl group. Non-limiting examples of (cycloalkyl)(alkyl) groups include:.

[0233] 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:.

[0234] 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- 59 - 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 has from 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.

[0235] 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.

[0236] 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).

[0237] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0238] 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.- 60 -

[0239] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.

[0240] 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.

[0241] 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.

[0242] 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]maxis 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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- 61 - value or parameter per se. For example, description referring to "about X" includes description of "X."

[0248] 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 organic acid 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).

[0249] 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.

[0250] 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- 62 - 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 that the 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.

[0251] 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.

[0252] 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.

[0253] 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.- 63 -

[0254] 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 or delaying 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.

[0255] 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.

[0256] 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.

[0257] 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.- 64 -

[0258] 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 concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable excipient is appropriate for the formulation employed.

[0259] A "sterile" formulation is aseptic or essentially free from living microorganisms and their spores.

[0260] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0261] 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.

[0262] 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.

[0263] The terms "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a "polypeptide" refers to a protein- 65 - which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0264] The term "specifically binds" to a protein or domain of a protein is a term that is well understood in the art, and methods to determine such specific binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular protein or domain of a protein than it does with alternative proteins or domains. It should be understood that a molecule that specifically or preferentially binds to a first protein or domain may or may not specifically or preferentially bind to a second protein or domain. As such, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.

[0265] 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.

[0266] 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- 66 - disorder of relevance to the treatment, or being at particular risk of contracting the disorder. Methods of Use

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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- 67 - 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.

[0274] 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.

[0275] 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, 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,- 68 - fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation, or ventricular fibrillation.

[0276] 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.

[0277] 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- 69 - 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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- 70 - pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof. Pharmaceutical Compositions

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] A pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.

[0287] A pharmaceutical composition of the present disclosure may be administered in the form of suppositories for rectal administration.

[0288] A pharmaceutical composition of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily- 71 - 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] In another aspect, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the- 72 - 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 stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and instructions for administering the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer 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.

[0295] In some aspects, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0296] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0297] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having any one or more of Formulae IIa, IIb, IIc, IId, IIe, IIf, IIq, IIr, and IIs, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0298] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having any one or more of Formulae IIg, IIh, IIi, IIj, IIk, IIm, IIt, IIu, and IIv, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.- 73 -

[0299] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound having any one or more of Formulae IIn, IIo, IIp, IIw, IIx, and IIy, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0300] In some aspects, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is 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. In some embodiments, the disease or disorder is pain.

[0301] In some aspects, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer 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.

[0302] The present disclosure also provides the following numbered embodiments.

[0303] Embodiment 1. A compound having Formula I:

[0304] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0305] M1is selected from N and CR1;

[0306] M2is selected from N and CR2;

[0307] M3is selected from N and CR3;

[0308] M4is selected from N and CR4;- 74 -

[0309] 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;

[0310] 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

[0311] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or

[0312] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0313] R5is a C1alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0314] n is 0, 1, or 2;

[0315] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-;

[0316] A is optionally substituted heteroaryl;

[0317] Z is selected from N and CRZ;

[0318] RZis selected from hydrogen and (C1-C6) alkyl;

[0319] R6is selected from 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;

[0320] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, R8R7N-(C3-C6) cycloalkyl-(C1-C6) alkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0321] 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

[0322] R6is a bond between the carbon to which it is attached and R5, or- 75 -

[0323] 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

[0324] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl; and

[0325] 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

[0326] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl.

[0327] Embodiment 2. A compound having Formula I:

[0328] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

[0329] M1is selected from N and CR1;

[0330] M2is selected from N and CR2;

[0331] M3is selected from N and CR3;

[0332] M4is selected from N and CR4;

[0333] 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;

[0334] 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- 76 -

[0335] two geminal R5, together with the atom to which they are attached, form an optionally substituted (C3-C6) cycloalkyl, or

[0336] two non-geminal R5together with the carbons to which they are attached form a (C3-C6) cycloalkyl, or

[0337] R5is a C1 alkyl group that forms a bond with each of two carbons of the ring to which it is attached;

[0338] n is 0, 1, or 2;

[0339] R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1-C6) alkyl-;

[0340] A is optionally substituted heteroaryl;

[0341] Z is selected from N and CRZ;

[0342] RZis selected from hydrogen and (C1-C6) alkyl;

[0343] R6is selected from 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;

[0344] W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, optionally substituted heterocyclyl, and optionally substituted heterocyclyl-(C1-C6) alkyl-, or

[0345] 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

[0346] R6is a bond between the carbon to which it is attached and R5, or

[0347] 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

[0348] R5and R6are taken together with the atoms to which they are attached to form an optionally substituted (C3-C6) cycloalkyl; and

[0349] 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- 77 -

[0350] R7and R8together with the atom to which they are attached form an optionally substituted heterocyclyl.

[0351] Embodiment 3. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis

[0352] Embodiment 4. 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.

[0353] Embodiment 5. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1is halogen.

[0354] Embodiment 6. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is hydrogen.

[0355] Embodiment 7. 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.

[0356] Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is halogen.

[0357] Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein- 78 -is selected from

[0358] Embodiment 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.

[0359] Embodiment 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from R8R7N-(C1-C6) alkyl-, optionally substituted nitrogen-containing heterocyclyl, and optionally substituted nitrogen-containing heterocyclyl-(C1-C6) alkyl-.

[0360] Embodiment 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7and R8are (C1-C6) alkyl.

[0361] Embodiment 13. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is selected from

[0362] Embodiment 14. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is selected from hydrogen, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, and optionally substituted (C6-C14) aryl.

[0363] Embodiment 15. 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, cyclopropyl, methoxy, and phenyl.- 79 -

[0364] Embodiment 16. 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 R8R7N-(C3-C7) cycloalkyl- or an optionally substituted nitrogen-containing heterocyclyl.

[0365] Embodiment 17. 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 cyclobutyl or an optionally substituted pyrrolidinyl.

[0366] Embodiment 18. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein- 80 -

[0367] Embodiment 19. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, whereinis

[0368] Embodiment 20. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is hydrogen.

[0369] Embodiment 21. 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 and optionally substituted pyridinyl.- 81 -

[0370] Embodiment 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein A is selected from

[0371] Embodiment 23. 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, IId, IIe, IIf, IIq, IIr, and IIs,

[0372] wherein:

[0373] p is selected from 0, 1, 2, and 3;

[0374] t is selected from 0, 1, and 2;

[0375] q is selected from 1, 2, and 3, with the proviso that if t is 0, q is selected from 2 and 3;

[0376] Z1is selected from CR15and N;

[0377] R12is selected from hydrogen and optionally substituted (C1-C6) alkyl; and

[0378] R15is selected from hydrogen, optionally substituted (C1-C6) alkyl, and -NR8R9.

[0379] Embodiment 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2.

[0380] Embodiment 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1 and q is 1.

[0381] Embodiment 26. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 1 and q is 2.

[0382] Embodiment 27. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein t is 0 and q is 3.

[0383] Embodiment 28. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z1is CR15.- 82 -

[0384] Embodiment 29. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R15is hydrogen.

[0385] Embodiment 30. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z1is N.

[0386] Embodiment 31. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12is methyl.

[0387] Embodiment 32. 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 IIg, IIh, IIi, IIj, IIk, IIm, IIt, IIu, and IIv;

[0388] wherein:

[0389] R10and R11are each independently selected from hydrogen, halogen, and (C1-C4) alkyl, or

[0390] R10and R11in Formulae IIg, IIh, and IIt 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

[0391] 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.

[0392] Embodiment 33. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R10and R11are hydrogen.

[0393] Embodiment 34. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13is halogen.

[0394] Embodiment 35. 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 IIn, IIo, IIp, IIw, IIx, and IIy.

[0395] Embodiment 36. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the- 83 - compound is a compound listed in Table A, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0396] Embodiment 37. A pharmaceutical composition comprising the compound of any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0397] Embodiment 38. 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.

[0398] Embodiment 39. 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.

[0399] Embodiment 40. The method of any one of the preceding embodiments, wherein the one or more sodium channels is NaV1.7.

[0400] Embodiment 41. 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.

[0401] Embodiment 42. The method of any one of the preceding embodiments, wherein the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

[0402] Embodiment 43. 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.

[0403] Embodiment 44. 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.

[0404] Embodiment 45. 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.- 84 -

[0405] Embodiment 46. 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.

[0406] Embodiment 47. The compound, use, or 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.

[0407] Embodiment 48. 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

[0408] 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- 85 - 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).

[0409] Unless otherwise noted, all reagents were used without further purification. Example 1 (R)-5-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamideStep 1. Preparation of - 5-chloro-N-(2,4-dimethoxybenzyl)-4-(3-(2- (dimethylamino)ethyl)azetidin-1-yl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0410] To a mixture of 2-(azetidin-3-yl)-N,N-dimethyl-ethanamine (0.0500 g, 0.248 mmol, hydrochloride) and cesium carbonate (0.405 g, 1.24 mmol) in dimethyl formamide (1 mL) was added 5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2- yl-benzenesulfonamide (0.120 g, 0.260 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give product 5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[2-(dimethylamino)ethyl]azetidin-1-yl]- 2-fluoro-N-thiazol-2-yl-benzenesulfonamide (0.146 g, crude) as a yellow oil. MS (ES+) m / z 569.4, 571.4 (M + 1) Step 2. Preparation of 5-chloro-4-(3-(2-(dimethylamino)ethyl)azetidin-1-yl)-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide

[0411] To a solution of 5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[2- (dimethylamino)ethyl]azetidin-1-yl]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (0.146 g, crude) in dichloromethane (10 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol).- 86 - The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and water (20mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; B%: 8–38%, 10 min and then re-purified by prep-HPLC (column: Waters Xbridge 150 mm × 25 mm ×mobile phase: [water ( ammonium bicarbonate)-acetonitrile]; B%: 15–45%,10 min) and at last re-purified by prep-HPLC (column: Waters Xbridge 150 mm × 25 mmmobile phase: [water (ammonia hydroxide v / v)- acetonitrile]; B%: 9–39%, 9 min). The desired fraction was collected and lyophilized to give 5-chloro-4-[3-[2-(dimethylamino)ethyl]azetidin-1-yl]-2- fluoro-N-thiazol-2-yl-benzenesulfonamide (0.0104 g, 0.0233 mmol, 9% yield, 94% purity) as an off white solid. MS (ES+) m / z 419.1, 421.1 (M + 1).1H NMR (400 MHz,CDCl3) δ 7.75 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 4.4 Hz, 1H), 6.48 (d, J = 4.4 Hz, 1H), 5.99 (d, J = 11.6 Hz, 1H), 4.32–4.21 (m, 2H), 3.88–3.79 (m, 2H), 3.09–2.96 (m, 2H), 2.82 (s, 6H), 2.78–2.71 (m, 1H), 2.22–2.16 (m, 2H).1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 4.4 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 6.36 (d, J = 12.0 Hz, 1H), 4.21 (t, J = 8.0 Hz, 2H), 3.75 (dd, J = 6.0, 8.0 Hz, 2H), 2.64–2.58 (m, 2H), 2.57 (m, 1H), 2.41 (s, 6H), 1.81 (q, J = 7.6 Hz, 2H). Preparation of 3-chloro-N-(3,4-dimethylbenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Intermediate 1)Step 1. Preparation of N-(3,4-dimethylbenzyl)-6-fluoropyridin-2-amine

[0412] 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- 87 - 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

[0413] 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).

[0414] The following further Examples listed in Table 1 were prepared analogously to Example 1 (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).- 88 - Table 1- 89 -Example 7 3-chloro-4-(3-(3-(dimethylamino)propyl)azetidin-1-yl)-2,6-difluoro-N-(thiazol-2- yl)benzenesulfonamideStep 1. methyl 3-(1-(2-chloro-3,5-difluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-2- yl)sulfamoyl)phenyl)azetidin-3-yl)propanoate

[0415] To a solution of methyl 3-(azetidin-3-yl)propanoate hydrochloride (0.200 g, 1.11 mmol, hydrochloride) and cesium carbonate (1.09 g, 3.34 mmol) in N,N- dimethylformamide (5 mL) was added 3-chloro-2,4,6-trifluoro-N-(4-methoxybenzyl)-N- (thiazol-2-yl)benzenesulfonamide (0.499 g, 1.11 mmol). The mixture was stirred at 25 °C for 12 h. Ethyl acetate (6 mL) and water (5 mL) were added and layers were separated.- 90 - The aqueous phase was extracted with ethyl acetate (2 ×6 mL). Combined extracts were washed with brine (18 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0–35% ethyl acetate / petroleum ether gradient at 25 mL / min) to give methyl 3-(1-(2-chloro-3,5- difluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)azetidin-3- yl)propanoate (0.480 g, 0.839 mmol, 76% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.81 (dd, J = 1.6, 12.8 Hz, 1H), 5.20 (s, 2H), 4.35 (t, J = 8.0 Hz, 2H), 3.86 (dd, J = 5.6, 8.0 Hz, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 2.79–2.66 (m, 1H), 2.33 (t, J = 7.2 Hz, 2H), 1.99 (q, J = 7.6 Hz, 2H). Step 2.3-chloro-2,6-difluoro-4-(3-(3-hydroxypropyl)azetidin-1-yl)-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0416] To a solution of methyl methyl 3-(1-(2-chloro-3,5-difluoro-4-(N-(4- methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)azetidin-3-yl)propanoate (0.480 g, 0.839 mmol) in tetrahydrofuran (8 mL) was added lithium aluminium hydride (1 M, 1.73 mL) at 0 °C. The mixture was heated to 25 °C for 2 h. The reaction mixture was quenched with sodium sulfafe decahydrate (0.8 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 (20 mL). The filtrate was concentrated under reduced pressure to give 3- chloro-2,6-difluoro-4-(3-(3-hydroxypropyl)azetidin-1-yl)-N-(4-methoxybenzyl)-N- (thiazol-2-yl)benzenesulfonamide (0.430 g, crude) as a yellow oil. Step 3.3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-(3-oxopropyl)azetidin-1-yl)-N- (thiazol-2-yl)benzenesulfonamide

[0417] To a solution of 3-chloro-2,6-difluoro-4-(3-(3-hydroxypropyl)azetidin-1-yl)-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.300 g, 0.551 mmol) in dichloromethane (6 mL) was added 3,5-dimethylpyrazole (0.468 g, 1.10 mmol) at 0 °C. The mixture was stirred at 40 °C for 12 h. The reaction mixture was cooled to room temperature. The mixture was diluted with saturated sodium bicarbonate (7 mL) and dichloromethane (6 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 7 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®;- 91 - 12 g SepaFlash® Silica Flash Column, Eluent of 0–50% ethyl acetate / petroleum ether gradient at 25 mL / min) to give 3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-(3- oxopropyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.150 g, 0.277 mmol, 51% yield) as a yellow oil. MS (ES+) m / z 542.2, 544.2 (M +1). Step 4.3-chloro-4-(3-(3-(dimethylamino)propyl)azetidin-1-yl)-2,6-difluoro-N-(4- methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0418] To a solution of 3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-(3- oxopropyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.150 g, 0.277 mmol) and dimethylamine (2 M, 0.410 mL) in dichloromethane (5mL) was added sodium triacetoxy borohydride (0.176 g, 0.830 mmol). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm× 10 µm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 35–65% B over 10 min). The desired fraction was collected and lyophilized. The crude product was re-purified by prep-HPLC (column: Welch Ultimate XB-CN 250 mm × 50 mm × 10 µm; mobile phase: [hexane- ethanol (0.1% ammonium hydroxide)]; gradient: 35–70% B over 15 min). The desired fraction was concentrated under reduced pressure to give 3-chloro-4-(3-(3- (dimethylamino)propyl)azetidin-1-yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2- yl)benzenesulfonamide (0.0150 g) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 5.87–5.75 (m, 1H), 5.20 (s, 2H), 4.34 (t, J = 8.0 Hz, 2H), 3.88–3.81 (m, 2H), 3.76 (s, 3H), 2.77–2.63 (m, 1H), 2.36–2.32 (m, 2H), 2.28 (s, 6H), 1.70–1.64 (m, 2H), 1.52–1.44 (m, 2H). Step 5.3-chloro-4-(3-(3-(dimethylamino)propyl)azetidin-1-yl)-2,6-difluoro-N-(thiazol-2- yl)benzenesulfonamide

[0419] To a solution of 3-chloro-4-(3-(3-(dimethylamino)propyl)azetidin-1-yl)-2,6- difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.0200 g, 0.0350 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 30 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dimethylsulfoxide (1 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 mmmobile phase: [water(ammonium bicarbonate)-acetonitrile]; gradient: 12–42% B over 10 min) to give 3-- 92 - chloro-4-(3-(3-(dimethylamino)propyl)azetidin-1-yl)-2,6-difluoro-N-(thiazol-2- yl)benzenesulfonamide (0.00390 g, 0.00856 mmol, 25% yield, 99% purity) as a white solid. MS (ES+) m / z 451.3, 453.3 (M +1).1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 4.4 Hz, 1H), 6.72 (d, J = 4.0 Hz, 1H), 6.19 (d, J = 11.6 Hz, 1H), 4.24 (t, J = 8.0 Hz, 2H), 3.76 (dd, J = 6.0, 8.0 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.65–2.60 (m, 1H), 2.53 (s, 6H), 1.63–1.55 (m, 2H), 1.55–1.46 (m, 2H). Example 8 3-chloro-2,6-difluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azetidin-1-yl)-N-(thiazol-2- yl)benzenesulfonamideStep 1. tert-butyl 3-(pyridin-4-ylmethyl)azetidine-1-carboxylate

[0420] To a mixture of tert-butyl 3-methyleneazetidine-1-carboxylate (0.330 g, 1.95 mmol) in tetrahydrofuran (1 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 M, 3.9 mL) under nitrogen atmosphere. The mixture was stirred at 60 °C for 12 h. After being cooled to room temperature, 1,1'-bis(diphenylphosphino)ferrocene) palladium(II) dichloride (0.0800 g, 0.0979 mmol), potassium phosphate (1.24 g, 5.84 mmol), 4- bromopyridine (0.379 g, 1.95 mmol, hydrochloride), tetrahydrofuran (5 mL) and water (0.6 mL) were added. The mixture was stirred at 60 °C under microwave conditions for 1 h. After being cooled to room temperature, reaction mixture was concentrated under reduced pressure. The residue was poured into water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to afford- 93 - tert-butyl 3-(pyridin-4-ylmethyl)azetidine-1-carboxylate (0.135 g, 0.543 mmol, 28% yield) as yellow oil.1H NMR (400 MHz,CDCl3) δ 8.52 (d, J = 5.6 Hz, 2H), 7.09 (d, J = 5.6 Hz, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.64 (dd, J = 5.2, 8.8 Hz, 2H), 2.95–2.89 (m, 2H), 2.85 (d, J = 8.0 Hz, 1H), 1.44 (s, 9H). Step 2. tert-butyl 3-(cyclohexylmethyl)azetidine-1-carboxylate

[0421] To a mixture of tert-butyl 3-(pyridin-4-ylmethyl)azetidine-1-carboxylate (0.115 g, 0.463 mmol) in acetic acid (2.5 mL) was added platinum dioxide(0.100 g, 0.440 mmol) under nitrogen atmosphere. The solution was purge with hydrogen for three times and then stirred at 25 °C for 12 h under hydrogen (50 psi). The resulting mixture was filtered over Celite. The filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 3-(piperidin-4- ylmethyl)azetidine-1-carboxylate (0.110 g, 0.432 mmol, 93% yield) as colorless oil.1H NMR (400 MHz,CDCl3) δ 4.01 (t, J = 8.0 Hz, 2H), 3.53 (dd, J = 5.6, 8.0 Hz, 2H), 3.40 (d, J = 1.6 Hz, 1H), 2.83 (s, 2H), 2.63–2.51 (m, 1H), 1.86 (t, J = 8.8 Hz, 1H), 1.76 (s, 2H), 1.61 (s, 3H), 1.48 (s, 2H), 1.43 (s, 9H). Step 3. tert-butyl 3-((1-methylpiperidin-4-yl)methyl)azetidine-1-carboxylate

[0422] To a mixture of tert-butyl 3-(piperidin-4-ylmethyl)azetidine-1-carboxylate (0.110 g, 0.432 mmol) in methanol (2 mL) was added formaldehyde (0.350 g, 4.32 mmol, 37% purity). The mixture was stirred at 25 °C for 1 h. Then sodium cyanoborohydride (0.0815 g, 1.30 mmol) was added. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with saturated sodium bicabronate (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford tert-butyl 3-((1- methylpiperidin-4-yl)methyl)azetidine-1-carboxylate (0.120 g, crude) as a yellow oil.1H NMR (400 MHz,CDCl3) δ 4.34 (s, 3H), 4.00 (t, J = 8.4 Hz, 2H), 3.53 (dd, J = 5.6, 8.4 Hz, 2H), 3.30–3.10 (m, 2H), 3.03 (d, J = 12.0 Hz, 2H), 2.65–2.53 (m, 1H), 2.41 (s, 2H), 2.22– 2.08 (m, 2H), 1.69 (d, J = 13.2 Hz, 2H), 1.58 (t, J = 7.2 Hz, 2H), 1.43 (s, 9H), 1.40–1.36 (m, 1H). Step 4. 4-(azetidin-3-ylmethyl)-1-methylpiperidine

[0423] A mixture of tert-butyl 3-((1-methylpiperidin-4-yl)methyl)azetidine-1-carboxylate (0.120 g, 0.447 mmol) in hydrogen chloride / dioxane (4 M, 3 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford 4- (azetidin-3-ylmethyl)-1-methylpiperidine (0.100 g, crude, hydrochloride) as a yellow- 94 - solid.1H NMR (400 MHz, MeOD-d4) δ 4.15–4.10 (m, 2H), 4.01 (s, 3H), 3.86–3.76 (m, 2H), 3.73 (s, 1H), 3.52–3.45 (m, 2H), 3.35 (s, 3H), 2.84 (s, 2H), 1.92 (d, J = 14.0 Hz, 2H), 1.72–1.66 (m, 2H). Step 5.3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-((1-methylpiperidin-4- yl)methyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

[0424] To a mixture of 4-(azetidin-3-ylmethyl)-1-methylpiperidine (0.100 g, 0.488 mmol, hydrochloride) and 3-chloro-2,4,6-trifluoro-N-(4-methoxybenzyl)-N-(thiazol-2- yl)benzenesulfonamide (0.219 g, 0.488 mmol) in dimethyl formamide (3 mL) was added cesium carbonate (0.795 g, 2.44 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 ×15 mL). The combined organic extracts was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was combined with batch of EW21562-1353 (0.020 mg of starting material 6). The residue was purified by prep- HPLC (column: Phenomenex luna C18150 mm × 25 mm× 10 μm; mobile phase: [water (formic acid):30%-50% B over 9 min). The desired fraction was collected and lyophilized to afford 3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-((1- methylpiperidin-4-yl)methyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.0350 g, 0.0586 mmol, 12% yield) as a white solid.1H NMR (400 MHz,CDCl3) δ 7.42 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.80 (dd, J = 1.2, 12.8 Hz, 1H), 4.36 (t, J = 8.0 Hz, 2H), 3.88–3.80 (m, 2H), 3.76 (s, 3H), 3.06 (d, J = 11.6 Hz, 2H), 2.84–2.75 (m, 1H), 2.40 (s, 3H), 2.13 (t, J = 11.2 Hz, 2H), 1.73–1.60 (m, 4H), 1.46 (dd, J = 3.2, 12.4 Hz, 2H), 1.36–1.28 (m, 1H). Step 6.3-chloro-2,6-difluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azetidin-1-yl)-N- (thiazol-2-yl)benzenesulfonamide

