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 Navl.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 I. Field of the Invention The application relates generally to sodium channel blocking compounds, derivatives thereof, and the use of such compounds as pharmacological agents. II. 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 these conditions. III. 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. (A) First Set of compounds: In one aspect, the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein, A is aryl or heteroaryl wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo-C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl, wherein the haloalkoxy chain may be fully or partially halogenated, or arylalkoxyl; B is aryl or heteroaryl wherein the aryl may have 1 to 4 substituents and heteroaryl may have 1 to 3 substituents, these substituents are independently selected from halogen, C1-C8alkyl, haloalkyl, or alkoxy; R1, R2, R3and R4are independently selected from H, halogen, -OH, C1-C6-alkyl, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8branched alkyl, C3-C8branched fluoroalkyl wherein the branched fluoroalkyl chain maybe fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, - NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; R5is H or C1-C3alkyl; and R6is -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R”, or Formula (II): wherein: X1and X2are both O, NH, or NR’; or X1is O and X2is either NH or NR’; R7is NH2, NHR’, NR’R”, C1-C3alkyl, C3-C8cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl. In various embodiments, the compound of the invention is a compound of Formula (III):

[0002] Formula (III) wherein, R1, R2, R3, R4, R5, R6, and B are described in Formula (I); Q, T and W is independently N or C R9; R9is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy; X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, - or OCF3; R8is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, or substituted or unsubstituted 3-6 membered cycloalkyl. In another embodiment, B is , wherein R6is described above; Z is CR10, N, or N+O-; wherein R10is H, halo, -CD3, C1-C8alkyl, haloalkyl, or alkoxy. In another embodiment, R6is wherein: X1and X2are both O, NH, or NR’; or X1is O and X2is either NH or NR’; R7is NH2, NHR’, NR’R”, C1-C3alkyl, C3-C8cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl. In another embodiment, R6is wherein: X1is O, X2is NH, and R7is C1-C3alkyl. In another embodiment, R6does not include -C(=O)NH2, -C(=O)NHR’, or - C(=O)NR’R”. In another embodiment, B is a phenyl ring. In another embodiment, B is a pyridine ring. In another embodiment, R1is H, -CH3, or F. In another embodiment, R2is chloro, -CF3, H, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl. In another embodiment, R3is H, -CF3, or F. In another embodiment, R4is H. In another embodiment, R8is H, -CH3, or -O-CH3. In another embodiment, R7is -CH3. In another embodiment, X is F or -CN. In another embodiment, Q is N or CH. In another embodiment W is CH and T is CH In another embodiment, Z is CR10and R10is H or F. In another embodiment, the compound is selected from a group consisting of:

[0003] (B) Second Set of Compounds In one aspect, the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein: A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo- C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, aloalkoxyl wherein the haloalkyoxy chain may be fully or partially halogenated, and arylalkoxyl; R1, R2, R3and R4are independently selected from hydrogen, -OH, halogen, C1-C6-alkyl, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8branched alkyl, C3-C8branched fluoroalkyl wherein the branched fluoroalkyl chain maybe fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, NR’R’’, 3-8, membered cycloalkyl, 3-8- membered cycloalkenyl 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, a saturated or unsaturated 5 or more membered ring or an aryl ring optionally containing 1 or more heteroatoms independently selected from O, S, and N, wherein each 5 or more membered ring is unsubstituted or substituted with one to five substituents selected from hydrogen, cyano, halo, or methyl; a fused ring formed by at least two of R1, R2, R3and R4wherein the fused ring is selected from a group consisting of: optionally saturated carbocyclyl or heterocyclyl containing 5-6 ring members, wherein the heterocyclyl include one or more heteroatoms; R5is H, or substituted or unsubstituted C1-C3alkyl; R6is -(CH2)nRa, -(CRbRc)nRa, -(CRbRc)n-(OCH2CH2)nRa, -(CRbRc)n-(NR’CH2CH2)nRa, , - (CRbRc)n-(NR’CH2CH2O)nRa, or -(CRbRc)n-(NHCH2CH2NH)nRa; wherein Rais H, C1-C6-alkyl, C2-C8branched alkyl, C3-C8cycloalkyl, aryl, heteroaryl, 4-7 member heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2)nRb,- NR’R”, -COONR’R” , -COOR’, alkylsulfonyl, arylsulfonyl, or -SO2NR’R”; Rbis independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 member carbocyclyl, 4-7 member heterocyclyl with one or more heteroatoms; Rcis H, C1-C6alkyl or F; Rcand Rboptionally form a 3-6 member carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R7is NH2, -NHR’, C1-C3alkyl, substituted or unsubstituted C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl. In various embodiments, the compound of the invention is a compound of Formula (II): (Formula II) wherein ring B, and groups R1, R2, R3, R4, R5, R6, and R7, are described in claim 1; R8is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; Q, T, and W are independently selected from N or CR9; R9is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or cycloalkoxy, each of which is optionally substituted; X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, or -OCF3. In another embodiment, the compound of the invention is a compound of Formula (III): Formula (III) wherein, R1, R2, R3, R4, R5, R6, and R7are described above in Formula (I); R8, W, T, Q, and X are described above in Formula (II); Zis CH, N, CF, or N+-O-In another embodiment, X is F. In another embodiment, R8is -CH3. In another embodiment, Q is N. In another embodiment, Q is N, W is CH, and T is CH. In another embodiment, R1is H or F. In another embodiment, R2is H, chloro, or CF3. In another embodiment, R3is H or CF3. In another embodiment, R4is H. In another embodiment, R5is H. In another embodiment, R7is methyl. In another embodiment, R6is azetidine, pyrrolidine, -CH2-OH, -CH-(CH3)-OH, -CH- CH2-NH-CH3, -CH2-NH2, CH-(CH3)-NH2, -CH2-NH2, -C-(CH3)2-NH2, or -cyclobutyl-NH2. In another embodiment, R9is H. In another embodiment, the compound of Formula (I) is selected from the group consisting of:

