Sodium channel blocking compounds, derivatives thereof, and methods of their use

Abstract

The invention provides compounds that are useful for treatment of conditions associated with aberrant activity of voltage gated sodium channel Nav1.8, and methods of treating a subject with those compounds for conditions such as pain, itch, and cough.

Description

[0001] SODIUM CHANNEL BLOCKING COMPOUNDS, DERIVATIVES THEREOF, AND METHODS OF THEIR USE Field of the Invention The application relates generally to sodium channel blocking compounds, derivatives thereof, and the use of such compounds as pharmacological agents. Background Millions of people suffer from conditions associated with pain, itch, and / or cough. Pain can be a symptom or cause of conditions such as neuropathy, hyperalgesia, and opioid use disorders. In many cases, drugs used to treat such condition fail to provide relief or produce intolerable side effects. Therefore, existing treatments are inadequate for many patients who suffer from a variety of conditions. Summary The invention provides compounds that are useful for treatment of conditions associated with aberrant activity of voltage gated sodium channel NaV1.8, such as pain, itch, and cough. In one aspect, the invention provides a Formula (I): (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-14 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-14 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of a monocyclic, bicyclic, or spirocyclic cycloalkyl ring, and a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, and wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring may be optionally substituted with one or more halogens or one or more haloalkyl groups; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II): wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3 is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rd is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6. In one aspect, the invention provides a compound of Formula (I):

[0002] , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-6 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of: a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of said cycloheteroalkyl are optionally substituted with haloalkyl wherein the haloalkyl chain may be fully or partially halogenated; and a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II): wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3 is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rdis H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6. In one aspect, the invention provides a compound of Formula (I): , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-6 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of: a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of said cycloheteroalkyl are optionally substituted with haloalkyl wherein the haloalkyl chain may be fully or partially halogenated; and a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II): wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3 is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rdis H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6. In certain embodiments, in the compound of Formula (I), R1is selected from H and C1-C3alkyl In certain embodiments, in the compound of Formula (I), R1is H. In certain embodiments, in the compound of Formula (I), R2is H. In certain embodiments, R2is not H. In certain embodiments, in the compound of Formula (I), R2is selected from H or formula (II): wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3; and R3 and R4are defined above. In certain embodiments, in the compound of Formula (I), R2is: wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3; R3and R4are defined above. In certain embodiments, in the compound of Formula (I), wherein R2is selected from H or formula (II): wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3 R3and R4are defined above. In certain embodiments, in the compound of Formula (I), wherein R2is wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3 R3 and R4are defined above. In certain embodiments, R2is represented by Formula (II) (described above), wherein X1is not O and / or X2is not O. In certain embodiments, R2is represented by Formula (II) (described above), wherein X1is not NH or NR’ and X2is not NH or NR’. In certain embodiments, wherein within Formula (II), X1is O and X2is NH. In certain embodiments, in Formula (II), X1and X2are O. In certain embodiments, in Formula (II), X1is O and X2is NH. In various embodiments, in the compound of Formula (I), R2is selected from a group consisting of: H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’. In certain embodiments, in the compound of Formula (I), R2is selected from a group consisting of: H,

[0003] In certain embodiments, in the compound of Formula (I), R2is selected from a group consisting of: H, , , In certain embodiments, in the compound of Formula (I), R2is: . In certain embodiments, in the compound of Formula (I), R2is: or a stereoisomer thereof. In certain embodiments, in the compound of Formula (I), A is an optionally substituted aryl, an optionally substituted heteroaryl an optionally substituted 5 or 6 members heteroaryl with one or more heteroatom; wherein the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, wherein A is optionally a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, and pyridazinyl N-oxide. In certain embodiments, in the compound of Formula (I), if the ring A is a heteroaryl, it contains one or more nitrogen atom in a ring. In certain embodiments, the A ring contains one nitrogen atom. In certain embodiments, such nitrogen atom may be in the form of an N-oxide, wherein the N-oxide is selected from a group consisting of pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide, pyridazinyl N-oxide. In certain embodiments, the A ring may include further substituents. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted aryl. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted heteroaryl with one heteroatom. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted heteroaryl with two heteroatoms. In certain embodiments, in the compound of Formula (I), ring A is substituted with at least trifluoromethyl. In certain embodiments, in the compound of Formula (I), trifluoromethyl is the only substitution on ring A. In certain embodiments, in the compound of Formula (I), ring A is substituted with at least cyclopropylmethyl. In certain embodiments, in the compound of Formula (I), A is represented by the following Formula(s): wherein each of Q1, Q2, Q3 and Q4 is independently N, N-O, or CR5; wherein R5 is H, hydroxyl group, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl wherein the alkyl chain may be fully or partially deuterated, branched alkyl, allyl, alkenyl, alkynyl, halo-C1-C4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, -CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-heteroaryl, -CF2-heterocyclyl, - CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, -C(=O)NHR’, - C(=O)NR’R”, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR’R”, -NHSO2R’, -NHC(=O)-alkyl -NH(C=O)NR’R”, trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted five (5) or more membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from N, O, or S. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q2and Q4is N, N-O; Q2 is N, N-O; Q4 is CR5; Q2is CR5; Q4is N, N-O; R6is H, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl, wherein the alkyl chain may be fully or partially deuterated, branched alkyl, alkenyl, alkynyl, halo-C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, NHC(=O)R’, NHSO2R, -C(=O)R’, - C(=O)NHR’, -C(=O)NR’R”, -O-R’, -O-C(=O)-R’, aryl, heteroaryl, -CF2CH3, -CF2CF3; R7 is H, hydroxyl group, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl wherein the alkyl chain may be fully or partially deuterated, branched alkyl, allyl, alkenyl, alkynyl, halo-C1-C4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, -CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-heteroaryl, -CF2- heterocyclyl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, - C(=O)NHR’, -C(=O)NR’R”, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR’R”, -NHSO2R’, -NHC(=O)-alkyl -NH(C=O)NR’R”, trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; wherein not more than two of Q1, Q2, Q3and Q4are N or N-O. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q3 and Q4 are N; wherein Q3 is N, N-O; Q4 is CR5; or wherein Q3 is CR5, Q4 is N, N-O; R5is defined above; and R6and R7are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein Q1 and Q4 are N, N-O; Q1 is N, N-O; Q4 is CR5; Q1 is CR5, Q4 is N, N-O; or Q1 and Q4are CR5; and wherein R6and R7are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q1and Q2are N; and R6and R7are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q1is CR5, and Q2is N; R6and R7are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein Q1 is N; and Q2 is CR5; and R6 and R7 are defined above. In certain embodiments, in the compound of Formula (I), the heteroaryl or aryl ring A is selected from the group consisting of: In certain embodiments, in the compound of Formula (I), the heteroaryl or aryl ring A is selected from the group consisting of: In certain embodiments, in the compound of Formula (I), ring B is selected from the group consisting of pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.l]heptane, azabicyclo[3.l.l]heptane, azabicyclo[4.l.0]heptane, azabicyclo[3.2.l]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa- azabicyclo[3.2.l]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxa- azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[l,2-a]pyrazine, hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.l.l3,8]undecane. In certain embodiments, in the compound of Formula (I), ring B is a spirocyclic cycloalkyl ring. In certain embodiments, spirocyclic cycloalkyl ring may be selected from spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, and spiro[6.3]decane, and may be attached at any position of the spirocyclic cycloalkyl group with an open valency. In certain embodiments, the spirocyclic cycloalkyl group may be substituted with halogen. In certain preferred embodiments, the halogen substituted on spirocyclic cycloalkyl group is fluorine. In certain embodiments, the spirocyclic cycloalkyl group may be substituted with haloalkyl groups. In certain preferred embodiments, the haloalkyl group substituted on the spirocyclic cycloalkyl ring is trifluoromethyl. In certain embodiments, the spirocyclic cycloheteroalkyl group is selected from the group consisting of spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, spiro[6.3]decane, and may be attached to any position of the spiro group with an open valency. In certain embodiments, the spirocyclic cycloheteroalkyl group contains at least one and up to four heteroatoms selected from N, O, or S. In certain embodiments, the spirocyclic cycloheteroalkyl group may be substituted with halogen. In certain preferred embodiments, the halogen substituted on the spirocyclic cycloheteroalkyl group is fluorine. In certain embodiments, the spirocyclic cycloheteroalkyl group may be substituted with haloalkyl groups. In certain preferred embodiments, the haloalkyl group substituted on the spirocyclic cycloheteroalkyl group is trifluoromethyl. In certain embodiments, the compound of Formula (I) is further described as Formula (III): , wherein: B, C, R1, and R2are defined above, and R6and R7are defined above. In certain embodiments, the compound of Formula (I) is further described as Formula (IV): , wherein: B, C, R1, and R2are defined above, and R5, R6 and R7 are defined above. In certain embodiments, the compound of Formula (I) is further described as Formula (V):

[0004] , wherein: B, C, R1, and R2are defined above, and R5, R6 and R7 are defined above. In certain embodiments, the compound of Formula (I) is further described as Formula (VI): . In certain embodiments, the compound of Formula (I) is further described as Formula (VII): . In certain embodiments, the compound of Formula (I) is further described as Formula (VIII):

[0005] . In certain embodiments, substituted or unsubstituted B is selected from a group consisting o , d . In certain embodiments, in the compounds of Formula (I), substituted or unsubstituted C is selected from a group consisting of: , In various embodiments, in the compound of Formula (I), ring C is optionally fused to at least one ring selected from the group consisting of: an optionally saturated carbocyclyl containing 5-6 ring members or an optionally saturated heterocyclyl containing 5-6 ring members and 1-4 optionally charged heteroatoms. In certain embodiments, in the compound of Formula (I), ring C is substituted or unsubstituted phenyl. In certain embodiments, in the compound of Formula (I), ring C is substituted or unsubstituted pyridyl. In certain embodiments, in the compound of Formula (I), the one or more substitutions on the ring A ring are selected from a group consisting of: halo, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6alkyl, aryl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, C3-C6 heteroaryl, and a combination thereof, wherein the heterocycloalkyl and heteroaryl comprise one or more hetero atoms selected from a group consisting of: N, O, or S. In certain embodiments, in the compound of Formula (I), the one or more substitutions on the A ring are selected from a group consisting of: methyl, trifluoromethyl, chloro, fluoro, bromo, C1-C6alkyl, phenyl, cycloalkyl, methyl pyrazole, fused 1, 4 dioxane, and methylcyano. In certain embodiments, the one or more substitutions on the ring A are selected from a group consisting of: -CH3, -CD3, -CF3, -Cl, -Br, -F, -CH2-CH2-CH=CH2, phenyl, -CH2-CN, - C(=O)-NH2, , , , , , , , , , , In certain embodiments, in the compound of Formula (I), the substitutions on the A ring are selected from the group consisting of H, halogen, alkyl, and haloalkyl. In certain embodiments, in the compound of Formula (I), the substitutions on the A ring are selected from the group consisting of methyl and -CF3. In certain embodiments, in the compound of Formula (I), the substitutions on the A ring are selected from the group consisting of H and -CF3. In certain embodiments, in the compound of Formula (I), A is a 6-membered aryl or heteroaryl ring. In certain embodiments, in the compound of Formula (I), A is phenyl. In certain embodiments, in the compound of Formula (I), A is pyridine. In certain embodiments, in the compound of Formula (I), C ring is a 6-membered aryl, heteroaryl, or cycloalkyl or heterocycloalkyl ring. In certain embodiments, in the compound of Formula (I), C ring is phenyl. In certain embodiments, in the compound of Formula (I), C ring is pyridine. In certain embodiments, in the compound of Formula (I), C ring is piperidine. In certain embodiments, in the compound of Formula (I), C ring is pyrrolidine. In certain embodiments, in the compound of Formula (I), R2is: wherein: X1is O and X2is NR’, and R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, R’ is H. In certain embodiments, R4is C1-C3alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is C3-C4cycloalkyl. In certain embodiments, in the compound of Formula (I), R2is: wherein: X1is O and X2is O, and R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, R’ is H. In certain embodiments, R4is C1-C3alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is C3-C4 cycloalkyl. In certain embodiments, in the compound of Formula (I), B ring is 4-8 membered substituted or unsubstituted cycloalkyl or cycloheteroalkyl, wherein heteroatoms in said cycloheteroalkyl are selected from the group consisting of N or O. In certain embodiments, said substitutions on B ring are selected from the group consisting of one or more of halogen, C1-C4 alkyl, oxyalkyl, alkyloxyalkyl, substituted or unsubstituted C3-C6cycloalkyl wherein said C3-C6cycloalkyl is spiro with B ring, and partially or completely halogenated C1-C4alkyl. In certain embodiments, the halogen is fluoro. In certain embodiments, the halogen is chloro. In certain embodiments, the C1-C4 alkyl is methyl. In certain embodiments, the C3-C6cycloalkyl is cyclopropyl. In certain embodiments, the substitutions are selected from the group consisting of - OCH3and -CH2-O-CH3. In certain embodiments, ring C comprises additional substitutions, i.e., substitutions in wherein the substitutions are selected from a group consisting of H, halo, and alkyl. In certain embodiments, the said halo substitution in ring C is F. In certain embodiments, R1is H. In certain embodiments, the compounds of the invention do not include the compounds provided in WO 2023 / 150201, which is incorporated herein by reference in its entirety. In certain embodiments, the compounds of the invention do not include Examples 1-257. Accordingly, in certain embodiments, the invention provides a compound of Formula (I), with the proviso that the compound of the invention does not include Examples 1-257. In certain aspects, the invention provides a compound selected from the group consisting of: In certain aspects, the invention provides a compound selected from the group consisting of: In certain aspects, the invention provides a compound selected from the group consisting of: Ċ

[0006] In certain embodiments, the compound of Formula (I) is selected from the group consisting of:

[0007] In certain embodiments, the compound of the invention is selected from a group consisting of: In certain embodiments, the compound of the invention is selected from a group consisting of: In certain embodiments, the compound of the invention is selected from a group consisting of:

[0008] In certain embodiments, the compound of the invention is selected from a group consisting of the compounds recited in Tables 1A-1F: Table 1A.

[0009] Table 1B:

[0010] Table 1C: Table 1D:

[0011] Table 1E: Table 1F: In certain embodiments, the compound of the invention is selected from a group consisting of the compounds in Tables 1G-1NN: Table 1G:

[0012] Table 1H:

[0013] Table 1J:

[0014] Table 1L:

[0015] Table 1M:

[0016] Table 1N:

[0017] Table 1P:

[0018] Table 1Q:

[0019] Table 1R:

[0020] Table 1S:

[0021] Table 1T:

[0022] Table 1U: Table 1V: Table 1X:

[0023] Table 1Y:

[0024] Table 1Z:

[0025] Table 1AA:

[0026] Table 1BB:

[0027] Table 1CC:

[0028] T

[0029] Table 1EE:

[0030] Table 1FF:

[0031] Table 1GG: Table 1HH: Table 1JJ:

[0032] Table 1KK:

[0033] Table 1LL:

[0034] Table 1MM:

[0035] Table 1NN:

[0036] In another aspect, the invention provides inhibitors of a voltage gated sodium channel NaV1.8. The inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above. In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above. The condition may be associated with aberrant activity of voltage gated sodium channels. The condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma / injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers- Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry's disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder. In another aspect, the invention provides methods of making a medicament using a compound of the invention, such as any of those described above. In another aspect the invention provides products comprising a compound of the invention, such as any of those described above, for treatment of a condition, such as any of those described above, in a subject. Detailed Description Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs. The definitions provided below are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure. Unless otherwise stated, the moieties described below are optionally substituted, i.e., they may be substituted at one or more positions. The terms substituted, whether preceded by the term “optionally” or not, and substituent, as used herein, refer to the ability to change one or more functional groups for another functional group or groups on a molecule, provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions). When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups R1, R2, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R1and R2can be substituted alkyls, or R1can be hydrogen and R2can be a substituted alkyl, and the like. The terms “a,” “an,” or “a(n),” when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below. Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. Unless otherwise explicitly defined, a “substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein. The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in the art, all valences must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ally 1, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like. The term “alkyl” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic saturated hydrocarbon group, or combination thereof, and can include di- and multivalent groups, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to C1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, λ, 10, 11, 12, 13, 14, 15, 16, 17, 18, 1λ, and 20 carbons, linear (i.e., “straight-chain”), branched, or cyclic saturated hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues and isomers thereof. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl. Thus, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms or a cyclic hydrocarbon group having from 3 to 15 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom, such as O, N, P, Si or S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, - CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, - CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)NR’, -NR’R”, -OR’, -SR, -S(O)R, and / or -S(O2)R’. “Cycloalkyl” refers to a saturated monocyclic or multicyclic ring system of from about 3 to about 15 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and / or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyeiohexenyl, cycloheptyl, and the like. The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C1-20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. The term “carbocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which all ring members are carbon atoms. Unless otherwise specified, a carbocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. The term “heterocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which at least one ring member is a heteroatom, such as N, O, or S. Unless otherwise specified, a heterocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. Examples of saturated and partially unsaturated non- aromatic heterocyclic groups include, but are not limited to, 3-oxetanyl, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiozolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl and haloalkoxy substituted derivatives of any of the aforementioned groups. The terms “cycloheteroalkyl” and “heterocycloalkyl” refer to a saturated ring system, such as a 3- to 10-member cycloalkyl ring system, that include one or more heteroatoms. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S). Examples of heterocycloalkyl include, but are not limited to, 1-(l, 2,5,6-tetrahydropyridyi), 1- piperidmyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms, such as oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples include, but are not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6- membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like. An unsaturated hydrocarbon, carbocyclyl, or heterocyclyl has one or more double bonds or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkenyl” as used herein refers to a monovalent group derived from a C2-C20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl. The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-C20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), l- propynyl, pentynyl, hexynyl, and heptynyl groups, and the like. The term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched, or cyclic. The alkylene group also can be optionally unsaturated and / or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (- CH2-CH2-); propylene (CH2)3, cyclohexylene (-C6H10-, -CH=CH-CH=CH-, -CH=CH-CH2-, - CH2CH2CH2CH2CH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)q-N(R)-(CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S- CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR’- represents both -C(O)OR’- and -R’OC(O)-. The term “spirocyclyl” refers to a polycyclic compound in which two rings have a single atom, e.g., carbon, as the only common member of two rings. Thus, a “spirocycloalkyl” refers to a cycloalkyl group with two rings having a single carbon in common, and a “spiroheterocycloalkyl” or “spiroheterocycloalkyl” refers to a cycloheteroalkyl group with two rings having a single carbon or other atom, e.g., nitrogen, in common. The term “aryl” means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to and groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyndyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzoihiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-qumolyl, and 6-quinolyl. Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively. Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., “3 to 7 membered”), the term “member” refers to a carbon atom or heteroatom. Each of the above terms is meant to include both substituted and unsubstituted forms of the indicated group. In some instances, the groups are explicitly defined as substituted, for example, “substituted aryl.” The optional substituents are provided below. Substituents can be one or more of a variety of groups selected from, but not limited to: - OR’, =O, =NR’, =N-OR’, -NR’R” -SR’, -halogen, -SiR’R”R”, -OC(O)R, -C(O)R, -CO2R - C(O)NR’R”, -OC(O)NR’R”, -NR”C(O)R, -NR’-C(O)NR”R’”, -NR”C(O)OR’, -NR- C(NR’R”)=NR”’, -S(O)R, -S(O)2R’, -S(O)2NR’R”, -NRSO2R’, -CN, CF3, fluorinated C1-C4 alkyl, and -NO2in a number ranging from zero to (2m’ +1), where m’ is the total number of carbon atoms in such groups. R’, R”, R’” and R”” each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 -3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. Other non- limiting examples of substituents include (C1-C6)alkyl, (C2-C8)alkenyl, (C3-C8)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -O(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C8)cycloalkyl, (C6-C10)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1- C6)alkyl(C6-C10)aryl, -C(O)(C1-C6)alkyl, -C(O)NR’R”, -S(O)(C1-C6)alkyl, -S(O)NR’R”, - S(O)2(C1-C6)alkyl, -S(O)2NR’R”, -O(C1-C6)alkyl-S(O)(C1-C6)alkyl, -O(C1-C6)alkyl-S(O)NR’R”, -O(C1-C6)alkyl-S(O)2(C1-C6)alkyl, and -O(C1-C6)alkyl-S(O)2NR’R”. As used herein, an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen. When a compound of the disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’” and R”” groups when more than one of these groups is present. When R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of ordinary skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e. g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’)q-U-, wherein T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH2)r-B-, wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, - S(O)2NR’- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’)s-X’-(C”R’”)d-, where s and d are independently integers of from 0 to 3, and X’ is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR’-. The substituents R, R’, R” and R” may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. As used herein, the term “acyl” refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR, esters, - RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H. The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-C20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like. The term “alkoxy alkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxymethyl group. “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl. “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplar)' aralkyloxyl group is benzyloxyl, i.e., C6H5CH2-O-. An aralkyloxyl group can optionally be substituted. “Alkoxycarbonyl” refers to an alkyl-O-C(=O)- group. Exemplary alkoxy carbonyl groups include methoxycarbonyl, ethoxy carbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl. “Aryloxycarbonyl” refers to an aryl-O-C(=O)- group. Exemplary aryloxy carbonyl groups include phenoxy- and naphthoxy-carbonyl. “Aralkoxycarbonyl” refers to an aralkyl -O-C(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. “Carbamoyl” refers to an amide group of the formula -C(=O)NH2. “Alkylcarbamoyl” refers to a R’RN -C(=O) group wherein one of R and R’ is hydrogen and the other of R and R’ is alkyl and / or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R'RN-C(=O)- group wherein each of R and R’ is independently alkyl and / or substituted alkyl as previously described. The term “carbonyldioxyl,” as used herein, refers to a carbonate group of the formula - OC(=O)-OR. “Acyloxyl” refers to an acyl-O- group wherein acyl is as previously described. The term “amino” refers to the -NH2group and refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic groups. For example, the terms “acyl amino” and “alkylamino” refer to specific N- substituted organic groups with acyl and alkyl substituent groups respectively. An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and / or R’” taken together may optionally be –(CH2)kwhere k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropyl amino, piperidino, trimethylamino, and propylamine. The amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like. “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described. The term “carbonyl” refers to the -C(=O)- group, and can include an aldehyde group represented by the general formula R-C(=O)H. The term “carboxyl” refers to the COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety. The term “cyano” refers to the -CN group. The terms “halo,” “halide,” and “halogen” refer to fluoro, chloro, bromo, and iodo groups. The term “haloalkyl” refers to an alkyl group substituted with one or more halogens. Additionally, the term “haloalkyl,” includes monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-4)alkyl” includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like. The terms “halocycloalky” and “cyclohaloalkyl” refer to a cycloalkly group with one or more halogens. The term “hydroxyl” refers to the -OH group. The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group. The term “mercapto” refers to the -SH group. The term “oxo” refers to an oxygen atom that is double bonded to a carbon atom or to another element. The term “nitro” refers to the -NO2group. The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom. The term “sulfate” refers to the - SO4group. The term thiohydroxyl or thiol, as used herein, refers to a group of the formula -SH. More particularly, the term “sulfide” refers to compound having a group of the formula - SR. The term “sulfone” refers to compound having a sulfonyl group -S(O2)R’. The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R The term ureido refers to a urea group of the formula -NH-CO-NH2. Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, m terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium, and which are readily converted from one isomeric form to another. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. The compounds of the present disclosure may exist as salts, and particularly as pharmaceutically acceptable salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or m a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow' the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. In addition to salt forms, the present disclosure provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. The term “protecting group” refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. For example, protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4- dimethoxybenzyl, while co existing amino groups may be blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a palladium(O)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Compounds: The invention provides compounds that modulate, e.g., inhibit, the activity of voltage gated sodium channels. In one aspect, the invention provides a Formula (I): , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-14 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-14 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of a monocyclic, bicyclic, or spirocyclic cycloalkyl ring, and a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, and wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring may be optionally substituted with one or more halogens or one or more haloalkyl groups; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II): wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3 is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rdis H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6. In one aspect, the invention provides a compound of Formula (I): , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-6 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of: a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of said cycloheteroalkyl are optionally substituted with haloalkyl wherein the haloalkyl chain may be fully or partially halogenated; and a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II): wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rd is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6. In one aspect, the invention provides a compound of Formula (I): , or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-6 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of: a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of said cycloheteroalkyl are optionally substituted with haloalkyl wherein the haloalkyl chain may be fully or partially halogenated; and a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II): wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rdis H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6. In certain embodiments, in the compound of Formula (I), R1is selected from H and C1-C3alkyl In certain embodiments, in the compound of Formula (I), R1is H. In certain embodiments, in the compound of Formula (I), R2is H. In certain embodiments, R2is not H. In certain embodiments, in the compound of Formula (I), R2is selected from H or formula (II): wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3; and R3and R4are defined above. In certain embodiments, in the compound of Formula (I), R2is: wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3; R3and R4are defined above. In certain embodiments, in the compound of Formula (I), wherein R2is selected from H or formula (II): wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3R3 and R4are defined above. In certain embodiments, in the compound of Formula (I), wherein R2is wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3R3and R4are defined above. In certain embodiments, R2is represented by Formula (II) (described above), wherein X1is not O and / or X2is not O. In certain embodiments, R2is represented by Formula (II) (described above), wherein X1is not NH or NR’ and X2is not NH or NR’. In certain embodiments, wherein within Formula (II), X1is O and X2is NH. In certain embodiments, in Formula (II), X1and X2are O. In certain embodiments, in Formula (II), X1is O and X2is NH. In various embodiments, R2is selected from a group consisting of: H, -C(=O)NH2, - C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and -S(=O)R’. In certain embodiments, in the compound of Formula (I), R2is selected from a group consisting of: H, , In certain embodiments, in the compound of Formula (I), R2is selected from a group consisting of: H, , , In certain embodiments, in the compound of Formula (I), R2is: . In certain embodiments, in the compound of Formula (I), R2is: or a stereoisomer thereof. In certain embodiments, in the compound of Formula (I), A is an optionally substituted aryl, an optionally substituted heteroaryl an optionally substituted 5 or 6 members heteroaryl with one or more heteroatom; wherein the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, wherein A is optionally a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, and pyridazinyl N-oxide. In certain embodiments, in the compound of Formula (I), if the ring A is a heteroaryl, it contains one or more nitrogen atom in a ring. In certain embodiments, the A ring contains one nitrogen atom. In certain embodiments, such nitrogen atom may be in the form of an N-oxide, wherein the N-oxide is selected from a group consisting of pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide, pyridazinyl N-oxide. In certain embodiments, the A ring may include further substituents. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted aryl. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted heteroaryl with one heteroatom. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted heteroaryl with two heteroatoms. In certain embodiments, in the compound of Formula (I), ring A is substituted with at least trifluoromethyl. In certain embodiments, in the compound of Formula (I), trifluoromethyl is the only substitution on ring A. In certain embodiments, in the compound of Formula (I), ring A is substituted with at least cyclopropylmethyl. In certain embodiments, in the compound of Formula (I), A is represented by the following Formula(s): wherein each of Q1, Q2, Q3and Q4is independently N, N-O, or CR5; wherein R5is H, hydroxyl group, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl wherein the alkyl chain may be fully or partially deuterated, branched alkyl, allyl, alkenyl, alkynyl, halo-C1-C4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, - CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2- heteroaryl, -CF2-heterocyclyl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH- alkyl, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R”, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR’R”, -NHSO2R’, -NHC(=O)-alkyl - NH(C=O)NR’R”, trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N. In certain embodiments, in the compound of Formula (I), ring A is an optionally substituted five (5) or more membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from N, O, or S. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q2 and Q4 is N, N-O; Q2is N, N-O; Q4is CR5; Q2is CR5; Q4is N, N-O; R6 is H, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl, wherein the alkyl chain may be fully or partially deuterated, branched alkyl, alkenyl, alkynyl, halo-C1-C4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, NHC(=O)R’, NHSO2R, -C(=O)R’, - C(=O)NHR’, -C(=O)NR’R”, -O-R’, -O-C(=O)-R’, aryl, heteroaryl, -CF2CH3, -CF2CF3; R7is H, hydroxyl group, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl wherein the alkyl chain may be fully or partially deuterated, branched alkyl, allyl, alkenyl, alkynyl, halo-C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, -CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-heteroaryl, -CF2- heterocyclyl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, - C(=O)NHR’, -C(=O)NR’R”, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR’R”, -NHSO2R’, -NHC(=O)-alkyl -NH(C=O)NR’R”, trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; wherein not more than two of Q1, Q2, Q3and Q4are N or N-O. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q3 and Q4 are N; wherein Q3 is N, N-O; Q4 is CR5; or wherein Q3 is CR5, Q4 is N, N-O; R5 is defined above; and R6and R7are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein Q1and Q4are N, N-O; Q1is N, N-O; Q4is CR5; Q1is CR5, Q4is N, N-O; or Q1and Q4are CR5; and wherein R6and R7are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q1 and Q2 are N; and R6 and R7 are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein: Q1is CR5, and Q2is N; R6 and R7 are defined above. In certain embodiments, in the compound of Formula (I), ring A is represented by the following Formula(s): wherein Q1 is N; and Q2 is CR5; and R6 and R7 are defined above. In certain embodiments, in the compound of Formula (I), the heteroaryl or aryl ring A is selected from the group consisting of:

[0037] In certain embodiments, in the compound of Formula (I), the heteroaryl or aryl ring A is selected from the group consisting of: In certain embodiments, in the compound of Formula (I), ring B is selected from the group consisting of pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.l]heptane, azabicyclo[3.l.l]heptane, azabicyclo[4.l.0]heptane, azabicyclo[3.2.l]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa- azabicyclo[3.2.l]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxa- azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[l,2-a]pyrazine, hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.l.l3,8]undecane. In certain embodiments, in the compound of Formula (I), ring B is a spirocyclic cycloalkyl ring. In certain embodiments, spirocyclic cycloalkyl ring may be selected from spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, and spiro[6.3]decane, and may be attached at any position of the spirocyclic cycloalkyl group with an open valency. In certain embodiments, the spirocyclic cycloalkyl group may be substituted with halogen. In certain preferred embodiments, the halogen substituted on spirocyclic cycloalkyl group is fluorine. In certain embodiments, the spirocyclic cycloalkyl group may be substituted with haloalkyl groups. In certain preferred embodiments, the haloalkyl group substituted on the spirocyclic cycloalkyl ring is trifluoromethyl. In certain embodiments, the spirocyclic cycloheteroalkyl group is selected from the group consisting of spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, spiro[6.3]decane, and may be attached to any position of the spiro group with an open valency. In certain embodiments, the spirocyclic cycloheteroalkyl group contains at least one and up to four heteroatoms selected from N, O, or S. In certain embodiments, the spirocyclic cycloheteroalkyl group may be substituted with halogen. In certain preferred embodiments, the halogen substituted on the spirocyclic cycloheteroalkyl group is fluorine. In certain embodiments, the spirocyclic cycloheteroalkyl group may be substituted with haloalkyl groups. In certain preferred embodiments, the haloalkyl group substituted on the spirocyclic cycloheteroalkyl group is trifluoromethyl. In certain embodiments, the compound of Formula (I) is further described as Formula (III): , wherein: B, C, R1, and R2are defined above, and R6and R7are defined above. In certain embodiments, the compound of Formula (I) is further described as Formula (IV): , wherein: B, C, R1, and R2are defined above, and R5, R6and R7are defined above. In certain embodiments, the compound of Formula (I) is further described as Formula (V):

[0038] , wherein: B, C, R1, and R2are defined above, and R5, R6 and R7 are defined above. In certain embodiments, the compound of Formula (I) is further described as Formula (VI): . In certain embodiments, the compound of Formula (I) is further described as Formula (VII): . In certain embodiments, the compound of Formula (I) is further described as Formula (VIII):

[0039] , wherein: B, C, R1, and R2are defined above, and each R5is independently defined above. In certain embodiments, substituted or unsubstituted B is selected from a group consisting o , d . In certain embodiments, in the compounds of Formula (I), substituted or unsubstituted C is selected from a group consisting of: , In various embodiments, in the compound of Formula (I), ring C is optionally fused to at least one ring selected from the group consisting of: an optionally saturated carbocyclyl containing 5-6 ring members or an optionally saturated heterocyclyl containing 5-6 ring members and 1-4 optionally charged heteroatoms. In certain embodiments, in the compound of Formula (I), ring C is substituted or unsubstituted phenyl. In certain embodiments, in the compound of Formula (I), ring C is substituted or unsubstituted pyridyl. In certain embodiments, in the compound of Formula (I), the one or more substitutions on the ring A ring are selected from a group consisting of: halo, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6alkyl, aryl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, C3-C6 heteroaryl, and a combination thereof, wherein the heterocycloalkyl and heteroaryl comprise one or more hetero atoms selected from a group consisting of: N, O, or S. In certain embodiments, in the compound of Formula (I), the one or more substitutions on the A ring are selected from a group consisting of: methyl, trifluoromethyl, chloro, fluoro, bromo, C1-C6alkyl, phenyl, cycloalkyl, methyl pyrazole, fused 1, 4 dioxane, and methylcyano. In certain embodiments, the one or more substitutions on the ring A are selected from a group consisting of: -CH3, -CD3, -CF3, -Cl, -Br, -F, -CH2-CH2-CH=CH2, phenyl, -CH2-CN, - C(=O)-NH2, , , , , , , , , , , , and any combination thereof. In certain embodiments, in the compound of Formula (I), the substitutions on the A ring are selected from the group consisting of H, halogen, alkyl, and haloalkyl. In certain embodiments, in the compound of Formula (I), the substitutions on the A ring are selected from the group consisting of methyl and -CF3. In certain embodiments, in the compound of Formula (I), the substitutions on the A ring are selected from the group consisting of H and -CF3. In certain embodiments, in the compound of Formula (I), A is a 6-membered aryl or heteroaryl ring. In certain embodiments, in the compound of Formula (I), A is phenyl. In certain embodiments, in the compound of Formula (I), A is pyridine. In certain embodiments, in the compound of Formula (I), C ring is a 6-membered aryl, heteroaryl, or cycloalkyl or heterocycloalkyl ring. In certain embodiments, in the compound of Formula (I), C ring is phenyl. In certain embodiments, in the compound of Formula (I), C ring is pyridine. In certain embodiments, in the compound of Formula (I), C ring is piperidine. In certain embodiments, in the compound of Formula (I), C ring is pyrrolidine. In certain embodiments, in the compound of Formula (I), R2is: wherein: X1is O and X2is NR’, and R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, R’ is H. In certain embodiments, R4is C1-C3alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is C3-C4 cycloalkyl. In certain embodiments, in the compound of Formula (I), R2is: wherein: X1is O and X2is O, and R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, R’ is H. In certain embodiments, R4is C1-C3alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is C3-C4cycloalkyl. In certain embodiments, in the compound of Formula (I), B ring is 4-8 membered substituted or unsubstituted cycloalkyl or cycloheteroalkyl, wherein heteroatoms in said cycloheteroalkyl are selected from the group consisting of N or O. In certain embodiments, said substitutions on B ring are selected from the group consisting of one or more of halogen, C1-C4 alkyl, oxyalkyl, alkyloxyalkyl, substituted or unsubstituted C3-C6cycloalkyl wherein said C3-C6cycloalkyl is spiro with B ring, and partially or completely halogenated C1-C4alkyl. In certain embodiments, the halogen is fluoro. In certain embodiments, the halogen is chloro. In certain embodiments, the C1-C4 alkyl is methyl. In certain embodiments, the C3-C6cycloalkyl is cyclopropyl. In certain embodiments, the substitutions are selected from the group consisting of - OCH3and -CH2-O-CH3. In certain embodiments, ring C comprises additional substitutions, i.e., substitutions in wherein the substitutions are selected from a group consisting of H, halo, and alkyl. In certain embodiments, the said halo substitution in ring C is F. In certain embodiments, R1is H. In certain embodiments, the compounds of the invention do not include the compounds provided in WO 2023 / 150201, which is incorporated herein by reference in its entirety. In certain embodiments, the compounds of the invention do not include Examples 1-257. Accordingly, in certain embodiments, the invention provides a compound of Formula (I), with the proviso that the compound of the invention does not include Examples 1-257. In certain aspects, the invention provides a compound selected from the group consisting of: In certain aspects, the invention provides a compound selected from the group consisting of: Ċ In certain aspects, the invention provides a compound selected from the group consisting o  In certain embodiments, the compound of Formula (I) is selected from the group consisting of: In certain embodiments, the compound of the invention is selected from a group consisting of:  In certain embodiments, the compound of the invention is selected from a group consisting of: In certain embodiments, the compound of the invention is selected from a group consisting of: In certain embodiments, the compound of the invention is selected from a group consisting of the compounds recited in Tables 1A-1F. In certain embodiments, the compound of the invention is selected from a group consisting of the compounds recited in Tables 1G – 1NN. Compositions The invention provides pharmaceutical compositions containing compounds of the inventions, such as those described above. The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No. 6,214,841 and U.S. Pub. No. 2003 / 0232877, the contents of which are incorporated herein by reference. Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating. Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and / or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. In certain embodiments, the formulation is a sustained release formulation. In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension. The composition may be formulated for administration by a particular mechanism. The composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, nasal, or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents). The composition may be formulated a single daily dosage. The composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six or more daily dosages. Methods of treating conditions The invention provides methods of treating a condition in a subject using compounds of the invention. The methods are useful for treating any condition associated with aberrant, e.g., increased, activity of voltage gated sodium channel NaV1.8. Conditions associated with increased activity at voltage gated sodium channels and the use of inhibitors to treat such conditions is known in the art and described in, for example, International Patent Publication Nos. WO 2020 / 014243, WO 2020 / 014246, WO 2020 / 092187, the contents of each of which are incorporated herein by reference. For example and without limitation, the condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma / injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry's disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post- thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder. Methods of treating a condition in a subject may include providing a composition of the invention to a subject. The composition may be provided to a subject by any suitable route or mode of administration. For example and without limitation, the composition may be provided buccally, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device. The composition may be provided according to a dosing regimen. A dosing regimen may include one or more of a dosage, a dosing frequency, and a duration. Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week. The dose may be provided in a single dosage, i.e., the dose may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose may be provided in a divided dosage, i.e., the dose may be provided as multiple tablets, capsules, pills, etc. The dosing may continue for a defined period. For example and without limitation, doses may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months or more. Examples Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven / desiccator dried. Solvents were ACS grade unless otherwise noted. All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or chemAxon. Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE™. Purification was performed with Biotage Isolera One Flash Chromatography Instrument or purified using one of the preparative HPLC methods mentioned below. Prep Method 1 Equipment: Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: Gemini 5 um C18column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 0.1% HCOOH, gradient may be slight adjusted for specific compound; Flow rate: 20 mL / min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm; Prep Method 2 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C18column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 0.1% TFA, gradient may be slight adjusted for specific compound; Flow rate: 20 mL / min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm. Prep Method 3 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C18column, 150x21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 0.05% ammonia, gradient may be slight adjusted for specific compound; Flow rate: 20 mL / min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm. Analytical LCMC were collected using one of following methods - Method 1 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C182.7 µm, 3.0 mm × 30 mm; Mobile Phase: MeCN (0.05% HCOOH) - Water (0.05% HCOOH); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA. Method 2 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; XBridge BEH C182.5µm, 3.0 mm × 30 mm Mobile Phase: MeCN - Water (0.1% NH4OH); Gradient: MeCN from 5% to 95% over 1.8 min, hold 0.7 min, total run time is 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA. Method 3 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C182.7 µm, 3.0 mm × 30 mm Mobile Phase: MeCN (0.05% TFA) - Water (0.05% TFA); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA. SFC chiral resolution was performed on Shimadzu Nexera UC Preparative SFC System (SFE-30A, LC-30ADSF, SFC-30A) using following methods: Method 1 Column: Daicel chiralpak-AS-H 5 um 250x20 mm; Mobile Phase: CO2 / MeOH [0.1% NH3(7M in MeOH)], CO2 / MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min. Method 2 Column: Daicel chiralpak-OJ-H 5 um 250 * 20 mm; Mobile Phase: CO2 / MeOH (0.1% HCOOH), CO2 / MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min. Method 3 Column: Daicel chiralpak-OD-H 5 um 250x20 mm; Mobile Phase: CO2 / MeOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min. Method 4 Column: Daicel chiralpak-AD-H 5 um 250x20 mm; Mobile Phase: CO2 / i-PrOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min. Method 5 Column: Daicel chiralpak-IC 5 um 250x20 mm; Mobile Phase: CO2 / EtOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min. Unless otherwise stated,1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz Digital NMR Spectrometer. Chemical shifts, δ, are quoted in parts per million (ppm) relative to TMS and calibrated using residual un-deuterated solvent as an internal reference. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz. Abbreviations and Acronyms When the following abbreviations are used herein, they have the following meaning: General synthetic schemes Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The present invention further provides processes for the preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention. Scheme A As illustrated in Scheme A, in general, compounds of the invention can be prepared by reacting substituted cyclic amines (B) using base such as DIEA or inorganic base such as K2CO3or Cs2CO3 to afford intermediate A-2. Intermediate A-2 can be converted to corresponding acid A-3 by treating A-2 with base such as KOH in aqueous EtOH or MeOH. Intermediates A-4, A-5 and A-7 can be formed either by treating A-3 and amine C, utilizing amide coupling conditions or by activation of appropriately functionalized carboxylic acid A-3 with (COCl)2or POCl3and with amine C base such as DIEA or pyridine in DCM. Intermediate A-4 can be prepared directly by treating A-2 and amine C in presence of Me3Al and toluene as a solvent. The compounds of formula A-4 and A-5 are independently treated with ammonium carbonate and PIDA in methanol to deliver compound of formula A-6. The compounds of formula A-6 can also be formed from intermediate A-7 by removing a protecting group, such as Boc under acidic conditions. Scheme B As illustrated in Scheme B, in general, compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-3 in dioxane with either (COC1)2or SOCl2 followed by addition of NH4OH to afford B-1. Intermediate B-1 can then be brought together with materials of variously substituted Br compounds, utilizing Xantphos-Pd-G2 mediated coupling conditions to deliver intermediate A-4 and A-7. The compounds of formula A-4 treated with ammonium carbonate and PIDA in methanol to deliver compound of formula A-6. The compounds of formula A-6 can also be formed from intermediate A-7 by removing a protecting group, such as Boc under acidic conditions. Scheme C