[0425] To a mixture of 3-chloro-2,6-difluoro-N-(4-methoxybenzyl)-4-(3-((1- methylpiperidin-4-yl)methyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.0320 g, 0.0535 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated. The residue was diluted with dimethyl sulfoxide (2 mL). The pH was adjust to 7-8 with diisopropylethylamine. The residue was purified by prep-HPLC (column: Waters Xbridge 150 mm × 25 mm × mobile phase: [water (ammonia hydroxide v / v)- acetonitrile]; gradient: 14–44% B over 9 min). The desired fraction was collected and lyophilized to afford 3-chloro-2,6-difluoro-4-(3-((1-methylpiperidin-4-yl)methyl)azetidin-- 95 - 1-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.0113 g, 0.0222 mmol, 42% yield, 94% purity) as a white solid. MS (ES+) m / z 477.3, 479.3 (M + 1).1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 4.0 Hz, 1H), 6.65 (d, J = 4.0 Hz, 1H), 6.16 (d, J = 12.0 Hz, 1H), 4.25 (t, J = 8.0 Hz, 2H), 3.71 (d, J = 7.2 Hz, 2H), 3.06 (d, J = 11.6 Hz, 2H), 2.74–2.67 (m, 1H), 2.45 (s, 3H), 2.41–2.32 (m, 2H), 1.67 (d, J = 12.0 Hz, 2H), 1.53 (t, J = 7.2 Hz, 2H), 1.35–1.16 (m, 3H). Example 11 3-chloro-4-[[2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]amino]-2,6-difluoro-N-(6- fluoro-2-pyridyl)benzenesulfonamideStep 1. tert-butyl 3-(cyanomethyl)-3-phenyl-azetidine-1-carboxylate

[0426] A mixture of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (4.00 g, 20.6 mmol), phenylboronic acid (3.77 g, 30.9 mmol), KOH (1.73 g, 30.9 mmol), chlororhodium;(1Z,5Z)-cycloocta-1,5-diene (0.304 g, 0.618 mmol) in dioxane (80.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction was poured into H2O (80.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified- 96 - by column chromatography (SiO2, Petroleum ether : Ethyl acetate = 30 / 1 to 1 / 1). Tert- butyl 3-(cyanomethyl)-3-phenyl-azetidine-1-carboxylate (2.30 g, 8.45 mmol, 41.0% yield) was obtained as yellow solid. Step 2. tert-butyl 3-(2-aminoethyl)-3-phenyl-azetidine-1-carboxylate

[0427] To a solution of tert-butyl 3-(cyanomethyl)-3-phenyl-azetidine-1-carboxylate (2.30 g, 8.45 mmol) in MeOH (23.0 mL) was added Raney-Ni (2.17 g, 25.3 mmol) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50 Psi) at 25 °C for 12hrs. The mixture was filtered and concentrated in vacuum. Tert-butyl 3-(2-aminoethyl)-3-phenyl-azetidine-1-carboxylate (2.30 g, 8.32 mmol, 98.5% yield) was obtained as colorless oil. Step 3. benzyl N-[(2R)-2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]carbamate

[0428] To a solution of tert-butyl 3-(2-aminoethyl)-3-phenyl-azetidine-1-carboxylate (1.00 g, 3.62 mmol) in MeOH (7.00 mL) was added HCHO (0.734 g, 9.05 mmol, 0.673 mL, 37% purity) and AcOH (0.021 g, 0.361 mmol, 0.020 mL) at 0 °C, the mixture was stirred at 0 °C for 30 min. Then added NaBH3CN (0.454 g, 7.24 mmol) at 0 °C, the mixture was stirred at 25 °C for 5 hrs. The reaction was poured into H2O (30.0 mL) and extracted with EtOAc (20.0 mL x 2). The combined organic phase was washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether : Ethyl acetate = 10 / 1 to Dichloromethane : Methanol = 10 / 1). Tert-butyl 3-[2-(dimethylamino)ethyl]-3-phenyl- azetidine-1-carboxylate (0.720 g, 2.37 mmol, 65.3% yield) was obtained as colorless oil. 1H NMR (400 MHz, CDCl3-d) δ 7.35 (t, J = 7.6 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.14 - 7.08 (m, 2H), 4.21 (d, J = 8.2 Hz, 2H), 4.01 (d, J = 8.2 Hz, 2H), 2.18 (s, 6H), 2.14 - 2.00 (m, 4H), 1.44 (s, 9H). Step 4. (N2-ethyl-N2,4,4-trimethyl-pentane-1,2-diamine

[0429] To a solution of tert-butyl 3-[2-(dimethylamino)ethyl]-3-phenyl-azetidine-1- carboxylate (0.720 g, 2.37 mmol) in EtOAc (3.50 mL) was added HCl / EtOAc (4.00 M, 1.50 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated in vacuum. N,N-dimethyl-2-(3-phenylazetidin-3-yl)ethanamine (0.430 g, 1.79 mmol, 75.5% yield, HCl) was obtained as white solid. Step 5.3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[[2-[ethyl(methyl)amino]-4,4- dimethyl-pentyl]amino]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide- 97 -

[0430] To a solution of 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-2,4,6-trifluoro-N-(6- fluoro-2-pyridyl)benzenesulfonamide (0.200 g, 0.407 mmol) and N,N-dimethyl-2-(3- phenylazetidin-3-yl)ethanamine (0.117 g, 0.488 mmol, HCl) in DMF (1.00 mL) was added Cs2CO3(0.331 g, 1.02 mmol). The mixture was stirred at 25 °C for 16 hrs. The reaction was poured into H2O (5.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic phase was washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, Dichloromethane : Methanol = 10 / 1). 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-4-[3- [2-(dimethylamino)ethyl]-3-phenyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2- pyridyl)benzenesulfonamide (0.120 g, 0.177 mmol, 43.6% yield) was obtained as white solid.1H NMR (400 MHz, CDCl3-d) δ 7.66 (q, J = 8.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.32 - 7.28 (m, 1H), 7.26 - 7.20 (m, 2H), 7.18 - 7.12 (m, 2H), 6.63 (dd, J = 7.8, 2.8 Hz, 1H), 6.41 - 6.34 (m, 2H), 5.93 (dd, J = 12.4, 1.4 Hz, 1H), 5.11 (s, 2H), 4.54 - 4.32 (m, 4H), 3.75 (d, J = 3.4 Hz, 6H), 3.50 (s, 2H), 2.23 (s, 9H). Step 6.3-chloro-4-[[2-[ethyl(methyl)amino]-4,4-dimethyl-pentyl]amino]-2,6-difluoro-N- (6-fluoro-2-pyridyl)benzenesulfonamide

[0431] To a solution of 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-4-[3-[2- (dimethylamino)ethyl]-3-phenyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2- pyridyl)benzenesulfonamide (0.120 g, 0.177 mmol) in DCM (1.00 mL) was added TFA (0.200 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was poured into NaHCO3(5.00 mL) and extracted with DCM (3.00 mL x 3). The combined organic phase was washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini NX- C18 (75 * 30 mm * 3 um); mobile phase: [H2O (0.05% NH3H2O + 10 mM NH4HCO3) - ACN]; gradient: 20% - 50% B over 8.0 min). 3-chloro-4-[3-[2-(dimethylamino)ethyl]-3- phenyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (0.024 g, 0.045 mmol, 25.7% yield) was obtained as white solid. MS (ES+) m / z 525.2 (M + 1).1H NMR (400 MHz, DMSO-d6) δ 11.27 - 10.12 (m, 1H), 7.56 (q, J = 8.2 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.32 - 7.21 (m, 3H), 6.64 (dd, J = 7.8, 1.6 Hz, 1H), 6.31 (d, J = 6.6 Hz, 1H), 6.20 (d, J = 12.6 Hz, 1H), 4.32 (s, 4H), 2.50 - 2.43 (m, 8H), 2.36 - 2.22 (m, 2H).- 98 - Example 12 3-chloro-4-(3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidin-1-yl)-2,6-difluoro-N- (thiazol-2-yl)benzenesulfonamideStep 1. tert-butyl 3-(1-(dimethylamino)-2-methyl-1-oxopropan-2-yl)azetidine-1- carboxylate

[0432] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylpropanoic acid (0.500 g, 2.06 mmol) in dichloromethane (5.0 mL) was added 1,1'-carbonyldiimidazole (0.400 g, 2.47 mmol). The mixture was stirred at 25 °C for 0.5 h. Then dimethylamine (2 M, 1.6 mL) (in tetrahydrofuran) was added. The resulting mixture was stirred at 25 °C for 2.5 h. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1 M hydrochloric acid (2 × 5 mL), brine (15 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue to give tert-butyl 3-(1-(dimethylamino)-2-methyl-1-oxopropan-2-yl)azetidine-1-carboxylate (0.310 g, crude) as a yellow oil. MS (ES+) m / z 271.2 (M + 1).1H NMR (400 MHz, CDCl3) δ 3.99 (t, J = 9.2 Hz, 2H), 3.64 (dd, J = 6.0, 9.2 Hz, 2H), 3.08–2.99 (m, 7H), 1.43 (s, 9H), 1.28 (s, 6H). Step 2. tert-butyl 3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidine-1-carboxylate

[0433] To a solution of tert-butyl 3-(1-(dimethylamino)-2-methyl-1-oxopropan-2- yl)azetidine-1-carboxylate (0.310 g, 1.15 mmol) (crude) in tetrahydrofuran (6.0 mL) was added borane dimethyl sulfide complex (10 M, 0.3 mL) at 0 °C under nitrogen. The mixture was heated to 50 °C for 2 h under nitrogen. The reaction mixture was cooled to- 99 - room temperature. The reaction mixture was quenched with methanol (20 ml) at 0 °C for 0.5 h. The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure to give a residue. The residue was diluted methanol (15 ml) and refluxed at 80 °C for 1 h and concentrated under reduced pressure to give tert-butyl 3-(1-(dimethylamino)-2- methylpropan-2-yl)azetidine-1-carboxylate (0.300 g, crude) as a yellow oil. MS (ES+) m / z 257.1 (M + 1). Step 3.2-(azetidin-3-yl)-N,N,2-trimethylpropan-1-amine

[0434] To a solution of tert-butyl 3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidine- 1-carboxylate (0.300 g, 1.17 mmol) (crude) in methanol (3.0 mL) was added acetyl chloride (0.459 g, 5.85 mmol). The mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue to give 2-(azetidin-3- yl)-N,N,2-trimethylpropan-1-amine (0.280 g, crude, 2 hydrochloride) as a colorless oil.1H NMR (400 MHz, MeOD-d4) δ 4.13–3.98 (m, 4H), 3.22–3.14 (m, 1H), 3.11 (s, 2H), 2.97 (s, 6H), 1.20 (s, 6H). Step 4.3-chloro-4-(3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidin-1-yl)-2,6- difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[0435] To a solution of 2-(azetidin-3-yl)-N,N,2-trimethylpropan-1-amine (0.100 g, 0.436 mmol, 2 hydrochloride) (crude) in dimethyl formamide (1.0 mL) were added 3-chloro- 2,4,6-trifluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.157 g, 0.349 mmol) and cesium carbonate (0.711 g, 2.18 mmol). The mixture was stirred at 25 °C for 12 h. Ethyl acetate (4 mL) and water (4 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 4 mL). Combined extracts were washed with brine (8 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: 28%–48% B over 2 min). The desired fraction was collected and lyophilized to give 3-chloro-4-(3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidin-1- yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.0700 g, 0.120 mmol, 27% yield) as a yellow solid. MS (ES+) m / z 585.2, 587.2 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 5.82 (dd, J = 1.2, 13.2 Hz, 1H), 5.20 (s, 2H), 4.22–4.12 (m, 2H), 4.05 (t, J = 7.2 Hz, 2H), 3.76 (s, 3H), 2.85–2.74 (m, 1H), 2.27 (s, 6H), 2.09 (s, 2H), 0.90 (s, 6H).- 100 - Step 5.3-chloro-4-(3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidin-1-yl)-2,6- difluoro-N-(thiazol-2-yl)benzenesulfonamide

[0436] To a solution of 3-chloro-4-(3-(1-(dimethylamino)-2-methylpropan-2-yl)azetidin- 1-yl)-2,6-difluoro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.0700 g, 0.120 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.0 mL). The mixture was stirred at 30 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dimethyl formamide (1.0 mL) and the pH was adjusted to ~8 with ammonium hydroxide (10% purity). The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 10%–30% B over 2 min). The desired fraction was collected and lyophilized to give 3-chloro-4-(3-(1-(dimethylamino)-2- methylpropan-2-yl)azetidin-1-yl)-2,6-difluoro-N-(thiazol-2-yl)benzenesulfonamide (0.00470 g, 0.00892 mmol, 7% yield, 97% purity, formate) as a white solid. MS (ES+) m / z 465.1, 467.1 (M + 1).1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.22 (dd, J = 1.2, 13.2 Hz, 1H), 4.17–4.08 (m, 2H), 4.04–3.94 (m, 2H), 2.77–2.63 (m, 1H), 2.24 (s, 6H), 2.11 (s, 2H), 0.85 (s, 6H). Example 14 3-chloro-4-(3-((dimethylamino)methyl)-3-methylazetidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamideStep 1. tert-butyl ((1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2- yl)sulfamoyl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)methyl)carbamate

[0437] A solution of tert-butyl ((3-methylazetidin-3-yl)methyl)carbamate (0.100 g, 0.422 mmol, hydrochloride), 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6-- 101 - fluoropyridin-2-yl)benzenesulfonamide (0.210 g, 0.428 mol) and cesium carbonate (0.550 g, 1.69 mmol) in N,N-dimethylformamide (2.0 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 (30 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl ((1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-3-methyl azetidin-3- yl)methyl)carbamate (0.300 g, crude) as a yellow oil. MS (ES+) m / z 671.1, 673.1 (M + 1). Step 2.4-(3-(aminomethyl)-3-methylazetidin-1-yl)-3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide

[0438] To a solution of tert-butyl ((1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-3-methyl azetidin-3- yl)methyl)carbamat (0.300 g, 0.447 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (1.0 mL). The mixture was stirred at 25 °C for 16 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 (trifluoroacetic acid)-acetonitrile]; gradient: 23%–53% B over 10 min). The desired fraction was collected and lyophilized to give 4-(3-(aminomethyl)-3-methylazetidin-1- yl)-3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0300 g, 0.0561 mmol, 13% yield, trifluoroacetate) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 11.76 (s, 1H), 7.87 (q, J = 8.0 Hz, 4H), 6.86 (dd, J = 1.6, 8.0 Hz, 1H), 6.74 (dd, J = 2.4, 8.0 Hz, 1H), 6.27 (d, J = 12.8 Hz, 1H), 4.15 (d, J = 8.8 Hz, 2H), 3.92 (d, J = 8.8 Hz, 2H), 3.10 (s, 2H), 1.32 (s, 3H) Step 3.3-chloro-4-(3-((dimethylamino)methyl)-3-methylazetidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide

[0439] To a solution of 4-(3-(aminomethyl)-3-methylazetidin-1-yl)-3-chloro-2,6- difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0300 g, 0.0561 mmol, trifluoroacetate) and formaldehyde (0.0460 g, 0.567 mmol) in methanol (2.0 mL) was added sodium cyanoborohydride (0.0110 g, 0.175 mmol). The 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: Waters Xbridge 150 mm × 25 mm × 5mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 18%–48% B over min). The desired fraction was collected and lyophilized to give 3-chloro-4-(3-- 102 - ((dimethylamino)methyl)-3-methylazetidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.0106 g, 0.0222 mmol, 40% yield, 94% purity) as a white solid. MS (ES+) m / z 449.1, 451.1 (M + 1).1H NMR (400 MHz, DMSO-d6) δ 7.78 (q, J = 8.0 Hz, 1H), 6.82–6.73 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.26 (d, J = 13.2 Hz, 1H), 4.02– 3.88 (m, 4H), 2.57 (s, 2H), 2.24 (s, 6H), 1.33 (s, 3H)

[0440] The following further Examples listed in Table 2 were prepared analogously to Example 14 (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 2- 103 - Example 15 3-chloro-4-(3-(2-(dimethylamino)ethyl)-3-ethylazetidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamideStep 1. tert-butyl 3-ethyl-3-(2-oxoethyl)azetidine-1-carboxylate

[0441] A mixture of tert-butyl 3-ethyl-3-(2-methoxy-2-oxo-ethyl)azetidine-1-carboxylate (1.20 g, 4.66 mmol, 1.0 eq) in THF (10 mL) was added Red-Al (1.5 M, 3.73 mL, 1.2 eq) at 0 °C under N2 atmosphere. Then the mixture was stirred at 0 °C for 3 hrs under N2 atmosphere. LC-MS (P1: RT = 0.389 min; MS = [M-99] = 128.3) showed reactantwas consumed completely and ~98.8% of desired compound was detected. TLC (Plate 1; I2; SiO2, Petroleum ether: Ethyl acetate = 2: 1; R1: Rf = 0.77; P1: Rf = 0.19) indicated reactant was consumed completely and one new spot formed. TLC (Plate 2; DNP; SiO2, Petroleum ether: Ethyl acetate = 2: 1; P1: Rf= 0.19) indicated reactant was consumed completely and one new spot formed. The reaction mixture was quenched by addition water 10 mL at 25 °C, and then extracted with EtOAc (8 mL * 3). The combined organic layers were washed with NaCl (10 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Plate 2; DNP; SiO2, Petroleum ether: Ethyl acetate = 2: 1; P1: Rf = 0.19). LCMS (P1: RT = 0.383 min; MS = [M-99] = 128.3) showed ~72.6% of desired compound was detected. Compound tert-butyl 3-ethyl-3-(2-oxoethyl)azetidine-1- carboxylate (850 mg, 3.74 mmol, 80.2% yield) was obtained as a colorless oil.1H NMR- 104 - (400 MHz, CDCl3) confirmed the obtained compound is the desired compound. MS128.3 (M -99). Step 2. tert-butyl 3-(2-(dimethylamino)ethyl)-3-ethylazetidine-1-carboxylate

[0442] To a solution of tert-butyl 3-ethyl-3-(2-oxoethyl)azetidine-1-carboxylate (450 mg, 1.98 mmol, 1.0 eq) , Me2NH (1.12 g, 9.90 mmol, 1.25 mL, 5.0 eq) in MeOH (10 mL) was added AcOH (1.19 mg, 19.8 μmol, 1.13 μL, 0.01 eq) and stirred at 25 °C for 10 min. Then NaBH3CN (622.06 mg, 9.90 mmol, 5.0 eq) was added slowly at 0 °C. The mixture was stirred at 25 °C for 5 hrs. LC-MS (EC16103-11-P1A; P1: RT = 0.281 min; MS = [M+1] = 257.2) showed reactant was consumed completely and ~12.6% purity of desired compound was detected. TLC (Plate 1; I2; SiO2, Petroleum ether: Ethyl acetate = 0: 1; R1: Rf= 0.93; P1: Rf= 0.07) indicated reactant was consumed completely and many new spots formed. The reaction mixture was quenched by addition of water (10 mL) at 25 °C, and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with NaCl (15 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Plate 1; I2; SiO2, Petroleum ether: Ethyl acetate = 0: 1; P1: Rf = 0.07). Compound tert-butyl 3-[2- (dimethylamino)ethyl]-3-ethyl-azetidine-1-carboxylate (420 mg, 1.64 mmol, 82.7% yield) was obtained as a colorless oil. MS (ES+) m / z 256.2, 257.2 (M +1). Step 3.2-(3-ethylazetidin-3-yl)-N,N-dimethylethan-1-amine

[0443] To a solution of tert-butyl 3-[2-(dimethylamino)ethyl]-3-ethyl-azetidine-1- carboxylate (420 mg, 1.64 mmol, 1.0 eq) was added HCl / dioxane (6 mL). The mixture was stirred at 25 °C for 2 hrs. LC-MS (P1: RT = 0.077 min; MS = [M+1] = 157.2) showed reactant was consumed completely and ~95.3% purity of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was used without purification. Compound 2-(3-ethylazetidin-3-yl)-N,N- dimethyl-ethanamine (500 mg, crude, HCl) was obtained as a colorless oil. MS (ES+) m / z 156.1, 157.2 (M +1). Step 4.3-chloro-N-(2,4-dimethoxybenzyl)-4-(3-(2-(dimethylamino)ethyl)-3- ethylazetidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0444] To a solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4,6-trifluoro-N-(6- fluoro-2-pyridyl)benzenesulfonamide (891 mg, 1.82 mmol, 1.0 eq)，2-(3-ethylazetidin-3- yl)-N,N-dimethyl-ethanamine (350 mg, 1.82 mmol, 1.0 eq, HCl) in DMF (10 mL) was added Cs2CO3(1.78 g, 5.45 mmol, 3.0 eq). The mixture was stirred at 25 °C for 2 hrs.- 105 - LC-MS (P1: RT = 0.431 min; MS = [M+H] = 627.2) showed reactant was consumed completely and ~38.9% of desired compound was detected. TLC (Plate 1; SiO2, Petroleum ether: Ethyl acetate = 0: 1; R1: Rf = 0.91; P1: Rf = 0.04) indicated reactant was not consumed completely and many new spots formed. The reaction mixture was quenched by addition of water (15 mL) at 25 °C, and then extracted with EtOAc (15 mL * 3). The combined organic layers were washed with NaCl (15 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Plate 2; SiO2, Petroleum ether: Ethyl acetate = 0: 1; P1: Rf = 0.04). LCMS (P1: RT = 0.434 min; MS = [M+1] = 627.3) showed ~80.2% purity of P1. Compound 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[2- (dimethylamino)ethyl]-3-ethyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2- pyridyl)benzenesulfonamide (250 mg, 398.65 μmol, 21.95% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) and19F NMR (400 MHz, CDCl3) confirmed the obtained compound is the desired compound. MS (ES+) m / z 626.1, 627.2 (M +1).1H NMR (400 MHz, CDCl3) δ 7.67 (q, J = 8.2 Hz, 1H), 7.16 - 7.26 (m, 2H), 6.64 (dd, J = 8.0, 2.8 Hz, 1H), 6.33 - 6.43 (m, 2H), 5.84 (d, J = 11.6 Hz, 1H), 5.03 - 5.16 (m, 2H), 3.93 (q, J = 8.4 Hz, 4H), 3.75 (d, J = 6.4 Hz, 7H), 2.35 - 2.48 (m, 7H), 1.81 - 1.96 (m, 2H), 1.67 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.6 Hz, 3H). Step 5.3-chloro-4-(3-(2-(dimethylamino)ethyl)-3-ethylazetidin-1-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide

[0445] A solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[2- (dimethylamino)ethyl]-3-ethyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2- pyridyl)benzenesulfonamide (200 mg, 319 μmol, 1.0 eq) in TFA (1 mL) and DCM (1 mL) was stirred at 25 °C for 2 hrs. LC-MS (P1: RT = 0.340 min; MS = [M+1] = 477.2) showed reactant was consumed completely and ~91.4% purity of desired compound was detected. The reaction mixture was quenched by addition NaHCO35 mL at 25 °C, and then extracted with DCM (3 mL * 3). The combined organic layers were washed with NaCl (5 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition; column: Welch Xtimate C18150 * 25 mm * 5 um; mobile phase: [water (HCl) - ACN]; gradient:15% - 45% B over 10 min). LCMS (P1: RT = 0.350 min; MS = [M+1] = 477.2) showed ~82.6% purity of desired copound. Compound 3-chloro-4-[3-[2-(dimethylamino)ethyl]- 3-ethyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (67.3 mg,- 106 - 133 μmol, 41.7% yield, 94.2% purity) was obtained as a off-white solid. LC-MS (P1: RT = 2.908 min; MS = [M+1] = 477.2) showed ~93.8% of desired compound mass was detected. HPLC (P1: RT = 2.043 min) showed ~94.2% of desired compound purity mass was detected.1H NMR (400 MHz, MeOD) and19F NMR (400 MHz, MeOD) confirmed the obtained compound is the desired compound. MS (ES+) m / z 476.1, 477.2 (M + 1).1H NMR (400 MHz, METHANOL-d4) δ 7.77 (q, J = 8.0 Hz, 1H), 6.92 (dd, J = 7.8, 2.0 Hz, 1H), 6.61 (dd, J =8.0, 2.4 Hz, 1H), 6.14 (dd, J = 13.2, 1.6 Hz, 1H), 3.94 - 4.11 (m, 4H), 3.18 (dt, J = 8.4, 4.4 Hz, 2H), 2.86 - 2.98 (m, 6H), 2.09 (dt, J = 8.4, 4.4 Hz, 2H), 1.70 (q, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0446] The following further Examples listed in Table 3 were prepared analogously to Example 15 (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 3Example 17 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azetidin-1- yl)benzenesulfonamide- 107 -Step 1. tert-butyl 3-(1-methyl-1H-pyrrol-2-yl)azetidine-1-carboxylate

[0447] To a solution of 1-methyl-1H-pyrrole (2.87 g, 35.3 mmol) and dipotassium;sulfonatooxy sulfate (0.955 g, 3.53 mmol) in dimethylsulfoxide (7.5 mL) and water (2.5 mL) were added tert-butyl 3-iodoazetidine-1-carboxylate (0.500 g, 1.77 mmol) and diisopropylethylamine (0.965 g, 7.46 mmol) under nitrogen. The mixture was stirred at 70 °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. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 3-(1- methyl-1H-pyrrol-2-yl)azetidine-1-carboxylate (0.0800 g, 0.322 mmol, 18% yield, 95% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.58 (t, J = 2.0 Hz, 1H), 6.12–6.05 (m, 2H), 4.31–4.22 (m, 2H), 4.00 (dd, J = 6.8, 8.0 Hz, 2H), 3.83–3.73 (m, 1H), 3.47 (s, 3H), 1.45 (s, 9H). Step 2. tert-butyl 3-(1-methylpyrrolidin-2-yl)azetidine-1-carboxylate

[0448] To a mixture of tert-butyl 3-(1-methyl-1H-pyrrol-2-yl)azetidine-1-carboxylate (0.0800 g, 0.322 mmol) in acetic acid (2.0 mL) was platinum dioxide (0.0730 g, 0.321 mmol) under nitrogen. The solution was purge with hydrogen for three times and then stirred at 50 °C for 12 h under hydrogen (50 psi). The reaction mixture was concentrated under reduced pressure to give tert-butyl 3-(1-methylpyrrolidin-2-yl)azetidine-1- carboxylate (0.100 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 4.15–3.96 (m, 2H), 3.76–3.60 (m, 2H), 3.43 (s, 1H), 2.95 (s, 2H), 2.66–2.57 (m, 1H), 2.52 (s, 3H), 1.88 (s, 3H), 1.72 (s, 1H), 1.43 (s, 9H). Step 3.2-(azetidin-3-yl)-1-methylpyrrolidine- 108 -

[0449] To a solution of tert-butyl 3-(1-methylpyrrolidin-2-yl)azetidine-1-carboxylate (0.100 g, 0.416 mmol) (crude) in methanol (4.0 mL) was added acetyl chloride (0.164 g, 2.09 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 2-(azetidin-3-yl)-1-methylpyrrolidine (0.0500 g, crude, 2 hydrochloride) as a yellow oil.1H NMR (400 MHz, MeOD-d4) δ 4.31–4.23 (m, 1H), 4.18 (t, J = 8.0 Hz, 2H), 4.12–4.04 (m, 1H), 3.83 (d, J = 8.0 Hz, 1H), 3.74–3.65 (m, 1H), 3.55–3.46 (m, 1H), 3.24–3.15 (m, 1H), 2.91 (s, 3H), 2.46–2.35 (m, 1H), 2.22–2.14 (m, 1H), 2.13–2.03 (m, 1H), 1.92–1.79 (m, 1H). Step 4.3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1- methylpyrrolidin-2-yl)azetidin-1-yl)benzenesulfonamide

[0450] A solution of 2-(azetidin-3-yl)-1-methylpyrrolidine (0.0500 g, 0.235 mmol, 2 hydrochloride), 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.115 g, 0.234 mmol) and cesium carbonate (0.383 g, 1.18 mmol) 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 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azetidin-1-yl)benzenesulfonamide (0.120 g, 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), 6.40–6.36 (m, 2H), 5.85 (dd, J = 1.6, 12.8 Hz, 1H), 5.10 (s, 2H), 4.44–4.37 (m, 1H), 4.29 (t, J = 8.8 Hz, 1H), 4.03–3.94 (m, 2H), 3.79–3.71 (m, 8H), 3.16–3.06 (m, 1H), 2.92 (d, J = 5.2 Hz, 1H), 2.55–2.43 (m, 1H), 2.39–2.32 (m, 3H), 2.01–1.92 (m, 1H), 1.85–1.77 (m, 2H). Step 5.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2- yl)azetidin-1-yl)benzenesulfonamide

[0451] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-(1-methylpyrrolidin-2-yl)azetidin-1-yl)benzenesulfonamide (0.120 g, 0.196 mmol) (crude) 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 mL). The mixture was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-- 109 - acetonitrile]; gradient: 10%–40% 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-(1- methylpyrrolidin-2-yl)azetidin-1-yl)benzenesulfonamide (0.0096 g, 0.0198 mmol, 10% yield, 95% purity) as a white solid. MS (ES+) m / z 461.0, 463.0 (M +1).1H NMR (400 MHz, DMSO-d6) δ 7.71–7.56 (m, 1H), 6.68 (d, J = 6.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 12.8 Hz, 1H), 4.32 (t, J = 8.4 Hz, 1H), 4.20 (t, J = 8.4 Hz, 1H), 3.97–3.92 (m, 1H), 3.89 (dd, J = 6.4, 8.4 Hz, 1H), 3.08 (d, J = 3.2 Hz, 1H), 2.91–2.84 (m, 1H), 2.81– 2.72 (m, 1H), 2.46–2.42 (m, 1H), 2.37 (s, 3H), 2.03–1.90 (m, 1H), 1.77–1.69 (m, 2H), 1.61–1.50 (m, 1H). Example 25 3-chloro-2,6-difluoro-4-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(pyridin-2- yl)benzenesulfonamideStep 1. tert-butyl 6-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2- yl)sulfamoyl)-3,5-difluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0452] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.100 g, 0.504 mmol) and cesium carbonate (0.493 g, 1.51 mmol) in dimethyl formamide (2.0 mL) was added 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.248 g, 0.505 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate (3 mL) and water (2 mL). The mixture was extracted with ethyl acetate (3 × 2 mL). The combined organic extracts were washed with brine (8 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, Eluentof 0–30% ethyl acetate / petroleum ether gradient at 30 mL / min) to give tert-butyl 6-(2-chloro-4-(N-(2,4-- 110 - dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (0.220 g, 0.326 mmol, 65% yield, 99% purity) as a colorless oil. MS (ES+) m / z 669.0, 671.0 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.66 (q, J = 8.0 Hz, 1H), 7.25–7.18 (m, 2H), 6.65 (d, J = 2.8 Hz, 1H), 6.42–6.33 (m, 2H), 5.88 (dd, J = 1.6, 12.4 Hz, 1H), 5.08 (s, 2H), 4.35 (s, 4H), 4.12–4.09 (m, 4H), 3.74 (d, J = 8.0 Hz, 6H), 1.45 (s, 9H). Step 2.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(2,6-diazaspiro[3.3]heptan-2- yl)benzenesulfonamide

[0453] To a solution of tert-butyl 6-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3,5-difluorophenyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (0.220 g, 0.326 mmol) in trifluoroacetic acid (1.0 mL) was added dichloromethane (10.0 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzenesulfonamide (0.230 g, crude, trifluoroacetate) as a brown solid. MS (ES+) m / z 418.9, 420.9 (M + 1).1H NMR (400 MHz, MeOD-d4) δ 7.76 (q, J = 8.0 Hz, 1H), 6.91 (dd, J = 1.6, 8.0 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 6.16 (d, J = 12.0 Hz, 1H), 4.45 (s, 4H), 4.27 (s, 4H) Step 3.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(6-isopropyl-2,6- diazaspiro[3.3]heptan-2-yl)benzenesulfonamide

[0454] A solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(2,6- diazaspiro[3.3]heptan-2-yl)benzenesulfonamide (0.0500 g, 0.0938 mmol, trifluoroacetate), acetone (0.0280 g, 0.482 mmol), acetic acid (0.0170 g, 0.283 mmol) and sodium cyanoborohydride (0.0180 g, 0.286 mmol) in methanol (0.5 mL) was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (hydrochloric acid)-acetonitrile]; gradient: 14%–44% B over 9 min). The desired fraction was collected and lyophilized to give 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)benzenesulfonamide (0.0221 g, 0.0418 mmol, 45% yield, 94% purity, hydrochloride) as a white solid. MS (ES+) m / z 461.1, 463.1 (M + 1).1H NMR (400 MHz, DMSO-d6) δ 11.97–11.50 (m, 1H), 11.20–10.70 (m, 1H), 7.86 (q, J = 8.0 Hz, 1H), 6.85 (dd, J = 1.6, 8.0 Hz, 1H), 6.73 (dd, J = 2.4, 8.0 Hz, 1H), 6.37 (d, J = 13.2 Hz, 1H), 4.54 –4.27 (m, 4H), 4.18 (s, 4H), 3.38–3.35 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H)- 111 -

[0455] The following further Examples listed in Table 4 were prepared analogously to Example 25 (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 4- 112 -Example 35 3,6-dichloro-2-fluoro-4-(6-methyl-2,6-diazaspiro[3.6]decan-2-yl)-N-(pyridin-2- yl)benzenesulfonamideStep 1. tert-butyl 6-methyl-2,6-diazaspiro[3.6]decane-2-carboxylate- 113 -

[0456] To a solution of tert-butyl 2,6-diazaspiro[3.6]decane-2-carboxylate (450.0 mg, 1.87 mmol) and formaldehyde (1.52 g, 37.0% purity, 18.75 mmol) in DCM (5.0 mL) was added sodium tris(acetoxy)borohydride (1.19 g, 5.63 mmol). The mixture was stirred at 20°C for 18 h. The solution was quenched with 5ml of saturated solution of NaHCO3. DCM (10 mL) and water (10 mL) were added and layers were separated. The aqueous phase was extracted with DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and filtered. A filtrate was concentrated under reduced pressure to give tert-butyl 6-methyl-2,6-diazaspiro[3.6]decane-2- carboxylate (400.0 mg, 1.57 mmol, 83.9% yield) as viscous oil. MS (ES+) m / z 255.2 (M + 1). Step 2.6-methyl-2,6-diazaspiro[3.6]decane dihydrochloride

[0457] To the stirring MeOH (5 ml) was added acetyl chloride (490.22 mg, 6.29 mmol) at 0°C. After 5 min of stirring was added tert-butyl 6-methyl-2,6-diazaspiro[3.6]decane-2- carboxylate (400.0 mg, 1.57 mmol) in MeOH (1 ml) and the solution was left stirring at 20°C for 6 h. The solution was concentrated in vacuo to give 6-methyl-2,6- diazaspiro[3.6]decane dihydrochloride (320.0 mg, 90.0% purity, 1.27 mmol, 80.7% yield).1H NMR (500 MHz, DMSO-d6) δ 11.28 - 11 (m, 1H), 9.67 - 9.21 (m, 2H), 4.3 - 4.18 (m, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.76 - 3.58 (m, 3H), 3.36 (dd, J = 13.7, 8.5 Hz, 1H), 3.28 - 3.18 (m, 1H), 3.13 - 3 (m, 1H), 2.78 (d, J = 4.6 Hz, 3H), 2.26 - 2.16 (m, 1H), 2 - 1.88 (m, 1H), 1.86 - 1.51 (m, 4H). MS (ES+) m / z 155.2 (M + 1). Step 3.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6- methyl-2,6-diazaspiro[3.6]decan-2-yl)benzenesulfonamide

[0458] Methyl-2,6-diazaspiro[3.6]decane dihydrochloride 3 (115 mg, 90.0% purity, 390 µmol) and DIPEA (152.79 mg, 1.18 mmol) were stirred in DMSO (5 mL). After 3 min of stirring 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoropyridin- 2-yl)benzene-1-sulfonamide (200.0 mg, 394.24 µmol) was added to the mixture and the mixture was stirred at 20°C for 12 h. The mixture was diluted with EtOAc (10 ml) and washed with saturated aqueous solution of NaHCO3 (5 ml) and water (5 ml). The organic phase was concentrated under reduced pressure to give 3,6-dichloro-N-[(2,4- dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoropyridin-2-yl)-4-6-methyl-2,6- diazaspiro[3.6]decan-2-ylbenzene-1-sulfonamide (240.0 mg, 94.0% purity, 351.64 µmol, 89.2% yield). MS (ES+) m / z 641.2, 643.2, 645.2 (M + 1).- 114 - Step 4.3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-methyl-2,6- diazaspiro[3.6]decan-2-yl)benzenesulfonamide

[0459] To a solution of 3,6-dichloro-N-[(2,4-dimethoxyphenyl)methyl]-2-fluoro-N-(6- fluoropyridin-2-yl)-4-6-methyl-2,6-diazaspiro[3.6]decan-2-ylbenzene-1-sulfonamide (240.0 mg, 94.0% purity, 351.64 µmol) in DCM (2 mL) was added trifluoroacetic acid (401.33 mg, 3.52 mmol). The mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution (0.5 mL) at 0 °C. The mixture was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by HPLC (Column: XBridge BEH C18100x19mm, 5um; eluent: 0-65% H2O / ACN / 0,1% NH4OH) to obtain 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-6-methyl-2,6- diazaspiro[3.6]decan-2-ylbenzene-1-sulfonamide (102.0 mg, 98.0% purity, 203.43 µmol, 57.8% yield).1H NMR (500 MHz, DMSO-d6) δ 7.77 - 7.65 (m, 1H), 6.78 - 6.67 (m, 1H), 6.59 - 6.47 (m, 1H), 6.36 (s, 1H), 3.97 (d, J = 9.3 Hz, 2H), 3.9 - 3.79 (m, 2H), 2.91 - 2.75 (m, 2H), 2.66 - 2.55 (m, 2H), 2.41 (s, 3H), 1.86 - 1.73 (m, 2H), 1.65 - 1.55 (m, 2H), 1.55 - 1.44 (m, 2H). MS (ES+) m / z 491.2, 493.2, 495.2 (M + 1).

[0460] The following further Examples listed in Table 5 were prepared analogously to Example 35 (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 5- 115 -- 116 -Example 46 3,6-dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazetidin-1-yl)-2-fluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamideStep 1.2-(3-methoxyazetidin-3-yl)ethan-1-ol hydrochloride

[0461] To a solution of tert-butyl 3-(2-hydroxyethyl)-3-methoxyazetidine-1-carboxylate (500 mg, 2.16 mmol) in dichloromethane (11 mL) was added hydrogen chloride (4 N solution in dioxane, 11 mL). The reaction mixture was stirred at 25^°C for 12 hours. The mixture was concentrated under reduced pressure to afford 2-(3-methoxyazetidin-3- yl)ethan-1-ol hydrochloride as a yellow oil (385 mg, quantitative yield, crude).1H-NMR (400 MHz; DMSO-d6): δ 9.49 (d, J = 47.5 Hz, 2H), 4.22 (s, 2H), 3.91-3.80 (m, 4H), 3.46 (t, J = 6.4 Hz, 2H), 3.16 (s, 3H), 2.00 (t, J = 6.4 Hz, 2H). Step 2.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2- hydroxyethyl)-3-methoxyazetidin-1-yl)benzenesulfonamide

[0462] In an experimental procedure similar to Example 25, Step 1, 3,6-dichloro-N–[(2,4- dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (600- 117 - mg, 1.18 mmol) in N,N-dimethylformamide (5.9 mL) was converted to 3,6-dichloro-N- (2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3- methoxyazetidin-1-yl)benzenesulfonamide as an off-white solid (630 mg, 87% yield). MS (ES+) m / z 533.2 (M+1), 535.2 (M+1).1H-NMR (400 MHz; DMSO-d6): δ 7.93 (q, J = 8.3 Hz, 1H), 7.13-7.06 (m, 2H), 6.90 (dd, J = 8.0, 2.7 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.47- 6.43 (m, 2H), 5.03 (s, 2H), 4.47-4.46 (m, 1H), 4.24-4.18 (m, 4H), 3.74 (d, J = 12.7 Hz, 6H), 3.51-3.48 (m, 2H), 3.19 (s, 3H), 2.00-1.97 (m, 2H). Step 3.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3- methoxy-3-(2-oxoethyl)azetidin-1-yl)benzenesulfonamide

[0463] 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2- hydroxyethyl)-3-methoxyazetidin-1-yl)benzenesulfonamide (630 mg, 1.02 mmol) was dissolved in dichloromethane (5.1 mL), and Dess–Martin periodinane (454 mg, 1.07 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and washed sequentially with aqueous sodium thiosulfate (20 mL) and brine (25 mL), then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 3,6-dichloro-N-(2,4- dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2- oxoethyl)azetidin-1-yl)benzenesulfonamide (630 mg, quantitative yield, crude) as a colorless solid. MS (ES+) m / z 616.2, 618.2 (M+1).1H-NMR (400 MHz; DMSO- d6): δ 9.65 (t, J = 2.0 Hz, 1H), 8.09-8.01 (m, 1H), 7.93 (q, J = 8.3 Hz, 1H), 7.12 (dd, J = 7.9, 2.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.0, 2.7 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.5, 2.4 Hz, 1H), 5.04 (s, 2H), 4.35 (q, J = 8.1 Hz, 4H), 3.74 (d, J = 13.1 Hz, 6H), 3.24 (s, 3H), 3.05 (d, J = 1.9 Hz, 2H) Step 4.3,6-dichloro-N-(2,4-dimethoxybenzyl)-4-(3-(2-(dimethylamino)ethyl)-3- methoxyazetidin-1-yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0464] To a solution of 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(2-oxoethyl)azetidin-1-yl)benzenesulfonamide (100 mg, 0.162 mmol) in tetrahydrofuran (0.81 mL) was added N- methylmethanamine;hydrochloride (33 mg, 0.406 mmol), followed by triethylamine (0.091 mL, 0.649 mmol) and titanium(IV) isopropoxide (0.540 mL, 0.162 mmol). The reaction mixture was stirred at 25^°C for 20 hours. Sodium cyanoborohydride (0.81 mL, 0.81 mmol, 1N in dioxane) was then added, and the reaction was stirred for an additional- 118 - 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3,6-dichloro-N-(2,4-dimethoxybenzyl)-4- (3-(2-(dimethylamino)ethyl)-3-methoxyazetidin-1-yl)-2-fluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (106 mg, quantitative yield) as a yellow oil. MS (ES+) m / z 645.4, 647.2 (M+1). Step 5.3,6-dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazetidin-1-yl)-2-fluoro-N- (6-fluoropyridin-2-yl)benzenesulfonamide

[0465] To a solution of 3,6-dichloro-N-(2,4-dimethoxybenzyl)-4-(3-(2- (dimethylamino)ethyl)-3-methoxyazetidin-1-yl)-2-fluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (106 mg, 0.162 mmol) in dichloromethane (0.81 mL) was added trifluoroacetic acid (0.81 mL). The reaction mixture was stirred at 25^°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient elution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fractions were collected and lyophilized to afford 3,6-dichloro-4-(3-(2-(dimethylamino)ethyl)-3-methoxyazetidin-1- yl)-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide namide (27.2 mg, 0.045 mmol, 28% yield, 98% purity) as an off-white solid. MS (ES+) m / z 495.0, 497.0 (M+1).1H- NMR (400 MHz; DMSO-d6): δ 7.47-7.41 (m, 1H), 6.52 (dd, J = 7.9, 2.6 Hz, 1H), 6.34 (t, J = 2.1 Hz, 1H), 6.15 (dd, J = 7.6, 2.7 Hz, 1H), 4.07-4.01 (m, 4H), 3.19 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 2.41 (s, 6H), 2.10-2.06 (m, 2H).

[0466] The following further Examples listed in Table 6 were prepared analogously to Example 46 (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).- 119 - Table 6- 120 -- 121 -Example 59 (R)-3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3- methylpiperidin-1-yl)ethyl)azetidin-1-yl)benzenesulfonamideStep 1.3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxyazetidine- 122 -

[0467] To a solution of 2-(3-methoxyazetidin-3-yl)ethanol hydrochloride (410 mg, 2.45 mmol) in dichloromethane (5.01 mL) was added tert-butyldimethylsilyl chloride (387 mg, 2.57 mmol) and triethylamine (1.0 mL, 7.34 mmol). The reaction mixture was stirred at 25^°C for 12 hours. Upon completion, the reaction was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxyazetidine as a light yellow oil (390 mg, 65% yield). MS (ES+) m / z 245.9 (M+1); no UV absorbance detected by DAD under standard LCMS conditions.1H-NMR (400 MHz; DMSO-d6): δ 3.64 (t, J = 6.8 Hz, 2H), 3.10-3.08 (m, 4H), 1.99-1.91 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H). Step 2.4-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxyazetidin-1-yl)-3-chloro-N- (2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0468] In an experimental procedure similar to Example 25, Step 1, 3-chloro-N–[(2,4- dimethoxyphenyl)methyl]-2,4,6-trifluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (600 mg, 1.22 mmol) was converted to a crude residue (0.876 g, quantitative yield) which was carried forward to the next step without further purification. MS (ES+) m / z 716.4 (M+1). Step 3.3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2- hydroxyethyl)-3-methoxyazetidin-1-yl)benzenesulfonamide

[0469] The crude starting material (1.00 g, 1.396 mmol) was dissolved in tetrahydrofuran (11.6 mL), and tetrabutylammonium fluoride (2.79 mL, 1 M solution in tetrahydrofuran) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 45 minutes, and completion was confirmed by LCMS. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with saturated aqueous sodium bicarbonate (25 mL), water (3 × 25 mL), and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using a gradient elution of 5% to 95% ethyl acetate in heptane to afford 3-chloro-N-(2,4- dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3- methoxyazetidin-1-yl)benzenesulfonamide (0.676 g, 80% yield). MS (ES+) m / z 602.2, 604.2 (M+1). Step 4.3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- methoxy-3-(2-oxoethyl)azetidin-1-yl)benzenesulfonamide- 123 -

[0470] In an experimental procedure similar to Example 46, Step 3, 3-chloro-N-(2,4- dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-(2-hydroxyethyl)-3- methoxyazetidin-1-yl)benzenesulfonamide (675 mg, 1.12 mmol) was converted to 3- chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3- (2-oxoethyl)azetidin-1-yl)benzenesulfonamide (370 mg, 55% yield) as a colorless solid. MS (ES+) m / z 600.2, 602.2 (M+1). Step 5. (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4- (3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azetidin-1-yl)benzenesulfonamide

[0471] In an experimental procedure similar to Example 46, Step 4, 3-chloro-N–[(2,4- dimethoxyphenyl)methyl]-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-[3-methoxy-3-(2- oxoethyl)azetidin-1-yl]benzenesulfonamide (175 mg, 0.292 mmol) was converted to the crude title compound (198 mg, quantitative yield) as a yellow oil. MS (ES+) m / z 683.4, 685.4 (M+1). Step 6. (R)-3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3- methylpiperidin-1-yl)ethyl)azetidin-1-yl)benzenesulfonamide

[0472] To a solution of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azetidin-1- yl)benzenesulfonamide (198 mg, 0.291 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL) and 1,3,5-trimethoxybenzene (49.0 mg, 0.292 mmol). The reaction mixture was stirred at 25^°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient elution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fractions were collected and lyophilized to afford (R)-3-chloro-2,6-difluoro- N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(2-(3-methylpiperidin-1-yl)ethyl)azetidin-1- yl)benzenesulfonamide (108.6 mg, 0.204 mmol, 70% yield, 100% purity) as a colourless solid. MS (ES+) m / z 533.2 (M+1), 535.2 (M+1).1H-NMR (400 MHz; DMSO- d6): δ 7.69 (q, J = 8.3 Hz, 1H), 6.76 (dd, J = 7.9, 2.2 Hz, 1H), 6.49 (dd, J = 7.8, 2.2 Hz, 1H), 6.25 (d, J = 12.7 Hz, 1H), 4.08 (q, J = 8.6 Hz, 4H), 3.38-3.31 (m, 2H), 3.20 (s, 3H), 2.98-2.86 (m, 2H), 2.69-2.63 (m, 1H), 2.39 (t, J = 11.6 Hz, 1H), 2.32-2.22 (m, 2H), 1.89- 1.63 (m, 4H), 1.07-0.97 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H).