[0004] ĨC) Third Set of Compounds In one aspect, the invention provides a compound of compound of Formula (I): and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C1-C8-alkyl, C1-C8fully or partially fluorinated fluoroalkyl, C2-C8branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R’’)-cycloalkyl, C(R’)(R’’)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; B is substituted or unsubstituted aryl or heteroaryl, wherein the substitutions are selected from the group consisting of substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, halo-C1-C4alkyl where the alkyl chain is fully or partially halogenated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl wherein the haloalkyoxyl chain may be fully or partially halogenated, or arylalkoxyl; C is substituted or unsubstituted aryl or heteroaryl, wherein the one or more substitutions are independently selected from a group consisting of halo, C1-C8alkyl, haloalkyl, alkoxy; R1is selected from a group consisting of: H and C1-C4alkyl; R2is selected from a group consisting of: Formula (II): (II), -C(=O)NH2, and -C(=O)NR’R”; wherein, m and n are independently 0 or 1; and X1is O and X2is either NH or NR’; or X1and X2are both O, NH, or NR’; or X1is O and X2is NR3; wherein R3is selected from a group consisting of: CD3, C1-C4alkyl or cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl, (C1-C6)alkyl- OH, (C1-C6)alkyl-NHR’, (C1-C6)alkyl-NR’R”, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-N-(C1-C6)alkyl ; R4is selected from a group consisting of: -NH2, -NR’R”, C1-C4alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl. In another embodiment, B is a 6 membered substituted or unsubstituted heteroaryl ring, comprising one or more N atoms. The N atoms in the heteroaryl ring may be in the form of a N- oxide. In certain embodiments, the N-oxide containing B-ring is selected from pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide. In another embodiment, the compound is a compound of Formula (III): Formula (III) wherein Q T and W are independently N or CR6; R6is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, - OCF3, or substituted or unsubstituted cycloalkoxy; R5is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2- cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6 membered cycloalkyl, any of which may have one or more substituents; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, - OCF3. In another embodiment, the compound is a compound of Formula (IV): Formula (IV), wherein: Z is CR10, N, or N+O-; wherein R10is H, halo, -CD3, C1-C8alkyl, haloalkyl, or alkoxy. In certain embodiments, ring A is substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S. In certain embodiments, ring A is substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In certain embodiments, ring A is substituted or unsubstituted 6 membered heteroaryl having at least one heteroatom, wherein the heteroatom is N. In certain embodiments, ring A is substituted or unsubstituted 6 membered heteroaryl having at least 2 N atoms. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein Q1, Q2, Q3and Q4are independently selected from a group consisting of: N, N+O-, or CR7; wherein at least two of Q1, Q2, Q3and Q4are CR7; R7is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O- cycloheteroalkyl. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q2and Q4are independently N or N+O- ; Q2is N or N+O- ; Q4is CR7; or Q2is CR7, Q4is N or N+O-; R8and R9are independently selected from a group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, aryl, heteroaryl, -CF2CH3, and -CF2CF3; In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q3and Q4are independently N or N+O- ; Q3is N or N+O- and Q4is CR7; or Q3is CR7, Q4is N or N+O-; wherein R7, R8and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q1and Q4are independently N or N+O-; Q1is N or N+O-, and Q4is CR7; Q1is CR7and Q4is N or N+O-; or Q1or Q4is CR7; wherein R7, R8, and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein Q1and Q2are N; wherein R8and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A wherein Q1is CR7, Q2is N; R7, R8, and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q1is N; Q2is CR7; R7, R8, and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2is: wherein m and n are independently 0 or 1; X1is O and X2is NH, and R4is alkyl, for example, methyl. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2is: wherein m and n are independently 0 or 1; X1is O and X2is O, and R4is NH2or alkyl, for example, methyl. In other embodiments, R2is -S(=O)CH3. In another embodiments, in the compound of Formula (III) and / or Formula (IV), Q is N or CH; R5is methyl or -OMe, X is F or CN. In other embodiments, in the compound of Formula (III) and / or Formula (IV), Q is CF. In other embodiments, R7, R8, and R9are independently selected from a group consisting of: H, methyl, fluoro, chloro, bromo, CF3, cyclopropyl, difluorophenyl, and dimethylpyrazole. In other embodiments, in the compound of Formula (III) and / or Formula (IV), R10is H or F. In other embodiments, in the compound of Formula (III) and / or Formula (IV), Z is N or CH. In certain embodiments of the invention, R2does not comprise -C(=O)NH2or - C(=O)NR’R”. In certain embodiments, R2is Formula (II): wherein, m and n are independently 0 or 1; and X1and X2are not both O, NH, or NR’. In other embodiments, the compound of the invention is selected from a group consisting of:

[0005] (D) Fourth Set of Compounds In one aspect, the invention provides a compound of Formula (I):

[0006] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C1-C8-alkyl, C1-C8fully or partially fluorinated fluoroalkyl, C2-C8branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; B is substituted or unsubstituted aryl or heteroaryl, wherein the substitutions are selected from the group consisting of substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, halo C1-C4alkyl where the alkyl chain is fully or partially halogenated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl wherein the haloalkyoxyl chain may be fully or partially halogenated, and arylalkoxyl; C is substituted or unsubstituted aryl or heteroaryl, wherein the one or more substitutions are independently selected from a group consisting of halo, C1-C8alkyl, haloalkyl, alkoxy; R1is selected from a group consisting of: H and C1-C4alkyl; R2is selected from a group consisting of: -(CH2)nRa, -(CRbRc)nRa, -(CRbRc)n- (OCH2CH2)nRa, -(CRbRc)n-(NR’CH2CH2)nRa, , -(CRbRc)n-(NR’CH2CH2O)nRa, and -(CRbRc)n- (NHCH2CH2NH)nRa; wherein Rais H, C1-C8-alkyl or branched alkyl, C3-C8cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2)nRb, -NR’R’’, -COONR’R’’ , -COOR’R’’, alkylsulfonyl, arylsulfonyl, or -SO2NR’R”; Rbis H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 memebered carbocyclyl or heterocyclyl with one or more heteroatoms; Rcis H, C1-C6alkyl, or F; Rcand Rbtogether optionally form a 3-6 member carbocyclic or heterocyclic ring; R3is selected from a group consisting of C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl. In another embodiment, the compound is a compound of Formula (II): Formula (II) wherein: A, C, R1, R2, and R3are described above; Q, T and W are independently N or CR5; R5is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, - OCF3, or cycloalkoxy; R4is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2- cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, or - OCF3. In another embodiment, the compound is a compound of Formula (III): wherein, Z is CH, N, CF, or N+O-; and A, W, T, Q, X, R1, R2, R3, and R4are described above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is substituted or unsubstituted 5-6 membered heteroaryl with one or more heteroatom. The 5-6 membered ring heteroaryl includes N as the one or more heteroatom. The heteroatom N 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, pyridazinyl N-oxide, and pyrimidinyl N- oxide. In other embodiments, A is a 6-membered heteroaryl comprising at least one heteroatom, wherein the heteroatom is N. In certain embodiments, A is a 6-membered heteroaryl comprising 2 N atoms. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A may be a substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein Q1, Q2, Q3and Q4are independently selected from a group consisting of: N, N+O-, or CR6; wherein at least two of Q1, Q2, Q3and Q4are CR6; R6is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O- aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein, Q2and Q4are independently N or N+O- ; Q2is N or N+O- and Q4is CR6; or Q2is CR6and Q4is N or N+O-; R7and R8 are independently selected from the group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, aryl, Heteroaryl, -CF2CH3, and -CF2CF3; R6is described above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein, Q3and Q4are N; Q3is N, N+O-; Q4is CR6; or Q3is CR6, Q4is N or N+O-; wherein R7 and R8are defined above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein Q1and Q4are independently N or N+O-; Q1is N or N+O- and Q4is CR6; or Q1is CR6and Q4is N or N+O-; wherein R6, R7, and R8are described above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein Q1and Q2is N; wherein R7and R8are described above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein Q1is CR6, and Q2is N; R6, R7, and R8are described above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), ring A is: wherein, Q1is N; Q2is CR6; R6, R7, and R8are described above. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), R1is H. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), R3is methyl. In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), R2is H, methyl, -CH2-NH2, -CH2-NH-CH3, -CH2-OH, -CH(NH2)(CH3), -CH2-OH, - CH(OH)(CH3), -CH(CF3)(NH2), -CH2-O-CH3, amino-cycopropyl, pyrrolidine, azetidine, oxetane, tetrahydrofuran, or hydroxypyrrolidone. In other embodiments, in the compounds of Formula (II) and / or Formula (III), T is N. In other embodiments, T is N, W is CH, and Q is CH. In other embodiments, in the compounds of Formula (II) and / or Formula (III), R4is methyl. In other embodiments, in the compounds of Formula (II) and / or Formula (III), X is F. In other embodiments, in the compounds of Formula (II) and / or Formula (III), Z is N or CH. In other embodiments, the compound of the invention is selected from a group consisting of:

[0007]

[0008] 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. IV. 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., C1-10 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 C1-20inclusive, including 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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 C1-8alkyl), 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. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, 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 C1-20alkylene 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-(1, 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-(1,4-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 C2-20 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 C2-20hydrocarbon of a designed number of carbon atoms containing at least one carbon- carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), 1-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. 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 C1-4alkyl, 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, halogen, 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-NH2, (C1- C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-N-(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., -CF3and -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 halogen, 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 C1-20 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 by13C- or14C-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. Abbreviations and Acronyms When the following abbreviations are used herein, they have the following meaning:

[0009] Compounds: The invention provides compounds that modulate, e.g., inhibit, the activity of voltage gated sodium channels. The compounds and their methods of manufacturing are provided in detail below. (A) First Set of Compounds In one aspect, the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein, A is aryl or heteroaryl wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo-C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl, wherein the haloalkoxy chain may be fully or partially halogenated, or arylalkoxyl; B is aryl or heteroaryl wherein the aryl may have 1 to 4 substituents and heteroaryl may have 1 to 3 substituents, these substituents are independently selected from halogen, C1-C8alkyl, haloalkyl, or alkoxy; R1, R2, R3and R4are independently selected from H, halogen, -OH, C1-C6-alkyl, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8branched alkyl, C3-C8branched fluoroalkyl wherein the branched fluoroalkyl chain maybe fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, - NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; R5is H or C1-C3alkyl; and R6is -C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R”, or Formula (II): wherein: X1and X2are both O, NH, or NR’; or X1is O and X2is either NH or NR’; R7is NH2, NHR’, NR’R”, C1-C3alkyl, C3-C8cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl. In various embodiments, the compound of the invention is a compound of Formula (III):

[0010] Formula (III) wherein, R1, R2, R3, R4, R5, R6, and B are described in Formula (I); Q, T and W is independently N or CR9; R9is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy; X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, - or OCF3; R8is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, or substituted or unsubstituted 3-6 membered cycloalkyl. In another embodiment, B is , wherein R6is described above; Z is CR10, N, or N+O-; wherein R10is H, halo, -CD3, C1- C8alkyl, haloalkyl, or alkoxy. In another embodiment, R6is wherein: X1and X2are both O, NH, or NR’; or X1is O and X2is either NH or NR’; R7is NH2, NHR’, NR’R”, C1-C3alkyl, C3-C8cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl. In another embodiment, R6is wherein: X1is O, X2is NH, and R7is C1-C3alkyl. In another embodiment, R6does not include -C(=O)NH2, -C(=O)NHR’, or - C(=O)NR’R”. In another embodiment, B is a phenyl ring. In another embodiment, B is a pyridine ring. In another embodiment, R1is H, -CH3, or F. In another embodiment, R2is chloro, -CF3, H, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl. In another embodiment, R3is H, -CF3, or F. In another embodiment, R4is H. In another embodiment, R8is H, -CH3, or -O-CH3. In another embodiment, R7is -CH3. In another embodiment, X is F or -CN. In another embodiment, Q is N or CH. In another embodiment W is CH and T is CH In another embodiment, Z is CR10and R10is H or F. In another embodiment, the compound is selected from a group consisting of:

[0011] The first set of compounds, provided herein, are prepared by methods and procedures described below. The intermediates described in this section may be relied upon for preparation of first set of compounds. 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 C18 column, 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. 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

[0012] As illustrated in Scheme A, in general, compounds of Formula (I) may be synthesized starting from carboxylic acids A-1 by reacting with a substituted aniline or heteroaryl aniline A-2 using standard amide coupling reagents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base, such as DIEA, to give intermediates of type A-3. Intermediates A-3 may contain a protecting group (PG) such as Boc which may be removed by treatment with an acid such as TFA to provide compounds of Formula(I) having structure A-4. Any suitable PG such as Cbz or Fmoc may be employed and can be removed accordingly. Alternatively, carboxylic acid A-1 may be treated with ammonia or a primary amine (R5NH2) in the presence of an amide coupling reagent such as HATU and a base such as DIEA to give carboxamide intermediate A-5 which can undergo metal-catalyzed coupling with a halogen-substituted aryl or heteroaryl compounds of type A-6 to give compounds of formula A-3. Compounds of Formula (I) can then be obtained from A-3 as described. Scheme B