[0040] As further illustrated in Scheme C, in general, compounds of the invention can be prepared by derivatization of compounds of formula A-6 with R3 or R’ substituents. Acylation of A-6 with an activated acid such as an acid chloride and TEA followed by removal of any protecting groups would provide compounds of formula A-8 or A-9. When A-8 or A-9 are an N- acylated sulfoximine, the carbonyl group may be reduced with borane to a methylene group (CH2) to provide the corresponding N-alkyl derivative. Alternatively, N-alkyl derivatives may be obtained by alkylation with an alkyl halide such as, but not limited to, methyl iodide and a base such as diisopropylethylamineor Pd mediated coupling of A-6 with alkyl boronic acids. Specific Synthesis Example 1 3-(Azepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide ( (Diacetoxyiodo)benzene, MeOH, rt. Step 1. methyl 3-(azepan-1-yl)-6-chloropyridazine-4-carboxylate: To a solution of methyl 3,6- dichloropyridazine-4-carboxylate (2.50g, 12.1 mmol) was in dioxane (20 mL) was added azepane (1.26g, 12.7 mmol) followed by DIEA (4.21 mL, 24.2 mmol) at rt. The mixture was stirred at rt for further 3h, at the end of this period solvent was evaporated and the crude was chromatographed over SiO2with a gradient of 0-25% EtOAc in DCM to provide methyl 3- (azepan-1-yl)-6-chloropyridazine-4-carboxylate (2.86g, 87.8%).1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 4.03 (s, 1H), 3.92 (s, 3H), 3.58 – 3.48 (m, 5H), 1.86 (qd, J = 6.2, 5.4, 2.4 Hz, 5H), 1.60 – 1.47 (m, 5H) Step 2. methyl 3-(azepan-1-yl)-6-iodopyridazine-4-carboxylate :A mixture of methyl 3-(azepan- 1-yl)-6-chloropyridazine-4-carboxylate (3.26g, 12.1 mmol) and HI (25 mL, 57% v / v) was stirred 50 to 55°C overnight, cooled to rt and the solid separated was filtered and washed with water (2x20 mL). The filtered cake was dissolved in EtOAc, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give methyl 3-(azepan-1-yl)-6-iodopyridazine-4- carboxylate (2.16g, 49.52%). LCMS: m / z 362.1[M+H]+Step 3. methyl 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: To a mixture of methyl 3-(azepan-1-yl)-6-iodopyridazine-4-carboxylate (2.16 g, 5.98 mmol) in HMPA (25 mL), CuI (1.62 g, 8.49 mmol) was added tetrabutylammoniumiodide (1.10g, 2.99 mmol) under nitrogen, the reaction mixture was degassed for 5 min to the above mixture methyl 2,2-difluoro- 2-(fluorosulfonyl) acetate(7.61 mL, 5λ.8 mmol) was added slowly and stirred at λ0 ℃ for 1.5 h. The mixture was filtered and washed with EtOAc (3x100 mL), to the filtrate water (50 mL) was added and extracted with EtOAc (3x120 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was evaporated, and the residue was chromatographed over SiO2eluting with a gradient of 0-20% EtOAc in Hexanes to afford methyl 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (0.667g, 37%). LCMS: m / z 304.1[M+H]+Step 4: 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of methyl 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate in a mixture of MeOH:THF:H2O (1:2:1, v / v) 20 mL was added LiOH.H2O at rt. Then the mixture was stirred at 50°C for 2h, at the end of this period reaction mixture was cooled to rt and the solvent was evaporated. The solid material was suspended in water (10 mL) and pH was adjusted to 3 using 1N HCl solution. The mixture was extracted with EtOAc (3x 50 mL), combined EtOAc was washed with brine (30 mL) and dried over Na2SO4, filtered and solvent evaporated to give 3-(azepan-1-yl)-6- (trifluoromethyl)pyridazine-4-carboxylic acid (0.489g, 77%).1HNMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 3.63 (t, J = 5.6 Hz, 4H), 1.90 – 1.71 (m, 4H), 1.60 – 1.36 (m, 4H) Step 5.3-(azepan-1-yl)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4- carboxamide: To a mixture of 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100g, 0.346 mmol), 3-(methylsulfanyl)aniline ( 0.0529g, 0.380 mmol) and HATU (0.263g, 0.691mmol) in DMF(3 mL) was added DIEA (0.151 mL, 0.864 mmol) at rt and stirring cintinued further for 6 h. At the end of this period water(5 mL) was added ands extracted with EtOAc (2x25 mL), combined EtOAc layer was washed with 1M LiCl (20 mL) followed by brine(20 mL) and dried over Na2SO4, filtered and solvent evaporated under reduced pressure. The crude product was chromatographed over SiO2with a gradient of EtOAc in DCM to provide 3-(azepan-1-yl)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.128g, 90%). LCMS: m / z 411.4[M+H]+Step 6.3-(azepan-1-yl)-N-{3-[imino(methyl)oxo-^⁶-sulfanyl]phenyl}-6- (trifluoromethyl)pyridazine-4-carboxamide: To a solution of 3-(azepan-1-yl)-N-[3- (methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.110 g, 0.268 mmol) in MeOH (5 mL) was added (NH4)2CO3 ( 0.0386g, 0.402 mmol) and PIDA ( 0.199g, 0.616 mmol) at rt. The mixture was stirred for 2h at rt. The solvent was evaporated to dryness and the crude was chromatographed over SiO2with a gradient of 0-15 MeOH in DCM to provide 3-(azepan-1- yl)-N-{3-[imino(methyl)oxo-λ6-sulfanyl]phenyl}-6-(trifluoromethyl)pyridazine-4-carboxamide (15.4g, 13%).1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 8.22 – 8.02 (m, 2H), 7.81 (dt, J = 8.0, 1.2 Hz, 1H), 7.70 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 3.68 (t, J = 5.7 Hz,4H), 3.12 (s, 3H), 1.85 (s, 4H), 1.54(bs, 4H). LC-MS: m / z 442.5[M+H]+Example 2 3-(azepan-1-yl)-5-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) 2-(methylthio)pyridin-4-amine, HATU, DIEA, DMF, rt; b) (NH4)2CO3 , (Diacetoxyiodo)benzene, MeOH, rt. Step 1: 3-(azepan-1-yl)-N-[2-(methylsulfanyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4- carboxamide: To a mixture of 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid ( 0.100g, 0.346 mmol), HATU(0.263g, 0.691 mmol) and 2-(methylsulfanyl)pyridin-4-amine (0.0485g, 0.346mmol) in DMF(3 mL) was added DIEA( 0.151 ml, 0.864 mmol) at rt. The mixture was stirred at rt for 16h. At the end of this period water (5 mL) was added and extracted with EtOAc (2x25 mL), EtOAc layers were combined and washed with 1M LiCl (10 mL) followed by brine and dried (Na2SO4) filtered and the solvent evaporated to give crude product. The crude was chromatographed over SiO2with a gradient of 0-20% EtOAc in DCM to provide 3-(azepan-1-yl)-N-[2-(methylsulfanyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4- carboxamide (0.030g, 21%). LC-MS: m / z 412.2[M+H]+Step 2: 3-(azepan-1-yl)-N-{2-[imino(methyl)oxo-^⁶-sulfanyl]pyridin-4-yl}-6- (trifluoromethyl)pyridazine-4-carboxamide: To a solution of 3-(azepan-1-yl)-N-[2- (methylsulfanyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.026 g, 0.0632 mmol) in MeOH (5 mL) was added (NH4)2CO3( 0.0911g, 0.0948 mmol) and PIDA ( 0.0468g, 0.145 mmol) at rt. The mixture was stirred for 2h at rt. The solvent was evaporated to dryness and the crude was chromatographed over SiO2with a gradient of 0-15 MeOH in DCM to provide 3-(azepan-1-yl)-N-{2-[imino(methyl)oxo-^⁶-sulfanyl]pyridin-4-yl}-6- (trifluoromethyl)pyridazine-4-carboxamide (0.121g, 43.3%)1H NMR (300 MHz, CDCl3) δ λ.61 (s, 1H), 8.65 (d, J = 5.5 Hz, 1H), 8.20 (dd, J = 5.5, 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 3.63 (q, J =4.8, 4.3 Hz, 4H), 3.26 (s, 3H), 1.85 (bs, 4H), 1.54(bs, 4H). LC-MS: m / z 443.5[M+H]+Example 3 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trif luoromethyl)nicotinamide

[0041] Reagents & conditions: a) 4,4-difluoroazepane hydrochloride, DIEA, dioxane, 80 ℃; b) trimethylboroxine, Pd(dppf)Cl2, K2CO3, dioxane / H2O, 100 ℃; c) NBS, DCM; d) Pd(dppf)Cl2, Et3N, EtOH, CO, 110 °C; e) KOH, MeOH / H2O, 70°C, f) tert-butyl ((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate, POCl3, pyridine; f) TFA, DCM Step 1: 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane: A mixture of 2,6- dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.6 mmol), 4,4-difluoroazepane hydrochloride (0.95 g, 5.5 mmol) and DIEA (1.1λ g, λ.2 mmol) in dioxane (20 mL) was heated at 80 ℃ for 5 hours. Then the mixture was concentrated and residue was purified by flash column chromatography on silica gel (PE / EtOAc = 5 / 1) to give 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4- difluoroazepane (900 mg, 62.5%). LCMS (ESI) calcd. for C12H13ClF5N2 [M + H]+m / z 315.07, found 315.05. Step 2: 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane : A mixture of 1-(6- chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (850 mg, 2.7 mmol), trimethylboroxine (3.39 g, 27 mmol), Pd(dppf)Cl2(98.73 mg, 0.135 mmol) and K2CO3(1.12 g, 8.1 mmol) in dioxane / H2O (4 / 1, 25 mL) was heated at 100 °C for 16 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 5 / 1) to give the 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2- yl)azepane (800 mg, 91%). LCMS (ESI) calcd. for C13H16F5N2[M + H]+m / z 295.13, found 295.00. Step 3: 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane: To a solution of 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane (700 mg, 2.38 mmol) in DCM (15 mL) was added NBS (508 mg, 2.85 mmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and directly purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give the 1-(3-bromo-6-methyl-5- (trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (650 mg, 65.9% ). LCMS (ESI) calcd. for C13H15BrF5N2[M + H]+m / z 373.04, found 372.95. Step 4: Ethyl 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate: A mixture of 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (600 mg, 1.6 mmol), Pd(dppf)Cl2(58.5 mg, 0.08 mmol) and triethylamine (485 mg, 4.8 mmol) in EtOH (10 mL) was heated at 110 °C under an atmosphere of CO (30 atm) for 16 hours in a high-pressure reactor. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give ethyl 2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinate (550 mg, 94% ). LCMS (ESI) calcd. for C16H20F5N2O2[M + H]+m / z 367.15, found 367.00. Step 5: 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of ethyl 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate (550 mg, 1.5 mmol) in MeOH / H2O (1 / 1, 20 mL) was added KOH (0.84 g, 15 mmol) at room temperature. The mixture was heated at 70 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH = 3-4 with 1 N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 2-(4,4- difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (420 mg, 83%). LCMS (ESI) calcd. for C14H16F5N2O2[M + H]+m / z 339.12, found 338.95. Step 6: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.35 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate Int-3 (115 mg, 0.43 mmol) in pyridine (6 mL) was added POCl3 (0.3 mL) dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (57 mg, 24.4% ) as a yellow oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M + H]+m / z 591.21, found 591.10. Step 7: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide: To a solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-6- methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (57 mg, 0.10 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 50% to 80% MeCN / H2O containing 0.1% formic acid) to afford 2- (4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl) nicotinamide (11.3 mg, 23.2%) as a white solid. LCMS (ESI) calcd. for C21H24F5N4O2S [M + H]+m / z 491.15, found 491.05.1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1 H), 8.31 (s, 1 H), 8.04-7.85 (m, 2 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 1 H), 3.71 (s, 2 H), 3.59-3.33 (m, 5 H), 3.13 (s, 3 H), 2.40-2.67 (m, 2 H), 2.03-1.83 (m, 4 H). Example 4 (R)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide Reagents & conditions: POCl3, pyridine, tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate : A mixture of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (250 mg, 0.740 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)λ6-sulfaneylidene)carbamate (220 mg, 0.814 mmol) in pyridine (4 mL) was added POCl3 (375 μL) dropwise at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 27.5%) as a yellow oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M + H]+m / z 591.21, found 591.15. Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-6- methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 0.200 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the filtrate was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)- 6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (55 mg, 56.12%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1 H), 8.2λ (s, 1 H), 7.λ4- 7.82 (m, 2 H), 7.65 (d, J = 8 Hz, 1 H), 7.59-7.55 (m, 1 H), 4.20 (s, 1 H), 3.49-3.47 (m, 2 H), 3.33-3.31 (m, 2H), 3.05 (s, 3 H), 2.33 (s, 3 H), 1.96-1.92 (m, 2 H), 1.89-1.86 (m, 4 H). LCMS (ESI) calcd. for C21H24F5N4O2S [M + H]+m / z 491.16, found 490.95. Example 5 (S)-2-(4,4-Difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide Reagents & conditions: a) POCl3, pyridine, tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate : A mixture of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (250 mg, 0.644 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (208.76 mg, 0.773 mmol) in pyridine (4 mL) was added POCl3(500 μL) dropwise at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6--sulfaneylidene)carbamate (130 mg, 34.21% ) as a white oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M + H]+m / z 591.21, found 591.40. Step 2: (S)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-6- methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (130 mg, 0.22 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was further purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (S)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)- 5-(trifluoromethyl)nicotinamide (62 mg, 57.51%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 10.79 (s, 1 H), 8.29 (s, 1 H), 7.95 (d, J = 10.5 Hz, 2 H), 7.70-7.52 (m, 2 H), 4.27 (bs, 1 H), 3.71 (s, 2 H), 3.47 (t, J = 5.5 Hz, 2 H), 3.07 (s, 3 H), 2.52 (s, 3 H), 2.33 (s, 2 H), 2.04-1.81 (m, 4 H). LCMS (ESI) calcd. for C21H24F5N4O2S [M + H]+m / z 491.16, found 491.20. Example 6 3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) DIEA, 4,4-difluoroazepane hydrochloride, dioxane, 60˚C; c) HI (57%), 40˚C, 5h; d) Cu, [Ph2SCF3]+[OTf]- 60˚C; e) KOH, MeOH, H2O 70˚C; e) (i) tert-butyl ((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate, pyridine, POCl3, 60˚C; (ii) TFA, DCM Step 1: methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate : To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (2 g, 9.7 mmol) and 4,4-difluoroazepane hydrochloride (2.0 g, 11.6 mmol) in 1,4-dioxane (30 mL) was added DIEA (3.75 g, 29.1 mmol). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give the methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate (1.6 g, 54.1%) as a yellow solid. LCMS (ESI) calcd. for C12H15ClF2N3O2[M + H]+m / z 306.08, found 305.90. Step 2: methyl 3-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-4-carboxylate :A solution of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate (1.6 g, 5.2 mmol) in HI (15 mL, 57% aqueous solution) was heated at 40 °C for overnight. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give the methyl 3-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-4-carboxylate (1.8 g, 87.4%) as a yellow solid. LCMS (ESI) calcd. for C12H15IF2N3O2[M + H]+m / z 398.02, found 397.85. Step 3: methyl 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate : A solution of methyl 3-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-4-carboxylate (1.8 g, 4.5 mmol), Cu (0.87 g, 13.6 mmol) and [Ph2SCF3]+[OTf]- (3.6 g, 9.0 mmol) in DMF (20 mL) was heated at 60 °C for 5 hours. LCMS showed the rection was completed. Then the mixture was filtered through celite. The filtrate was diluted with water and extracted with EtOAc (80 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 4) to give methyl 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (1.2 g, 78.9%) as a yellow solid. LCMS (ESI) calcd. for C12H14F3F2N3O2[M + H]+m / z 340.11, found 339.95. Step 4: 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid : To a solution of methyl 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 2.35 mmol) in MeOH / H2O (1 / 1, 20 mL) was added KOH (1.05 g, 18.8 mmol) at room temperature. The mixture was heated at 70 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (620 mg, 81.2% ) as a yellow solid. LCMS (ESI) calcd. for C12H13F5N3O2[M + H]+m / z 326.09, found 325.95. Step 5: To a solution of 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (80 mg, 0.246 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate (66.5 mg, 0.246 mmol) in pyridine (2.5 mL) was added POCl3 (20 uL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated to give the crude intermediate. The crude intermediate was dissolved in DCM (3 mL) and added TFA (1 mL). The solution was stirred at room temperature for 1 hour then concentrated and purified by Prep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give the title compound (18.1 mg, 15.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.26 (s, 1 H), 8.08 (s, 1 H), 7.λ4 (d, J = 8.8 Hz, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.25 (s, 1 H), 3.87 (m, 2 H), 3.58 (m, 2 H), 3.06 (s, 3 H), 2.36 (m, 2 H), 2.12-1.86 (m, 4 H). LCMS (ESI) calcd. for C19H21F5N5O2S [M + H]+m / z 478.13, found 478.05. Example 7 3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide Reagents & conditions: a) Nitromethane, Et3N, DMSO; b) DIEA, azepane, dioxane, 60˚C; c) HI (57%), 40˚C, 5h; d) Cu, [Ph2SCF3]+[OTf]- 60˚C; e) KOH, MeOH, H2O 70˚C; f) tert-butyl ((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate, pyridine, POCl3, 60˚C; g) TFA, DCM Step 1: methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate: To a solution of methyl 3,6- dichloropyridazine-4-carboxylate (1 g, 4.86 mmol) in DMSO (10 mL) was added MeNO2(1.48 g, 24.3 mmol). The mixture was stirred at room temperature for 30 min. Then TEA (0.74 g, 7.29 mmol) was added dropwise to the reaction at 0 °C. The reaction was stirred at room temperature for 3h. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give methyl 3,6-dichloro-5- methylpyridazine-4-carboxylate (0.9 g, 84.3%) as a white solid. LCMS (ESI) calcd. for C7H7Cl2N2O2[M + H]+m / z 220.99, found 220.85. Step 2: methyl 3-(azepan-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate: To a solution of methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (900 mg, 4.09 mmol) and azepane (484 mg, 4.89 mmol) in 1,4-dioxane (10 mL) was added DIEA (1583 mg, 12.27 mmol). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give the methyl 3-(azepan-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate (680 mg, 58.8%) as yellow solid. LCMS (ESI) calcd. for C13H19ClN3O2[M + H]+m / z 284.11, found 284.10. Step 3: methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate: A solution of methyl 3-(azepan-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate (680 mg, 2.4 mmol) in HI (10 mL, 57% aqueous solution) was heated at 40 °C for overnight. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give the methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (500 mg, 55.5% ) as a yellow solid. LCMS (ESI) calcd. for C13H19IN3O2[M + H]+m / z 376.05, found 376.10. Step 4: methyl 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate : A solution of methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (500 mg, 1.33 mmol), Cu (257 mg, 4.02 mmol) and [Ph2SCF3]+[OTf]- (1064 mg, 2.66 mmol) in DMF (10 mL) was heated at 60 °C for 5 hours. LCMS showed the rection was completed. Then the mixture was filtered through celite. The filtrate was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 4 / 1) to give methyl 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (350 mg, 82.7%) as a yellow solid. LCMS (ESI) calcd. for C14H19F3N3O2[M + H]+m / z 318.14, found 318.05. Step 5: 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl) pyridazine-4-carboxylic acid : To a solution of methyl 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (350 mg, 1.1 mmol) in MeOH / H2O (1 / 1, 8 mL) was added KOH (580 mg, 8.8 mmol) at room temperature. The mixture was heated at 70 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove the MeOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (250 mg, 74.8%) as a yellow solid. LCMS (ESI) calcd. for C13H17F3N3O2[M + H]+m / z 304.12, found 304.05. Step 6: tert-butyl ((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 3-(azepan-1- yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.33 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (89 mg, 0.33 mmol) in pyridine (4 mL) was added POCl3 (30 uL) at room temperature. The mixture was heated at 60 °C for 1 hour. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 2) to give tert-butyl((3-(3-(azepan-1-yl)-5-methyl-6- (trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl)(oxo)-λ6-sulfaneylidene) carbamate (20 mg, 10.9% ) as a yellow oil. LCMS (ESI) calcd. for C25H32F3N5O4S [M + H]+m / z 556.22, found [M +H]+556.15. Step 7: 3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide : To a solution of tert-butyl ((3-(3-(azepan-1-yl)-5- methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate (20 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0 °C. The mixture was stirred room temperate for 2 hours. The mixture was concentrated and the residue was purified by Prep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 30%-40%-70%) to give 3-(azepan-1-yl)-5-methyl-N-(3- (S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (5 mg, 30.5% ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1 H), 8.28 (s, 1 H), 7.88 (d, J = 7.9 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.34 (s, 1 H), 3.73 (t, J = 5.9 Hz, 4 H), 3.08 (s, 3 H), 2.30 (s, 3 H), 1.76 (s, 4 H), 1.49 (s, 4 H). LCMS (ESI) calcd. for C20H25F3N5O2S [M + H]+m / z 456.17, found 456.05. Example 8 N-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)-3-(azepan-1-yl)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxamide To a solution of 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.33 mmol) in DCM (2 mL) was added oxalyl chloride (30 μL) at room temperature. The mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL) and added dropwise to a mixture of (3-aminophenyl)(imino)(methyl)-λ6-sulfanone (73 mg, 0.43 mmol) and DIEA (64 mg, 0.49 mmol) in THF (1 mL). The mixture was stirred at 40 °C for 2h. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate and concentrated. The residue was purified by Prep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give N-((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)-3-(azepan-1-yl)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxamide (10 mg, 6.7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.31 (t, J = 7.9 Hz, 1 H), 7.17 (s, 1 H), 7.10 (d, J = 7.7 Hz, 1 H), 6.88 (dd, J = 8.1, 1.9 Hz, 1 H), 5.79 (s, 2 H), 3.75-3.62 (m, 4 H), 3.60 (s, 3 H), 2.27 (s, 3 H), 1.74 (s, 4 H), 1.56- 1.37 (m, 4 H). LCMS (ESI) calcd. for C20H25F3N5O2S [M + H]+m / z 456.17, found 456.00. Example 9 4-(azepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3- carboxamide