[0473] The following further Examples listed in Table 7 were prepared analogously to Example 59 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by- 124 - common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC). Table 7Examples 61 and 62 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-((R)-6-((R)-3-methylpiperidin-1-yl)-2- azaspiro[3.5]nonan-2-yl)benzenesulfonamide (Stereoisomers 1 and 2)Step 1.2-azaspiro[3.5]nonan-6-one hydrochloride

[0474] To a solution of tert-butyl 6-oxo-2-azaspiro[3.5]nonane-2-carboxylate (400 mg, 1.67 mmol) in dichloromethane (8.4 mL) was added hydrogen chloride (4 N solution in dioxane, 8.4 mL, 33.4 mmol). The reaction mixture was stirred at 25^°C for 12 hours. The mixture was concentrated under reduced pressure to afford 2-azaspiro[3.5]nonan-6- one hydrochloride (319 mg, quantitative yield, crude) as a yellow oil.1H NMR (400- 125 - MHz; DMSO-d6) δ 9.42 (d, J = 48.8 Hz, 2H), 3.74-3.68 (m, 2H), 3.64-3.58 (m, 2H), 2.65 (s, 2H), 2.21 (t, J = 6.7 Hz, 2H), 1.98 (t, J = 5.9 Hz, 2H), 1.75-1.69 (m, 2H). Step 2.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6- oxo-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0475] In an experimental procedure similar to Example 25, Step 1, 3,6-dichloro-N-[(2,4- dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (220 mg, 0.434 mmol) in DMF (2.2 mL) was converted to 3,6-dichloro-N-(2,4- dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-oxo-2-azaspiro[3.5]nonan-2- yl)benzenesulfonamide (0.176 g, 65% yield) as colourless solid. MS (ES+) m / z 626.2 (M+1), 628.2 (M+1).1H NMR (400 MHz; CDCl3): δ 7.65 (q, J = 8.1 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 7.9, 1.9 Hz, 1H), 6.61 (dd, J = 8.0, 3.0 Hz, 1H), 6.41 (d, J = 7.3 Hz, 2H), 6.18 (d, J = 1.6 Hz, 1H), 5.19 (s, 2H), 4.02 (q, J = 6.3 Hz, 4H), 3.78 (d, J = 3.3 Hz, 6H), 2.66 (s, 2H), 2.37 (t, J = 6.6 Hz, 2H), 2.05 (dd, J = 7.7, 4.9 Hz, 2H), 1.94-1.88 (m, 2H). Step 3.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6- ((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0476] In an experimental procedure similar to Example 46, Step 4, 3,6-dichloro-N-(2,4- dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-oxo-2-azaspiro[3.5]nonan-2- yl)benzenesulfonamide (175 mg, 0.279 mmol) was converted to 3,6-dichloro-N-(2,4- dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)-2- azaspiro[3.5]nonan-2-yl)benzenesulfonamide (198 mg, quantitative yield, crude) as a yellow oil. MS (ES+) m / z 709.4, 711.3 (M+1). Step 4.3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)- 2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0477] To a solution of 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]nonan-2- yl)benzenesulfonamide (198 mg, 0.279 mmol) in dichloromethane (1.41 mL) was added trifluoroacetic acid (1.41 mL) and 1,3,5-trimethoxybenzene (47.0 mg, 0.279 mmol). The reaction mixture was stirred at 25^°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography using a gradient elution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fractions were collected and lyophilized to afford 3,6- dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-((R)-3-methylpiperidin-1-yl)-2-- 126 - azaspiro[3.5]nonan-2-yl)benzenesulfonamide as a colourless solid (97.3 mg, 0.158 mmol, 56% yield, 98% purity). MS (ES+) m / z 559.2 (M+1), 561.2 (M+1).1H NMR (400 MHz; DMSO-d6) δ 7.62 (q, J = 8.4 Hz, 1H), 6.67 (dd, J = 8.0, 2.2 Hz, 1H), 6.42-6.39 (m, 1H), 6.31 (d, J = 1.0 Hz, 1H), 4.00-3.98 (m, 1H), 3.91-3.83 (m, 3H), 3.26-3.17 (m, 2H), 2.96- 2.92 (m, 1H), 2.72-2.64 (m, 1H), 2.45-2.39 (m, 1H), 2.32-2.24 (m, 1H), 1.89-1.70 (m, 7H), 1.37-1.23 (m, 3H), 1.07-0.96 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H). Step 5.3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-(3-methylpiperidin-1-yl)-2- azaspiro[3.5]nonan-2-yl)benzenesulfonamide (Stereoisomers 1 and 2)

[0478] Stereoisomers of 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6-(3- methylpiperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide (0.0350 g, 0.0578 mmol) were separated by chiral SFC (Column :Daicel Chiralpak AD column (250 × 30 mm, 10 µm). Mobile Phase: 55% ethanol (0.1% ammonium hydroxide) in Supercritical carbon dioxide. Flow Rate: 70 g / min. Cycle Time: 2.6 min. Back Pressure: 100 bar to keep the carbon dioxide in Supercritical flow. UV: 220nm). Two peaks were separated.

[0479] Peak 1 (Retention time = 1.385 min) was purified by prep-HPLC (column: Waters xbridge 150 mm × 25 mm ×10 µm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient:38%-58% B over 8.0 min). The desired fraction was concentrated and lyophilized to give 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6- (3-methylpiperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide (Stereoisomer 1) (0.0022 g, 0.0039 mmol, 98% purity, 99% ee) as a colourless solid. MS (ES+) m / z 559.2, 561.2, 563.2 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.56–7.47 (m, 1H), 7.11–7.05 (m, 1H), 6.40–6.31 (m, 1H), 6.08 (s, 1H), 3.91–3.75 (m, 3H), 3.71–3.61 (m, 1H), 3.54– 3.39 (m, 2H), 3.19–3.04 (m, 1H), 2.69–2.62 (m, 1H), 2.44 (d, J = 2.8 Hz, 1H), 2.36–2.25 (m, 3H), 2.18–2.07 (m, 2H), 2.00–1.95 (m, 1H), 1.91–1.84 (m, 2H), 1.80 (d, J = 13.2 Hz, 2H), 1.67–1.60 (m, 1H), 1.28 (d, J = 4.4 Hz, 1H), 1.01–0.94 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).

[0480] Peak 2 (Retention time = 1.852 min) was purified by prep-HPLC (column: Phenomenex Luna C18150 mm × 25 mm ×10 µm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient:29%-49% B over 10.0 min). The desired fraction was concentrated and lyophilized to give 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(6- ((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide (Stereoisomer 2) (0.0046 g, 0.0081 mmol, 99% purity, 98% ee) as a colourless solid. MS (ES+) m / z 559.1, 561.1, 563.1 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.58–7.47 (m, 1H),- 127 - 7.07 (dd, J = 2.0, 8.0 Hz, 1H), 6.37 (dd, J = 2.4, 7.6 Hz, 1H), 6.07 (s, 1H), 3.87 (td, J = 9.2, 18.0 Hz, 3H), 3.73–3.63 (m, 1H), 3.62–3.52 (m, 1H), 3.45–3.35 (m, 1H), 3.26–3.17 (m, 1H), 2.77–2.59 (m, 3H), 2.56–2.34 (m, 2H), 2.20–2.04 (m, 2H), 2.02–1.95 (m, 1H), 1.95–1.86 (m, 2H), 1.85–1.76 (m, 2H), 1.67 (t, J = 12.4 Hz, 1H), 1.34 (s, 1H), 0.96 (d, J = 6.4Hz, 4H).

[0481] The following further Examples listed in Table 8 were prepared analogously to Examples 61 and 62 (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 8- 128 -- 129 -- 130 -- 131 -- 132 -- 133 -- 134 -- 135 -- 136 -Examples 116 and 117 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)-2,6-difluoro-N- (pyridin-2-yl)benzenesulfonamide (Stereoisomers 1 and 2)- 137 -Step 1. tert-butyl 5-cyano-2-azaspiro[3.4]octane-2-carboxylate

[0482] To a solution of tert-butyl 5-oxo-2-azaspiro[3.4]octane-2-carboxylate (0.500 g, 2.22 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (0.865 g, 4.43 mmol ) in 1,2-dimethoxyethane (7.5 mL) and methanol (0.5 mL) was added potassium 2- methylpropan-2-olate (1 M, 6.7 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (8 mL). The pH was neutralized to 7 with 1 N hydrochloric acid. The mixture was diluted with ethyl acetate (8 mL), the layers were separated and the aqueous phase was extracted with ethyl acetate (3 × 7 mL). The combined organic extracts were washed with brine (13 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether) to give tert- butyl 5-cyano-2-azaspiro[3.4]octane-2-carboxylate (0.350 g, 1.48 mmol, 67% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 4.14 (d, J = 9.2 Hz, 1H), 3.91–3.66 (m, 3H), 2.91–2.82 (m, 1H), 2.14–1.64 (m, 6H), 1.45 (s, 9H). Step 2. To a mixture of tert-butyl 5-cyano-2-azaspiro[3.4]octane-2-carboxylate (0.350 g, 1.48 mmol) in methanol (20.0 mL) and ammonia liquor (5 mL) was added Raney-nickel (0.350 g, 4.09 mmol) under nitrogen.^ The solution was purged with hydrogen for three times and then stirred at 25 °C for 16 h under hydrogen (50 psi).^ The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to give tert-butyl 5-(aminomethyl)-2-azaspiro[3.4]octane-2-carboxylate (0.350 g, crude) as a- 138 - yellow oil.^1H NMR (400 MHz, CDCl3) δ 3.92 (d, J = 8.8 Hz, 1H), 3.81–3.66 (m, 2H), 3.58–3.46 (m, 1H), 2.96 (dd, J = 4.4, 12.0 Hz, 1H), 2.56 (dd, J = 9.2, 12.4 Hz, 1H), 1.90– 1.82 (m, 4H), 1.65–1.53 (m, 2H), 1.44 (s, 9H), 1.38–1.28 (m, 1H).^ Step 3. tert-butyl 5-((dimethylamino)methyl)-2-azaspiro[3.4]octane-2-carboxylate

[0483] To a solution of tert-butyl 5-(aminomethyl)-2-azaspiro[3.4]octane-2-carboxylate (0.120 g, 0.499 mmol) and formaldehyde (0.405 g, 4.99 mmol, 37% in water) in methanol (1.0 mL) was added sodium cyanoborohydride (0.0950 g, 1.51 mmol). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated. The residue was diluted with dichloromethane (3 mL) and sodium bicarbonate (3 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 4 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert- butyl 5-((dimethylamino)methyl)-2-azaspiro[3.4]octane-2-carboxylate (0.105 g, crude) as a yellow oil. MS (ES+) m / z 269.1 (M + 1). Step 4. N,N-dimethyl-1-(2-azaspiro[3.4]octan-5-yl)methanamine

[0484] In an experimental procedure similar to Example 35, Step 2, tert-butyl 5- ((dimethylamino)methyl)-2-azaspiro[3.4]octane-2-carboxylate (0.105 g, 391 mmol) was converted to N,N-dimethyl-1-(2-azaspiro[3.4]octan-5-yl)methanamine (0.0950 g, crude, 2 hydrochloride) as a colorless oil.1H NMR (400 MHz, MeOD-d4) δ 4.23–4.10 (m, 2H), 3.91–3.74 (m, 2H), 3.46 (d, J = 12.8 Hz, 1H), 3.17 (t, J = 12.0 Hz, 1H), 2.97 (d, J = 10.4 Hz, 6H), 2.48–2.37 (m, 1H), 2.10–2.03 (m, 2H), 2.01–1.94 (m, 1H), 1.81–1.72 (m, 2H), 1.59–1.48 (m, 1H). Step 5.3-chloro-N-(2,4-dimethoxybenzyl)-4-(5-((dimethylamino)methyl)-2- azaspiro[3.4]octan-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0485] In an experimental procedure similar to Example 25, Step 1, N,N-dimethyl-1-(2- azaspiro[3.4]octan-5-yl)methanamine (0.0950 g, 0.394 mmol, 2 hydrochloride) was converted to 3-chloro-N-(2,4-dimethoxybenzyl)-4-(5-((dimethylamino)methyl)-2- azaspiro[3.4]octan-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfon amide (0.110 g, 0.159 mmol, 40% yield, 99% purity, formate) as a white solid. MS (ES+) m / z 639.2, 641.2 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.66 (q, J = 8.0 Hz, 1H), 7.26–7.20 (m, 2H), 6.64 (dd, J = 3.2, 8.0 Hz, 1H), 6.43–6.32 (m, 2H), 5.91–5.79 (m, 1H), 5.10 (s, 2H), 4.24 (d, J = 8.8 Hz, 1H), 4.13–4.01 (m, 2H), 3.85 (d, J = 8.4 Hz, 1H), 3.74 (d, J =- 139 - 6.8 Hz, 6H), 2.56 (dd, J = 4.8, 12.0 Hz, 1H), 2.42–2.28 (m, 7H), 2.09–1.99 (m, 1H), 1.98– 1.86 (m, 3H), 1.65 (quin, J = 7.6 Hz, 2H), 1.48–1.36 (m, 1H). Step 6.3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0486] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-(5- ((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (0.110 g, 0.159 mmol, formate) in dichloromethane (3.0 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150 mm × 25 mmmobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 18%–38% B over 10 min). The desired fraction was collected and lyophilized to give 3-chloro-4-(5-((dimethylamino)methyl)-2- azaspiro[3.4]octan-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0500 g, 0.0992 mmol, 62% yield, 97% purity) as a white solid. MS (ES+) m / z 489.0, 491.0 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.63 (q, J = 8.0 Hz, 1H), 7.12 (dd, J = 2.0, 8.0 Hz, 1H), 6.49 (dd, J = 2.4, 8.0 Hz, 1H), 5.76 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 8.8 Hz, 1H), 4.13–3.94 (m, 2H), 3.83 (d, J = 8.8 Hz, 1H), 2.92–2.84 (m, 1H), 2.56–2.40 (m, 7H), 2.29–2.17 (m, 1H), 2.04–1.81 (m, 3H), 1.74–1.62 (m, 2H), 1.53–1.40 (m, 1H). Step 7.3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide (Stereoisomers 1 and 2)

[0487] 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)-2,6-difluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.0500 g, 0.0992 mmol) was purified by chiral SFC (column: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 µm); mobile phase: [carbon dioxide - ethyl alcohol ((0.1% ammonium hydroxide)]; B%: 30%, isocratic elution mode). Two peaks were isolated and collected. Stereochemistry was assigned arbitrarily.

[0488] Peak 1 (retention time = 7.389 min) was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)- acetonitrile]; gradient: 23%–43% B over 10 min) and lyophilized to give 3-chloro-4-(5- ((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomer 1) (0.0146 g, 0.0268 mmol, 29% yield, 98% purity, formate, 96% ee) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.61 (q, J = 8.4 Hz, 1H), 7.07 (dd, J = 1.6, 8.0 Hz, 1H), 6.44 (dd, J = 2.4, 8.0 Hz, 1H), 5.72 (d, J = 12.8 Hz, 1H),- 140 - 4.20 (d, J = 8.8 Hz, 1H), 4.11–3.95 (m, 2H), 3.81 (d, J = 8.8 Hz, 1H), 3.12 (dd, J = 2.4, 12.4 Hz, 1H), 2.73–2.50 (m, 7H), 2.26 (d, J = 6.4 Hz, 1H), 2.02 (dd, J = 7.2, 13.2 Hz, 1H), 1.95–1.80 (m, 2H), 1.69 (quin, J = 7.6 Hz, 2H), 1.49 (dd, J = 7.6, 13.2 Hz, 1H). MS (ES+) m / z 489.1, 491.1 (M + 1).

[0489] Peak 2 (retention time = 8.310 min) was re-purified by chiral SFC (column: DAICEL CHIRALCEL OX (250 mm × 30 mm × 10 µm); mobile phase: [carbon dioxide - ethyl alcohol (0.1% ammonium hydroxide)]; B%: 30%, isocratic elution mode) followed by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 24%–44% B over 8 min) and lyophilized to give 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.4]octan-2-yl)- 2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (Stereoisomer 2) (0.0151 g, 0.0277 mmol, 30% yield, 98% purity, formate, 96% ee) as a white solid. MS (ES+) m / z 489.1, 491.1 (M + 1).1H NMR (400 MHz, CDCl3) δ 7.61 (q, J = 8.0 Hz, 1H), 7.06 (dd, J = 2.0, 8.0 Hz, 1H), 6.44 (dd, J = 2.4, 8.0 Hz, 1H), 5.71 (d, J = 12.4 Hz, 1H), 4.20 (d, J = 8.8 Hz, 1H), 4.10–3.98 (m, 2H), 3.81 (d, J = 8.4 Hz, 1H), 3.10 (dd, J = 2.8, 12.8 Hz, 1H), 2.67–2.49 (m, 7H), 2.32–2.19 (m, 1H), 2.01 (dd, J = 7.2, 13.2 Hz, 1H), 1.94–1.82 (m, 2H), 1.69 (quin, J = 7.2 Hz, 2H), 1.55–1.43 (m, 1H). Examples 118 and 119 3-chloro-4-(5-((dimethylamino)methyl)-2-azaspiro[3.3]heptan-2-yl)-2,6-difluoro-N-(6- fluoropyridin-2-yl)benzenesulfonamide (Stereoisomers 1 and 2)

[0490] Examples 118 and 119 were prepared analogously to Examples 116 and 117.

[0491] Example 118:1H NMR (400 MHz, CDCl3) δ 7.57 (q, J = 8.0 Hz, 1H), 7.14–7.05 (m, 1H), 6.36 (dd, J = 2.4, 5.6 Hz, 1H), 5.81 (d, J = 12.0 Hz, 1H), 4.38 (d, J = 8.8 Hz, 1H), 4.11–3.95 (m, 3H), 3.23–3.10 (m, 1H), 2.82–2.71 (m, 1H), 2.65–2.58 (m, 1H), 2.54 (s, 6H), 2.26–2.10 (m, 3H), 1.75–1.62 (m, 1H). MS (ES+) m / z 475.1, 477.1 (M + 1).