[0013] As further illustrated in Scheme B, in general, compounds of the invention can be prepared by reacting intermediates A-1 with an amine B-1, utilizing amide coupling conditions or by activation of an appropriately functionalized carboxylic acid A-1 with (COCl)2or POCl3and with amine B-1 and base such as DIEA or pyridine in DCM, DMF or THF to give compounds of type B-2. The compounds of formula B-3 can be formed by removing a protecting group, such as Boc under acidic conditions. In some instances, B-3 can be separated into the corresponding R and S isomers using chiral HPLC. R- and S-isomers also can be prepared by coupling of the acid to enantiomerically pure amine B-1 followed by deprotection. Scheme C

[0014] As illustrated in Scheme C, in general, compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-1 in organic solvent with either (COC1)2or SOCl2followed by addition of NH4OH to afford C-1. Intermediate C-1 can then be brought together with materials of variously substituted Br compounds C-2, utilizing Xantphos- Pd-G2 mediated coupling conditions to deliver intermediate C-3. The compounds of formula C-3 may be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to provide compounds of formula B-3. In some instances, B-3 was separated to the corresponding R and S isomers using chiral HPLC conditions. Compounds of formula B-4 were obtained using standard amide coupling reagents such as, not limited to, HATU, a base such as DIEA, and C-4. The above schemes are intended to be illustrative and not limiting in any way. Those skilled in the art may prepare the Compounds of Formula (I) using these general schemes as a guideline but other methods are available to accomplish the synthesis of compounds of the invention. Specific methods are provided for each of the Examples to further illustrate the synthesis of Compounds of Formula (I). Intermediates Intermediate 1 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid Reagents & conditions: a) 2,2,6,6-Tetramethylpiperidine, n-BuLi, THF, 0˚ to -78˚C, CO2; b) SOCl2, MeOH, 80˚C; c) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, MeCN, 80˚C; d) KOH, MeOH, H2O, rt Step 1: 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid: To a solution of Me4-piperidine (3.2 g, 23 mmol) in THF (30 mL) was added n-BuLi (2.4 M in hexane, 9.58 mL, 23 mmol) dropwise at 0 °C under an atmosphere of N2. The mixture was stirred at 0 °C for 1 hour. Then a solution of 1-chloro-4-fluoro-2-(trifluoromethyl)benzene (3 g, 15 mmol) in THF (30 mL) was added dropwise to the mixture at -78 °C . The mixture was stirred at -78 °C for 2 hours. The resulting solution was added dry ice (about 5 g). Then the reaction mixture was slowly warmed to 0 °C and stirred for 1 hour at the same temperature. The final mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (100 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 (DCM / MeOH = 20 / 1) to give 5-chloro-2-fluoro-4- (trifluoromethyl)benzoic acid (2 g, 54.6 %) as a yellow solid. LCMS (ESI) calcd. for C8H2ClF4O2[M - H]- m / z 240.97, found 240.85. Step 2: methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate: A solution of 5-chloro-2- fluoro-4-(trifluoromethyl)benzoic acid (2 g, 8.30 mmol) in SOCl2(20 mL) was heated at 80 °C for 1h. Then the mixture was concentrated in vacuum. The residue was added to MeOH (30 mL) and stirred at room temperature for 1 hour. The final mixture was concentrated under vacuum to give the crude methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (1.8 g) which was used directly in next step without further purification. Step 3: methyl 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzoate: A solution of methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (1.8 g, 7.03 mmol), 6-fluoro-2-methylpyridin-3-ol (982 mg, 7.73 mmol), and Cs2CO3(4.6 g, 14.06 mmol) in MeCN (40 mL) was heated at 80 °C for 16 hours. Upon completion of the reaction, the mixture was concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (PE / EtAOc = 3 / 1) to give methyl 5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate (2.4 g, 93.93%) as a yellow solid. LCMS (ESI) calcd. for C15H11ClF4NO3[M + H]+m / z 364.04, found 363.70. Step 4: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid: To a solution of methyl 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzoate (1 g, 2.76 mmol) in MeOH / H2O (1 / 1, 30 mL) was added KOH (907 mg 13.77 mmol). The mixture was stirred at room temperature for 2 hours. Then the organic solvent was removed under reduced pressure. The aqueous solution was adjusted to pH = 2-3 with 2N HCl. The precipitate was collected by filtration, washed with water and dried under vacuum to provide 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (900 mg, 93.65% ) as a yellow solid. LCMS (ESI) calcd. for C14H9ClF4NO3[M + H]+m / z 350.02, found 349.65. Intermediate 2 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid

[0015] Reagents & conditions: a) MeI, K2CO3, DMF; b) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, DMF, 100˚C; c) LiOH.H2O, THF / H2O Step 1: methyl 2-fluoro-4-(trifluoromethyl)benzoate: To a solution of 2-fluoro-4- (trifluoromethyl)benzoic acid (500 mg, 2.4 mmol) and K2CO3(993 mg, 7.2 mmol) in DMF (5 mL) CH3I (677 mg, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers 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 5 / 1) to give methyl 2-fluoro-4- (trifluoromethyl)benzoate (490 mg, 81.7%) as a white oil. LCMS (ESI) calcd. for C9H7F4O2[M + H]+m / z 223.04, found 223.04. Step 2: methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate: A solution of methyl 2-fluoro-4-(trifluoromethyl)benzoate (400 mg, 1.8 mmol) in DMF (5 mL) Cs2CO3(1.75 g, 5.4 mmol), 6-fluoro-2-methylpyridin-3-ol (342 mg, 2.7 mmol) was added. The mixture was heated to 100 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The solution was concentrated under vacuum and purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1 to 3 / 1) to provide methyl 2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate (350 mg, 86%) as a light-yellow solid. LCMS (ESI) calcd. for C15H12F4NO3[M + H]+m / z 330.08, found 330.00. Step 3: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid: To a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate (350 mg, 1.06 mmol) in THF (4 mL) and H2O (4 mL) was added LiOH.H2O (267 mg, 6.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the residue was adjusted to pH = 3-4 with HCl (1 M). Then the aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 92%) as a white solid. LCMS (ESI) calcd. for C14H10F4NO3[M + H]+m / z 316.06, found 315.90. Intermediate 3 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid Reagents & conditions: a) MeI, K2CO3, DMF; b) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, MeCN; c) Fe, NH4Cl, MeOH / H2O, 60 °C; d) TsOH.H2O, NaNO2, KI, MeCN; e) K2CO3, Pd(dppf)Cl2, 1,4-dioxane / H2O, 100 °C; f) LiOH, MeOH, THF, H2O Step 1: methyl 6-fluoro-2-methyl-3-nitrobenzoate: To a solution of 6-fluoro-2-methyl-3- nitrobenzoic acid (2.00 g, 10.04 mmol) in DMF (20 mL) was added K2CO3(2.78 g, 20.09 mmol) and MeI (2.14 g, 15.07 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was completed, solution was diluted with DCM (100 mL) and washed with brine (100 mL x 3), dried over sodium sulfate, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1 to 1 / 3) to provide methyl 6-fluoro-2- methyl-3-nitrobenzoate (2.00 g, 93.4%) as a white solid. Step 2: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate: A mixture of methyl 6-fluoro-2-methyl-3-nitrobenzoate (1.70 g, 7.98 mmol) and 6-fluoro-2- methylpyridin-3-ol (1.22 g, 9.57 mmol) in MeCN (30 mL) was added Cs2CO3(3.31 g, 23.93 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. After the reaction was completed, the solution was diluting with DCM (150 mL) and washed with brine (150 mL), dried over sodium sulfate, then concentrated and purified by flash column chromatography on silica gel (Pe / EtOAc = 5 / 1 to 3 / 1) to provide methyl 6-((6-fluoro-2- methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate (1.80 g, 70.5%) as a white solid. LCMS (ESI) calcd. for C15H14FN2O5[M + H]+m / z 321.09, found 321.05. Step 3: methyl 3-amino-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methylbenzoate: A solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate (1.70 g, 5.31 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (1.99 g, 37.16 mmol), Fe (1.48 g, 26.54 mmol). The mixture was heated to 60 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 3-amino-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-2-methylbenzoate (1.50 g, 97.3%) as a red oil. LCMS (ESI) calcd. for C15H16FN2O3[M + H]+m / z 291.12, found 291.05. Step 4: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate: To a solution of TsOH.H2O (2.95 g, 15.50 mmol) and methyl 3-amino-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-2-methylbenzoate (1.50 g, 5.17 mmol) in MeCN (30 mL) was added a solution of NaNO2(713 mg, 10.33 mmol) and KI (2.14 g, 12.92 mmol) in H2O (5 mL) at 0 °C. The mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the mixture was quenched with water (100 mL), adjusted to pH = 8-9 with saturated aqueous NaHCO3. The solution was extracted with EtOAc (200 mL x 3). The combined organic layers 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 1 / 1) to provide methyl 6-((6-fluoro-2- methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate (1.50 g, 72.4%) as yellow solid. LCMS (ESI) calcd. for C15H14FINO3[M + H]+m / z 402.00, found 401.90. Step 5: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H- pyrazol-4-yl)benzoate: A mixture of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2- methylbenzoate (400 mg, 1.00 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (188 mg, 1.50 mmol) in 1,4-dioxane / H2O (4 / 1, 10 mL) was added potassium carbonate (413 mg, 2.99 mmol) and Pd(dppf)Cl2(146 mg, 0.20 mmol). The mixture was heated at 100 °C for 6 hours 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 combine 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 methyl 6-((6-fluoro-2-methylpyridin-3- yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoate (250 mg, 70.6%) as a yellow oil. LCMS (ESI) calcd. for C19H19FN3O3[M + H]+m / z 356.14, found 356.10. Step 6: 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)benzoic acid: To a solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1- methyl-1H-pyrazol-4-yl)benzoate (250 mg, 0.70 mmol) in MeOH / THF / H2O (1 / 1 / 1, 9 mL) was added LiOH (168 mg, 7.04 mmol) at room temperature. The reaction mixture was heated at 50 °C for 12 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H- pyrazol-4-yl)benzoic acid (90 mg, 37.5%) as a white solid. LCMS (ESI) calcd. for C18H17FN3O3[M + H]+m / z 342.13, found 342.05. Intermediate 4 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid

[0016] Reagents & conditions: a) methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, DMF, 120 °C; b) LiOH, THF / MeO / H2O, 60 °C Step 1: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate: To a solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- iodo-2-methylbenzoate (500 mg, 1.25 mmol) and CuI (475 mg, 2.49 mmol) in DMF (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.20 g, 6.23 mmol) dropwise at room temperature under an atmosphere of N2. The mixture was heated at 120 °C for 6 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 = 10 / 1 to 1 / 1) to give methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- methyl-3-(trifluoromethyl)benzoate (350 mg, 81.6%). LCMS (ESI) calcd. for C16H14F4NO3[M + H]+m / z 344.09, found 344.05. Step 2: 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid: To a solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate (350 mg, 1.02 mmol) in MeOH / THF / H2O (1 / 1 / 1, 9 mL) was added LiOH (244 mg, 10.20 mmol) at room temperature. The reaction mixture was heated at 60 °C for 12 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoic acid (75 mg, 22.3%) as a white solid. LCMS (ESI) calcd. for C15H12F4NO3[M + H]+m / z 330.08, found 330.05. Intermediate 5 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid Reagents & conditions: a) K2CO3, MeI, DMF; b) 6-fluoro-2-methylpyridin-3-ol, (1S,2S)-N1,N2- dimethylcyclohexane-1,2-diamine, K2CO3, Cu, pyridine, CuI, 1,4-dioxane, 100 °C; c) LiOH, THF / H2O Step 1: methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate: A mixture of 6-bromo-2- fluoro-3-(trifluoromethyl)benzoic acid (1 g, 3.48 mmol), K2CO3(1.44 g, 10.44 mmol), MeI (988 mg, 6.96 mmol) in DMF (10 mL) was stirred at 25 °C for 16 hours. The resulting solution was diluted with water (80 mL) and extracted with EtOAc (50 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 = 3 / 1) to give methyl 6-bromo-2-fluoro- 3-(trifluoromethyl)benzoate (950 mg, 90.9%) as a yellow solid.1H NMR (400 MHz, CD3OD) δ 8.05-7.72 (m, 2 H), 3.97 (s, 3 H). Step 2: methyl 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzoate: A solution of methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (300 mg, 0.99 mmol), 6-fluoro-2-methylpyridin-3-ol (253 mg, 1.99 mmol), (1S,2S)-N1,N2- dimethylcyclohexane-1,2-diamine (28 mg, 0.20 mmol), K2CO3(410 mg, 2.97 mmol), pyridine (235 mg, 2.97 mmol), Cu (13 mg, 0.20 mmol) and CuI (38 mg, 0.20 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 16 hours under N2. LCMS showed the rection was completed. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give methyl 2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoate (250 mg, 72.5%) as a yellow oil. LCMS (ESI) calcd. for C15H11F5NO3[M + H]+m / z 348.07, found 348.00. Step 3: 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid: To a solution of methyl 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzoate (250 mg, 0.72 mmol) in THF / H2O (1 / 1, 10 mL) was added LiOH (173 mg, 7.2 mmol) at room temperature. The mixture was stirred at room temperature 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 (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated under reduced pressure to give 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid (180 mg, 74.8%) as a yellow solid. LCMS (ESI) calcd. for C14H9F5NO3[M + H]+m / z 334.05, found 334.00. Intermediate 6 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid Reagents & conditions: a) Cs2CO3, MeCN, 80 °C; b) LiOH, THF / H2O Step1. methyl 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoate: A solution of methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (220 mg, 0.86 mmol), 4- hydroxy-3-methoxybenzonitrile (192 mg, 1.29 mmol) and Cs2CO3(838 mg, 2.57 mmol) in ACN (5 mL) was heated to 80 °C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with water (20 mL x 3). The combined organic layers 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 provide methyl 5-chloro-2-(4-cyano-2- methoxyphenoxy)-4-(trifluoromethyl)benzoate (120 mg, 36.2% yield) as yellow solid. LCMS (ESI) calcd. for C17H12ClF3NO4[M + H]+m / z 386.14, found 386.0. Step2. 