[0042] Reagents & condit , [Ph2SCF3]+[OTf]- 60˚C; d) tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, Me3Al, toluene, λ0˚C Step 1: methyl 4-(azepan-1-yl)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (5 g, 24.3 mmol) and azepane (2.89 g, 29.2 mmol) in 1,4- dioxane (60 mL) was added DIEA (9.4 g, 72.9 mmol). The mixture was heated at 80°C for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give the methyl 4-(azepan-1- yl)-6-chloropyridazine-3-carboxylate (3.5 g, 53.8%) as a yellow solid. LCMS (ESI) calcd. for C12H17ClN3O2[M + H]+m / z 270.10, found 270.05. Step 2: methyl 4-(azepan-1-yl)-6-iodopyridazine-3-carboxylate: A solution of methyl 4- (azepan-1-yl)-6-chloropyridazine-3-carboxylate (3.5 g, 11.8 mmol) in HI (30 mL, 57% aqueous solution) was stirred at 40°C for overnight. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water and dried under vacuum to give the methyl 4- (azepan-1-yl)-6-iodopyridazine-3-carboxylate (3.5 g, 82.2%) as a yellow solid. LCMS (ESI) calcd. for C12H17IN3O2[M + H]+m / z 362.03, found 362.00. Step 3: methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate : A solution of methyl 4-(azepan-1-yl)-6-iodopyridazine-3-carboxylate (2.5 g, 6.9 mmol), Cu (1.35 g, 20.7 mmol) and [Ph2SCF3]+[OTf]- (5.5 g, 13.8 mmol) in DMF (30 mL) was heated at 60°C for 5 hours. LCMS showed the rection was completed. Then the mixture was filtered through celite. The filtrate was diluted with water and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 3) to give methyl 4-(azepan-1-yl)- 6-(trifluoromethyl)pyridazine-3-carboxylate (1 g, 47.7% ) as a yellow solid. LCMS (ESI) calcd. for C13H17F3N3O2[M + H]+m / z 304.12, found 303.95. Step 4: 4-(azepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3- carboxamide . To a solution of tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate 534 mg, 1.98 mmol) in toluene (5 mL) was added Me3Al (1M in hexane, 2.18 mL, 2.18 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then a solution of methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.66 mmol) in toluene (3 mL) was added at the same temperature. The resulting mixture was heated at 90 °C for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated, purified by prep-HPLC (Column: Gemini- C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give 4-(azepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3- carboxamide (60 mg, 20.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1 H), 8.37 (s, 1 H), 7.96 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 7.34 (s, 1 H), 4.22 (s, 1 H), 3.64-3.48 (m, 4 H), 3.07 (s, 3 H), 1.74 (s, 4 H), 1.48 (s, 4 H). LCMS (ESI) calcd. for C19H23F3N5O2S [M + H]+m / z 442.14, found 442.00. Example 10 (R)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: POCl3, pyridine, tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate : A mixture of 3-(azepan-1-yl)- 5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.330 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (133.70 mg, 0.495 mmol) in pyridine (2 mL) was added dropwise added POCl3 (150 μL) at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (R)-((3-(3-(azepan-1-yl)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 32.72% ) as a yellow oil. LCMS (ESI) calcd. for C25H33F3N5O4S [M + H]+m / z 556.22, found 556.40. Step 2: (R)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide : A solution of tert-butyl (R)-((3-(3-(azepan-1-yl)-5- methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-l6- sulfaneylidene)carbamate (60 mg, 0.108 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150x21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to obtain (R)-3-(azepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (15 mg, 30%, 96.05% purity, 99% ee) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1 H), 8.27 (s, 1 H), 7.92-7.85 (m, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.26 (s, 1 H), 3.73 (t, J = 5.8 Hz, 4 H), 3.07 (s, 3 H), 2.30 (s, 3 H), 1.76 (s, 4 H), 1.49 (s, 4 H). LCMS (ESI) calcd. for C20H23F3N5O2S [M - H]- m / z 454.15, found 454.10. Example 11 (S)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: POCl3, pyridine, tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (S)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate: A mixture of 3-(azepan-1-yl)- 5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.330 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (133.70 mg, 0.495 mmol) in pyridine (2 mL) was added POCl3(150 μL) at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give tert-butyl (S)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (47 mg, 25.7%) as a yellow oil. LCMS (ESI) calcd. for C25H33F3N5O4S [M + H]+m / z 556.22, found 556.15. Step 2: (S)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide : A solution of tert-butyl (S)-((3-(3-(azepan-1-yl)-5- methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (47 mg, 0.08 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep- HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to obtain (S)-3-(azepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (18 mg, 49.45%, 98% purity, 100% ee) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1 H), 8.27 (s, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.64-7.60 (m, 1 H), 4.26 (s, 1 H), 3.74- 3.71 (m, 4 H), 3.07 (s, 3 H), 2.29 (s, 3 H), 1.76 (s, 4 H), 1.49 (s, 4 H). LCMS (ESI) calcd. for C20H25F3N5O2S [M + H]+m / z 456.17, found 456.10. Example 12 5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide Reagents & conditions: a) DIEA, 6-azaspiro[2.5]octane hydrochloride, dioxane, 100°C; b) NCS, DMF; c) KOH, MeOH, H2O, 60°C; d) POCl3, Pyridine, tert-butyl ((3- bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene; e) TFA, DCM, rt Step 1: methyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate : A mixture of methyl 2-chloro- 6-methylnicotinate (1.3 g, 7 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.03 g, 7 mmol) in 1,4-dioxane (20 mL) was added DIEA (1.82 g, 14 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide methyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1 g, 55.6%) as a white solid. LCMS (ESI) calcd. for C15H21N2O2[M + H]+m / z 261.16, found 260.95. Step 2: methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate : To a mixture of methyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.950 g, 3.64 mmol) in DMF (10 mL) was added NCS (0.534 g, 4 mmol). The reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give methyl 5-chloro-6-methyl-2-(6- azaspiro[2.5]octan-6-yl)nicotinate (0.750 g, 70.0%) as a white oil. LCMS (ESI) calcd. for C15H20ClN2O2[M + H]+m / z 295.12, found 294.95. Step 3: 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid : To a solution methyl 5- chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.700 g, 2.5 mmol) in MeOH / H2O (1 / 1, 15 mL) was added KOH (0.561 g, 25 mmol) at room temperature. The mixture was heated at 60 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (20 mL). Then the aqueous phase was adjusted to pH = 3 with 1N HCl and extracted with DCM (20 mL x 3). The combined organic phases were dried with Na2SO4and concentrated under reduced pressure to give 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinic acid (560 mg, 79.6%) as a white solid. LCMS (ESI) calcd. for C14H18ClN2O2[M + H]+m / z 281.10, found 280.95. Step 4: tert-butyl ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate : To a mixture of 5-chloro-6- methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (500 mg, 1.78 mmol) and tert-butyl ((3- aminophenyl)(methyl)(oxo) -λ6-sulfaneylidene)carbamate (723 mg, 2.67 mmol) in pyridine (4 mL) at room temperature was added POCl3 (750 μL). The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan- 6-yl)nicotinamido)phenyl)(methyl)(oxo) -λ6-sulfaneylidene)carbamate (120 mg, 12.64%) as a yellow oil. LCMS (ESI) calcd. for C26H34ClN4O4S [M + H]+m / z 533.20, found 533.05. Step 5: 5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide : A solution of tert-butyl ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.23 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to afford the title compound (41 mg, 41.44% ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1 H), 8.3λ (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.80 (s, 1 H), 7.65 (d, J = 8 Hz, 1 H), 7.60-7.56 (m, 1 H), 4.21(s, 1 H), 3.36-3.32 (m, 4 H), 3.05 (s, 3 H), 2.46 (s, 3 H), 1.38- 1.35 (s, 4 H), 0.28 (s, 4 H). LCMS (ESI) calcd. for C21H26ClN4O2S [M + H]+m / z 433.14, found 433.05. Example 13 6-(3-Buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl) phenyl)nicotinamide Reagents & conditions: a) DIEA, 4,4-difluoroazepane hydrochloride, Acetonitrile, rt; b) (cyclopropylmethyl)zinc(II) bromide, CuI, PdCl2(PPh3)2, DMF; c) KOH, MeOH, H2O; d) (COCl)2, DMF, DCM, NH4OH; e) Cs2CO3, tert-butyl ((3-bromophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, Xantphos-Pd-G2, dioxane, 100°C; f) TFA, DCM, rt Step 1: methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate: A mixture of methyl 2,6- dichloronicotinate 1 (2.0 g, 9.7 mmol), 4,4-difluoroazepane hydrochloride (1.67 g, 9.7 mmol) and DIEA (3.75 g, 2λ.1 mmol) in dioxane (25 mL) was heated at 80 ℃ for 5 hours. Then the mixture was concentrated and directly purified by flash column chromatography on silica gel (PE / EtOAc = 6 / 1) to give methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (2.22 g, 67% ). LCMS (ESI) calcd. for C13H16ClF2N2O2[M + H]+m / z 305.09, found 305.90. Step 2: methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinate: A mixture of Zn power (2.2 g, 33.6 mmol) and I2(850 mg, 3.36 mmol) in a 250 mL three-necked flask was evacuated and backfilled with N2 three times and then charged with N2. The flask was heated carefully with a hot air blower until I2 was sublimated. Then a solution of (bromomethyl)cyclopropane (2.27 g, 16.8 mmol) in DMF (8 mL) was added intermediately via a syringe. The mixture was stirred for 10 minutes while keeping the temperature was about 80 °C. Then the heater and stirrer were removed. The upper layer clear solution was added dropwise into a stirred solution of methyl 6- chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (1.7 g, 5.6 mmol), CuI (320 mg, 1.68 mmol) and Pd(pph3)2Cl2(390 mg, 0.56 mmol) in DMF (4 mL) under an atmosphere of N2. The mixture was heated at 110 °C for 5 hours. Then the mixture was quenched with water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated to give the crude. The residue was purified by silica gel column chromatography (PE / EA, 4 / 1) to afford methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazepan- 1-yl)nicotinate (1.3 g, 64% ) as a white solid. LCMS (ESI) calcd. for C1+ 7H23F2N2O2[M + H] m / z 325.17, found 325.25. Step 3: 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid: To a solution of methyl 6-(3- buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinate (400 mg, 1.23 mmol) in MeOH / H2O (1 / 1, 8 mL) was added KOH (0.69 g, 12.3 mmol) at room temperature. The mixture was heated at 70 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4,and concentrated under reduced pressure to give 6-(3-buten-1-yl)-2-(4,4- difluoroazepan-1-yl)nicotinic acid (360 mg, 84.7%). LCMS (ESI) calcd. for C16H21F2N2O2[M + H]+m / z 311.16, found 311.00. Step 4: 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamide: To a solution of 6-(3-buten-1- yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (100 mg, 0.32 mmol) in DCM (5 mL) and DMF (10 μL) was added oxalyl chloride (81.84 mg, 0.64 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the mixture was concentrated to remove the solvent. Then the residue was dissolved in THF (5 mL) and was added to vigorously stirred NH3- H2O (2 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum to give crude 6-(3- buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamide (96 mg, 86.7%) which was used in the next step without further purification. LCMS (ESI) calcd. for C16H22F2N3O [M + H]+m / z 310.17, found 309.95. Step 5: tert-butyl ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A solution of 6-(3-buten-1- yl)-2-(4,4-difluoroazepan-1-yl)nicotinamide 5 (90 mg, 0.29 mmol), tert-butyl ((3- bromophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (195 mg, 0.58 mmol), Cs2CO3 ( 285 mg, 0.87 mmol) and Xantphos-Pd-G2 (26 mg, 0.029 mmol) in 1,4-dioxane (5 mL) was heated at 110 °C for overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give tert-butyl ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido) phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (50 mg, 27% ) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M + H]+m / z 563.25, found 563.20. Step 6: 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide: To a solution of tert-butyl ((3-(6-(3-buten-1-yl)-2- (4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (50 mg, 0.089 mmol) in DCM (3 mL) was added TFA (1 mL) at rt. The mixture was stirred room temperature for 2 hours. The resulting mixture was concentrated and the residue was purified byprep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA),Gradient: 50%-80%) to give 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl) phenyl)nicotinamide (15 mg, 35%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1 H), 8.34 (s, 1 H), 7.λ2 (d, J = 8.1 Hz, 1 H), 7.63 (m, 2 H), 7.56-7.61 (t, J = 7.9 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.93-5.81 (m, 1 H), 5.08-4.94 (m, 2 H), 4.19 (s, 1 H), 3.63 (s, 2 H), 3.42 (t, J = 5.7 Hz, 2 H), 3.05 (s, 3 H), 2.73 (t, J = 7.5 Hz, 2 H), 2.48-2.42 (m, 2 H), 2.39-2.26 (m, 2 H), 2.01-1.80 (m, 4 H). LCMS (ESI) calcd. for C23H29F2N4O2S [M + H]+m / z 463.20, found 463.10. Example 14 N-(3-(S-methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) DIEA, 6-azaspiro[2.5]octane hydrochloride, dioxane, 80°C; b) HI, 40°C; c) Cu, [Ph2SCF3]+[OTf]- , DMF, 60˚C ; d) KOH, MeOH, H2O, 70°C; e) POCl3, Pyridine, tert-butyl ((3-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene; e) TFA, DCM, rt Step 1: methyl 6-chloro-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (3): A mixture of methyl 3,6-dichloropyridazine-4-carboxylate (1.5 g, 7.2 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.06 g, 7.2 mmol) in 1,4-dioxane (20 mL) was added DIEA (1.87 g, 14.4 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give methyl 6-chloro-3-(6- azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (1.1 g, 54.37% ) as a yellow oil. LCMS (ESI) calcd. for C13H17ClN3O2[M + H]+m / z 282.10, found 281.95. Step 2: methyl 6-iodo-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate: To a solution of methyl 6-chloro-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (1.1 g, 3.91 mmol) was added HI (55%, 10 mL) at room temperature. The mixture was heated at 40 °C for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (20 mL x 3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give crude methyl 6-iodo-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4- carboxylate (800 mg, 54.9% ) as a yellow solid which was used directly in next Step without further purification. LCMS (ESI) calcd. for C13H17IN3O2[M + H]+m / z 374.04, found 373.90. Step 3: methyl 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: A mixture of methyl 6-iodo-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (600 mg, 1.6 mmol) and Cu (30.7 mg, 4.8 mmol) and [Ph2SCF3]+[OTf]- ( 123 mg, 3.2 mmol) in DMF (10 mL) was heated at 60 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give methyl 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (330 mg, 65.6 %) as a yellow solid. LCMS (ESI) calcd. for C14H17F3N3O2[M + H]+m / z 316.13, found 316.00. Step 4: 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution methyl 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (330 mg, 1.05 mmol) in MeOH / H2O (10 mL) was added KOH (560 mg, 10 mmol) at room temperature. The mixture was heated at 70 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water and extracted with DCM (20 mL). The aqueous phase was adjusted to pH = 3 with 1N HCl and extracted with DCM (20 mL x 3). The combined organic phases were dried with Na2SO4and concentrated under reduced pressure to give 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (240 mg, 75.9% ) as a white solid. LCMS (ESI) calcd. for C13H15F3N3O2[M + H]+m / z 302.11, found 301.90. Step 5: tert-butyl ((3-(3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate: A mixture of 3-(6- azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (240 mg, 0.8 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (325 mg, 1.2 mmol) in pyridine (4 mL) was added POCl3 (350 μL) at room temperature. The mixture was stirred at room for 2 hours. Then the mixture was diluted with water (4 mL) and extracted with DCM (4 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl ((3-(3-(6-azaspiro[2.5]octan-6-yl)-6- (trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- -λ6-sulfaneylidene)carbamate (85 mg, 19.1% ) as a yellow oil. LCMS (ESI) calcd. for C25H31F3N5O4S [M + H]+m / z 554.21, found 554.10. Step 6: N-(3-(S-methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide : A solution of tert-butyl ((3-(3-(6- azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-l6- sulfaneylidene)carbamate (85 mg, 0.153 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was first purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to obtain N-(3-(S- methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4- carboxamide (44 mg, purity 98.3%) as a white solid. (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.29 (s, 1 H), 8.02 (s, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.25 (s, 1 H), 3.71-3.67 (m, 4 H), 3.06 (s, 3 H), 1.46-1.42 (m, 4 H), 0.35 (s, 4 H). LCMS (ESI) calcd. for C20H23F3N5O2S [M + H]+m / z 454.15, found 454.10. Example 15 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) DIEA, 4,4-difluoroazepane hydrochloride, dioxane; b) NCS, DMF; c) MeOH / H2O, KOH, 70 °C; d) tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, pyridine, POCl3 ; e) DCM, TFA Step 1: methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate: A mixture of methyl 2-chloro-6- methylnicotinate (1.0 g, 5.4 mmol), 4,4-difluoroazepane hydrochloride (1.11 g, 6.4 mmol) and DIEA (1.3λ g, 10.8 mmol) in dioxane (20 mL) was heated at 80 ℃ for 5 hours. Then the mixture was concentrated, and the residue was purified by flash column chromatography on silica gel (PE / EtOAc = 5 / 1) to give methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (720 mg, 42.6%). LCMS (ESI) calcd. for C14H18F2N2O2[M + H]+m / z 285.14, found 285.15. Step 2: methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate: To a solution of methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (700 mg, 2.46 mmol) in DMF (10 mL) was added NCS (394 mg, 2.95 mmol). The mixture was stirred for 5 hours at room temperature. Then the mixture was diluted with water (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated to give the crude. The crude was purified by silica gel column chromatography (PE / EtOAc, 4 / 1) to afford methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (680 mg, 78% ) as a yellow solid. LCMS (ESI) calcd. for C14H18ClF2N2O2[M + H]+m / z 319.10, found 319.00. Step 3: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid: To a solution of methyl 5- chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (650 mg, 2.03 mmol) in MeOH / H2O (1 / 1, 10 mL) was added KOH (1.14 g, 20.4 mmol) at room temperature. The mixture was heated at 70 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 5-chloro-2-(4,4- difluoroazepan-1-yl)-6-methylnicotinic acid (600 mg, 86.9%). LCMS (ESI) calcd. for C13H16ClF2N2O2[M + H]+m / z 305.09, found 304.90. Step 4: tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 5- chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (120 mg, 0.39 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (160 mg, 0.59 mmol) in pyridine (6 mL) was added POCl3 (0.3 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide tert-butyl ((3-(5-chloro-2- (4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate (65 mg, 27%) as a yellow oil. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M +H]+m / z 557.18, found 557.15. Step 5: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : To a solution of tert-butyl ((3-(5-chloro-2-(4,4- difluoroazepan-1-yl)-6-methylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 0.12 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 50% to 80% MeCN / H2O containing 0.1% formic acid) to afford 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide (10.1 mg, 18.8%) as a white solid. LCMS (ESI) calcd. for C20H24ClF2N4O2S [M + H]+m / z 457.13, found 457.00.1H NMR (400 MHz, DMSO-d6) δ 0.74 (s, 1 H), 8.32 (s, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.77 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 3.64-3.57 (m, 2 H), 3.42-3.38 (m, 2 H), 3.09 (s, 3 H), 2.45 (s, 3 H), 2.35-2.25 (m, 2 H), 2.02-1.89 (m, 2 H), 1.87-1.80 (m, 2 H). Example 16 (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: POCl3, pyridine, tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 5-chloro- 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (250 mg, 0.820 mmol) and tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (244 mg, 0.902 mmol) in pyridine (4 mL) was added POCl3 (373 μL) at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give tert-butyl (R)- ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (120 mg, 26.3% ) as a yellow oil. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M + H]+m / z 557.18, found 557.10. Step 2: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4,4- difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 0.210 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the filtrate was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (R)-5-chloro-2-(4,4- difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (67 mg, 69.8% , 100% ee) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.72 (s, 1 H), 8.30 (s, 1 H), 7.93 (d, J = 8 Hz, 1 H), 7.77 (s, 1 H), 7.65 (d, J = 8 Hz, 1 H), 7.59-7.55 (m, 1 H), 4.21 (s, 1 H), 3.62-3.60 (m, 2 H), 3.42-3.39 (m, 2 H), 3.05 (s, 3 H), 2.28 (s, 3 H), 2.29-2.26 (m, 2 H), 1.95-1.91 (m, 2 H), 1.85-1.73 (m, 2 H). LCMS (ESI) calcd. for C20H24ClF2N4O2[M + H]+m / z 457.13, found 456.90. Example 17 (S)-5-Chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) POCl3, pyridine, tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6- methylnicotinamido)phenyl)(methyl)(oxo) -λ6-sulfaneylidene)carbamate: A mixture of 5-chloro- 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (250 mg, 0.8224 mmol) and tert-butyl (S)- ((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (266.447 mg, 0.9868 mmol) in pyridine (5 mL) was added dropwise added POCl3 (500 μL) dropwise at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (S)- ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (150 mg, 32.80% ) as a white solid.LCMS (ESI) calcd. for C25H32ClF2N4O4S [M + H]+m / z 557.17, found 557.05. Step 2: (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (S)-((3-(5-chloro-2-(4,4- difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to give (S)-5-chloro-2-(4,4-difluoroazepan- 1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (54.5 mg, 44.3%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1 H), 8.31 (s, 1 H), 7.λ4 (d, J = 8.4 Hz, 1 H), 7.77 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 3.61 (dd, J = 6.4, 3.6 Hz, 2 H), 3.40 (s, 2 H), 3.09 (s, 3 H), 2.45 (s, 3 H), 2.30 (d, J = 14.7 Hz, 2 H), 1.95 (t, J = 12.2 Hz, 2 H), 1.88-1.78 (m, 2 H). LCMS (ESI) calcd. for C20H24ClF2N4O2S [M + H]+m / z 457.12, found 457.20. Example 18 (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, POCl3, pyridine; b) TFA, DCM Step 1: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 3-(4,4- difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (91 mg, 0.34 mmol) in pyridine (5 mL) was added POCl3(50 μL) dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (82 mg, 45.8%) as a yellow solid. LCMS (ESI) calcd. for C24H29F5N5O4S [M + H]+m / z 578.19, found 578.05. Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (R)-((3-(3-(4,4- difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (90 mg, 0.16 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hours. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep- HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to afford (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (38 mg, 50%, 99% ee) as a white solid. LCMS (ESI) calcd. for C19H21F5N5O2S [M + H]+m / z 478.14, found 478.25.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.26 (s, 1 H), 8.08 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.25 (s, 1 H), 3.87 (s, 2 H), 3.58 (t, J = 5.7 Hz, 2 H), 3.06 (s, 3 H), 2.39 (s, 2 H), 2.19-1.98 (m, 2 H), 1.96-1.85 (d, J = 5.1 Hz, 2 H). Example 19 (S)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, POCl3, pyridine; b) TFA, DCM Step 1: tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo) -λ6-sulfaneylidene)carbamate To a solution of 3-(4,4- difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (91 mg, 0.34 mmol) in pyridine (5 mL) was added POCl3 (50 μL) dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 50.8%) as a yellow solid. LCMS (ESI) calcd. for C19H21F5N5O2S [M - Boc + H]+m / z 478.14, found 478.05. Step 2: (S)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (S)-((3-(3-(4,4- difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (90 mg, 0.16 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep- HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to afford (S)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (53 mg, 71.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.28 (s, 1 H), 8.08 (s, 1 H), 7.λ5 (d, J = 7.9 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 3.87 (s, 2 H), 3.58 (t, J = 5.4 Hz, 2 H), 3.10 (s, 3 H), 2.45-2.31 (m, 2 H), 2.12-2.00 (m, 2 H), 1.98-1.88 (m, 2 H). LCMS (ESI) calcd. for C19H21F5N5O2S [M + H]+m / z 478.14, found 478.50. Example 20 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine- 4-carboxamide