[0492] Example 119:1H NMR (400 MHz, CDCl3) δ 7.60–7.50 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 12.8 Hz, 1H), 4.38 (d, J = 8.4 Hz, 1H), 4.07– 4.01 (m, 3H), 3.19 (d, J = 11.6 Hz, 1H), 2.82–2.71 (m, 1H), 2.67–2.60 (m, 1H), 2.56 (s, 6H), 2.25–2.14 (m, 3H), 1.74–1.63 (m, 1H). MS (ES+) m / z 475.1, 477.1 (M + 1) Examples 120 and 121 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3- yl)azetidin-1-yl)benzenesulfonamide (Stereoisomers 1 and 2)- 141 -Step 1. benzyl 3-hydroxy-3-(1-methyl-2-oxopyrrolidin-3-yl)azetidine-1-carboxylate

[0493] A mixture of 1-methylpyrrolidin-2-one (3.00 g, 30.2 mmol, 2.94 mL) in tetrahydrofuran (20.0 mL) was degassed and purged with nitrogen for 3 times, and then lithium di(propan-2-yl)azanide (2 M, 18.2 mL) was added into the solution at -78 ºC, the mixture was stirred at -78 °C for 1 hr, then the tetrahydrofuran (15.0 mL) solution of benzyl 3-oxoazetidine-1-carboxylate (6.21 g, 30.3 mmol) was added into the solution under nitrogen atmosphere at -78 °C. Then the reaction mixture was stirred at -78 °C for 1 hr. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18150*25*7um ; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 23%-53% B over 13.0 min). Compound benzyl 3-hydroxy-3-(1-methyl-2-oxopyrrolidin-3-yl)azetidine-1- carboxylate (6.20 g, 20.4 mmol, 67.3% yield) was obtained as a white solid. MS (ES-) m / z 305.0 (M+1). Step 2. benzyl 3-methoxy-3-(1-methyl-2-oxo-pyrrolidin-3-yl)azetidine-1-carboxylate

[0494] A mixture of benzyl 3-hydroxy-3-(1-methyl-2-oxo-pyrrolidin-3-yl)azetidine-1- carboxylate (5.20 g, 17.1 mmol) in N,N-Dimethylformamide (50.0 mL) and tetrahydrofuran (50.0 mL) was degassed and purged with nitrogen for 3 times, and then sodium hydrogen (1.37 g, 34.2 mmol, 60.0% purity) was added into the solution at 0 °C, the mixture was stirred at 0 °C for 1 hr under nitrogen atmosphere. Then iodomethane (4.85 g, 34.2 mmol, 2.13 mL) was added into the solution at 0 °C, the mixture was stirred- 142 - at 20 °C for 15 hrs. The reaction mixture was quenched by ammonium chloride (300 mL), extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC hexanes : Ethyl acetate. Compound benzyl 3-methoxy-3-(1-methyl-2-oxo- pyrrolidin-3-yl)azetidine-1-carboxylate (5.30 g, 16.6 mmol, 97.4% yield) was obtained as yellow oil. MS (ES-) m / z 319.0 (M+1). Step 3. benzyl 3-methoxy-3-(1-methylpyrrolidin-3-yl)azetidine-1-carboxylate

[0495] A mixture of benzyl 3-methoxy-3-(1-methyl-2-oxo-pyrrolidin-3-yl)azetidine-1- carboxylate (1.40 g, 4.40 mmol) in tetrahydrofuran (15.0 mL) was degassed and purged with nitrogen for 3 times, and then borane-methyl sulfide complex (10.0 M, 2.20 mL) was added into the solution at 0 °C, the mixture was stirred at 25 °C for 16 hrs under nitrogen atmosphere The reaction mixture was quenched by methanol (30.0 mL). Then the solution was concentrated under reduced pressure to remove solvent. Compound benzyl 3-methoxy-3-(1-methylpyrrolidin-3-yl)azetidine-1-carboxylate (1.00 g, 3.29 mmol, 74.7% yield) was obtained as colourless oil. MS (ES-) m / z 305.2 (M+1).1H NMR: (400 MHz, DMSO-d6) δ 7.37 - 7.32 (m, 5H), 5.05 (s, 2H), 3.96 - 3.77 (m, 4H), 3.24 (s, 3H), 3.11 - 3.01 (m, 3H), 2.90 - 2.83 (m, 1H), 2.63 (s, 3H), 2.21 - 2.11 (m, 1H), 1.71 - 1.63 (m, 2H). Step 4.3-(3-methoxyazetidin-3-yl)-1-methyl-pyrrolidine

[0496] To a solution of benzyl 3-methoxy-3-(1-methylpyrrolidin-3-yl)azetidine-1- carboxylate (500 mg, 1.64 mmol) in tetrahydrofuran (10.0 mL) was added wet palladium carbon (300 mg, 281 μmol, 10.0% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25°C for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated. Compound 3-(3-methoxyazetidin-3-yl)-1-methyl-pyrrolidine (278 mg, 1.63 mmol, 99.4% yield) was obtained as colourless oil.1H NMR: (400 MHz, DMSO-d6) δ 3.50 - 3.47 (m, 1H), 3.24 - 3.12 (m, 5H), 2.63 - 2.56 (m, 1H), 2.47 - 2.44 (m, 1H), 2.40 - 2.31 (m, 2H), 2.21 (s, 3H), 1.85 - 1.65 (m, 2H). Step 5.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpyrrolidin-3-yl)azetidin-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (Stereoisomers 1 and 2)- 143 -

[0497] To a solution of 3-chloro-2,4,6-trifluoro-N-(6-fluoro-2-pyridyl)-N-[(4- methoxyphenyl)methyl]benzenesulfonamide (500 mg, 1.09 mmol), 3-(3- methoxyazetidin-3-yl)-1-methyl-pyrrolidine (277 mg, 1.63 mmol) in N,N- Dimethylformamide (5.00 mL) was added triethylamine (329 mg, 3.26 mmol, 453 μL). The mixture was stirred at 20 °C for 1 hr. . The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (silica, Dichloromethane : Methanol = 10: 1, TLC: Dichloromethane : Methanol = 10: 1, Rf= 0.47 (P1)). The residue was purified by SFC (column: Chiral-OX-30- DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH: CAN = 7:3 (0.1% NH3•H2O)]; B%:42%, isocratic elution mode). Compound 3-chloro-2,6- difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azetidin-1- yl)-N-(4-methoxybenzyl)benzenesulfonamide (Stereoisomer 1) (150 mg, 245 μmol, 22.6% yield) and 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpyrrolidin-3-yl)azetidin-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (Stereoisomer 2) (140 mg, 229 μmol, 21.1% yield) was obtained as colourless oil. LCMS: MS (ES-) m / z 611.4 (M+1). Step 6.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpyrrolidin-3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 1)

[0498] To a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3- (1-methylpyrrolidin-3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 1) (150 mg, 245 μmol) in dichloromethane (2.50 mL) was added trifluoroacetic acid (3.84 g, 33.7 mmol, 2.50 mL). The mixture was stirred at 20 °C for 10 min. The reaction mixture was poured into the saturated solution of sodium hydrogen carbonate (50.0 mL), extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica, Dichloromethane : Methanol = 10: 1. Compound 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azetidin-1- yl)benzenesulfonamide (Stereoisomer 1) (63.5 mg, 126 μmol, 51.6% yield, 98.0% purity) was obtained as a white solid. MS (ES-) m / z 491.0 (M+1).1H NMR: (400 MHz, DMSO- d6) δ 10.9 (br s, 1H), 7.56 (q, J = 8.4 Hz, 1H), 6.64 (dd, J = 2.0, 8.0 Hz, 1H), 6.31 (br d, J- 144 - = 6.8 Hz, 1H), 6.25 (br d, J = 12.4 Hz, 1H), 4.14 - 4.08 (m, 4H), 3.26 (s, 3H), 3.20 - 3.10 (m, 2H), 3.01 - 2.95 (m, 3H), 2.66 (s, 3H), 2.09 - 2.06 (m, 1H), 1.84 - 1.75 (m, 1H). Step 7.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpyrrolidin-3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 2)

[0499] To a solution of 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3- (1-methylpyrrolidin-3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 2) (140 mg, 229 μmol) in dichloromethane (2.50 mL) was added trifluoroacetic acid (3.84 g, 33.7 mmol, 2.50 mL). The mixture was stirred at 20 °C for 10 min. The reaction mixture was poured into the saturated solution of sodium hydrogen carbonate (50.0 mL), extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica, Dichloromethane : Methanol = 10: 1,. Compound 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3-yl)azetidin-1- yl)benzenesulfonamide (Stereoisomer 2) (79.1 mg, 157 μmol, 68.9% yield, 98.0% purity) was obtained as a white solid. MS (ES-) m / z 491.1 (M+1).1H NMR (400 MHz, DMSO- d6) δ 10.89 (br s, 1H), 7.56 (q, J = 8.4 Hz, 1H), 6.64 (dd, J = 2.0, 8.0 Hz, 1H), 6.31 (br d, J = 6.8 Hz, 1H), 6.25 (br d, J = 12.4 Hz, 1H), 4.14 - 4.07 (m, 4H), 3.26 (s, 3H), 3.20 - 3.10 (m, 2H), 3.01 - 2.96 (m, 3H), 2.64 (s, 3H), 2.09 - 2.04 (m, 1H), 1.82 - 1.75 (m, 1H). Examples 122 and 123 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3- yl)azetidin-1-yl)benzenesulfonamide (Stereoisomers 1 and 2)- 145 -Step 1. benzyl 3-hydroxy-3-(1-methyl-2-oxo-3-piperidyl)azetidine-1-carboxylate

[0500] In an experimental procedure similar to Examples 120 and 121, Step 1, benzyl 3- hydroxy-3-(1-methyl-2-oxo-3-piperidyl)azetidine-1-carboxylate (9.50 g, 29.8 mmol, 96.5% yield) was prepared and obtained as a white solid. MS (ES-) m / z 319.1 (M+1). Step 2. benzyl 3-methoxy-3-(1-methyl-2-oxo-3-piperidyl)azetidine-1-carboxylate

[0501] In an experimental procedure similar to Examples 120 and 121, Step 2, benzyl 3- hydroxy-3-(1-methyl-2-oxo-3-piperidyl)azetidine-1-carboxylate (5.00 g, 15.7 mmol) was converted to benzyl 3-methoxy-3-(1-methyl-2-oxo-3-piperidyl)azetidine-1-carboxylate (5.20 g, 15.6 mmol, 99.6% yield) as a colourless oil. MS (ES-) m / z 333.3 (M+1). Step 3. benzyl 3-methoxy-3-(1-methyl-3-piperidyl)azetidine-1-carboxylate

[0502] A mixture of benzyl 3-methoxy-3-(1-methyl-2-oxo-3-piperidyl)azetidine-1- carboxylate (2.00 g, 6.02 mmol) in tetrahydrofuran (20.0 mL) was degassed and purged with nitrogen for 3 times, and then borane-methyl sulfide complex (10.0 M, 3.61 mL) was added into the solution at 0 °C, the mixture was stirred at 60 °C for 16 hr under nitrogen atmosphere. The reaction mixture was quenched by methanol (30.0 mL). Then the solution was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (silica, Commercial hexanes: Ethyl acetate = 1: 1, TLC: commercial hexanes: ethyl acetate = 1: 1, Rf= 0.54 (P1)). Compound benzyl 3-methoxy-- 146 - 3-(1-methyl-3-piperidyl)azetidine-1-carboxylate (350 mg, 1.10 mmol, 18.2% yield) was obtained as colourless oil. MS (ES-) m / z 319.2 (M+1).1H NMR: (400 MHz, DMSO-d6) δ 7.3 -7.31 (m, 5H), 5.04 (s, 2H), 3.99-3.74 (m, 4H), 3.21 (s, 3H), 2.85-2.77 (m, 1H), 2.75- 2.71 (m, 1H), 2.63-2.56 (m, 1H), 2.53 (s, 3H), 2.33 (t, J = 11.6 Hz, 1H), 2.10-1.98 (m, 1H), 1.74-1.71 (m, 1H), 1.59-1.55 (m, 2H), 1.20-1.10 (m, 1H). Step 4.3-(3-methoxyazetidin-3-yl)-1-methyl-piperidine

[0503] To a solution of benzyl 3-methoxy-3-(1-methyl-3-piperidyl)azetidine-1- carboxylate (350 mg, 1.10 mmol) in tetrahydrofuran (5.00 mL) was added wet palladium carbon (300 mg, 281 μmol, 10.0% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. Compound 3-(3-methoxyazetidin-3-yl)-1-methyl-piperidine (200 mg, crude) was obtained as colourless oil. Step 5.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpiperidin-3-yl)azetidin-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (Stereoisomers 1 and 2)

[0504] To a solution of 3-chloro-2,4,6-trifluoro-N-(6-fluoro-2-pyridyl)-N-[(4- methoxyphenyl)methyl]benzenesulfonamide (400 mg, 868 μmol), 3-(3-methoxyazetidin- 3-yl)-1-methyl-piperidine (191 mg, 1.04 mmol) in dimethylformamide (5.00 mL) was added triethylamine (263 mg, 2.60 mmol, 362 μL). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica, dichloromethane: methanol = 10: 1, The residue was purified by SFC (Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm × 30 mm,10 um); mobile phase: [CO2-EtOH (0.1% NH3•H2O)]; B%:42%, isocratic elution mode). Compound 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy- 3-(1-methylpiperidin-3-yl)azetidin-1-yl)-N-(4-methoxybenzyl)benzenesulfonamide (Stereoisomer 2) (70.0 mg, 111 μmol, 12.9% yield) and 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azetidin-1-yl)-N-(4- methoxybenzyl)benzenesulfonamide (Stereoisomer 1) (65.0 mg, 103 μmol, 11.9% yield) were obtained as colourless oil. MS (ES-) m / z 625.4 (M+1).- 147 - Step 6.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpiperidin-3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 1)

[0505] To a solution of 3-chloro-2,6-difluoro-N-(6-fluoro-2-pyridyl)-4-[3-methoxy-3-[1- methyl-3-piperidyl]azetidin-1-yl]-N-[(4-methoxyphenyl)methyl]benzenesulfonamide (Stereoisomer 1) (70.0 mg, 112 μmol) in dichloromethane (2.00 mL) was added trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL). The mixture was stirred at 25 °C for 10 min. The reaction mixture was poured into the saturated solution of sodium hydrogen carbonate (50.0 mL), extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica, dichloromethane: methanol = 10: 1, Compound 3-chloro-2,6-difluoro- N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azetidin-1- yl)benzenesulfonamide (Stereoisomer 1) (24.5 mg, 47.0 μmol, 42.0% yield, 97.0% purity) was obtained as a white solid. MS (ES-) m / z 505.1 (M+1).1H NMR: (400 MHz, DMSO- d6) δ 7.55 (q, J = 8.0 Hz, 1H), 6.62 (br d, J = 7.2 Hz, 1H), 6.37-6.30 (m, 1H), 6.19 (br d, J = 12.8 Hz, 1H), 4.18 - 4.00 (m, 4H), 3.26 (s, 3H), 3.23 (br s, 2H), 2.64 (br s, 1H), 2.59 (br s, 3H), 2.22-2.16 (m, 1H), 1.84-1.80 (m, 1H), 1.73-1.62 (m, 2H), 1.29-1.19 (m, 2H). Step 7.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpiperidin-3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 2)

[0506] To a solution of 3-chloro-2,6-difluoro-N-(6-fluoro-2-pyridyl)-4-[3-methoxy-3-[1- methyl-3-piperidyl]azetidin-1-yl]-N-[(4-methoxyphenyl)methyl]benzenesulfonamide (Stereoisomer 2) (65.0 mg, 104 μmol) in dichloromethane (2.00 mL) was added trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL). The mixture was stirred at 25 °C for 10 min. LCMS (EC28542-298-P1A) showed 73.2% of desired MS (Rt = 0.380 min, MS (ES-) m / z 505.1 (M+1)) was detected. The reaction mixture was poured into the saturated solution of sodium hydrogen carbonate (50.0 mL), extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica, dichloromethane: methanol = 10: 1, TLC: dichloromethane: methanol = 10: 1, Rf= 0.45 (P1)). Compound 3-chloro-2,6- difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpiperidin-3-yl)azetidin-1- yl)benzenesulfonamide (Stereoisomer 2) (17.8 mg, 34.5 μmol, 33.2% yield, 98.0% purity) was obtained as a white solid. MS (ES-) m / z 505.1 (M+1).1H NMR: 400 MHz, DMSO-- 148 - d6) δ 7.55 (q, J = 8.0 Hz, 1H), 6.62 (br d, J = 7.2 Hz, 1H), 6.37-6.30 (m, 1H), 6.19 (br d, J = 12.8 Hz, 1H), 4.18 - 4.02 (m, 4H), 3.26 (s, 3H), 3.22 (br s, 2H), 2.62 (br s, 1H), 2.58 (br s, 3H), 2.20 - 2.15 (m, 1H), 1.83-1.80 (m, 1H), 1.73-1.61 (m, 2H), 1.28-1.19 (m, 2H). Example 124 3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-((R)-3-methylpiperidin-1-yl)-5-oxa- 2-azaspiro[3.5]nonan-2-yl)benzenesulfonamideStep 1. tert-butyl 3-hydroxy-3-(4-hydroxy-2-methylenebutyl)azetidine-1-carboxylate

[0507] To a solution of 3-methylbut-3-en-1-ol (1.29 g, 15.0 mmol) in tetrahydrofuran (200 mL) was added n-butyllithium (18 mL, 45.0 mmol, 2.5 M in hexanes), followed by dropwise addition of N,N,N′,N′-tetramethylethylenediamine (0.67 mL, 4.50 mmol) in tetrahydrofuran (50 mL) at −10^°C. The mixture was stirred at this temperature for 1 hour, then a solution of tert-butyl azetidine-3-one-1-carboxylate (2.77 g, 16.2 mmol) in tetrahydrofuran (50 mL) was added. The reaction mixture was stirred at 0^°C for 2 hours. TLC (heptane / ethyl acetate = 7:3) indicated completion of the reaction (Rf = 0.10). The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using a gradient elution of 5% to 90% ethyl acetate in heptane to afford tert-butyl 3-hydroxy-3-(4- hydroxy-2-methylenebutyl)azetidine-1-carboxylate (0.67g, 17% yield) as a colourless oil. 1H NMR (400 MHz; CDCl3): δ 4.97 (dd, J = 17.1, 7.6 Hz, 2H), 3.91-3.80 (m, 5H), 3.74 (t, J = 6.0 Hz, 2H), 3.65-3.57 (m, 1H), 2.33 (t, J = 5.9 Hz, 2H), 1.69-1.58 (m, 1H), 1.44- 1.42 (m, 9H).- 149 - Step 2. tert-butyl 8-methylene-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

[0508] Tert-butyl 3-hydroxy-3-(4-hydroxy-2-methylenebutyl)azetidine-1-carboxylate (667 mg, 2.59 mmol) was dissolved in tetrahydrofuran (4.2 mL), and n-butyllithium (1.7 mL, 2.72 mmol, 2.5 M in hexanes) was added dropwise at −78^°C under a nitrogen atmosphere. A solution of p-toluenesulfonyl chloride (519 mg, 2.72 mmol) in tetrahydrofuran (1 mL) was then added dropwise at −78^°C. After the addition was complete, the reaction mixture was stirred at 0^°C for 30 minutes. n-Butyllithium (1.7 mL, 2.72 mmol, 2.5 M in hexanes) was added at 0^°C, and the mixture was warmed to ambient temperature and stirred for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. TLC (heptane / ethyl acetate = 75:25) showed the product at Rf = 0.80. The crude material was purified by column chromatography on silica gel using a gradient elution of 0% to 50% ethyl acetate in heptane to afford tert-butyl 8-methylene-5-oxa-2- azaspiro[3.5]nonane-2-carboxylate (0.285 g, 46% yield) as a colourless oil.1H NMR (400 MHz; CDCl3): δ 4.83-4.81 (m, 2H), 3.79 (d, J = 9.4 Hz, 2H), 3.70-3.68 (m, 2H), 3.63 (t, J = 5.6 Hz, 2H), 2.40 (s, 2H), 2.19 (t, J = 5.6 Hz, 2H), 1.44 (s, 9H). Step 3. tert-butyl 8-oxo-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate

[0509] To a solution of tert-butyl 8-methylene-5-oxa-2-azaspiro[3.5]nonane-2- carboxylate (285 mg, 1.19 mmol) and pyridine (0.29 mL, 3.57 mmol) in tert-butanol (12 mL) was added an aqueous solution of sodium periodate (7.1 mL, 3.57 mmol, 0.5 M) followed by osmium tetroxide (1.8 mL, 0.0705 mmol, 4 wt% in water). The reaction mixture was stirred at ambient temperature for 16 hours. An additional portion of aqueous sodium periodate (7.1 mL, 3.57 mmol, 0.5 M) was then added, and the mixture was stirred for an additional 4 hours. Brine was added, and the reaction mixture was extracted twice with dichloromethane (2 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using a gradient elution of 5% to 70% ethyl acetate in heptane to afford tert-butyl 8-oxo-5-oxa-2- azaspiro[3.5]nonane-2-carboxylate (0.213 g, 74% yield) as a colourless solid. TLC (heptane / ethyl acetate = 70:30) showed Rf = 0.17.1H NMR (400 MHz; CDCl3): δ 3.93 (dd, J = 11.0, 5.8 Hz, 4H), 3.78-3.75 (m, 2H), 2.69 (s, 2H), 2.46 (t, J = 6.0 Hz, 2H), 1.43 (s, 9H)- 150 - Step 4.5-oxa-2-azaspiro[3.5]nonan-8-one hydrochloride

[0510] To a solution of tert-butyl 8-oxo-5-oxa-2-azaspiro[3.5]nonane-2-carboxylate (213 mg, 0.883 mmol) in dichloromethane (4.4 mL) was added hydrochloric acid (4.4 mL, 17.7 mmol, aqueous). The reaction mixture was stirred at 25^°C for 4 hours. The mixture was then concentrated under reduced pressure, and the resulting residue (152 mg, 98%) was carried forward to the next step without further purification. Step 5.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8- oxo-5-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0511] In an experimental procedure similar to Example 25, Step 1, 3,6-dichloro-N-[(2,4- dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (290 mg, 0.572 mmol) was converted to 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(8-oxo-5-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide (0.233 g, 65% yield). MS (ES+) m / z 628.2, 630.2 (M+1).1H NMR (400 MHz; DMSO- d6): δ 7.93 (q, J = 8.2 Hz, 1H), 7.13-7.06 (m, 2H), 6.91 (dd, J = 8.0, 2.7 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.51 (s, 1H), 6.45 (dd, J = 8.4, 2.3 Hz, 1H), 5.03 (s, 2H), 4.24 (q, J = 12.1 Hz, 4H), 3.94 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 2.77 (s, 2H), 2.42 (t, J = 5.9 Hz, 2H). Step 6.3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8- ((R)-3-methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0512] In an experimental procedure similar to Example 46, Step 4, 3,6-dichloro-N-(2,4- dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-oxo-5-oxa-2- azaspiro[3.5]nonan-2-yl)benzenesulfonamide (227 mg, 0.361 mmol) was converted to 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-((R)-3- methylpiperidin-1-yl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide (256 mg, quantitative yield, crude) as a yellow oil. MS (ES+) m / z 712.4, 714.2 (M+1). Step 7.3,6-dichloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(8-((R)-3-methylpiperidin-1-yl)- 5-oxa-2-azaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0513] To a solution of 3,6-dichloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-[6-((R)-3-methylpiperidin-1-yl)-2-azaspiro[3.5]nonan-2- yl]benzenesulfonamide (256 mg, 0.359 mmol) in dichloromethane (1.81 mL) was added trifluoroacetic acid (1.81 mL) and 1,3,5-trimethoxybenzene (60.7 mg, 0.361 mmol). The reaction mixture was stirred at 25^°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography- 151 - using a gradient elution of 5% to 95% water in acetonitrile containing 0.5% formic acid. The desired fractions were collected and lyophilized to afford the title compound (114.8 mg, 0.182 mmol, 50% yield, 96% purity) as a colourless solid. MS (ES+) m / z 561.2 (M+1), 561.3 (M+1).1H NMR (400 MHz; DMSO-d6): δ 7.78 (q, J = 8.2 Hz, 1H), 6.78 (dd, J = 7.9, 1.9 Hz, 1H), 6.62-6.60 (m, 1H), 6.46 (s, 1H), 4.26-4.24 (m, 1H), 4.16 (d, J = 9.6 Hz, 2H), 4.08-4.06 (m, 1H), 3.93-3.89 (m, 1H), 3.47-3.41 (m, 1H), 3.30-3.13 (m, 3H), 2.61-2.56 (m, 1H), 2.43-2.27 (m, 2H), 1.87-1.55 (m, 8H), 1.07-0.94 (m, 2H), 0.89 (d, J = 6.5 Hz, 3H). Examples 125 and 126

[0514] 3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1- methylpiperidin-2-yl)methyl)azetidin-1-yl)benzenesulfonamide (Stereoisomers 1 and 2)- 152 -Step 1. tert-butyl 3-hydroxy-3-(pyridin-2-ylmethyl)azetidine-1-carboxylate

[0515] N-butyllithium (4.13 g, 64.48 mmol, 25.79 ml, 1.2 equiv) was added dropwise to 2-methylpyridine (5.0 g, 53.73 mmol) 2 in THF (300 mL) at -70°C under Ar. The mixture was stirred at -70°C for 3 h to afford an orange solution, then tert-butyl 3-oxoazetidine-1- carboxylate (9.19 g, 53.73 mmol) in THF (50 mL) was dropwise added, and the solution was stirred at 20°C for 2 h to give light yellow solution. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give tert-butyl 3-hydroxy-3-[(pyridin-2- yl)methyl]azetidine-1-carboxylate (7.5 g, 92.0% purity, 26.1 mmol, 48.6% yield).1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 4.4 Hz, 1H), 7.71 - 7.6 (m, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.23 - 7.15 (m, 1H), 5.78 (s, 1H), 3.97 - 3.86 (m, 2H), 3.64 - 3.54 (m, 2H), 3.02 (s, 2H), 1.31 (s, 9H). MS (ES+) m / z 265.2 (M + 1). Step 2. tert-butyl 3-methoxy-3-(pyridin-2-ylmethyl)azetidine-1-carboxylate- 153 -

[0516] To the solution of tert-butyl 3-hydroxy-3-[(pyridin-2-yl)methyl]azetidine-1- carboxylate (6.4 g, 24.23 mmol) in DMF (50 ml) was added sodium hydride (60% in mineral oil, 1070 mg, 26.65 mmol) in portions at 0°C. After stirring for 2 h iodomethane (4.13 g, 29.07 mmol) was added dropwise to the solution at 0°C. After 8 h of stirring the solution was poured into water (50 ml) and diluted with MTBE (100 ml). The organic phase was washed with brine (40 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give tert-butyl 3-methoxy-3-[(pyridin-2-yl)methyl]azetidine-1- carboxylate (5.0 g, 90.0% purity, 16.17 mmol, 66.7% yield).1H NMR (500 MHz, CDCl3) δ 8.54 (d, J = 4.4 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.2 (d, J = 7.7 Hz, 1H), 7.18 - 7.12 (m, 1H), 4.04 - 3.83 (m, 4H), 3.33 (s, 3H), 3.26 (s, 2H), 1.41 (s, 9H). MS (ES+) m / z 279.2 (M + 1). Step 3.2-((1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)methyl)-1-methylpyridin-1- ium iodide

[0517] To the stirring solution of tert-butyl 3-methoxy-3-[(pyridin-2-yl)methyl]azetidine- 1-carboxylate (5.0 g, 90.0% purity, 16.18 mmol) in MeCN (15 ml) was added iodomethane (2.98 g, 21.03 mmol) and the solution was left stirring for 12 h at 40°C. The solution was evaporated and treated with MTBE (10 ml) to give 2-(1-[(tert- butoxy)carbonyl]-3-methoxyazetidin-3-ylmethyl)-1-methylpyridin-1-ium iodide (6.4 g, 96.0% purity, 14.62 mmol, 90.4% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 6.2 Hz, 1H), 8.4 - 8.29 (m, 1H), 8 - 7.87 (m, 2H), 4.68 - 4.57 (m, 3H), 4.18 - 4.07 (m, 2H), 4.04 - 3.89 (m, 2H), 3.86 - 3.74 (m, 2H), 3.36 (s, 3H), 1.43 (s, 9H). MS (ES+) m / z 293.2 (M + 1). Step 4. tert-butyl 3-methoxy-3-((1-methyl-1,2,5,6-tetrahydropyridin-2- yl)methyl)azetidine-1-carboxylate

[0518] To the solution of 2-(1-[(tert-butoxy)carbonyl]-3-methoxyazetidin-3-ylmethyl)-1- methylpyridin-1-ium iodide (6.4 g, 96.0% purity, 14.62 mmol) in MeOH (100 ml) was added sodium borohydride (945.11 mg, 24.85 mmol) and the solution was left stirring at 50°C for 24 h. The solution was diluted with EtOAc (300 ml) and washed with water (50 ml x2) and brine (50 ml). The organic solution was concentrated in vacuum to give tert- butyl 3-methoxy-3-[(1-methyl-1,2,5,6-tetrahydropyridin-2-yl)methyl]azetidine-1- carboxylate (4.3 g, 87.0% purity, 12.62 mmol, 86.3% yield). MS (ES+) m / z 297.2 (M + 1). Step 5. tert-butyl 3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azetidine-1-carboxylate- 154 -

[0519] A mixture of tert-butyl 3-methoxy-3-[(1-methyl-1,2,5,6-tetrahydropyridin-2- yl)methyl]azetidine-1-carboxylate (4.3 g, 87.0% purity, 12.62 mmol) and palladium on carbon (10%, 120 mg) in 30 mL of MeOH was hydrogenated at 1 atm hydrogen pressure (balloon) at 20°C for 12 h. The catalyst was filtered off and the filtrate was evaporated down in vacuo, to afford tert-butyl 3-methoxy-3-[(1-methylpiperidin-2- yl)methyl]azetidine-1-carboxylate (4.0 g, 87.0% purity, 11.66 mmol, 92.4% yield).1H NMR (400 MHz, CDCl3) δ 3.89 (dd, J = 19.2, 9 Hz, 2H), 3.75 (d, J = 9.1 Hz, 1H), 3.65 (d, J = 9.1 Hz, 1H), 3.45 (s, 2H), 3.21 (d, J = 1.6 Hz, 3H), 2.79 (d, J = 11.3 Hz, 1H), 2.27 (s, 3H), 2.23 - 1.98 (m, 3H), 1.74 - 1.58 (m, 3H), 1.41 (d, J = 1.3 Hz, 9H), 1.31 - 1.13 (m, 2H). MS (ES+) m / z 299.2 (M + 1). Step 6.2-((3-methoxyazetidin-3-yl)methyl)-1-methylpiperidine dihydrochloride

[0520] In an experimental procedure similar to Example 35, Step 2, tert-butyl 3-methoxy- 3-[(1-methylpiperidin-2-yl)methyl]azetidine-1-carboxylate (80.0 mg, 87.0% purity, 233.23 µmol) was converted to 2-[(3-methoxyazetidin-3-yl)methyl]-1-methylpiperidine dihydrochloride (70.0 mg, 90.0% purity, 232.28 µmol, 99.5% yield). MS (ES+) m / z 199.2 (M + 1). Step 7. (S)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4- (3-methoxy-3-((1-methylpiperidin-2-yl)methyl)azetidin-1-yl)benzenesulfonamide and (R)-3-chloro-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3- methoxy-3-((1-methylpiperidin-2-yl)methyl)azetidin-1-yl)benzenesulfonamide

[0521] In an experimental procedure similar to Example 35, Step 3, 2-[(3- Methoxyazetidin-3-yl)methyl]-1-methylpiperidine dihydrochloride (70.0 mg, 90.0% purity, 317.9 µmol) was converted to crude product. After HPLC purification (Column: :XBridge BEH C18100*19mm 5um, mobile phase: H2O / ACN / 0,1% NH4OH) racemic 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6-fluoropyridin-2- yl)-4-3-methoxy-3-[(1-methylpiperidin-2-yl)methyl]azetidin-1-ylbenzene-1-sulfonamide (0.06 g, 97% purity) was obtained.

[0522] Chiral HPLC (Column: Chiralcel OD-H (250 x 20 mm, 5 mkm); mobile phase : Hexane(0.5%NH3):IPA:MeOH. Flow Rate: 20 mL / min) 2 fractions were obtained:

[0523] Peak 1: 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazetidin-1- yl)benzene-1-sulfonamide (Stereoisomer 1) (20.0 mg, 97.0% purity, 28.99 µmol, 9.1% yield) (Rt = 15.66 min). Analytical SFC: Chiralcel OD-H 250x4.6 mm, 5 um / mobile- 155 - phase:70 / 15 / 15 Hexane(0.1% EDA) / IPA(0.1% EDA) / MeOH(0.1% EDA). Retention Time=15.66 min; ee = 100%. MS (ES+) m / z 669.2, 671.2 (M + 1).

[0524] Peak 2: 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazetidin-1- yl)benzene-1-sulfonamide (Stereoisomer 2) (21.0 mg, 97.0% purity, 30.44 µmol, 9.6% yield) (Rt = 18.58 min). Analytical SFC: Chiralcel OD-H 250x4.6 mm, 5 um / mobile phase:70 / 15 / 15 Hexane(0.1% EDA) / IPA(0.1% EDA) / MeOH(0.1% EDA). Retention Time=18.58 min; ee = 98.24%. MS (ES+) m / z 669.2, 671.2 (M + 1). Step 8.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1- methylpiperidin-2-yl)methyl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 1)

[0525] To a solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazetidin-1- yl)benzene-1-sulfonamide (Stereoisomer 1) (20.0 mg, 97.0% purity, 28.99 µmol)in DCM (1 mL) was added trifluoroacetic acid (32.95 mg, 289.03 µmol). The mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution (0.5 mL) at 0 °C. The mixture was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by HPLC (Column: XBridge BEH C18100*19mm 5um, mobile phase: [H2O / ACN / 0,1%NH4OH]) to obtain pure 3-chloro-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazetidin-1- yl)benzene-1-sulfonamide (Stereoisomer 1) (9.6 mg, 18.5 µmol, 64% yield).1H NMR (500 MHz, CD3OD) δ 7.59 - 7.5 (m, 1H), 6.84 - 6.77 (m, 1H), 6.32 (dd, J = 7.7, 2 Hz, 1H), 6 - 5.9 (m, 1H), 4.23 - 4.16 (m, 1H), 4.16 - 4.06 (m, 2H), 4.04 - 3.96 (m, 1H), 3.24 (s, 2H), 2.77 (s, 3H), 2.43 (d, J = 13.7 Hz, 1H), 2.17 (d, J = 26.4 Hz, 1H), 2 - 1.92 (m, 1H), 1.88 - 1.44 (m, 6H). MS (ES+) m / z 519.0, 521.0 (M + 1). Step 9.3-chloro-2,6-difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-((1- methylpiperidin-2-yl)methyl)azetidin-1-yl)benzenesulfonamide (Stereoisomer 2)

[0526] To a solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,6-difluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2-yl]methylazetidin-1- yl)benzene-1-sulfonamide (Stereoisomer 2) (21.0 mg, 97.0% purity, 30.44 µmol) in DCM (1 mL) was added trifluoroacetic acid (34.7 mg, 304.44 µmol). The mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution (0.5- 156 - mL) at 0 °C. The mixture was extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by HPLC (Column: XBridge BEH C18100*19mm 5um, mobile phase: [H2O / ACN / 0,1%NH4OH], flow rate: 30ml / min) to obtain pure 3-chloro-2,6- difluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-[1-methylpiperidin-2- yl]methylazetidin-1-yl)benzene-1-sulfonamide (Stereoisomer 2) (10.0 mg, 19.27 µmol, 63.3% yield).1H NMR (500 MHz, CD3OD) δ 7.62 - 7.51 (m, 1H), 6.83 - 6.74 (m, 1H), 6.39 - 6.28 (m, 1H), 6.05 - 5.93 (m, 1H), 4.25 - 4.19 (m, 1H), 4.19 - 4.13 (m, 1H), 4.13 - 4.06 (m, 1H), 4.04 (s, 1H), 3.27 - 3.2 (m, 1H), 2.83 - 2.64 (m, 3H), 2.47 - 2.36 (m, 1H), 2.2 - 2.07 (m, 1H), 1.99 - 1.9 (m, 1H), 1.87 - 1.43 (m, 6H). MS (ES+) m / z 519.0, 521.0 (M + 1). Examples 127 and 128 3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-6-methyl-4-(3-methyl-3-(1-methylpyrrolidin- 3-yl)azetidin-1-yl)benzenesulfonamide (Stereoisomers 1 and 2)Step 1.

[0527] To a solution of (COCl)2(8.44 g, 66.5 mmol, 5.82 mL, 2.06 eq) in DCM (32.5 mL) was added dropwise DMSO (10.4 g, 133 mmol, 10.4 mL, 4.12 eq) in DCM (32.5 mL) at -78 °C under nitrogen. After stirring for 0.5 hr, tertbutyl 3-(hydroxymethyl)-3- methyl-azetidine-1-carboxylate (6.50 g, 32.3 mmol, 1.00 eq) in DCM (32.5 mL) was added dropwise and stirring for 0.5 hr. To the mixture was added triethylamine (26.0 g, 257 mmol, 35.7 mL, 7.95 eq) in DCM (32.5 mL) and the resulting mixture was stirred at -- 157 - 78 °C for 0.15 hr, then warmed to 20 °C and stirred for 1 hr. The reaction mixture was quenched by addition water (200 mL) at 20 °C, and then extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (200 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 3-formyl-3- methyl-azetidine-1-carboxylate (6.50 g, crude) as a colorless oil. Step 2.

[0528] To a solution of methyl 2-dimethoxyphosphorylacetate (9.60 g, 52.7 mmol, 7.59 mL, 1.50 eq), tert-butyl 3-formyl-3-methyl-azetidine-1-carboxylate (7.00 g, 35.1 mmol, 1.00 eq) in THF (70.0 mL) was added t-BuOK (3.94 g, 35.1 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition water (200 mL) at 0 °C, and then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (200 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate = 100:0 to 94:6) to give tert-butyl 3-[(E)-3-methoxy-3-oxo-prop-1-enyl]-3-methyl-azetidine- 1-carboxylate (6.50 g, 21.8 mmol, 62.1% yield, 85.7% purity) as a colorless oil. Step 3.

[0529] A mixture of tert-butyl 3-[(E)-3-methoxy-3-oxo-prop-1-enyl]-3-methyl-azetidine- 1-carboxylate (6.50 g, 25.5 mmol, 1.00 eq), CH3NO2 (9.32 g, 153 mmol, 8.27 mL, 6.00 eq), DBN (6.32 g, 50.9 mmol, 6.09 mL, 2.00 eq) in MeOH (80.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60 °C for 16 hrs under N2atmosphere. The reaction mixture was quenched by addition water (300 mL) at 0 °C, and then extracted with EtOAc (150 mL * 3). The combined organic layers were washed with brine (200 mL * 2), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate = 100: 0 to 80: 20) to give tert-butyl 3-[3-methoxy-1- (nitromethyl)-3-oxo-propyl]-3-methyl-azetidine-1-carboxylate (3.15 g, 9.96 mmol, 39.1% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.30 - 4.52 (m, 2H), 3.74 (dd, J = 8.4, 2.8 Hz, 2H), 3.71 (s, 3H), 3.54 (dd, J = 8.4, 4.8 Hz, 2H), 2.98 - 3.11 (m, 1H), 2.34 - 2.43 (m, 2H), 1.44 (s, 9H), 1.28 (s, 3H). Step 4.

[0530] A mixture of tert-butyl 3-[3-methoxy-1-(nitromethyl)-3-oxo-propyl]-3-methyl- azetidine-1-carboxylate (3.00 g, 9.48 mmol, 1.00 eq), Raney-Ni (406 mg, 4.74 mmol,- 158 - 0.50 eq) in EtOH (30.0 mL) was degassed and purged with H2for 3 times, and then the mixture was stirred at 60 °C for 6 hrs under H2 atmosphere (30 Psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 100: 0 to 92: 8) to give tert- butyl 3-methyl-3-(5-oxopyrrolidin-3-yl)azetidine-1-carboxylate (400 mg, 1.35 mmol, 14.2% yield, 85.8% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 5.87 (s, 1H), 3.57 (d, J = 8.4 Hz, 2H), 3.45 - 3.52 (m, 2H), 3.40 (t, J = 9.2 Hz, 1H), 2.98 - 3.07 (m, 1H), 2.63 (dt, J = 16.0, 8.4 Hz, 1H), 2.31 (dd, J = 17.2, 9.2 Hz, 1H), 2.02 (dd, J = 17.2, 8.0 Hz, 1H), 1.34 (s, 9H), 1.15 (s, 3H) Step 5.

[0531] To a solution of tert-butyl 3-methyl-3-(5-oxopyrrolidin-3-yl)azetidine-1- carboxylate (200 mg, 786 μmol, 1.00 eq) in THF (4.00 mL) was added NaH (78.6 mg, 1.97 mmol, 60.0% purity, 2.50 eq) at 0 °C, and was stirred at 0 °C for 0.5 hr. Then to the mixture was added iodomethane (335 mg, 2.36 mmol, 146.9 μL, 3.00 eq) at 0 °C, and was stirred at 20 °C for 0.5 hr. The reaction mixture was quenched by addition NH4Cl (10 mL) at 0 °C, and then diluted with water (20.0 mL) and extracted with EtOAc (15.0 mL * 3). The combined organic layers were washed with brine (30.0 mL * 2), dried over [Na2SO4], filtered and concentrated under reduced pressure to give tert-butyl 3-methyl-3- (1-methyl-5-oxo-pyrrolidin-3- yl)azetidine-1-carboxylate (200 mg, crude) as a white solid without purification. MS (ES+) m / z 291.0 (M+23), 213.0 (M-55) Step 6.

[0532] To a solution of tert-butyl 3-methyl-3-(1-methyl-5-oxo-pyrrolidin-3-yl)azetidine- 1-carboxylate (300 mg, 1.12 mmol, 1.00 eq) in THF (9.00 mL) was replaced with nitrogen three times, and cooled to 0 ° C in an ice water bath. BH3.THF (1 M, 3.35 mL, 3.00 eq) was added dropwise. When the addition was completed, the ice bath was removed. The reaction was stirred at 60 °C for 3 hrs. LC-MS (EC26825-223-P1A1, P1: Rt = 2.224 min) showed ~0% of reactant 1 remained and ~25.2% of desired compound was detected. The reaction was cooled to 0 °C and quenched by dropwise addition of methanol (2.00 mL). Then the mixture was evaporated to give tert-butyl 3-methyl-3-(1- methylpyrrolidin-3-yl)azetidine-1-carboxylate (300 mg, crude) as a yellow oil without purification. MS (ES+) m / z 199.1 (M-55).- 159 - Step 7.

[0533] A mixture of tert-butyl 3-methyl-3-(1-methylpyrrolidin-3-yl)azetidine-1- carboxylate (300 mg, 1.18 mmol, 1.00 eq) in DCM (5.00 mL) and TFA (1.00 mL) was stirred at 20 °C for 1 hr. LC-MS (P1: Rt = 1.460 min) showed ~0% of reactant 1 remained and ~76.7% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to give 1-methyl-3-(3-methylazetidin-3- yl)pyrrolidine (200 mg, crude) as a yellow oil without purification. MS (ES+) m / z 155.2 (M+1). Step 8.

[0534] To a solution of 1-methyl-3-(3-methylazetidin-3-yl)pyrrolidine (197 mg, 1.28 mmol, 2.00 eq) in DMF (5.00 mL) was added 3-chloro-N-[(3,4-dimethylphenyl)methyl]- 2,4-difluoro-N-(6-fluoro-2-pyridyl)-6-methyl- benzenesulfonamide (290 mg, 638 μmol, 1.00 eq) and Cs2CO3 (415 mg, 1.28 mmol, 2.00 eq). The mixture was stirred at 20 °C for 1 hr. LC-MS (P1: Rt = 1.512 min) showed ~0% of reactant 1 remained ~89.5% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: CD25-WePure Biotech XPT PHS C18150*25*7μm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 32%-62% B over 10.0 min) to give product as yellow solid (300 mg, 79.8% yield). LCMS (Rt = 0.501 min) showed ~100% purity of desired compound mass was detected. The residue was further separated by SFC (EC26825-231- P1A, column: Chiral-Cellulose-2-30-Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 μm; mobile phase: [CO2 - MeOH: ACN = 7: 3 (0.1% NH3.H2O)]; B%: 45%, isocratic elution mode). To give peak 13-chloro-N-[(3,4-dimethylphenyl)methyl]-2-fluoro-N-(6-fluoro-2- pyridyl)-6-methyl-4-[3-methyl-3-(1-methylpyrrolidin-3-yl)azetidin-1- yl]benzenesulfonamide (Stereoisomer 1) (125 mg, crude) as a white solid. and Peak 23- chloro-N-[(3,4-dimethylphenyl)methyl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-4-[3- methyl-3-(1-methylpyrrolidin-3-yl)azetidin-1-yl]benzenesulfonamide (Stereoisomer 2) (125 mg, crude) as a white solid. Peak 1: Rt = 1.512 min; MS (ES+) m / z 621.3 (M+1). Peak 2: Rt = 0.501 min; MS (ES+) m / z 621.5 (M+1) Step 9.

[0535] A mixture of 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoro-2- pyridyl)-6-methyl-4-[3- methyl-3-[1-methylpyrrolidin-3-yl]azetidin-1- yl]benzenesulfonamide (Stereoisomer 1) (120 mg, 204 μmol, 1.00 eq) in TFA (0.20 mL)- 160 - and DCM (2.00 mL) was stirred at 20 °C for 0.5 hr. LC-MS (EC26825-251-p1ayj, P1: Rt = 1.157 min) showed no Reactant 1 remained and ~99.2% of desired compound was detected. The reaction mixture was diluted with NaHCO3 solutions (20.0 mL) and extracted with DCM (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-4-[3-methyl-3-[1- methylpyrrolidin-3-yl]azetidin-1-yl]benzenesulfonamide (Stereoisomer 1) (48.0 mg, 101 μmol, 49.7% yield, 99.3% purity) as a white solid. MS (ES+) m / z 471.1 (M+1).1H NMR (400 MHz, CDCl3) δ 7.56 (q, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.0, 2.0 Hz, 1H), 6.41 (dd, J = 8.0, 2.4 Hz, 1H), 5.91 (s, 1H), 4.05 (dd, J = 16.0, 8.0 Hz, 2H), 3.80 (t, J = 8.8 Hz, 2H), 3.50 (s, 1H), 2.89 - 3.04 (m, 3H), 2.81 (t, J = 9.2 Hz, 1H), 2.63 (s, 3H), 2.51 - 2.62 (m, 4H), 2.03 - 2.14 (m, 1H), 2.02 (s, 1H), 1.75 - 1.89 (m, 1H), 1.32 (s, 3H). Step 10.