[0043] Reagents & conditions: a) K2CO3, Pd(dppf)Cl2, phenylboronic acid, dioxane / water, 100°C; b) MeOH / H2O, KOH, 70 °C; c) SOCl2, 1h, rt, NH4OH; d) 1-bromo-3-(methylsulfinyl)benzene, Cs2CO3, Xantphos-Pd-G2, dioxane, 100°C; e) PhI(OAc)2, NH2CO2NH4, MeOH, 70 °C. Step 1: methyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (600 mg, 1.88 mmol) and phenylboronic acid (1.146 g, 9.401 mmol) in 1,4-dioxane / H2O (4 / 1, 10 mL), potassium carbonate (77λ mg, 5.641 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (137 mg, 0.188 mmol) was heated at 100 °C for 6 h under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 3 / 1) to give methyl 3-(4,4- difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate (600 mg, 88.2%) as a white oil. LCMS (ESI) calcd. for C19H22F2N3O2[M + H]+m / z 362.17, found 362.00. Step 2: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid: To a solution methyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate (0.550 g, 1.519 mmol) in MeOH / H2O (1 / 1, 10 mL) was added KOH (0.852 g, 15.19 mmol) at room temperature. The mixture was heated at 70 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (10 mL). Then the aqueous phase was adjusted to pH = 3 with 1N HCl and extracted with DCM (10 mL x 3). The combined organic phases were dried with Na2SO4and concentrated under reduced pressure to give 3-(4,4- difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid (500 mg, 65.8%) as a white solid. LCMS (ESI) calcd. for C18H20F2N3O2[M + H]+m / z 348.15, found 348.00. Step 3: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid (450 mg, 1.293 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated. The residue was diluted with THF and added dropwise to a stirred solution of ammonium hydroxide (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 3-(4,4-difluoroazepan-1- yl)-5-methyl-6-phenylpyridazine-4-carboxamide (420 mg, 93.8%) as a white solid. LCMS (ESI) calcd. for C18H21F2N4O [M + H]+m / z 347.17, found 347.05. Step 4. 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6- phenylpyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6- phenylpyridazine-4-carboxamide (400 mg, 1.152 mmol) in dioxane (8 mL) was added 1-bromo- 3-(methylsulfinyl)benzene (946 mg, 3.456 mmol), cesium carbonate (975 mg, 2.995 mmol) and Xantphos-Pd-G2 (204 mg, 0.230 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6- phenylpyridazine-4-carboxamide (120 mg, 21.5%) as a white solid. LCMS (ESI) calcd. for C25H27F2N4O2S [M + H]+m / z 485.18, found 485.10. Step 5: 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- phenylpyridazine-4-carboxamide: To a solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3- (methylsulfinyl)phenyl)-6-phenylpyridazine-4-carboxamide (120 mg, 0.247 mmol) in MeOH (5 mL) was added PhI(OAc)2(199 mg, 0.618 mmol) and ammonium carbamate ( 58 mg, 0.741 mmol) at room temperature. The reaction mixture was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide (28 mg, 20%) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.08 (s, 1 H), 8.32 (s, 1 H), 7.8λ (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8 Hz, 1 H), 7.62 (d, J = 8 Hz, 1 H), 7.59-7.57 (m, 2 H), 7.55-7.51 (m, 2H), 7.49-7.46 (m, 1 H), 4.24 (s, 1 H), 3.78-3.76 (m, 2 H), 3.67-3.64 (m, 2 H), 3.06 (s, 3 H), 2.35-2.32 (m, 2 H), 2.19 (s, 3 H), 2.06-2.04 (m, 2 H), 1.89-1.87 (m, 2 H). LCMS (ESI) calcd. for C25H28F2N5O2S [M + H]+m / z 500.20, found 499.95. Example 21 4-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide Reagents & conditions: a) DIEA, 4,4-difluoroazepane hydrogen chlorid, dioxane, 80°C; b) NH3- MeOH, 65°C; c) HI, 40°C; d) Cu, [Ph2SCF3]+[OTf]- , DMF, 60˚C; e) Cs2CO3, 1-bromo-3- (methylsulfinyl)benzene, Xantphos-Pd-G2, dioxane, 100°C; f) PhI(OAc)2, NH2CO2NH4, MeOH. Step 1: methyl 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (5.0 g, 24.3 mmol) and 4,4-difluoroazepane hydrogen chloride (4.98 g, 29.2 mmol) in 1,4-dioxane (50 mL) was added DIEA (6.27 g, 48.6 mmol). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE / EtOAc = 15 / 1) to give the methyl 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3- carboxylate (4.8 g, 64.9%) as a white solid. LCMS (ESI) calcd. for C12H15ClF2N3O2[M + H]+ m / z 306.08, found 305.90. Step 2: 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxamide: A solution of methyl 6- chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxylate (4.8 g, 15.7 mmol) in NH3-MeOH (7M, 15 mL) was heated at 60 ℃ for 16 hours in a high-pressure reactor. The reaction mixture was concentrated to give crude 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxamide (4.8 g) which was used in the next Step without purification. LCMS (ESI) calcd. for C11H14ClF2N4O [M + H]+m / z 291.08, found 290.95. Step 3: 4-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-3-carboxamide: A solution of 6-chloro-4- (4,4-difluoroazepan-1-yl)pyridazine-3-carboxamide (2.5 g, 8.62 mmol) in HI (10 mL, 57% aqueous solution) was heated at 40 °C for 5 hours. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give the 4- (4,4-difluoroazepan-1-yl)-6-iodopyridazine-3-carboxamide (2.2 g, 66.8% ) as a white solid. LCMS (ESI) calcd. for C11H14F2IN4O [M + H]+m / z 383.02, found 382.85. Step 4: 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: A mixture of 4-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-3-carboxamide (2.2 g, 5.76 mmol), Cu (1.1 g, 17.28 mmol) and [Ph2SCF3]+[OTf]- (4.6 g, 11.52 mmol) in DMF (15 mL) was heated at 60 °C for 5 hours. LCMS showed the rection was completed. Then the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 5 / 1) to give 4-(4,4- difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (1.3 g, 69.5%) as a yellow oil. LCMS (ESI) calcd. for C12H14F5N4O [M + H]+m / z 325.11, found 324.95. Step 5: 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine- 3-carboxamide: A solution of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide (200 mg, 0.60 mmol), 1-bromo-3-(methylsulfinyl)benzene (262 mg, 1.2 mmol), Cs2CO3(587 mg, 1.8 mmol) and Xantphos-Pd-G2 (55 mg, 0.06 mmol) in 1,4-dioxane (6 mL) was heated at 100 °C for overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1) to give 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide (120 mg, 43%) as an white oil. LCMS (ESI) calcd. for C19H20F5N4O2S [M + H]+m / z 463.12, found 463.00. Step 6: 4-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4,4-difluoroazepan-1-yl)-N-(3- (methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (120 mg, 0.25 mmol) in MeOH (5 mL) was added PhI(OAc)2(347.49 mg, 1.08 mmol) and ammonium carbamate (100.98 mg, 1.29 mmol) at room temperature. The reaction mixture was heated at 70 °C for 3 hours. Then the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 50% to 55% ACN-H2O containing 0.1% FA) to afford 4-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide (15 mg, 12.1%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1 H), 8.38 (s, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 7.43 (s, 1 H), 4.25 (s, 1 H), 3.67 (s, 2 H), 3.56 (t, J = 5.7 Hz, 2 H), 3.07 (s, 3 H), 2.37-2.23 (m, 2 H), 2.12-1.00 (m, 2 H), 1.94-1.84 (s, 2 H). LCMS (ESI) calcd. for C19H21F5N5O2S [M + H]+m / z 478.14, found 478.05. Example 22 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide Reagents & conditions: a) K3PO4, Pd(dppf)Cl2, cyclopropylboronic acid, THF / water, 90°C, MW; b) MeOH / H2O, KOH, 70 °C; c) SOCl2, 1h, rt, NH4OH; d) 1-bromo-3-(methylsulfinyl)benzene, Cs2CO3, Xantphos-Pd-G2, dioxane, 100°C; e) PhI(OAc)2, NH2CO2NH4, MeOH, 70 °C Step 1. methyl 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (600 mg, 1.880 mmol) and cyclopropylboronic acid (323 mg, 3.760 mmol) in THF (10 mL) was added potassium phosphate (7λ7 mg, 3.760 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (137 mg, 0.188 mmol) under nitrogen at room temperature. After addition, the reaction mixture was heated at 90 °C in a microwave reactor for 1 hour. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 3 / 1) to give methyl 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine- 4-carboxylate (550 mg, 90.0%) as a white oil. LCMS (ESI) calcd. for C16H22F2N3O2[M + H]+m / z 326.17, found 326.00. Step 2: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylic acid: To a solution to methyl 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (500 mg, 1.538 mmol) in MeOH / H2O (1 / 1, 10 mL) was added KOH (861 mg, 15.38 mmol) at room temperature. The mixture was heated at 70 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (10 mL). Then the aqueous phase was adjusted to pH = 3 with 1N HCl and extracted with DCM (10 mL x 3). The combined organic phases were dried with Na2SO4and concentrated under reduced pressure to give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylic acid (380 mg, 79.5%) as a white solid. LCMS (ESI) calcd. for C15H20F2N3O2[M + H]+m / z 312.15, found 312.00. Step 3: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamide: A solution of 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylic acid (350 mg, 1.125 mmol) in SOCl2(5 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was dissolved in THF (3 mL) and added dropwise to a stirred solution of ammonium hydroxide (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the filtrate was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamide (280 mg, 80.4%) as a white solid. LCMS (ESI) calcd. for C15H21F2N4O [M + H]+m / z 311.17, found 311.05. Step 4: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3- (methylsulfinyl)phenyl)pyridazine-4-carboxamide: A solution of give 6-cyclopropyl-3-(4,4- difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamide (250 mg, 0.803 mmol) in dioxane (8 mL) was added 1-bromo-3-(methylsulfinyl)benzene (526 mg, 2.411 mmol), cesium carbonate (678 mg, 2.087 mmol) and Xantphos-Pd-G2 (143 mg, 0.161 mmol) at room temperature. The reaction mixture was heated at 100 °C under nitrogen for 16 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3- (methylsulfinyl)phenyl)pyridazine-4-carboxamide (90 mg, 25.1% ) as a white solid. LCMS (ESI) calcd. for C22H27F2N4O2S [M + H]+m / z 449.18, found 450.10. Step 5: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: To a solution of 6-cyclopropyl-3-(4,4- difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide (90 mg, 0.200 mmol) in MeOH (5 mL) was added PhI(OAc)2(161 mg, 0.501 mmol) and ammonium carbamate ( 46 mg, 0.600 mmol) at room temperature. The reaction mixture was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (15 mL), and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5- methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (52 mg, 56%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1 H), 8.3λ (s, 1 H), 7.λ2 (d, J = 8 Hz, 1 H), 7.77 (d, J = 7.2 Hz, 1 H), 7.70-7.66 (m, 1 H), 3.67-3.63 (m, 2 H), 3.58-3.55 (m, 2 H), 2.50 (s, 3 H), 2.33 (s, 3 H), 2.29-2.15 (m, 3 H), 2.01-2.00 (m, 2 H), 1.83-1.81 (m, 2 H), 1.01-0.98 (m, 4 H). LCMS (ESI) calcd. for C22H28F2N5O2S [M + H]+m / z 464.20, found 464.00. Example 23 (S)-6-(Cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide

[0044] Reagents & conditions: a) KOH, THF, H2O, 80˚C; b) tert-butyl (S)-((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate, POCl3, pyridine; c) potassium (cyclopropylmethyl)trifluoroborate, Cs2CO3, Pd(OAc)2, Ru-Phos, toluene / H2O, 100˚C; d) TFA, DCM Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid: To a solution of methyl 6-chloro-2- (4,4-difluoroazepan-1-yl)nicotinate (200 mg, 0.66 mmol) in THF / H2O (1 / 1, 10 mL) was added KOH (368 mg, 6.6 mmol) at room temperature. The mixture was heated at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH = 3-4 with 1N HCl then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated under reduced pressure to afford 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid (180 mg, 94.7% yield) as a white solid. LCMS (ESI) calcd. for C12H14ClF2N2O2[M + H]+m / z 291.07, found 290.95. Step 2: tert-butyl (S)-((3-(6-chloro-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 6-chloro-2- (4,4-difluoroazepan-1-yl)nicotinic acid (120 mg, 0.41 mmol) and tert-butyl (S)-((3- aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (224mg, 0.83 mmol) in pyridine (5 mL) was added POCl3 (100 μL) dropwise at 0 °C. The reaction solution was stirred at 0 °C for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (S)-((3-(6-chloro-2-(4,4- difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 49.5%) as a yellow oil. LCMS (ESI) calcd. for C24H29ClF2N4O4SNa [M + H]+m / z 565.16, found 565.10. Step 3: tert-butyl (S)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture tert-butyl (S)- ((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (90 mg, 0.167 mmol), (cyclopropylmethyl)trifluoroborate potassium (83 mg, 0.52 mmol), cesium carbonate (163 mg, 0.5 mmol), Pd(OAc)2(15 mg, 0.07 mmol) and Ru-phos (24 mg, 0.052 mmol) in toluene / H2O (10 / 1, 11 mL) was heated at 100 °C for 16 h under an atmosphere of N2. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give tert-butyl (S)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (50 mg, 53.8% ) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M + H]+m / z 563.25, found 563.20. Step 4: (S)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (S)-((3-(6- (cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (50 mg, 0.09 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 35% to 85% MeCN / H2O containing 0.1% trifluoroacetic acid) to provide (S)-6- (cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide (13.3 mg, 32.4% ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1 H), 8.34 (s, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.73-7.47 (m, 3 H), 6.70 (d, J = 7.6 Hz, 1 H), 4.18 (s, 1 H), 3.63 (s, 2 H), 3.42 (t, J = 5.8 Hz, 2 H), 3.04 (s, 3 H), 2.53 (d, J = 7.0 Hz, 2 H), 2.32 (t, J = 10.9 Hz, 2 H), 2.03-1.90 (m, 2 H), 1.89-1.76 (m, 2 H), 1.12-1.02 (m, 1 H), 0.58-0.39 (m, 2 H), 0.26-0.17 (m, 2 H). LCMS (ESI) calcd. for C23H29F2N4O2S [M + H]+m / z 463.20, found 463.10. Example 24 (R)-6-(Cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, POCl3, pyridine; b) potassium (cyclopropylmethyl)trifluoroborate, Cs2CO3, Pd(OAc)2, Ru-Phos, toluene / H2O, 100˚C; c) TFA, DCM Step 1: tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 6-chloro-2- (4,4-difluoroazepan-1-yl)nicotinic acid (150 mg, 0.52 mmol) and tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (279 mg, 1.03 mmol) in pyridine (5 mL) was added POCl3 (100 μL) dropwise at 0 °C. The reaction solution was stirred at 0 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (R)-((3-(6-chloro-2-(4,4- difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (140 mg, 49.8%) as a yellow oil. LCMS (ESI) calcd. for C24H29ClF2N4O4SNa [M + Na]+m / z 565.16, found 565.10. Step 2: tert-butyl (R)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture tert-butyl (R)- ((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (140 mg, 0.26 mmol), (cyclopropylmethyl)trifluoroborate potassium (83 mg, 0.52 mmol), cesium carbonate (250 mg, 0.78 mmol), Pd(OAc)2 (15 mg, 0.07 mmol) and Ru-phos (24 mg, 0.052 mmol) in toluene / H2O (10 / 1, 11 mL) was heated at 100 °C for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature.The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give tert-butyl (R)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (75 mg, 51.3%). LCMS (ESI) calcd. for C28H37F2N4O4S [M + H]+m / z 563.25, found 563.25. Step 3: (R)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (R)-((3-(6- (cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (75 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated and the residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 35% to 85% MeCN / H2O containing 0.1% trifluoroacetic acid) to provide (R)-6- (cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide (26.2 mg, 39% ) as a white solid.1H NMR (400 MHz,DMSO-d6) δ 10.64 (s, 1 H), 8.34 (s, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.73-7.47 (m, 3 H), 6.70 (d,J = 7.6 Hz, 1 H), 4.18 (s, 1 H), 3.63 (s, 2 H), 3.42 (t, J = 5.8 Hz, 2 H), 3.04 (s, 3 H), 2.53 (d, J = 7.0 Hz, 2 H), 2.32 (t, J = 10.9 Hz, 2 H), 2.03-1.90 (m, 2 H), 1.89-1.76 (m, 2 H), 1.12-1.02 (m, 1 H), 0.58-0.39 (m, 2 H), 0.26-0.17 (m, 2 H). LCMS (ESI) calcd. for C23H29F2N4O2S [M + H]+m / z 463.20, found 463.15. Example 25 6-Methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-5- (trifluoromethyl)nicotinamide Reagents & conditions: a) 6-azaspiro[2.5]octane hydrochloride, DIEA, dioxane; b) trimethylboroxine, Pd(dppf)Cl2, K2CO3, dioxane / H2O, 100 ℃; c) NBS, DCM; d) Pd(dppf)Cl2, Et3N, EtOH, CO, 110 °C; e) KOH, MeOH / H2O, 70°C, f) tert-butyl ((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate; POCl3, pyridine; g) TFA, DCM Step 1: 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: A mixture of 2,6- dichloro-3-(trifluoromethyl)pyridine (3 g, 13.95 mmol) and 6-azaspiro[2.5]octane hydrochloride (2.06 g, 13.95 mmol) in 1,4-dioxane (50 mL) was added DIEA (3.60 g, 27.90 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 20 / 1) to provide 6-(6-chloro-5- (trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (2.5 g, 61.6% ) as a yellow oil. LCMS (ESI) calcd. for C13H15ClF3N2 [M + H]+m / z 291.09, found 291.00. Step 2: 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: A mixture of 6-(6- chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (2.5 g, 8.59 mmol), trimethylboroxine (10.78 g, 85.9 mmol), Pd(dppf)Cl2 (628 mg, 0.86 mmol) and K2CO3 (3.55 g, 25.77 mmol) in dioxane / H2O (4 / 1, 25 mL) was heated at 100 °C for 16 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 20 / 1) to give the 6-(6-methyl-5- (trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.9 g, 81.6% ) as a yellow oil. LCMS (ESI) calcd. for C14H18F3N2[M + H]+m / z 271.14, found 271.10. Step 3: 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: To a solution of 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.9 g, 7.01 mmol) in DCM (30 mL) was added NBS (1.37 g, 7.71 mmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and directly purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give the 6-(3-bromo-6-methyl-5- (trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.5 g, 65.9%) as a yellow oil. LCMS (ESI) calcd. for C14H17BrF3N2[M + H]+m / z 351.05, found 351.00. Step 4 : ethyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinate: A mixture of 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.5 g, 4.30 mmol), Pd(dppf)Cl2 (157.16 mg, 0.21 mmol) and triethylamine (1.30 g, 12.9 mmol) in EtOH (10 mL) was heated at 110 °C under an atmosphere of CO (30 atm) for 16 hours in a high-pressure reactor. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give ethyl 6-methyl-2-(6-azaspiro[2.5]octan- 6-yl)-5-(trifluoromethyl)nicotinate (1.3 g, 94%) as a yellow solid. LCMS (ESI) calcd. for C17H22F3N2O2[M + H]+m / z 343.17, found 343.15. Step 5: 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinic acid: To a solution of ethyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinate (1.3 g, 3.79 mmol) in MeOH / H2O (1 / 1, 40 mL) was added KOH (2.12 g, 37.9 mmol) at room temperature. The mixture was heated at 70 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 6- methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinic acid (900 mg, 75.4%) as a yellow solid. LCMS (ESI) calcd. for C15H18F3N2O2[M + H]+m / z 315.13, found 315.15. Step 6: tert-butyl (methyl(3-(6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5- (trifluoromethyl)nicotinamido)phenyl)(oxo)- λ6-sulfaneylidene)carbamate: To a mixture of 6- methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinic acid (250 mg, 0.7936 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (322.62 mg, 1.1904 mmol) in pyridine (8 mL) was added POCl3 (750 μL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (methyl(3-(6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5- (trifluoromethyl)nicotinamido)phenyl)(oxo)- λ6-sulfaneylidene)carbamate (190 mg, 42.2%) as a yellow solid. LCMS (ESI) calcd. for C27H34F3N4O4S [M + H]+m / z 567.23, found 567.15. Step 7: 6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-5- (trifluoromethyl)nicotinamide: A solution of tert-butyl (methyl(3-(6-methyl-2-(6- azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamido)phenyl)(oxo)- λ6- sulfaneylidene)carbamate (190 mg, 0.3351 mmol) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 40% to 85% ACN-H2O containing 0.1% formic acid) to afford (50 mg, 32%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1 H), 8.34 (s, 1 H), 7.λ7-7.86 (m, 2 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 3.64-3.52 (m, 4 H), 3.07 (s, 3 H), 2.50 (s, 3 H), 1.41-1.32 (m, 4 H), 0.31 (s, 4 H). LCMS (ESI) calcd. for C22H26F3N4O2S [M + H]+m / z 467.18, found 467.10. Example 26 (R)-5-Chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide Reagents & conditions: a) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, POCl3, pyridine; b) TFA, DCM Step 1: tert-butyl (R)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate: A mixture of 5-chloro-6- methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (250 mg, 0.892 mmol) and tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (265 mg, 0.982 mmol) in pyridine (4 mL) was added POCl3 (375 μL) at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give tert-butyl (R)- ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (120 mg, 25.3%) as a yellow oil. LCMS (ESI) calcd. for C26H34ClN4O4S [M + H]+m / z 533.20, found 533.15. Step 2: (R)-5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 0.225 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (R)-5-chloro-6-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (70 mg, 71.4%) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.82 (s, 1 H), 8.41 (s, 1 H), 7.8λ (d, J = 7.6 Hz, 1 H), 7.80 (s, 1 H), 7.67 (d, J = 8 Hz, 1 H), 7.62-7.58 (m, 1 H), 3.36-3.33 (m, 4 H), 3.11 (s, 3 H), 2.46 (s, 3 H), 1.38-1.36 (m, 4 H), 0.29 (s, 4 H). LCMS (ESI) calcd. for C21H26ClN4O2S [M + H]+m / z 433.15, found 433.05. Example 27 (S)-5-Chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide Reagents & conditions: a) tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, POCl3, pyridine; b) TFA, DCM Step 1: tert-butyl (S)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-6- methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (200 mg, 0.7143 mmol) and tert-butyl (S)-((3- aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (232.29 mg, 0.8571 mmol) in pyridine (5 mL) was added POCl3(500 μL) dropwise at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (S)-((3-(5-chloro-6- methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (120 mg, 31.5%) as a white solid. LCMS (ESI) calcd. for C26H34ClN4O4S [M + H]+m / z 533.20, found 533.15. Step 2: (S)-5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide: A solution of tert-butyl (S)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 0.2169 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 45% to 95% ACN-H2O containing 0.1% formic acid) to provide (S)-5-chloro- 6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (42 mg, 44.72%) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.81 (s, 1 H), 8.3λ (s, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.80 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.59 (t, J = 7.9 Hz, 1 H), 3.36 (d, J = 5.2 Hz, 4 H), 3.06 (s, 3 H), 2.47 (s, 3 H), 1.43-1.31 (m, 4 H), 0.29 (s, 4 H). LCMS (ESI) calcd. for C21H26ClN4O2S [M + H]+m / z 433.15, found 433.10. Example 28 (R)-3-(4,4-Difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide

[0045] Reagents & conditions: a) DIEA, 4,4-difluoroazepane hydrochloride, dioxane, 80°C; b) KOH, MeOH, H2O, 70°C; c) POCl3, Pyridine, tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate d) TFA, DCM, rt Step 1: ethyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: A solution of ethyl 3-chloro-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 2.99 mmol), 4,4-difluoroazepane hydrochloride (613 mg, 3.58 mmol) and DIEA (1155 mg, 8.96 mmol) in dioxane (10 mL) was heated at 80 °C for 1h. LCMS showed the reaction was completed. The mixture concentrated under vacuum and purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide ethyl 3-(4,4-difluoroazepan-1-yl)-5- methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 73.1%) as a yellow solid. LCMS (ESI) calcd. for C15H19F5N3O2[M + H]+m / z 368.14, found 367.95. Step 2: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid : To a solution of ethyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxylate (800 mg, 2.48 mmol) in MeOH / H2O (1 / 1, 10 mL) was added KOH (872 mg, 21.80 mmol) at room temperature. The mixture was heated at 70 °C for 5 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4,and concentrated under reduced pressure to afford 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxylic acid (600 mg, 81.2%) as a yellow solid. LCMS (ESI) calcd. for C13H15F5N3O2[M + H]+m / z 340.11, found 340.00. Step 3: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 3-(4,4- difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (175 mg, 0.65 mmol) in pyridine (10 mL) was added POCl3 (100 μL) dropwise at 50 °C. The mixture was heated at 50 °C for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 3) to provide tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (90 mg, 25.9% ) as a yellow solid. LCMS (ESI) calcd. for C20H23F5N5O2S [M - Boc + H]+m / z 492.15, found 492.15. Step 4: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (R)-((3-(3-(4,4- difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (90 mg, 0.15 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% ammonium hydroxide) to afford (R)-3- (4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide (15 mg, 20.3% ) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1 H), 8.27 (s, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 4.28 (s, 1 H), 3.85 (s, 2 H), 3.69 (t, J = 5.9 Hz, 2 H), 3.08 (s, 3 H), 2.33 (s, 3 H), 2.11-1.99 (m, 2 H), 1.93-1.81 (m, 2 H), 1.23 (s, 2 H). LCMS (ESI) calcd. for C20H23F5N5O2S [M + H]+m / z 492.15, found 492.10. Example 29 (S)-3-(4,4-Difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide

[0046] Reagents & conditions: a) POCl3, pyridine, tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate b) TFA, DCM, rt Step 1: tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine- 4-carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 3-(4,4- difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (191.16 mg, 0.708 mmol) in pyridine (3.2 mL) was added POCl3 (400 μL) dropwise at 50 °C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl- 6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (120 mg, 34.2%) as a yellow solid. LCMS (ESI) calcd. for C25H31F5N5O4S [M + H]+m / z 592.19, found 592.15. Step 2: (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide : A solution of give tert-butyl (S)-((3-(3-(4,4- difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 0.203 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (20 mg, 20%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1 H), 8.27 (s, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.73 (d, J = 7.9 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 3.85 (s, 2 H), 3.69 (t, J = 5.8 Hz, 2 H), 3.08 (s, 3 H), 2.37 (d, J = 16.1 Hz, 2 H), 2.33 (s, 3 H), 2.12-2.02 (m, 2 H), 1.92-1.85 (m, 2 H). LCMS (ESI) calcd. for C20H23F5N5O2S [M + H]+m / z 492.15, found 492.00. Example 30 (S)-6-(3-Buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) POCl3, Pyridine, tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate b) TFA, DCM, rt Step 1: tert-butyl (S)-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 6-(3-buten-1- yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (175 mg, 0.564 mmol) and tert-butyl ( - aminophenyl)(methyl)(oxo) -λ6-sulfaneylidene)carbamate (168 mg, 0.620 mmol) in pyridine (4 mL) was added POCl3 (250 μL) at 50 °C. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give tert-butyl (S)-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan- 1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (80 mg, 25.15% ) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M + H]+m / z 563.25, found 563.20. Step 2: (S)-6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (S)-((3-(6-(3-buten-1-yl)-2- (4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.143 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (S)-6-(3-buten-1-yl)- 2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23 mg, 35%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1 H), 8.37 (s, 1 H), 7.λ1 (d, J = 7.6 Hz, 1 H), 7.66-7.56 (m, 2 H), 6.65 (d, J=8 Hz, 1 H), 5.92-5.82 (m, 1 H), 5.07-4.95 (m, 2 H), 3.64- 3.62 (m, 2 H), 3.43-3.40 (m, 2 H), 3.14 (s, 3 H), 2.74-2.67 (m, 2 H), 2.45-2.43 (m, 2 H), 2.34- 2.32 (s, 2 H), 1.93-1.84 (m, 4 H). LCMS (ESI) calcd. for C23H29F2N4O2S [M + H]+m / z 463.20, found 463.10. Example 31 3-(4,4-Difluoroazepan-1-yl)-5-methyl-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4- carboxamide Reagents & conditions: a) POCl3, pyridazin-4-amine, pyridine A mixture of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (150 mg, 0.44 mmol) and pyridazin-4-amine (84 mg, 0.88 mmol) in pyridine (6 mL) was added POCl3 (150 μL) dropwise at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (DCM / MeOH = 20 / 1) then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 35% to 75% ACN-H2O containing 0.1% TFA) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(pyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide (25.2 mg, 13% ) as a white solid. LCMS (ESI) calcd. for C17H18F5N6O [M + H]+m / z 417.15, found 417.00.1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1 H), 9.31 (d, J = 2.3 Hz, 1 H), 9.18 (d, J = 5.9 Hz, 1 H), 8.07 (dd, J = 5.8, 2.7 Hz, 1 H), 3.83 (s, 2 H), 3.61 (t, J = 5.9 Hz, 2 H), 2.37 (d, J = 15.7 Hz, 2 H), 2.32 (s, 3 H), 2.16-1.94 (m, 2 H), 1.94-1.79 (m, 2 H). Example 32 4-(4,4-Difluoroazepan-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide Reagents & conditions: a) Tf2O, Et3N, DCM, 0 °C; b) 4-(4,4-difluoroazepan-1-yl)-6- (trifluoromethyl)pyridazine-3-carboxamide, Cs2CO3,Xantphos-Pd-G2, pyridazin-4-yl trifluoromethane sulfinate, dioxane, 100 °C. Step 1: pyridazin-4-yl trifluoromethanesulfonate: To a solution of pyridazin-4-ol (300 mg, 3.12 mmol) and Et3N (630 mg, 6.24 mmol) in DCM (20 mL) was added Tf2O (1056 mg, 3.74 mmol) at 0 °C. The mixture was stirred at the same temperature for 30 minutes. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide pyridazin-4-yl trifluoromethane sulfinate (100 mg, 14% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 2.7 Hz, 1 H), 6.63 (dd, J = 8.6, 2.8 Hz, 1 H). Step 2: 4-(4,4-difluoroazepan-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide: To a solution of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl) pyridazine-3- carboxamide (100 mg, 0.31 mmol), pyridazin-4-yl trifluoromethane sulfinate (100 mg, 0.46 mmol) and Cs2CO3(202 mg, 0.62 mmol) in 1,4-dioxane (5 mL) was added Xantphos-Pd-G2 (53 mg, 0.06 mmol). Then the mixture was heated at 100 °C for 16 hours under an atmosphere of N2. The resulting mixture was filtered through celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1), then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 4-(4,4-difluoroazepan-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide (7 mg, 6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1 H), λ.51 (d, J = 2.2 Hz, 1 H), 9.13 (d, J = 5.9 Hz, 1 H), 8.10 (dd, J = 5.8, 2.5 Hz, 1 H), 7.49 (s, 1 H), 3.71- 3.60 (m, 2 H), 3.49 (t, J = 5.6 Hz, 2 H), 2.32 (s, 2 H), 2.04 (t, J = 12.4 Hz, 2 H), 1.90 (d, J = 4.9 Hz, 2 H). LCMS (ESI) calcd. for C16H16F5N6O [M + H]+m / z 403.12, found 402.95. Example 33 (R)-2-(4,4-Difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide Reagents & conditions: a) 4,4-4,4-difluoroazepane hydrochloride, DIEA, dioxane, 100˚C; b) KOH, THF:H2O(1:1, v / v), 70 °C; c) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate, POCl3, pyridine, rt; d) TFA, DCM, rt Step 1: ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate : A solution of ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate (prepared by a known method WO2019166822) (800 mg, 2.9962 mmol), 4,4-difluoroazepane hydrochloride (1.03 g, 5.99 mmol) and DIEA (1.16 g, 8.99 mmol) in dioxane (12 mL) was heated at 100 °C for 4 hours. LCMS showed the reaction was completed. The mixture concentrated under vacuum and purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide ethyl 2-(4,4- difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (710 mg, 64.74%) as a yellow solid. LCMS (ESI) calcd. for C16H20F5N2O2[M + H]+m / z 367.15, found 367.10. Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid : To a solution of ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (710 mg, 1.94 mmol) in THF / H2O (1 / 1, 10 mL) was added KOH (1.09 g, 19.40 mmol) at room temperature. The mixture was heated at 70 °C for 5 hours. After the reaction was completed, the mixture was concentrated to remove most THF. The aqueous phase was adjusted to pH = 3-4 with 1N HCl then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4,and concentrated under reduced pressure to afford 2-(4,4-difluoroazepan-1- yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (540 mg, 82.4% ) as a yellow solid. LCMS (ESI) calcd. for C14H16F5N2O2[M + H]+m / z 339.12, found 339.05. Step 3: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6 (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate : A mixture of 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (100 mg, 0.2958 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (96.21 mg, 0.3550 mmol) in pyridine (3 mL) was added POCl3 (100 μL) dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (50 mg, 29%) as a yellow solid. LCMS (ESI) calcd. for C26H32F5N4O4S [M + H]+m / z 591.22, found 591.15. Step 4: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4- methyl-6-(trifluoromethyl) nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (50 mg, 0.0846 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 50% to 55% ACN-H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (14.4 mg, 34.7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.λ0 (s, 1 H), 8.33 (s, 1 H), 7.λ0 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.16 (s, 1 H), 3.68-3.63 (m, 2 H), 3.58 (t, J = 6.0 Hz, 2 H), 3.10 (s, 3 H), 2.36-2.21 (m, 5 H), 2.06-1.95 (m, 2 H), 1.88-1.75 (m, 2 H). LCMS (ESI) calcd. for C21H24F5N4O2S [M + H]+m / z 491.16, found 491.00. Example 34 (S)-2-(4,4-Difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide Reagents & conditions: a) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate, POCl3, pyridine, rt; b) TFA, DCM, rt Step 1: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate: A mixture of 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (150 mg, 0.4438 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (144.32 mg, 0.5325 mmol) in pyridine (3 mL) was added POCl3 (100 μL) dropwise at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (S)- ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6sulfaneylidene)carbamate (50 mg, 19.06%) as a yellow solid. LCMS (ESI) calcd. for C26H32F5N4O4S [M + H]+m / z 591.22, found 591.15. Step 2: (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4- methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (50 mg, 0.0846 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 50% to 55% ACN-H2O containing 0.1% formic acid) to provide (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide (20.6 mg, 49.3%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 10.λ0 (s, 1 H), 8.33 (s, 1 H), 7.λ0 (d, J = 8.0 Hz, 1 H), 7.72-7.57 (m, 2 H), 7.16 (s, 1 H), 3.65 (d, J = 7.9 Hz, 2 H), 3.58 (t, J = 6.0 Hz, 2 H), 3.09 (s, 3 H), 2.36-2.20 (m, 5 H), 2.08-1.94 (m, 2 H), 1.87-1.77 (m, 2 H). LCMS (ESI) calcd. for C21H24F5N4O2S [M + H]+m / z 491.16, found 491.00. Example 35 (R)-6-(But-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate, POCl3, pyridine, rt; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 6-(but-3-en- 1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (250 mg, 0.806 mmol) and tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (239 mg, 0.887 mmol) in pyridine (4 mL) was added POCl3 (350 μL) at 50 °C. The mixture was stirred at room temperature for 1 h, then cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give tert-butyl (R)-((3-(6-(but-3-en-1-yl)-2- (4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (60 mg, 13% ) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M + H]+m / z 563.25, found 563.15. Step 2: (R)-6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (R) -((3-(6-(but-3-en-1-yl)- 2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (80 mg, 0.143 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 50% to 80% ACN-H2O containing 0.1% formic acid) to obtain (R)-6-(but-3-en-1- yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23 mg, 35%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1 H), 8.43 (s, 1 H), 7.68-7.63 (m, 1 H), 7.62-7.61 (m, 3 H), 6.66 (d, J =7.6 Hz, 1 H), 5.89-5.82 (m, 1 H), 5.02-4.95 (m, 2 H), 3.64-3.62 (m, 2 H), 3.43-3.40 (m, 2 H), 3.31 (s, 3 H), 2.75-2.71 (m, 2 H), 2.45-2.43 (m, 2 H), 2.42-2.32 (m, 2 H), 1.93-1.84 (m, 4 H). LCMS (ESI) calcd. for C23H29F2N4O2S [M + H]+m / z 463.20, found 463.05. Example 36 4-(Azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide Reagents & conditions: a) 2-methoxypyridin-4-amine, Me3Al (1M in hexane), toluene, 0 °C; b) TMSI, CH3CN, 0-50˚C Step 1: 4-(azepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl) pyridazine-3- carboxamide : To a solution of 2-methoxypyridin-4-amine (368 mg, 2.97 mmol) in toluene (4 mL) was added Me3Al (1M in hexane, 3.26 mL, 3.26 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then a solution of methyl 4-(azepan-1-yl)-6- (trifluoromethyl)pyridazine-3-carboxylate (300 mg, 0.99 mmol) in toluene (2 mL) was added at the same temperature. The mixture was heated at 90 °C for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 1) to give 4-(azepan- 1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl) pyridazine-3-carboxamide (300 mg, 76.9%) as a yellow solid. LCMS (ESI) calcd. for C18H21F3N5O2[M + H]+m / z 396.16, found 396.00. Step 2: 4-(azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide: To a solution of 4-(azepan-1-yl)-N-(2-methoxypyridin-4-yl)-6- (trifluoromethyl)pyridazine-3-carboxamide 7 (200 mg, 0.51 mmol) in ACN (3 mL) was added TMSI (141 mg, 1.01 mmol) at room temperature. The mixture was heated at 50 °C for 5 hours. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by Prep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give 4- (azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (15 mg, 7.8% ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1 H), 11.05 (s, 1 H), 7.35 (t, J = 3.5 Hz, 2 H), 6.84 (d, J = 1.9 Hz, 1 H), 6.44 (dd, J = 7.2, 1.8 Hz, 1 H), 3.57-3.50 (m, 4 H), 1.74 (s, 4 H), 1.48 (s, 4 H). LCMS (ESI) calcd. for C17H19F3N5O2[M + H]+m / z 382.15, found 382.00. Example 37 4-(Azepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide Reagents & conditions: a) 3-(methylsulfonyl)aniline, Me3Al, toluene, λ0 ⁰C To a solution of 3-(methylsulfonyl)aniline (338 mg, 1.98 mmol) in toluene (5 mL) was added Me3Al (1M in hexane, 2.18 mL, 2.18 mmol) dropwise at 0 °C. The mixture was stirred at 0°C for 0.5 h. Then a solution of methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.66 mmol) in toluene (3 mL) was added at the same temperature. The resulting mixture was heated at 90 °C for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4,concentrated, purified by prep-HPLC (Column: Gemini- C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give 4-(azepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (80 mg, 28% ) as a white solid. NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1 H), 8.3λ (s, 1 H), 8.01 (d, J = 7.5 Hz, 1 H), 7.76-7.62 (m, 2 H), 7.36 (s, 1 H), 3.63-3.52 (m, 4 H), 3.24 (s, 3 H), 1.74 (s, 4 H), 1.47 (s, 4 H). LCMS (ESI) calcd. for C19H22F3N4O3S [M + H]+m / z 443.13, found 443.10. Example 38 N-(3-Carbamoylphenyl)-4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide Reagents & conditions: a) 3-bromobenzonitrile, Cs2CO3, Xantphos-Pd-G2, 1,4-dioxane, 100˚C; b) K2CO3, H2O2(30%, v / v), DMSO, rt. Step 1: A mixture of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (250 mg, 0.62 mmol), 3-bromobenzonitrile (335 mg, 1.86 mmol), Cs2CO3( 606 mg, 1.86 mmol) and Xantphos-Pd-G2 (52 mg, 0.06 mmol) in 1,4-dioxane (5 mL) was heated at 100 °C overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1) to give N-(3-cyanophenyl)-4-(4,4- difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 75.7%) as a white solid. LCMS (ESI) calcd. for C19H17F5N5O [M + H]+m / z 426.14, found 426.00. Step 2: N-(3-carbamoylphenyl)-4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide: To a solution of N-(3-cyanophenyl)-4-(4,4-difluoroazepan-1-yl)-6- (trifluoromethyl)pyridazine-3-carboxamide (100 mg, 0.24 mmol) in DMSO (5 mL) was added K2CO3 (100 mg, 0.72 mmol) and H2O2(30% solution, 0.5 mL). The solution was stirred at room temperature for 4 hours. LCMS showed the reaction was completed. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.05% NH3), Gradient: 20%-80%) to give N-(3-carbamoylphenyl)-4-(4,4-difluoroazepan-1-yl)- 6-(trifluoromethyl)pyridazine-3-carboxamide (40 mg, 38%) as a white solid. LCMS (ESI) calcd. for C19H20F5N5O2[M + H]+m / z 444.15, found 444.30. (400 MHz, DMSO-d6) δ 11.11 (s, 1 H), 8.22 (s, 1 H), 7.99 (s, 1 H), 7.86 (d, J = 8.2 Hz, 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.41 (s, 2 H), 3.72-3.63 (m, 2 H), 3.58 (t, J = 5.7 Hz, 2 H), 2.37-2.24 (m, 2 H), 2.13-2.19 (m, 2 H), 1.93-1.84 (m, 2 H). Example 39 4-(4,4-Difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3- carboxamide Reagents & conditions: a) 1-bromo-3-(methylsulfonyl)benzene, Cs2CO3, Xantphos-Pd-G2, 1,4- dioxane, 100 °C A solution of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (100 mg, 0.30 mmol), 1-bromo-3-(methylsulfonyl)benzene (143 mg, 0.61 mmol), Cs2CO3 (293 mg, 0.9 mmol) and Xantphos-Pd-G2 (27 mg, 0.03 mmol) in 1,4-dioxane (3 mL) was heated at 100 °C overnight under an atmosphere of N2. LCMS showed the reaction was complete. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (Column: Gemini-C18, 150 x 21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.05% FA), Gradient: 35%-85%) to give 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide (36 mg, 25%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1 H), 8.40 (s, 1 H), 8.05 (d, J = 7.5 Hz, 1 H), 7.88 - 7.61 (m, 2 H), 7.44 (s, 1 H), 3.70-3.63 (m, 2 H), 3.55 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.37 - 2.24 (s, 2 H), 2.16 - 1.96 (m, 2 H), 1.94 -1.83 (m, 2 H). LCMS (ESI) calcd. for C19H20F5N4O3S [M + H]+m / z 479.12, found 479.05. Example 40 4-(4,4-Difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide Reagents & conditions: a) 4-bromo-2-methoxypyridine, Cs2CO3, Xantphos-Pd-G2, 1,4-dioxane, 100˚C; b) TMSI, CH3CN, 0-50˚C Step 1: 4-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide: A mixture of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide (250 mg, 0.77 mmol), 4-bromo-2-methoxypyridine (215 mg, 1.16 mmol), Cs2CO3 (625 mg, 1.93 mmol) and Xantphos-Pd-G2 (18 mg, 0.02 mmol) in dioxane (5 mL) was heated at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 3) to provide 4-(4,4- difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 61.9%) as a yellow solid. LCMS (ESI) calcd. for C18H19F5N5O2[M + H]+m / z 432.15, found 432.10. Step 2: 4-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6- (trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4,4-difluoroazepan-1-yl)-N-(2- methoxypyridin-4-yl)-6-(trifluoromethyl) pyridazine-3-carboxamide (150 mg, 0.35 mmol) in MeCN (2 mL) was added TMSI (97 mg, 0.70 mmol) at room temperature. The mixture was heated at 50 °C for 5 hours. LCMS showed the reaction was completed. The final mixture was concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1), then further purified by prep-HPLC (Gemini 5 um C18column, 150x21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 4- (4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3- carboxamide (62 mg, 43%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1 H), 11.08 (s, 1 H), 7.44 (s, 1 H), 7.36 (d, J = 7.0 Hz, 1 H), 6.86 (d, J = 1.8 Hz, 1 H), 6.47 (d, J = 7.1 Hz, 1 H), 3.70-3.58 (m, 2 H), 3.51 (t, J = 5.6 Hz, 2 H), 2.36-2.24 (m, 2 H), 2.11-2.01 (m, 2 H), 1.92-1.85 (m, 2 H). LCMS (ESI) calcd. for C17H17F5N5O2[M + H]+m / z 418.13, found 418.05. Example 41 5-Chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide Reagents & conditionsμ a) NCS, MeCN, 60˚C; b) KOH, EtOH, THF, 80˚C; tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate, POCl3, pyridine, 80˚C; d) TFA, DCM, rt Step 1: methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate: To a solution of methyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.42 mmol) in MeCN (10 mL) was added NCS (228 mg, 1.70 mmol) at 25 °C. The mixture was heated at 60 °C for 6 hours. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 2). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl- 6-(trifluoromethyl)nicotinate (450 mg, 79.0%) as a yellow solid. LCMS (ESI) calcd. for C16H19ClF5N2O2[M + H]+m / z 401.11, found 400.95. Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: To a solution of ethyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (450 mg, 1.12 mmol) in THF / EtOH / H2O (1 / 1, 10 mL) was added KOH (1.25 g, 22.44 mmol) at room temperature. The mixture was heated at 80 °C for 5 hours. After the reaction was completed, the mixture was concentrated to remove most THF and EtOH. The aqueous phase was adjusted to pH = 3-4 with 1N HCl then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4,and concentrated under reduced pressure to afford 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (350 mg, 83.7%) as a yellow solid. LCMS (ESI) calcd. for C14H15ClF5N2O2[M + H]+m / z 373.08, found 373.05. Step 3: tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (200 mg, 0.73 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (174 mg, 0.87 mmol) in pyridine (5 mL) was added POCl3 (150 μL) dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (50 mg, 28.6% ) as a yellow solid. LCMS (ESI) calcd. for C26H30ClF5N4O4SNa [M + H]+m / z 647.15, found 647.10. Step 4: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide: A solution of tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)- 4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.08 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 85% MeCN / H2O containing 0.1% formic acid) to provide 5-chloro-2-(4,4- difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)nicotinamide (14.1 mg, 33.5%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 10.λ8 (s, 1 H), 8.2λ (s, 1 H), 7.8λ (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 4.24 (s, 1 H), 3.62 (dt, J = 12.0, 5.3 Hz, 4 H), 3.07 (s, 3 H), 2.41-2.21 (m, 5 H), 2.08-1.96 (m, 2 H), 1.86-1.78 (m, 2 H). LCMS (ESI) calcd. for C21H23ClF5N4O2S [M + H]+m / z 525.12, found 525.10. Example 42 2-(4,4-Difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- phenylnicotinamide