[0536] A mixture of 3-chloro-N-[(2,5-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoro-2- pyridyl)-6-methyl-4-[3- methyl-3-[1-methylpyrrolidin-3-yl]azetidin-1- yl]benzenesulfonamide (Stereoisomer 1) (125 mg, 212 μmol, 1.00 eq) in TFA (0.20 mL) and DCM (2.00 mL) was stirred at 20 °C for 0.5 hr. LC-MS (P1: Rt = 1.776 min) showed ~0% of reactant 1 remained. Several new peaks were shown on LC-MS and ~93.1% of desired compound was detected. The reaction mixture was quenched by addition NaHCO3(10 mL) at 0 °C, and then diluted with water (20.0 mL) and extracted with EtOAc (15.0 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give 3-chloro-2-fluoro-N-(6-fluoro-2- pyridyl)-6-methyl-4-[3-methyl-3-[1-methylpyrrolidin-3-yl]azetidin-1- yl]benzenesulfonamide (Stereoisomer 2) (78.0 mg, 162 μmol, 76.4% yield, 97.9% purity) as a white solid. MS (ES+) m / z 471.1 (M+1).1H NMR (400 MHz, CDCl3) δ 7.61 (q, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.48 (dd, J = 8.0, 2.4 Hz, 1H), 5.93 (s, 1H), 4.05 (dd, J = 14.0, 8.4 Hz, 2H), 3.83 (t, J = 8.4 Hz, 2H), 2.95 - 3.18 (m, 3H), 2.79 - 2.90 (m, 1H), 2.65 (s, 3H), 2.62 (s, 4H), 2.07 - 2.21 (m, 1H), 1.77 - 1.92 (m, 1H), 1.32 (s, 3H), 1.26 (s, 1H) Example 129 3-chloro-4-(3-((1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)methyl)-3-methylazetidin-1- yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide- 161 -Step 1. tert-butyl 3-(iodomethyl)-3-methylazetidine-1-carboxylate

[0537] To a mixture of tert-butyl 3-(bromomethyl)-3-methyl-azetidine-1-carboxylate (12.0 g, 45.4 mmol, 1.00 eq) in acetone (50.0 mL) was added KI (15.1 g, 90.9 mmol, 2.00 eq) and stirred at 45 °C for 12 hrs. There was a large amount of white solid precipitation. The mixture was filtered and the filtrate was concentrated under reduced pressure. The oil was stirred in isopropyl ether (30 mL) at 20 °C for 1 hr and filtered to remove solid, the filtrate was concentrated to give tert-butyl 3-(iodomethyl)-3-methyl-azetidine-1- carboxylate (10.0 g, 32.1 mmol, 70.8% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ 3.71-3.66 (m, 2H), 3.63-3.58 (m, 2H), 3.39 (s, 2H), 1.44 (s, 9H), 1.39 (s, 3H). Step 2. tert-butyl 3-((1-cyanocyclobutyl)methyl)-3-methylazetidine-1-carboxylate

[0538] To a mixture of tert-butyl 3-(bromomethyl)-3-methyl-azetidine-1-carboxylate (12.0 g, 45.4 mmol, 1.00 eq) in acetone (50.0 mL) was added KI (15.1 g, 90.9 mmol, 2.00 eq) and stirred at 45 °C for 12 hrs. There was a large amount of white solid precipitation. The mixture was filtered and the filtrate was concentrated under reduced pressure. The oil was stirred in isopropyl ether (30 mL) at 20 °C for 1 hr and filtered to remove solid, the filtrate was concentrated to give tert-butyl 3-(iodomethyl)-3-methyl-azetidine-1- carboxylate (10.0 g, 32.1 mmol, 70.8% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ 3.71-3.66 (m, 2H), 3.63-3.58 (m, 2H), 3.39 (s, 2H), 1.44 (s, 9H), 1.39 (s, 3H) Step 3. tert-butyl 3-((1-carbamoylcyclobutyl)methyl)-3-methylazetidine-1-carboxylate

[0539] To a mixture of tert-butyl 3-[(1-cyanocyclobutyl)methyl]-3-methyl-azetidine-1- carboxylate (1.00 g, 3.78 mmol, 1.00 eq) and K2CO3(1.05 g, 7.57 mmol, 2.00 eq) in DMSO (10.0 mL) was added H2O2(1.72 g, 15.1 mmol, 1.45 mL, 30% purity, 4.00 eq) at 0 °C slowly under N2. The mixture was warmed to 20 °C and stirred at 20 °C for 2 hrs. LCMS showed desired MS was detected. The mixture was quenched by H2O (50 mL) and extracted with EtOAc (3 * 30 ml). The organic layers were washed with water and- 162 - brine then dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3-[(1- carbamoylcyclobutyl) methyl]-3-methyl-azetidine-1-carboxylate (985 mg, 3.49 mmol, 92.2% yield) as a white solid. MS (ESI) m / z = 283.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 5.68-5.40 (m, 2H), 3.73 (d, J = 8.4 Hz, 2H), 3.52 (d, J = 8.4 Hz, 2H), 2.46-2.36 (m, 2H), 2.15 (s, 2H), 2.09-2.01 (m, 2H), 1.97-1.84 (m, 2H), 1.44 (s, 9H), 1.33 (s, 3H). Step 4. tert-butyl 3-((1-aminocyclobutyl)methyl)-3-methylazetidine-1-carboxylate

[0540] To a mixture of tert-butyl 3-[(1-carbamoylcyclobutyl)methyl]-3-methyl-azetidine- 1-carboxylate (680 mg, 2.41 mmol, 1.00 eq) in EtOH (10.0 mL) and NaOH (10.0 mL, 15% purity in H2O) was added NaClO (4.48 g, 3.61 mmol, 3.72 mL, 6% purity, 1.50 eq). The mixture was stirred at 20 °C for 2 hrs. LCMS (EC25620-258-P1A1) showed desired MS was detected. The mixture was diluent with ethyl acetate (50 mL) and washed with H2O (40 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The oil was purification by silica gel chromatography (100-200 mesh silica gel, commercial hexanes: Ethyl acetate = 5: 1 to 0: 1, TLC: Commercial hexanes: Ethyl acetate = 3: 1, P1: Rf = 0.02) to give tert-butyl 3-[(1- aminocyclobutyl)methyl] -3-methyl-azetidine-1-carboxylate (395 mg, 1.55 mmol, 64.5% yield) as a yellow oil. LCMS: RT = 1.472 min, MS (ESI) m / z = 255.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 3.78 (d, J = 8.4 Hz, 2H), 3.58 (d, J = 8.4 Hz, 2H), 2.14-2.02 (m, 2H), 1.92-1.79 (m, 5H), 1.78-1.65 (m, 3H), 1.44 (s, 9H), 1.34 (s, 3H). Step 5. tert-butyl 3-((1-(3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)cyclobutyl)methyl)-3- methylazetidine-1-carboxylate

[0541] To a mixture of tert-butyl 3-[(1-aminocyclobutyl)methyl]-3-methyl-azetidine-1- carboxylate (570 mg, 2.24 mmol, 1.00 eq) and 3,3-dimethyltetrahydrofuran-2,5-dione (316 mg, 2.46 mmol, 278 μL, 1.10 eq) in CHCl3(15.0 mL) was added TEA (680 mg, 6.72 mmol, 936 μL, 3.00 eq) and stirred at 70 °C for 12 hrs. Then CDI (545 mg, 3.36 mmol, 1.50 eq) was added into the solution and stirred at 70 °C for 3 hrs. LCMS (EC25620- 260-P1A3) showed desired MS was detected. The mixture was cooled to 0 °C and added 0.5 M HCl (15 mL), then extracted with DCM (20 mL*2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The oil was purification by silica gel chromatography (100-200 mesh silica gel, commercial hexanes: ethyl acetate = 20: 1 to 5: 1, TLC: Commercial hexanes: Ethyl acetate = 3: 1, P1: Rf = 0.3) to give tert-butyl 3-[[1-(3,3-dimethyl-2,5 -dioxo-pyrrolidin-1- yl)cyclobutyl]methyl]-3-methyl-azetidine-1-carboxylate (620 mg, 1.70 mmol, 75.9%- 163 - yield) as a yellow oil. MS (ESI) m / z = 387.2 [M+Na]+.1H NMR (400 MHz, CDCl3) δ 3.58 (d, J = 8.0 Hz, 2H), 3.44 (d, J = 8.0 Hz, 2H), 2.53-2.44 (m, 4H), 2.43-2.37 (m, 2H), 2.26 (s, 2H), 1.90-1.78 (m, 2H), 1.46 (s, 3H), 1.43-1.39 (m, 9H), 1.29 (s, 6H). Step 6.3,3-dimethyl-1-(1-((3-methylazetidin-3-yl)methyl)cyclobutyl)pyrrolidine-2,5- dione

[0542] To a mixture of tert-butyl 3-[[1-(3,3-dimethyl-2,5-dioxo-pyrrolidin-1- yl)cyclobutyl]methyl]-3-methyl -azetidine-1-carboxylate (540 mg, 1.48 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 9.09 eq) and stirred at 25 °C for 0.5 hr. LCMS showed desired MS was detected. The mixture was concentrated under reduced pressure to give 3,3-dimethyl-1-[1-[(3-methylazetidin-3-yl) methyl]cyclobutyl]pyrrolidine-2,5-dione (840 mg, crude, TFA) as a brown oil. MS (ESI) m / z = 265.2 [M+H]+. Step 7.3,3-dimethyl-1-(1-((3-methylazetidin-3-yl)methyl)cyclobutyl)pyrrolidine

[0543] To a mixture of 3,3-dimethyl-1-[1-[(3-methylazetidin-3- yl)methyl]cyclobutyl]pyrrolidine-2,5-dione (840 mg, 2.22 mmol, 1.00 eq, TFA) in THF (20.0 mL) was added LAH (2.50 M, 10.0 mL, 11.3 eq) slowly at 0 °C under N2. The mixture was warmed to 70 °C slowly and stirred at 70 °C for 12 hrs under N2. LCMS showed desired was detected. The reaction mixture was quenched by the slow addition of Na2SO4.10H2O (20 g) and filtered to remove solid. The filtrate was concentrated to give 3,3-dimethyl-1-[1-[(3-methylazetidin-3-yl)methyl]cyclobutyl]pyrrolidine (750 mg, crude) as a yellow oil without purification. MS (ESI) m / z = 237.3 [M+H]+. Step 8.3-chloro-N-(3,4-dimethylbenzyl)-4-(3-((1-(3,3-dimethylpyrrolidin-1- yl)cyclobutyl)methyl)-3-methylazetidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide

[0544] To a mixture of 3-chloro-N-[(3,4-dimethylphenyl)methyl]-2,4,6-trifluoro-N-(6- fluoro-2-pyridyl) benzenesulfonamide (0.45 g, 981 μmol, 1.00 eq) and 3,3-dimethyl-1-[1- [(3-methylazetidin-3-yl)methyl] cyclobutyl]pyrrolidine (750 mg, 3.17 mmol, 3.24 eq) in DMF (5.00 mL) was added TEA (248 mg, 2.45 mmol, 341 μL, 2.50 eq) and stirred at 25 °C for 0.5 hr. The mixture was diluted with ethyl acetate (20 mL) and washed with H2O (10 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The oil was purified by silica gel chromatography (100-200 mesh silica gel, Commercial hexanes: Ethyl acetate = 2: 1 to 1: 1, TLC: Commercial hexanes: Ethyl acetate = 1: 1, P1: Rf= 0.2) to give 3-chloro-N-[(3,4-- 164 - dimethylphenyl)methyl]-4-[3-[[1-(3,3-dimethylpyrrolidin-1-yl) cyclobutyl]methyl]-3- methyl-azetidin-1-yl]-2,6-difluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (360 mg, 533 μmol, 54.4% yield) as a yellow oil. MS (ESI) m / z = 707.4 [M+H]+. Step 9.3-chloro-4-(3-((1-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)methyl)-3- methylazetidin-1-yl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0545] To a mixture of 3-chloro-N-[(3,4-dimethylphenyl)methyl]-4-[3-[[1-(3,3- dimethylpyrrolidin-1-yl)cyclobutyl] methyl]-3-methyl-azetidin-1-yl]-2,6-difluoro-N-(6- fluoro-2-pyridyl)benzenesulfonamide (360 mg, 533 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 25.3 eq) and stirred at 25°C for 0.5 hrs. LCMS (EC25620-273-P1A1) showed desired MS was detected. The mixture was concentrated under reduced pressure to give oil. The oil was dissolved in MeOH (10 mL), the solution was filtered to remove solid and concentrated. The oil was purification by prep-HPLC (column: CD18-Welch Utimate C18150*40*7um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 18%-48% B over 17.0 min) to give 3-chloro-4-[3-[[1-(3,3- dimethylpyrrolidin-1-yl)cyclobutyl]methyl]-3-methyl -azetidin-1-yl]-2,6-difluoro-N-(6- fluoro-2-pyridyl)benzenesulfonamide (85.0 mg, 123 μmol, 23.0% yield, 96.9% purity, TFA) as a white solid. m / z = 557.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.57-9.80 (m, 1H), 7.87 (q, J = 8.0 Hz, 1H), 6.86 (dd, J = 2.0, 8.0 Hz, 1H), 6.74 (dd, J = 2.0, 8.0 Hz, 1H), 6.32 (d, J = 13.2 Hz, 1H), 4.06 (d, J = 3.8 Hz, 4H), 3.70-3.53 (m, 1H), 3.33 (dd, J = 5.2, 10.6 Hz, 2H), 2.87-2.75 (m, 1H), 2.39-2.24 (m, 2H), 2.19-1.99 (m, 5H), 1.95-1.72 (m, 3H), 1.55 (s, 3H), 1.14 (d, J = 17.6 Hz, 6H). Examples 130, 131, 132, and 133 3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azetidin-1-yl]-2-fluoro-N-(6-fluoro-2- pyridyl)-6-methyl-benzenesulfonamide (Stereoisomers 1, 2, 3, and 4)- 165 -Step 1.

[0546] To a solution of 1-tert-butoxycarbonyl-2-methyl-azetidine-3-carboxylic acid (4.90 g, 22.7 mmol, 1.0 eq) in DMF (100 mL) was added HATU (12.9 g, 34.1 mmol, 1.50 eq), DIEA (8.83 g, 68.2 mmol, 11.9 mL, 3.0 eq) and N-methylmethanamine (2.41 g, 29.5 mmol, 2.7 mL, 1.30 eq, HCl salt). The mixture was stirred at 25 °C for 2 hrs. TLC (Commercial hexanes: Ethyl acetate = 0: 1, P1: Rf = 0.13, ninhydrin) indicated Reactant 1 was not remained, and one major new spot was detected. The reaction mixture was diluted with water 100 mL and extracted with EtOAc 400 mL (100 mL * 4). The combined organic layers were washed with water 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate = 0: 1, P1: Rf= 0.13, Commercial hexanes: Ethyl acetate = 500: 1 to 0: 1) to give tert-butyl 3- (dimethylcarbamoyl)-2-methyl-azetidine-1-carboxylate (4.00 g, 16.5 mmol, 72.5% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (quin, J = 6.0 Hz, 1H), 4.02 - 4.15 (m, 1H), 3.90 (s, 1H), 3.22 (dt, J = 8.8, 6.0 Hz, 1H), 2.84 (s, 3H), 2.82 (s, 3H), 1.37 (s, 12 H). Step 2.

[0547] To a solution of tert-butyl 3-(dimethylcarbamoyl)-2-methyl-azetidine-1- carboxylate (4.00 g, 16.5 mmol, 1.0 eq) in THF (50.0 mL) was replaced with nitrogen three times, and cooled to 0 °C in an ice water bath. BH3.THF (1.0 M, 49.5 mL, 3.0 eq) was added dropwise slowly at 0 °C, and the addition was completed, and the ice bath was removed. The reaction was stirred at 60 °C for 3 hrs. TLC (Commercial hexanes: Ethyl- 166 - acetate = 0: 1, P1: Rf= 0.51, ninhydrin) indicated Reactant 1 was not remained, and one major new spot was detected. The reaction was cooled to 0 °C in an ice water bath and quenched by dropwise addition of methanol (40 mL) and then the mixture was stirred at 60 °C for 1 hr. Then the solvent was evaporated to give tert-butyl 3- [(dimethylamino)methyl]-2-methyl-azetidine-1-carboxylate (4.00 g, crude) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 3.77 (s, 1H), 3.60 (dd, J = 8.8, 6.8 Hz, 1H), 3.12 - 3.31 (m, 1H), 2.99 (d, J = 4.8 Hz, 2H), 2.65 (dd, J = 13.2, 6.8 Hz, 1H), 2.58 (s, 6H), 1.44 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Step 3.

[0548] To a solution of tert-butyl 3-[(dimethylamino)methyl]-2-methyl-azetidine-1- carboxylate (4.00 g, 17.5 mmol, 1.0 eq) in DCM (50.0 mL) was added TFA (14.4 g, 127 mmol, 9.4 mL, 7.2 eq). The mixture was stirred at 20 °C for 1 hr. TLC (Commercial hexanes: Ethyl acetate = 0: 1, P1: Rf = 0.16, ninhydrin) indicated Reactant 1 was not remained, and one major new spot was detected. The reaction mixture was concentrated under reduced pressure to remove DCM and TFA to give N,N-dimethyl-1-(2- methylazetidin-3-yl)methanamine (4.00 g, crude, TFA salt) as a colorless oil. Step 4.

[0549] A mixture of N,N-dimethyl-1-(2-methylazetidin-3-yl)methanamine (995 mg, 4.10 mmol, 2.0 eq, TFA salt) , 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-(6- fluoro-2-pyridyl)-6-methyl-benzenesulfonamide (1.00 g, 2.00 mmol, 1.0 eq), Cs2CO3(2.00 g, 6.10 mmol, 3.0 eq) in DMF (20.0 mL), and then the mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with water 20 mL and extracted with EtOAc 60 mL (20 mL * 3). The combined organic layers were washed with water 40 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: CD05-Phenomenex Luna C18 100*40mm*10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:26%-56% B over 13.0 min). Compound 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3- [(dimethylamino)methyl]-2-methyl-azetidin-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6- methyl-benzenesulfonamide (400 mg, 672 μmol, 32.7% yield) was obtained as a white solid. MS (ES+) m / z: 595.2 / 596.9 (M+1). Step 5.

[0550] 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3-[(dimethylamino)methyl]-2- methyl-azetidin-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6-methyl-benzenesulfonamide- 167 - (400 mg) was purified by SFC column: Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm * 30 mm, 10um); mobile phase: [CO2-EtOH(0.1% NH3H2O)]; B%: 17%, isocratic elution mode) to obtain 150 mg Peak 1 and 150 mg Peak 2.

[0551] 150 mg Peak 1 was purified by SFC column: Chiral-OX-30-DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 um); mobile phase: [CO2-MeOH: CAN = 7: 3 (0.1% NH3.H2O)]; B%: 40%, isocratic elution mode) to obtain 60 mg Peak 1 and 60 mg Peak 2.

[0552] 150 mg Peak 2 was purified by SFC: Chiral-OX-30-DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 um); mobile phase: [CO2-MeOH: CAN = 7: 3 (0.1% NH3.H2O)]; B%: 40%, isocratic elution mode) to obtain 60 mg Peak 1and 60 mg Peak 2.

[0553] The four diastereoisomers were carried out to deprotection using the general procedure described below.

[0554] To a solution of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[3- [(dimethylamino)methyl]-2-methyl- azetidin-1-yl]-2-fluoro-N-(6-fluoro-2-pyridyl)-6- methyl-benzenesulfonamide (60.0 mg, 100 μmol, 1.0 eq) in DCM (5 mL) was added TFA (153 mg, 1.3 mmol, 0.1 mL, 13.3 eq). The mixture was stirred at 25 °C for 1 hr. TLC indicated Reactant 1 was consumed completely and one new spot formed. (The reaction mixture was quenched by addition NaHCO3solutions to adjust pH to ~7.0 at 0 °C, and then filtered, the filtrate was extracted with DCM 45 mL (15 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give the final compound.

[0555] 3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azetidin-1-yl]-2-fluoro-N-(6- fluoro-2-pyridyl)-6-methyl-benzenesulfonamide (Stereoisomer 1) (19.65 mg, 43.07 μmol, 42.72% yield) was obtained as a white solid. MS (ES+) m / z: 445.1 / 447.0 (M+1)1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (q, J = 8.0 Hz, 1H), 6.69 - 6.83 (m, 1H), 6.58 (dd, J = 8.0, 1.6 Hz, 1H), 6.31 (s, 1H), 4.46 (t, J = 8.0 Hz, 1H), 4.03 - 4.21 (m, 1H), 3.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.61 (s, 3H), 2.21 (s, 6H), 1.36 (d, J = 6.0 Hz, 3H), 1.23 (s, 2H).

[0556] 3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azetidin-1-yl]-2-fluoro-N-(6- fluoro-2-pyridyl)-6-methyl-benzenesulfonamide (Stereoisomer 2) (29.1 mg, 64.9 μmol, 64.39% yield, 99.162% purity) was obtained as a white solid. MS (ES+) m / z: 445.1 / 447.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (q, J = 8.0 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 6.31 (s, 1H), 4.46 (t, J = 8.0 Hz, 1H), 4.04 - 4.24 (m,- 168 - 1H), 3.57 - 3.63 (m, 1H), 2.60 - 2.64 (m, 3H), 2.56 (s, 1H), 2.24 (s, 6H), 1.36 (d, J = 6.0 Hz, 3H), 1.23 (s, 1H).

[0557] 3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azetidin-1-yl]-2-fluoro-N-(6- fluoro-2-pyridyl)-6-methyl-benzenesulfonamide (Stereoisomer 3) (26.9 mg, 56.4 μmol, 56.0% yield, 93.144% purity) was obtained as a white solid. MS (ES+) m / z: 445.1 / 447.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (q, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.0, 1.6 Hz, 1H), 6.67 (dd, J = 8.0, 2.4 Hz, 1H), 6.34 (s, 1H), 4.67 - 4.84 (m, 1H), 4.14 - 4.28 (m, 1H), 4.02 - 4.12 (m, 1H), 3.51 (s, 1H), 3.06 - 3.22 (m, 3H), 2.50 (s, 9H), 1.24 (d, J = 6.4 Hz, 3H).

[0558] 3-chloro-4-[3-[(dimethylamino)methyl]-2-methyl-azetidin-1-yl]-2-fluoro-N-(6- fluoro-2-pyridyl)-6-methyl-benzenesulfonamide (Stereoisomer 4) (30.6 mg, 64.0 μmol, 63.4% yield, 92.916% purity) was obtained as a white solid. MS (ES+) m / z: 445.1 / 447.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (q, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.0, 2.0 Hz, 1H), 6.68 (dd, J = 8.0, 2.4 Hz, 1H), 6.35 (s, 1H), 4.68 - 4.79 (m, 1H), 4.17 - 4.26 (m, 1H), 4.11 (t, J = 8.0 Hz, 1H), 3.21 - 3.28 (m, 2H), 3.16 (d, J = 9.2 Hz, 1H), 2.69 (s, 6H), 2.63 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). Example 140 2,3-dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-3- yl)azetidin-1-yl)benzenesulfonamide

[0559] 2,3-dichloro-6-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpyrrolidin-3-yl)azetidin-1-yl)benzenesulfonamide was prepared according to procedures analogous to the procedures used to prepare Examples 120 and 121, which provided the title compound as a white solid. (0.12 g, 25% yield): 1H-NMR (400 MHz; DMSO-d6): δ 7.65-7.59 (m, 1H), 6.67 (dd, J = 8.0, 2.3 Hz, 1H), 6.47-6.44 (m, 1H), 6.40- 6.38 (m, 1H), 4.17-4.09 (m, 4H), 3.25 (d, J = 1.0 Hz, 3H), 3.18-3.08 (m, 2H), 3.07-2.91 (m, 3H), 2.64-2.61 (m, 3H), 2.10-2.03 (m, 1H), 1.80-1.75 (m, 1H), missing N-H proton signal; MS (ES+) m / z: 507.0 (M + H), 509.0 (M + H).- 169 - Examples 141 and 142 5-chloro-4-(3-(2-(dimethylamino)ethyl)cyclobutyl)-2-fluoro-N-(6-fluoropyridin-2- yl)benzenesulfonamide (Stereoisomers 1 and 2)Step 1

[0560] To a solution of 6-fluoropyridin-2-amine (7.50 g, 66.9 mmol, 1.00 eq) in DCM (75 mL) was added Pyridine (15.9 g, 200 mmol, 16.2 mL, 3.00 eq) and DMAP (1.63 g, 13.4 mmol, 0.20 eq). Then 4-bromo-5-chloro-2-fluoro-benzenesulfonyl chloride (20.6 g, 66.9 mmol, 1.00 eq) in DCM (100 mL) was dropwise slowly added at 0 °C. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was quenched by addition water 200 mL at 25 °C and filtered to give filtrate. Then the filtrate was extracted with dichloromethane (100 mL * 3). The combined organic layers were washed with hydrogen chloride (1M, 100 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate) to give compound 4- bromo-5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (20.0 g, 52.1 mmol, 77.9% yield) as a yellow solid. MS (ES+) m / z 382.9 / 384.8 (M+1). Step 2

[0561] To a solution of 4-bromo-5-chloro-2-fluoro-N-(6-fluoro-2- pyridyl)benzenesulfonamide (18.0 g, 46.9 mmol, 1.00 eq) in DMF (180 mL) was added K2CO3(13.0 g, 93.8 mmol, 2.00 eq). Then SEM-Cl (9.38 g, 56.3 mmol, 9.96 mL, 1.20- 170 - eq) was added at 0 °C. The mixture was stirred at 25 °C for 3 hrs. The reaction mixture was quenched by addition water 400 mL at 25 °C, and then extracted with Ethyl acetate (300 mL * 3). The combined organic layers were washed with brine (300 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate) to give compound 4-bromo-5-chloro-2-fluoro-N-(6-fluoro-2- pyridyl)-N-(2-trimethylsilylethoxymethyl)benzenesulfonamide (20.0 g, 38.9 mmol, 82.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 - 8.23 (m, 3H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.08 (dd, J = 8.0, 2.4 Hz, 1H), 5.33 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.75 - 0.86 (m, 2H), 0.07 (s, 9H). Step 3

[0562] To an 100 mL vial equipped with a stir bar was added 4-bromo-5-chloro-2-fluoro- N-(6-fluoro-2-pyridyl)-N-(2-trimethylsilylethoxymethyl)benzenesulfonamide (28.5 g, 55.4 mmol, 1.00 eq), 2-bromo-5,8-dioxaspiro[3.4]octane (13.9 g, 72.1 mmol, 1.30 eq), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4- tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (622 mg, 554 μmol, 0.01 eq, CAS: 870987-63-6), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;dichloronickel (331 mg, 832 μmol, 0.015 eq, CAS: 1034901-50-2), bis(trimethylsilyl)silyl-trimethyl-silane (13.8 g, 55.5 mmol, 17.1 mL, 1.00 eq; CAS: 1873-77-4), 2,6-dimethylpyridine (11.9 g, 111 mmol, 12.9 mL, 2.00 eq) in DME (600 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a blue LED lamp (395 nm, 200W light), with cooling water to keep the reaction temperature at 25 °C for 1.5 hrs. The reaction mixture was quenched by addition water (500 mL) at 25 °C, and then extracted with Ethyl acetate (200 mL * 3). The combined organic layers were washed with brine (300 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl) to give compound 5-chloro-4-(5,8-dioxaspiro[3.4]octan-2-yl)-2-fluoro-N- (6-fluoro-2-pyridyl)-N-(2-trimethylsilylethoxymethyl)benzenesulfonamide (19.0 g, 34.7 mmol, 62.6% yield) as a yellow oil. MS (ES+) m / z 569.2 (M+23).1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 - 8.13 (m, 1H), 7.87 - 7.98 (m, 1H), 7.52 - 7.64 (m, 1H), 7.34 - 7.41 (m, 1H), 7.02 - 7.08 (m, 1H), 5.35 (d, J = 2.4 Hz, 2H), 3.85 - 3.93 (m, 1H), 3.79 - 3.84 (m, 1H), 3.57 - 3.70 (m, 3H), 3.46 - 3.53 (m, 1H), 3.21 - 3.28 (m, 2H), 2.63 - 2.75- 171 - (m, 1H), 2.41 - 2.46 (m, 1H), 2.37 - 2.41 (m, 1H), 0.77 - 0.87 (m, 2H), 0.08 - 0.04 (m, 9H). Step 4

[0563] 5-chloro-4-(5,8-dioxaspiro[3.4]octan-2-yl)-2-fluoro-N-(6-fluoro-2-pyridyl)-N-(2- trimethylsilylethoxymethyl)benzenesulfonamide (18.0 g, 32.9 mmol, 1.00 eq) was dissolved in HCOOH (180 mL). The mixture was stirred at 50 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent to give a residue. The residue was diluted with Ethyl acetate 30 mL and adjusted the pH to 7~8 with Sodium bicarbonate aqueous solution. Then mixture was extracted with Ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (50 mL *1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Compound 5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-4-(3- oxocyclobutyl)benzenesulfonamide (13.0 g, crude) as a yellow oil. MS (ES+) m / z 372.9 (M+1). Step 5

[0564] To a solution of 5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-4-(3- oxocyclobutyl)benzenesulfonamide (12.5 g, 33.5 mmol, 1.00 eq) in Tol. (125 mL) was added ethyl 2-(triphenyl-phosphanylidene)acetate (12.9 g, 36.9 mmol, 1.1 eq). The mixture was stirred at 70 °C for 2 hrs. . The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate) to give compound ethyl 2-[3-[2-chloro-5- fluoro-4-[(6-fluoro-2-pyridyl)sulfamoyl]phenyl]cyclobutylidene]acetate (7.00 g, 15.8 mmol, 47.1% yield) as a white solid. MS (ES+) m / z 443.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (br s, 1H) 7.82 - 7.97 (m, 2H) 7.63 (br d, J = 11.2 Hz, 1H) 6.92 (br d, J = 7.2 Hz, 1H) 6.75 (br d, J = 6.4 Hz, 1H) 5.71 (br s, 1H) 4.07 (q, J = 7.2 Hz, 2H) 3.87 (dt, J = 16.4, 8.4 Hz, 1H) 3.46 - 3.63 (m, 2H) 2.96 - 3.19 (m, 2H) 1.18 (br t, J = 7.2 Hz, 3H). Step 6

[0565] To a solution of ethyl 2-[3-[2-chloro-5-fluoro-4-[(6-fluoro-2- pyridyl)sulfamoyl]phenyl]cyclobutylidene]acetate (6.50 g, 14.7 mmol, 1.00 eq) in EtOH (65 mL) was added CoCl2•6H2O (698 mg, 2.94 mmol, 0.20 eq). Then NaBH4(2.78 g, 73.4 mmol, 5.00 eq) was added slowly at -40 °C. The mixture was stirred at -40 °C for 2 hrs. The reaction mixture was filtered and the filter cake was washed with EtOH (30 ml).- 172 - Then filtrate was concentrated under reduced pressure to give a residue. The residue was quenched by addition water (50 mL) at 25 °C, and then extracted with Ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound ethyl 2-[3-[2-chloro-5-fluoro-4-[(6-fluoro-2- pyridyl)sulfamoyl]phenyl]cyclobutyl]acetate (6.00 g, crude) as a yellow oil. MS (ES+) m / z 445.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 - 7.87 (m, 1H), 7.46 - 7.61 (m, 1H), 7.19 - 7.41 (m, 1H), 6.56 - 6.70 (m, 1H), 6.19 - 6.36 (m, 1H), 3.98 - 4.09 (m, 2H), 3.81 (quin, J = 8.4 Hz, 1H), 3.47 - 3.61 (m, 1H), 2.51 - 2.64 (m, 2H), 2.39 - 2.49 (m, 2H), 2.21 - 2.36 (m, 1H), 2.08 - 2.20 (m, 1H), 1.72 - 1.87 (m, 1H), 1.13 - 1.20 (m, 3H). Step 7

[0566] Solution 1: {ethyl 2-[3-[2-chloro-5-fluoro-4-[(6-fluoro-2- pyridyl)sulfamoyl]phenyl]cyclobutyl]acetate (1.80 g, 4.05 mmol, 1.00 eq) } in {THF, 20.5 ml}. Solution 2: {lithium;tert-butoxy(diisobutyl)alumanuide (0.5 M, 20.2 mL, 2.5 eq) }. The solution 1 was pumped by Pump 1 {S1, P1, 6.366 mL / min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1 / 8") mm, 64.114875 mL, -40.0°C}. The solution 2 was pumped by Pump 2 {S2, P2, 6.457 mL / min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1 / 8") mm, 64.114875 mL, -40.0°C}. The residence time of flow reactor 1 was 5.0 min. The reaction mixture was quenched by addition of water (20 ml) and HCl (1 M, 50 mL) at 0 °C, and then extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 5-chloro-2-fluoro-N- (6-fluoro-2-pyridyl)-4-[3-(2-oxoethyl)cyclobutyl]benzenesulfonamide (2.00 g, crude) as a yellow solid without purification. MS (ES+) m / z 401.0 (M+1). Step 8

[0567] To a solution of 5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-4-[3-(2- oxoethyl)cyclobutyl]benzenesulfonamide (2.00 g, 4.99 mmol, 1.00 eq), N- methylmethanamine;hydrochloride (610 mg, 7.48 mmol, 1.50 eq) in DCM (20 mL) was added NaBH(OAc)3 (2.12 g, 9.98 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched by addition water 50 mL at 25 °C, and then extracted with dichloromethane (30 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (25 ml) at 25 °C for 3 hrs. Then filtered- 173 - and the filter cake was washed with MTBE (25 ml). The filter cake concentrated under reduced pressure to give crude product (~800 mg). The crude product was purified by column chromatography (SiO2, Dichloromethane : Methanol to give peak 1 (~350 mg; P1) as a white solid and peak 2 (~400 mg, P2) as a white solid. Peak 1 was purified by prep-HPLC (basic condition: column: CD02-Waters Xbridge BEH C18100 * 25 mm * 10 um; mobile phase: [H2O (0.05% NH3H2O)-ACN]; gradient: 7% - 37% B over 10.0 min) to give Stereoisomer 1 (80.0 mg, 186 μmol, 10.0% yield). Peak 2 was not further purified (Stereoisomer 2) (400 mg, 930 μmol, 50.0% yield).

[0568] Example 141: MS (ES+) m / z 430.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (d, J = 6.4 Hz, 1H), 7.42 - 7.52 (m, 1H), 7.29 (d, J = 10.8 Hz, 1H), 6.60 (dd, J = 8.0, 2.4 Hz, 1H), 6.19 (dd, J = 7.6, 2.8 Hz, 1H), 3.59 - 3.72 (m, 1H), 2.86 - 2.93 (m, 2H), 2.72 (s, 6H), 2.13 - 2.23 (m, 3H), 2.03 - 2.12 (m, 2H), 1.83 - 1.92 (m, 2H).

[0569] Example 142: MS (ES+) m / z 430.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 6.4 Hz, 1H), 7.41 - 7.56 (m, 1H), 7.21 (br d, J = 10.8 Hz, 1H), 6.54 (dd, J = 7.6, 2.4 Hz, 1H), 6.21 (br dd, J = 7.6, 2.4 Hz, 1 H), 3.48 - 3.59 (m, 1H), 2.85 - 2.96 (m, 2H), 2.73 (s, 6H), 2.41 - 2.49 (m, 2H), 2.23 (dt, J = 14.8, 7.2 Hz, 1H), 1.67 - 1.82 (m, 4H). Example 143 3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2- yl)azetidin-1-yl)-6-methylbenzenesulfonamide- 174 - Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2- yl)-4-(3-hydroxyazetidin-1-yl)-6-methylbenzenesulfonamide

[0570] A vial charged with 3-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6- fluoropyridin-2-yl)-6-methylbenzenesulfonamide (3.6 g, 7.3 mmol), anhydrous cesium carbonate (5.9 g, 18 mmol), and anhydrous N,N-dimethylformamide (29 mL) was cooled in an ice / water bath. The vial was charged with azetidin-3-ol hydrochloride (1.2 g, 11 mmol) and the reaction mixture was allowed to warm to ambient temperature. After stirring for 2 h, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated ammonium chloride (2 × 50 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography, eluting with 10 to 100% ethyl acetate in heptane, afforded the title compound as a colourless oil (3.5 g, 89% yield): MS (ES+) m / z: 540.0 (M + 1), 542.0 (M + 1). Step 2. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2- yl)-6-methyl-4-(3-oxoazetidin-1-yl)benzenesulfonamide

[0571] A flask was charged with anhydrous dichloromethane (9.2 mL), and oxalyl chloride (0.191 mL, 2.22 mmol) under a nitrogen atmosphere. The reaction mixture was cooled in a dry ice / acetone bath before anhydrous dimethyl sulfoxide (0.35 g, 4.44 mmol) was added. The mixture was stirred at -78 °C for 20 min before an anhydrous dichloromethane (9.2 mL) solution of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(3-hydroxyazetidin-1-yl)-6-methylbenzenesulfonamide (1.0 g, 1.9 mmol) was added, immediately followed by triethylamine (0.93 mL, 6.7 mmol). The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was diluted with dichloromethane (300 mL) and transferred to a separatory funnel. The organic layer was washed with saturated ammonium chloride (2 × 50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The compound was used as in the next step without further purification (0.99 g, 100% yield): MS (ES+) m / z : 560.0 (M + Na), 562.0 (M + Na). Step 3. Preparation of methyl 4-(1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3-fluoro-5-methylphenyl)-3-hydroxyazetidin-3-yl)-4- nitrobutanoate

[0572] To a flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-6-methyl-4-(3-oxoazetidin-1-yl)benzenesulfonamide (0.99 g, 1.9- 175 - mmol) was added ethanol (4 mL), methyl 4-nitrobutanoate (0.41 g, 2.8 mmol), and triethylamine (0.19 g, 1.9 mmol). The reaction mixture was stirred at ambient temperature for 18 h before being diluted with ethyl acetate (300 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 10 to 80% ethyl acetate in heptane afforded the title compound as a yellow solid (0.64 g, 50% yield): MS (ES+) m / z : 685.2 (M + H), 687.2 (M + H). Step 4. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2- yl)-4-(3-hydroxy-3-(5-oxopyrrolidin-2-yl)azetidin-1-yl)-6-methylbenzenesulfonamide

[0573] To a flask containing methyl 4-(1-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(6- fluoropyridin-2-yl)sulfamoyl)-3-fluoro-5-methylphenyl)-3-hydroxyazetidin-3-yl)-4- nitrobutanoate (0.64 g, 0.93 mmol) was added iron powder (0.72 g, 13 mmol), and glacial acetic acid (15 mL). The reaction mixture was heated to 80 °C for 12 h before cooling to ambient temperature. The reaction mixture was diluted with ethyl acetate (250 mL), filtered through a bed of sodium sulfate, and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 25 to 100% ethyl acetate in heptane followed by 0 to 20% methanol in ethyl acetate afforded the title compound as a colourless oil (0.50 g, 86% yield): MS (ES+) m / z : 645.2 (M + Na), 647.2 (M + Na). Step 5. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2- yl)-4-(3-methoxy-3-(1-methyl-5-oxopyrrolidin-2-yl)azetidin-1-yl)-6- methylbenzenesulfonamide

[0574] To a flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(3-hydroxy-3-(5-oxopyrrolidin-2-yl)azetidin-1-yl)-6- methylbenzenesulfonamide (0.53 g, 0.85 mmol) was added anhydrous N,N,- dimethylformamide (8.6 mL), iodomethane (0.53 g, 3.8 mmol), followed by sodium hydride 60% mineral oil dispersion (0.15 g, 3.8 mmol). The reaction mixture was stirred at ambient temperature for 24 h before being diluted with ethyl acetate (150 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL), water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 60 to 100% ethyl acetate in heptane followed by 0 to 20% methanol in ethyl acetate afforded the title compound as a colourless oil (0.46 g, 82% yield): MS (ES+) m / z : 673.2 (M + Na), 675.2 (M + Na).- 176 - Step 6. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2- yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azetidin-1-yl)-6-methylbenzenesulfonamide

[0575] A flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methyl-5-oxopyrrolidin-2-yl)azetidin-1-yl)-6- methylbenzenesulfonamide (0.46 g, 0.71 mmol) was charged with a 0.5 M solution of 9- borabicyclo[3.3.1]nonane in tetrahydrofuran (6.0 mL) and heated to 60 °C for 1 h. The reaction mixture was cooled to ambient temperature before being diluted with ethyl acetate (250 mL). The organic layer was washed with saturated ammonium chloride (2 × 50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 10 to 80% ethyl acetate (containing 10% triethylamine and 10% isopropanol) in heptane afforded the title compound as a colorless oil (0.45 g, 99% yield): MS (ES+) m / z : 637.4 (M + H), 639.4 (M + H). Step 7. Preparation of 3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(3-methoxy-3-(1- methylpyrrolidin-2-yl)azetidin-1-yl)-6-methylbenzenesulfonamide

[0576] A flask containing 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6- fluoropyridin-2-yl)-4-(3-methoxy-3-(1-methylpyrrolidin-2-yl)azetidin-1-yl)-6- methylbenzenesulfonamide (0.45 g, 0.71 mmol) was charged with 1,3,5- trimethoxybenzene (0.119 g, 0.71 mmol), anhydrous dichloromethane (2 mL), and trifluoroacetic acid (2 mL). The reaction mixture was stirred at ambient temperature for 1 h before being concentrated in vacuo. Purification of the residue by reverse phase column chromatography, eluting with a gradient of 5 to 35% acetonitrile in water containing 0.5% formic acid afforded the title compound as a colorless solid after lyophilization (0.13 g, 36% yield):1H-NMR (400 MHz; DMSO-d6): δ 7.79 (q, J = 8.3 Hz, 1H), 6.76 (dd, J = 7.9, 2.0 Hz, 1H), 6.62 (dd, J = 7.9, 2.4 Hz, 1H), 6.30 (s, 1H), 4.18 (dd, J = 9.7, 3.4 Hz, 2H), 4.12-4.08 (m, 2H), 3.32 (s, 3H), 3.06-3.01 (m, 1H), 2.93-2.90 (m, 1H), 2.61 (s, 3H), 2.43- 2.36 (m, 4H), 2.00-1.93 (m, 1H), 1.73-1.63 (m, 3H), missing N-H proton signal; MS (ES+) m / z: 487.2 (M + H), 489.2 (M + H). Biological Assays Example 144: Electrophysiology Assays (In Vitro) Sodium currents were measured using the patch-clamp technique in whole-cell configuration using the Qube 384 (Sophion Bioscience A / S, Copenhagen, Denmark)- 177 - automated voltage-clamp platform. Electrophysiology experiments were performed with HEK293 cells, stably transfected with expression vectors containing the full-length cDNA coding for one of the human sodium channel α-subunits: human NaV1.7 (NM_002977); human NaV1.1 (NM_006920); human NaV1.2 (NM_021007); human NaV1.5 (NM_198056); human NaV1.6 (NM_014191) and co-expressed with the human NaV β1 subunit (NM_199037). Cells were grown in culture media containing 10% fetal bovine serum, 1% penicillin-streptomycin-glutamine, and 0.5 mg / mL Geneticin (G418) at 37°C with 5% CO2. The recording solutions contained: Intracellular solution (ICS): 5 mM NaCl, 10 mM CsCl, 120 mM CsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES (4 (2 hydroxyethyl)-1-piperazineethanesulfonic acid buffer), 10 mM EGTA (ethylene glycol tetraacetic acid); adjusted to pH 7.2 with CsOH. Extracellular solution (ECS): 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES; adjusted to pH 7.4 with NaOH. Osmolarity in all ICS and ECS solutions was adjusted with glucose to 300 mOsm / kg and 310 mOsm / kg, respectively. To measure inhibition, the membrane potential was maintained at a voltage where inactivation of the channel was complete. For each NaV channel subtype, the holding potential used to quantify compound inhibition was as follows: NaV1.6 (-45 mV), NaV1.1 (45 mV), NaV1.2 (45 mV), NaV1.5 (-60 mV), NaV1.7 (-60 mV). The voltage was briefly repolarized to a negative voltage every 10 seconds ( 150 mV) for 20 milliseconds to allow recovery from fast inactivation, followed by a test pulse to -20 mV for 10 milliseconds to quantify the inhibition of the current by compound. The 20 ms repolarization was sufficient for compound-free channels to completely recover from fast inactivation, but compound-bound channels to remain blocked. The fractional decrease in sodium current following 20 minutes wash-on of compound was taken as the fractional block of sodium channels by compound. Qube experiments were all performed at 30°C ± 2°C. Selectivity

[0577] Those of ordinary skill in the art will understand that determining selectivity can be determined by assessing the ratio of NaV1.x to NaV1.7 inhibition. Compounds are deemed selective if this ratio is ≥ 5.- 178 - CNS Exposure

[0578] Brain and plasma levels of test compounds are analyzed by electrospray mass spectroscopy after administration in mice. Compounds are deemed CNS penetrant if the ratio of brain to plasma exposure is > 0.05.

[0579] Data for representative Compounds of the Disclosure are provided in Table 9. Table 9- 179 -- 180 -- 181 - * (+) = > 2 µM; (++) = 1-2 µM; (+++) = < 1 µM

[0580] Having now fully described the methods, compounds, and compositions herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof. All patents, patent applications, and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

- 182 - WHAT IS CLAIMED IS:

1. A compound having Formula I:or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound 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 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; R9is selected from hydrogen, (C1-C6) alkyl, and optionally substituted (C6-C14) aryl-(C1- C6) alkyl-; A is optionally substituted heteroaryl; Z is selected from N and CRZ;- 183 - RZis selected from hydrogen and (C1-C6) alkyl; R6is selected from 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; W is selected from R8R7N-, R8R7N-(C1-C6) alkyl-, R8R7N-(C3-C6) cycloalkyl-, R8R7N-(C3- C6) cycloalkyl-(C1-C6) alkyl-, 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; and 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.

2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, whereinis3. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein each of R1, R2, R3, and R4is independently hydrogen, (C1-C6) alkyl, or halogen.- 184 - 4. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R1is halogen.

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

6. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R3is selected from hydrogen and halogen.

7. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R4is halogen.

8. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, whereinis selected from9. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein Z is N.- 185 - 10. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein W is selected from R8R7N-(C1-C6) alkyl-, optionally substituted nitrogen-containing heterocyclyl, and optionally substituted nitrogen-containing heterocyclyl-(C1-C6) alkyl-.

11. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R7and R8are (C1-C6) alkyl.

12. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein W is selected from13. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R6is selected from hydrogen, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, and optionally substituted (C6-C14) aryl.

14. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R6is selected from hydrogen, methyl, ethyl, cyclopropyl, methoxy, and phenyl.

15. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R6and W are taken together with the atom to which they are attached to form an R8R7N-(C3-C7) cycloalkyl- or an optionally substituted nitrogen-containing heterocyclyl.- 186 - 16. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R6and W are taken together with the atom to which they are attached to form an optionally substituted cyclobutyl or an optionally substituted pyrrolidinyl.

17. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein- 187 -18. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R9is hydrogen.

19. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein A is selected from optionally substituted thiazolyl and optionally substituted pyridinyl.

20. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein A is selected from21. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, having any one or more of Formulae IIa, IIb, IIc, IId, IIe, IIf, IIq, IIr, and IIs:- 188 -- 189 -wherein: p is selected from 0, 1, 2, and 3; t is selected from 0, 1, and 2; q is selected from 1, 2, and 3, with the proviso that if t is 0, q is selected from 2 and 3; Z1is selected from CR15and N; R12is selected from hydrogen and optionally substituted (C1-C6) alkyl; and- 190 - R15is selected from hydrogen, optionally substituted (C1-C6) alkyl, and -NR8R9.

22. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein p is 1 or 2.

23. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein t is 1 and q is 1.

24. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein t is 1 and q is 2.

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

26. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein Z1is CR15.

27. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R15is hydrogen.

28. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein Z1is N.

29. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R12is methyl.- 191 - 30. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, having any one or more of Formulae IIg, IIh, IIi, IIj, IIk, IIm, IIt, IIu, and IIv:- 192 -- 193 -wherein: R10and R11are each independently selected from hydrogen, halogen, and (C1-C4) alkyl, or R10and R11in Formulae IIg, IIh, and IIt 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 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.

31. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R10and R11are hydrogen.- 194 - 32. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein R13is halogen.

33. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, having any one or more of Formulae IIn, IIo, IIp, IIw, IIx, and IIy:- 195 -34. The compound of any one of the preceding claims, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof, wherein the compound is a compound listed in Table A, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or stereoisomer thereof.

35. A pharmaceutical composition comprising the compound of any one of the preceding claims and a pharmaceutically acceptable excipient.- 196 - 36. 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.

37. 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.

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

7.

39. 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.

40. The method of any one of the preceding claims 39, wherein the disease or disorder is selected from pain, depression, a cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof.

41. 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.

42. 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.

43. 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.

44. 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- 197 - cardiovascular disease, a respiratory disease, a psychiatric disease, diabetes, pruritus, and combinations thereof in a subject in need thereof.

45. 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.

46. 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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