[0047] Reagents & conditions: a) 4,4-dimethoxybutan-2-one, AcOH, NCCH2CN, piperidine, toluene; b) H2SO4, H2O, 50 ⁰C; c) H2SO4, H2O, 120 ⁰C; d) SOCl2, MeOH, 70 ⁰C; e) NBS, DCM, 0 ⁰C; f) PhOPOCl2170 ⁰C; g) KOH, THF, H2O, 80 ⁰C; h) 4,4-difluoroazepane.HCl, K2CO3, DIEA, NMP, 140 ⁰C; i) tert-butyl ((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate, POCl3, pyridine, 50 ⁰C; j) phenylboronic acid, K2CO3, Pd(dppf)Cl2, dioxane, H2O, 100 ⁰C; k) TFA, DCM Step 1: 2-(4,4-dimethoxybutan-2-ylidene)malononitrile: To a stirred solution of 4,4- dimethoxybutan-2-one (100 g, 0.76 mol), acetic acid ((4.54 g, 0.076 mol) and malononitrile (45 g, 0.68 mol) in toluene (250 mL) was added piperidine (6.44 g, 0.076mol) in portions over 20 minutes. The reaction mixture was stirred overnight at room temperature. The mixture was washed with H2O (200 mL), dried over Na2SO4 and concentrated in vacuo to afford the crude 2- (4,4-dimethoxybutan-2-ylidene)malononitrile (50 g) which was used directly in the next step. Step 2: 4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile: Crude 2-(4,4-dimethoxybutan-2- ylidene)malononitrile (50 g, about 278 mmol) was added dropwise to a stirred solution of concentrated H2SO4(30 mL) at a rate that the reaction temperature did not exceed 30 °C. The reaction mixture was then heated at 50 °C for 2 h. The resulting reaction mixture was cooled to room temperature and added slowly into ice-H2O (200 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give the 4-methyl-2-oxo-1,2- dihydropyridine-3-carbonitrile (25 g, 67%) as white solid. LCMS (ESI) calcd. for C7H7N2O [M + H]+m / z 135.06, found 134.95. Step 3: 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid: A solution of 4-methyl-2-oxo- 1,2-dihydropyridine-3-carbonitrile (25 g, 187 mmol) in 50% aqueous H2SO4 (40 mL) was heated at 120 °C for 8 hours. Then the reaction mixture was cooled to room temperature slowly poured into ice-water. The precipitate was collected by filtration, washed with water, and dried under vacuum to give crude 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 g, 52.1% yield) which was used in the next step without further purification. LCMS (ESI) calcd. for C7H8NO3 [M + H]+m / z 154.05, found 154.0. Step 4: methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: To a solution of 4-methyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 65.3 mmol) in MeOH (120 mL) was added SOCl2(15 mL) dropwise. Then the mixture was heated at 65°C for 16 hours. LCMS showed the rection was completed. The mixture was concentrated to give the crude. The crude was diluted with ice-water, extracted with DCM (3× 80 mL). The combined organic phases were washed with brine, dried with Na2SO4,and concentrated under reduced pressure to afford crude methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10 g, 91.7%) which was used in the next step without further purification. LCMS (ESI) calcd. for C8H10NO3 [M + H]+m / z 168.07, found 168.0. Step 5: methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: To a solution of methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10.0 g, 59.8 mmol) in DCM (100 mL) was added NBS (10.64 g, 59.8 mmol) at 0 °C. The solution was stirred at the same temperature for 30 minutes. Then the mixture was washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford crude methyl 5-bromo-4-methyl-2-oxo-1,2- dihydropyridine-3-carboxylate (16.5 g, 80% purity, 89.6%). LCMS (ESI) calcd. for C8H9BrNO3[M + H]+m / z 245.98, found 246. Step 6: methyl 5-bromo-2-chloro-4-methylnicotinate: A solution of methyl 5-bromo-4-methyl-2- oxo-1,2-dihydropyridine-3-carboxylate (4.0 g, 16.3 mmol) in phenyl dichlorophosphate (30 mL) was heated at 170 °C for 4 hours. The solution was cooled to room temperature, diluted with water, and extracted with DCM (2 x 70 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4,concentrated under reduced pressure to afford the crude. The crude was purified by flash column chromatography on silica gel (PE / EtOAc = 12 / 1) to give methyl 5- bromo-2-chloro-4-methylnicotinate (2.7 g, 63.2% ). LCMS (ESI) calcd. for C8H8BrClNO2[M + H]+m / z 263.94, found 263.75. Step 7: 5-bromo-2-chloro-4-methylnicotinic acid: To a solution of methyl 5-bromo-2-chloro-4- methylnicotinate (1.5 g, 5.7 mmol) in THF / H2O (1 / 1, 30 mL) was added KOH (3.19 g, 57 mmol) at room temperature. The mixture was heated at 80 °C for 16 hours. After the reaction was completed, the mixture was concentrated to remove most THF. The aqueous phase was adjusted to pH = 3-4 with 1N HCl then extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried with Na2SO4,and concentrated under reduced pressure to afford 5-bromo-2-chloro-4-methylnicotinic acid (1.30 g, 90.9%) as a white solid. LCMS (ESI) calcd. for C7H6BrClNO2[M + H]+m / z 249.93, found 251.85. Step 8: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A solution of 5-bromo-2- chloro-4-methylnicotinic acid (400 mg, 1.59 mmol), 4,4-difluoroazepane hydrochloride (543 mg, 3.18 mmol), K2CO3 (1.43 g, 10.34 mmol) and DIEA (821 mg, 6.36 mmol) in NMP (10 mL) was heated at 140 °C for 6 hours. LCMS showed the reaction was completed. The mixture concentrated under vacuum and directly purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1 to 1 / 1) to provide 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (320 mg, 60% purity, 34.7% yield) as a yellow solid. LCMS (ESI) calcd. for C13H16BrF2N2O2[M + H]+m / z 351.04, found 350.9. Step 9: tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 5-bromo- 2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (150 mg, 0.43 mmol) and tert-butyl ((3- aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (232 mg, 0.86 mmol) in pyridine (3 mL) was added POCl3(100 μL) dropwise at 50 °C. The reaction solution was stirred at 50 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl ((3-(5-bromo-2-(4,4- difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (80 mg, 31% ) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M + H]+m / z 603.13, found 603.05. Step 10: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5- phenylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (50 mg, 0.083 mmol), phenylboronic acid (31 mg, 0.25 mmol), potassium carbonate (34.5 mg, 0.25 mmol) and [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (6 mg, 0.008 mmol) in 1,4- dioxane / H2O (4 / 1, 2 mL) was heated at 100 °C for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 3 / 1) to give tert-butyl ((3- (2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (40 mg, 80%) as a white oil. LCMS (ESI) calcd. for C31H37F2N4O4S [M + H]+m / z 599.25, found 599.20. Step 11: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- phenylnicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5- phenylnicotinamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (40 mg, 0.067 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 85% ACN-H2O containing 0.1% FA) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-5-phenylnicotinamide (14.5 mg, 42.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1 H), 8.38 (s, 1 H), 8.08 (s, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 7.37 (dd, J = 19.8, 7.2 Hz, 3 H), 4.22 (s, 1 H), 3.58 (s, 4 H), 3.06 (s, 3 H), 2.31 (d, J = 13.4 Hz, 2 H), 2.15 (s, 3 H), 2.01 (s, 2 H), 1.82 (d, J = 5.8 Hz, 2 H). LCMS (ESI) calcd. for C26H29F2N4O2S [M + H]+m / z 499.20, found 499.10. Example 43 (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) HATU, DIEA, N-(tert-butoxycarbonyl)-N-methylglycine, DMF, rt; b) TFA, DCM, rt Step 1: tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (150 mg, 0.31 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (87 mg, 0.46 mmol) in DMF (10 mL) was added HATU (175 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1 to 1 / 1) to give tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 53.6%) as a white oil. LCMS (ESI) calcd. for C28H36F5N6O5S [M + H]+m / z 663.24, found 663.20. Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% NH3) to obtain (R)-3-(4,4- difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide (51.3 mg, 56.9%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1 H), 8.2λ (s, 1 H), 7.λ4 (d, J = 7.8 Hz, 1 H), 7.75-7.66 (m, 2 H), 2.85 (s, 2 H), 3.68 (t, J = 6.0 Hz, 2 H), 3.47 (s, 3 H), 3.19 (s, 2 H), 2.41-2.30 (m, 5 H), 2.23 (s, 3 H), 2.14-1.97 (m, 2 H), 1.95-1.83 (m, 2 H). LCMS (ESI) calcd. for C23H28F5N6O3S [M + H]+m / z 563.19, found 563. Example 44 (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Reagents & conditions: a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF, rt; b) TFA, DCM, rt Step 1: tert-butyl (S)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate: A mixture of (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide(100 mg, 0.204 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (66 mg, 0.346 mmol) in DMF ( 10 mL) was added HATU (101 mg, 0.265 mmol) and DIEA (85 mg, 0.653 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1 to 1 / 1) to give tert-butyl (S)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl- 6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)- 2-oxoethyl)(methyl)carbamate (85 mg, 62.96%) as a white oil. LCMS (ESI) calcd. for C28H36F5N6O5S [M + H]+m / z 663.24, found 663.15. Step 2: (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide : A solution of tert-butyl (S)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (85 mg, 0.128 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% formic acid) to obtain (S)-3-(4,4- difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide (43.98 mg, 60.93%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.3λ (bs, 1 H), 8.28 (s, 1 H), 7.λ2 (d, J = 7.2 Hz, 1 H), 7.67-7.63 (m, 2 H), 3.85-3.78 (m, 2 H), 3.71-3.68 (m, 2 H), 3.45 (s, 3 H), 3.14 (s, 2 H), 2.40-2.38 (m, 2 H), 2.32 (s, 3 H), 2.23 (s, 3 H), 2.08-2.01 (m, 2 H), 1.89-1.87 (m, 2 H). LCMS (ESI) calcd. for C23H28F5N6O3S [M + H]+m / z 563.19, found 563.15. Example 45 (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide

[0048] Reagents & conditions: a) (COCl)2, DCM, DMF, DIEA, THF, tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate, 50˚C; b) (1-methyl-1H-pyrazol-4- yl)boronic acid, Pd(dppf)Cl2, K2CO3, 1,4-dioxane / H2O, 100 °C; c) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 5- bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (2 g, 5.75 mmol) in DCM (20 mL) was added (COCl)2(1.3 g, 10.34 mmol) and DMF (0.05 mL). The mixture was stirred at room temperature for 0.5 h. Then the mixture was concentrated in vacuum. The residue was diluted with THF (20 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-l6- sulfaneylidene)carbamate (1.7 g, 6.33 mmol) and DIEA (2.2 g, 17.25 mmol) in THF (20 mL). The reaction solution was heated at 50 °C for 1 hour. After the reaction was completed, the resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to give tert-butyl (R)-((3-(5-bromo-2-(4,4- difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (2.1 g, 61.05%) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M + H]+m / z 603.13, found 603.00. Step2: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate : A mixture of tert-butyl(R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ^6-sulfaneylidene)carbamate (900 mg, 1.5 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (378 mg, 3.0 mmol), K2CO3(621 mg, 4.5 mmol) and [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (120 mg, 0.16 mmol) in 1,4- dioxane / H2O (4 / 1, 40 mL) was heated at 100 °C for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combine organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to provide tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1- methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (750 mg, 83%) as a white oil. LCMS (ESI) calcd. for C29H37F2N6O4S [M + H]+m / z 603.26, found 603.15. Step 3: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide:A solution of tert-butyl (R)-((3-(2-(4,4- difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (650 mg, 1.08 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep- HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 85% MeCN / H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl- 1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (311 mg, 57.4%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1 H), 8.37 (s, 1 H), 8.17 (s, 1 H), 7.89 (d, J = 3.4 Hz, 2 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.63-7.55 (m, 2 H), 4.22 (s, 1 H), 3.88 (s, 3 H), 3.65-3.49 (m, 4 H), 3.06 (s, 3 H), 2.30-2.24 (m, 5 H), 1.98 (t, J = 11.3 Hz, 2 H), 1.80 (d, J = 5.6 Hz, 2 H). LCMS (ESI) calcd. for C24H29F2N6O2S [M + H]+m / z 503.20, found 503.15. Example 46 (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl- N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide

[0049] Reagents & conditions: a) HATU, DIEA, DMF, rt; b) TFA, DCM, rt Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate : A solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1- methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (60 mg, 0.12 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (45.2 mg, 0.24 mmol) and HATU (59 mg, 0.155 mmol) in DMF (5 mL) was added DIEA (46.3 mg, 0.36mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (55 mg, 68%) as a yellow oil. LCMS (ESI) calcd. for C32H42F2N7O5S [M + H]+m / z 674.29, found 674.25. Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl- N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: To a solution of tert-butyl (R)-(2-(((3-(2- (4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (55 mg, 0.17 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 35% to 75% MeCN / H2O containing 0.05% NH3) to afford (R)-2-(4,4-difluoroazepan-1-yl)-4- methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)nicotinamide (15.3 mg, 16%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.λ4 (s, 1 H), 8.38 (s, 1 H), 8.18 (s, 1 H), 7.λ8 (dt, J = 6.5, 2.1 Hz, 1 H), 7.90 (s, 1 H), 7.67 (dd, J = 9.6, 4.2 Hz, 2 H), 7.61 (s, 1 H), 3.89 (s, 3 H), 3.68-3.58 (m, 2 H), 3.54 (t, J = 6.1 Hz, 2 H), 3.45 (s, 3 H), 3.20 (s, 2 H), 2.32-2.19 (m, 8 H), 1.99 (dd, J = 15.6, 9.9 Hz, 2 H), 1.80 (d, J = 5.7 Hz, 2 H). LCMS (ESI) calcd. for C27H34F2N7O3S [M + H]+m / z 574.24, found 574.20. Example 47 (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid , K2CO3, Pd(dppf)Cl2, 1,4-dioxane / H2O, 100˚C; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 4-methylnicotinamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate: A mixture of tert- butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (120 mg, 0.67 mmol), K2CO3(93 mg, 0.67 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol) in dioxane (8 mL) and H2O (2 mL) was heated at 100 °C for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1 to 1 / 2) to give tert-butyl (R)-((3-(2-(4,4- difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (190 mg, 87.7%) as a yellow solid. LCMS (ESI) calcd. for C33H39F2N4O6S [M + H]+m / z 657.26, found 657.15 Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3- (S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4- difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (190 mg, 0.29 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The half of residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 50% to 90% MeCN / H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23.1 mg, 29%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1 H), 8.38 (s, 1 H), 8.03 (s, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.71-7.52 (m, 2 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.86-6.72 (m, 2 H), 4.28 (s, 4 H), 4.21 (s, 1 H), 3.68-3.49 (m, 4 H), 3.05 (s, 3 H), 2.31-2.20 (m, 2 H), 2.15 (s, 3 H), 2.07-1.95 (m, 2 H), 1.84-1.76 (m, 2 H). LCMS (ESI) calcd. for C28H31F2N4O4S [M + H]+m / z 557.21, found 557.15. Example 48 (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3- (S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) HATU, DIEA, N-(tert-butoxycarbonyl)-N-methylglycine, DMF, rt; b) TFA, DCM, rt Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6- yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide(100 mg, 0.18 mmol) and N-(tert-butoxycarbonyl)-N- methylglycine (41 mg, 0.22 mmol) in DMF ( 10 mL) was added HATU (103 mg, 0.27 mmol) and DIEA (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1 to 1 / 1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate (75 mg, 57.2%) as a yellow solid. LCMS (ESI) calcd. for C36H44F2N5O7S [M + H]+m / z 728.30, found 728.25. Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N- (3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide:A solution of tert-butyl (R)- (2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate (75 mg, 0.10 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S- methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (30.3 mg, 48.2%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.λ4 (s, 1H), 8.3λ (s, 1H), 8.10-7.91 (m, 2 H), 7.72-7.60 (m, 2 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.85-6.72 (m, 2 H), 4.28 (s, 4 H), 3.68-3.51 (m, 4 H), 3.45 (s, 3 H), 3.19 (s, 2 H), 2.35-2.19 (m, 5 H), 2.15 (s, 3 H), 2.07-1.94 (m, 2 H), 1.84-1.76 (m, 2 H). LCMS (ESI) calcd. for C31H36F2N5O5S [M + H]+m / z 628.24, found 628.15. Example 49 (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) Pd(dppf)Cl2, (4-cyanophenyl)boronic acid, 1,4- dioxane / H2O, 100 °C; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (500 mg, 0.83 mmol), (4-cyanophenyl)boronic acid (380 mg, 2.50 mmol), potassium carbonate (345 mg, 2.50 mmol) and [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (130 mg, 0.17 mmol) in 1,4- dioxane / H2O (4 / 1, 50 mL) was heated at 100 °C for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (200 mL) and extracted with DCM (80 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)- 4-methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (510 mg, 98%) as a yellow solid. LCMS (ESI) calcd. for C32H36F2N5O4S [M + H]+m / z 624.24, found 624.20. Step 2: (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ^6-sulfaneylidene)carbamate (510 mg, 0.82 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was quenched with saturated aqueous NaHCO3(50 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep- HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% formic acid) to obtain (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4- methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (245 mg, 57%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.8λ (s, 1 H), 8.36 (s, 1 H), 8.13 (s, 1H), 7.λ3-7.89 (m, 3 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.60-7.56 (m, 3 H), 4.22 (s, 1 H), 3.68-3.66 (m, 2 H), 3.61-3.58 (m, 2 H), 3.06 (s, 3 H), 2.32-2.29 (m, 2 H), 2.16 (s, 3 H), 2.02-2.00 (m, 2 H), 1.83-1.82 (m, 2 H). LCMS (ESI) calcd. for C27H28F2N5O2S [M + H]+m / z 524.19, found 524.15. Example 50 (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)nicotinamide Reagents & conditions: a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF, rt; b)TFA, DCM, rt Step 1: tert-butyl (R)-(2-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate: A mixture of (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4- methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (130 mg, 0.25 mmol), N-(tert- butoxycarbonyl)-N-methylglycine (94.5 mg, 0.5 mmol) and HATU (141.6 mg, 0.37 mmol) in DMF (3 mL) was added DIEA (96.3 mg, 0.74 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give tert-butyl (R)-(2-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate (100 mg, 57.6%) as a yellow solid. LCMS (ESI) calcd. for C35H41F2N6O5S [M + H]+m / z 695.28, found 695.25. Step 2: (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-(4- cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (100 mg, 0.144 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S- methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (55.3 mg, 64.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1 H), 8.38 (s, 1 H), 8.14 (s, 1 H), 8.00-7.96 (m, 1 H), 7.93 (d, J = 8.1 Hz, 2 H), 7.68-7.63 (m, 2 H), 7.58 (d, J = 8.1 Hz, 2 H), 3.68 (d, J = 4.5 Hz, 2 H), 3.59 (t, J = 6.0 Hz, 2 H), 3.45 (s, 3 H), 3.19 (s, 2 H), 2.31 (d, J = 7.6 Hz, 2 H), 2.23 (s, 3 H), 2.16 (s, 3 H), 2.06-1.96 (m, 2 H), 1.86-1.80 (m, 2 H). LCMS (ESI) calcd. for C30H33F2N6O3S [M + H]+m / z 595.23, found 595.15. Example 51 (R)-N-(3-(N-(azetidine-3-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)- 4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate Reagents & conditions: a) HATU, 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid, DIEA, DMF, rt; b) TFA, DCM, rt Step ...

Claims

Claims:

1. A compound of Formula (I):, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-14 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-14 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N;B is selected from the group consisting of a monocyclic, bicyclic, or spirocyclic cycloalkyl ring, and a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, and wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring may be optionally substituted with one or more halogens or one or more haloalkyl groups; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II):wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3 is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms;Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rdis H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6.

2. A compound of Formula (I):, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein:A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-6 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of: a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of said cycloheteroalkyl are optionally substituted with haloalkyl wherein the haloalkyl chain may be fully or partially halogenated; and a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl;R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II):wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3 is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n- (NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd;wherein Rdis H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6.

3. A compound of Formula (I):, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted with one or more substituents selected from a group consisting of: H, halo, substituted or unsubstituted C1-C6alkyl, C1-C6branched alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6cycloalkoxy, C3-C6haloalkoxy, nitro, cyano, -CH2-(C3-C8)- cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)- (C1-C6)-alkyl, -C(=O)-cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR’R’’, -NHSO2R1, -NHC(=O)-alkyl -NH(C=O)NR’R’’, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, bromo, chloro, fluoro, iodo, cyclopropylmethyl, sulfonylmethyl; 3-8-membered cycloalkyl; 3-8-membered heterocycloalkyl, 6-14 membered aryl, or 5-7 membered heteroaryl,any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or 5-6 membered heteroaryls comprise at least one heteroatom independently selected from O, S, and N; B is selected from the group consisting of: a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of said cycloheteroalkyl are optionally substituted with haloalkyl wherein the haloalkyl chain may be fully or partially halogenated; and a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; wherein one or more carbons of the cycloalkyl or cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, and bridged cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl, and bridged cycloalkyl comprises one or more substitutions (in addition to the R2group) selected from a group consisting of H, halo, alkyl, cyano, haloalkyl, and nitro; R1is selected from H and C1-C3alkyl; R2is H, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R” , -C(=O)OH, alkylamino, and - S(=O)R’or Formula (II):wherein: X1is O and X2is NH or NR’; X1is O and X2is NR3; or X1and X2are independently selected from NH or NR’; wherein, R3is independently selected from -(C=O)-(CH2)nRa, -(C=O)-(CH2)n-(OCH2CH2)nRa, - (C=O)-(CH2)n-(OCH2CH2O)nRa, -(C=O)-(CH2)n-(NHCH2CH2)nRa, , -(C=O)-(CH2)n-(NHCH2CH2O)nRa, -(CH2)nRa, -(CH2)n(CRbRc)Ra, -(C=O)-(NHCH2CH2NH)nRa, -(C=O)-(CH Rb)Ra, -(CH2)n(CRbRc) (CH2)nRa, or -(C=O)-(CRbRc)Ra; Rais H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CF2-aryl, - NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 membered heterocyclic ring with one or more hetero atoms; Rbis selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl with one or more heteroatoms; Rcis C1-C6-alkyl or F; RcRbtogether with the carbon atom to which attached form a 3-6 membered carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl wherein R4is optionally substituted with one or more Rd; wherein Rd is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalky, -CH(CH3)-cycloalkyl, - CF2-aryl, -NH2, -NR’R”, amino cycloalkyl, 4 to 7 member heterocyclyl, -OH, -COONH2, - COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; and n = 0, 1, 2, 3, 4, 5, 6.

4. The compound of any of claims 1-3, wherein R2is selected from H or formula (II):wherein: m and p are either 0 or 1; andX1is O and X2is either NH or NR’; or X1is O and X2is NR3 R3 is defined in claim 1.

5. The compound of any of claims 1-3, wherein R2is:wherein: m and p are either 0 or 1; and X1is O and X2is either NH or NR’; or X1is O and X2is NR3 R3is defined in claim 1.

6. The compound of any of claims 1-3, wherein A is an optionally substituted aryl, an optionally substituted heteroaryl an optionally substituted 5 or 6 members heteroaryl with one or more heteroatom; wherein the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, wherein A is optionally a pyridyl N- oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, and pyridazinyl N-oxide.

7. The compound of any of claims 1-3, wherein A contains a nitrogen atom in the heteroaryl ring, such nitrogen atom may be in the form of an N-oxide selected from a group consisting of pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, and pyridazinyl N-oxide, and wherein A may be substituted with one or more substituents.

8. The compound of any of claims 1-3, wherein A is an optionally substituted aryl.

9. The compound of any of claims 1-3, wherein A is an optionally substituted heteroaryl with one heteroatom.

10. The compound of any of claims 1-3, wherein A is an optionally substituted heteroaryl with two heteroatoms.

11. The compound of any of claims 1-3, wherein the heteroaryl A is substituted with at least triflouoromethyl.

12. The compound of any of claims 1-3, wherein the heteroaryl ring A is substituted with at least cyclopropylmethyl.

13. The compound of any of claims 1-3, wherein A is represented by the following Formula(s):wherein each of Q1, Q2, Q3 and Q4 is independently N, N-O, or CR5; wherein R5is H, hydroxyl group, halogen, -CD3, substituted or unsubstituted C1-C6alkyl, deuterated C1-C6alkyl wherein the alkyl chain may be fully or partially deuterated, branched alkyl, allyl, alkenyl, alkynyl, halo-C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2- cycloalkyl, -CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CH2- aryl, -CF2-heteroaryl, -CF2-heterocyclyl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R”, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR’R”, -NHSO2R’, -NHC(=O)- alkyl -NH(C=O)NR’R”, trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N.

14. The compound of any of claims 1-3, wherein A is an optionally substituted 5 or more membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from N, O, or S.

15. The compound of any of claims 1-3, wherein, A is represented the following Formula(s):wherein: Q2 and Q4 is N, N-O; Q2is N, N-O; Q4is CR5; Q2 is CR5; Q4 is N, N-O; R6 is H, halogen, -CD3, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, NHC(=O)R’, NHSO2R, -C(=O)R’, - C(=O)NHR’, -C(=O)NR’R”, aryl, Heteroaryl, -CF2CH3, -CF2CF3; R7 is H, hydroxyl group, halogen, -CD3, C1-C6alkyl, branched alkyl, allyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, - CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalky, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2- heteroaryl, -CF2-heterocyclyl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)- NH-alkyl, -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R”, hydroxy, -COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR’R”, -NHSO2R’, -NHC(=O)-alkyl - NH(C=O)NR’R”, trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-6 membered cylcoalkyl; 3-6 membered heterocycloalkyl, any of which may have one or more substitutents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; wherein not more than two of Q1, Q2, Q3 and Q4 or N or N-O.

16. The compound of any of claims 1-3, wherein, A is represented the following Formula(s):wherein: Q3 and Q4 are N; wherein Q3 is N, N-O; Q4 is CR5; or wherein Q3 is CR5, Q4 is N, N-O; R5 is defined in claim 9; and R6and R7are defined above in claim 15.

17. The compound of any of claims 1-3, wherein, A is represented the following Formula(s):wherein Q1 and Q4 are N, N-O; Q1 is N, N-O; Q4 is CR5; Q1 is CR5, Q4 is N, N-O; or Q1 and Q4 are CR5; and wherein R6 and R7 are defined above in claim 15.

18. The compound of any of claims 1-3, wherein, A is represented the following Formula(s):wherein: Q1and Q2are N; and R6 and R7 are defined above in claim 15.

19. The compound of any of claims 1-3, wherein, A is represented the following Formula(s):wherein: Q1is CR5, and Q2is N; R6and R7are defined above in claim 15.

20. The compound of any of claims 1-3, wherein, A is represented the following Formula(s):wherein Q1is N; and Q2is CR5; and R6and R7are defined above in claim 15.

21. The compound of any of claims 1-3, wherein the heteroaryl or aryl ring A is selected from the group consisting of:

22. The compound of any of claims 1-3, wherein B is selected from the group consisting of pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.l]heptane, azabicyclo[3.l.l]heptane, azabicyclo[4.l.0]heptane, azabicyclo[3.2.l]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa- azabicyclo[3.2.l]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxa-azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[l,2- a]pyrazine, hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.l.l3,8]undecane.

23. The compound of any of claims 1-3, wherein C is phenyl.

24. The compound of any of claims 1-3, wherein C is pyridyl.

25. The compound of any of claims 1-3, wherein within Formula (II), X1is O and X2is NH.

26. The compound of any of claims 1-3, wherein the compound is a compound of Formula (III):, wherein: B, C, R1, R2, R6 and R7 are defined above.

27. The compound of any of claims 1-3, wherein the compound is a compound of Formula (IV):, wherein B, C, R1, and R2, R5, R6 and R7 are defined above.

28. The compound of any of claims 1-3, wherein the compound is a compound of Formula (V):, wherein B, C, R1, R2, R5, R6 and R7 are defined above.

29. The compound of any of claims 1-3, wherein the compound is a compound of Formula (VI):, wherein B, C, R1, R2, R6, and R7 are defined above.

30. The compound of any of claims 1-3, wherein the compound is a compound of Formula (VII):, wherein B, C, R1, R2, R6 and R7 are defined above.

31. The compound of any of claims 1-3, wherein the compound is a compound of Formula (VIII):, wherein: B, C, R1, R2, and R5are defined above.

32. The compound of any of claims 1-3, wherein substituted or unsubstituted B is selected from a group consisting of: , , , , ,, d.

33. The compound of any of claims 1-3, wherein C is selected from a group consisting of: ,34. The compound of any of claims 1-3, wherein R1is H.

35. The compound of any of claims 1-3, wherein R2is selected from a group consisting of:,36. The compound of any of claims 1-3, wherein R2is:.

37. The compound of any of claims 1-3, wherein C comprises additional substitutions, wherein the substitutions are selected from a group consisting of H, halo, and alkyl.

38. The compound of claim 37, wherein the halo is F.

39. The compound of any of claims 1-3, wherein the one or more substitutions on the A ring are selected from a group consisting of: halo, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6alkyl, aryl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, C3-C6heteroaryl, and any combination thereof, wherein the heterocycloalkyl and heteroaryl comprise one or more hetero atoms are selected from a N, O, or S.

40. The compound of any of claims 1-3, wherein the one or more substitutions on the A ring are selected from a group consisting of: methyl, trifluoromethyl, chloro, fluoro, bromo, C1-C6 alkyl, phenyl, cycloalkyl, methyl pyrazole, fused 1, 4 dioxane, and methylcyano.

41. The compound of any of claims 1-3, wherein the one or more substitutions on the A ring are selected from a group consisting of: -CH3, -CD3, -CF3, -Cl, -Br, -F, -CH2-CH2- CH=CH2, phenyl, -CH2-CN, -C(=O)-NH2, , ,, ,42. The compound of any of claims 1-3, wherein the substitutions on the A ring are selected from the group consisting of H, halogen, alkyl, and haloalkyl.

43. The compound of any of claims 1-3, wherein the substitutions on the A ring are selected from the group consisting of methyl and -CF3.

44. The compound of any of claims 1-3, wherein the substitutions on the A ring are selected from the group consisting of H and -CF3.

45. The compound of any of claims 1-3, wherein A is a 6-membered aryl or heteroaryl ring.

46. The compound of claim 45, wherein A is phenyl.

47. The compound of claim 45, wherein A is pyridine.

48. The compound of any of claims 1-3, wherein C ring is a 6-membered aryl, heteroaryl, or cycloalkyl or heterocycloalkyl ring.

49. The compound of any of claims 1-3, wherein C ring is phenyl.

50. The compound of any of claims 1-3, wherein C ring is pyridine.

51. The compound of any of claims 1-3, wherein C ring is piperidine.

52. The compound of any of claims 1-3, wherein C ring is pyrrolidine.

53. The compound of any of claims 1-3, wherein R2is:wherein: X1is O and X2is NR’, and R4is selected from C1-C3alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

54. The compound of any of claims 1-3, wherein R2is:wherein: X1is O and X2is O, and R4is selected from C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

55. The compound of claim 53 or claim 54, wherein R’ is H.

56. The compound of claim 53 or claim 54, wherein R4is C1-C3alkyl.

57. The compound of claim 53 or claim 54, wherein R4is methyl.

58. The compound of claim 53 or claim 54, wherein R4is ethyl.

59. The compound of claim 53 or claim 54, wherein R4is C3-C4 cycloalkyl.

60. The compound of any of claims 1-3, wherein B ring is 4-8 membered substituted or unsubstituted cycloalkyl or cycloheteroalkyl, wherein heteroatoms in said cycloheteroalkyl are selected from the group consisting of N or O.

61. The compound of claim 59, wherein said substitutions on B ring are selected from the group consisting of one or more of halogen, C1-C4alkyl, oxyalkyl, alkyloxyalkyl, substituted or unsubstituted C3-C6cycloalkyl wherein said C3-C6cycloalkyl is spiro with B ring, and partially or completely halogenated C1-C4alkyl.

62. The compound of claim 61, wherein the halogen is fluoro.

63. The compound of claim 61, wherein the halogen is chloro.

64. The compound of claim 61, wherein the C1-C4 alkyl is methyl.

65. The compound of claim 61, wherein the C3-C6cycloalkyl is cyclopropyl.

66. The compound of claim 61, wherein the substitutions are selected from the group consisting of -OCH3and -CH2-O-CH3.

67. A compound selected from the group consisting of68. A compound selected from the group consisting of:

69. A compound selected from the group consisting of:

70. A compound selected from the group consisting of the compounds recited in Tables 1A- 1F: Table 1A.Table 1B:Table 1C:Table 1D:Table 1E:Table 1F:

71. A compound selected from the group consisting of the compounds in Tables 1G-1NN: Table 1G:Table 1H:Table 1J:Table 1L:Table 1M:Table 1N:Table 1P:Table 1Q:Table 1R:Table 1S:Table 1T:Table 1U:Table 1V:Table 1Y:Table 1Z:Table 1AA:Table 1BB:Table 1CC:Table 1DD:Table 1EE:Table 1FF:Table 1GG:Table 1HH:Table 1JJ:Table 1LL:Table 1MM:Table 1NN:

72. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound in any of claims 1-71.

73. The method of claim 72, wherein the compound is selected from any one of the compounds recited in claims 1-71.

Images