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid: A mixture of methyl 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoate (120 mg, 0.31 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH (45 mg, 1.87 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=3-4 with aqueous HCl (1 M). Then the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid (70 mg, 60.5 % yield) as colorless oil which was used without further purification. Intermediate 7 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid Reagents & conditions: a) H2SO4, fuming HNO3; b) K2CO3, MeI, DMF; c) Fe, NH4Cl, MeOH / H2O; d) NBS, DMF; e) K2CO3, Pd(dppf)Cl2, 1,4-dioxane / H2O; f) I2, t-BuONO, THF, 80˚C; g) CuI, DMF, 100˚C; h) Cs2CO3, MeCN, 80˚C; i) KOH, t-BuOH, THF / H2O, 80˚C Step 1. 6-fluoro-2-methyl-3-nitrobenzoic acid: A solution of 2-fluoro-6-methylbenzoic acid (3 g, 19.5 mmol) in H2SO4(2 mL) was added H2SO4 / fuming HNO3(6 / 1, 7 mL) at 0 °C and stirred for 5 hours at room temperature. Then the mixture was added to ice-cold water. The precipitate was collected by filtration and dried under vacuum to obtain 6-fluoro-2-methyl-3- nitrobenzoic acid (2.5 g, 64.4%) as a yellow solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 8.12 (dd, J = 9.1, 5.2 Hz, 1 H), 7.46 (t, J = 8.8 Hz, 1 H), 2.45 (s, 3 H). Step 2. methyl 6-fluoro-2-methyl-3-nitrobenzoate: A solution of 6-fluoro-2-methyl-3- nitrobenzoic acid (2.5 g, 12.6 mmol) and CH3I (3.57 g, 25.1 mmol) in DMF (20 mL) was added K2CO3(5.22 g, 37.8 mmol) and stirred at room temperature for 18 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 methyl 6-fluoro-2-methyl-3- nitrobenzoate (1.5 g, 55.9%) as a yellow solid. Step 3. methyl 3-amino-6-fluoro-2-methylbenzoate: A solution of methyl 6-fluoro-2- methyl-3-nitrobenzoate (2 g, 9.39 mmol) in MeOH / H2O (3:1, 8 mL) was added Fe powder (3.68 g, 65.7 mmol) and NH4Cl (3.52 g, 65.7 mmol) at room temperature. The mixture was stirred 65 °C for 5 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 / 3) to give methyl 3-amino-6-fluoro-2-methylbenzoate (1.5 g, 87.2%) as a yellow solid. LCMS (ESI) calcd. for C9H11FNO2[M + H]+m / z 184.08, found 183.90. Step 4. methyl 3-amino-4-bromo-6-fluoro-2-methylbenzoate: A solution of NBS (1.75 g, 9.8 mmol) in DMF (10 mL) was added methyl 3-amino-6-fluoro-2-methylbenzoate (1.5 g, 8.2 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was concentrated. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 15 / 1 to 10 / 1) to give methyl 3-amino-4-bromo-6-fluoro-2-methylbenzoate (900 mg, 37.8%) as yellow oil. LCMS (ESI) calcd. for C9H10BrFNO2[M + H]+m / z 261.99, found 216.95. Step 5. methyl 3-amino-4-cyclopropyl-6-fluoro-2-methylbenzoate: A solution of cyclopropylboronic acid (590.0 mg, 6.87 mmol), Pd(dppf)Cl2(251.3 mg, 0.34 mmol) and K2CO3(1.42 g, 10.3 mmol) in 1,4-dioxane / H2O (4:1, 10 mL) was added methyl 3-amino-4-bromo-6- fluoro-2-methylbenzoate (900 mg, 3.43 mmol) at room temperature. The reaction mixture was heated at 100 °C for 16 hours under N2. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 = 10 / 1 to 5 / 1) to give methyl 3-amino-4-cyclopropyl-6-fluoro-2-methylbenzoate (700 mg, 73.1%) as yellow oil. LCMS (ESI) calcd. for C12H15FNO2[M + H]+m / z 224.11, found 223.90. Step 6. methyl 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoate: A solution of methyl 3- amino-4-cyclopropyl-6-fluoro-2-methylbenzoate 6 (700 mg, 3.14 mmol) and I2 (1.19 g, 4.70 mmol) in THF (10 ml) was added t-BuONO (485.0 mg, 4.70 mmol) at room temperature. The reaction mixture was heated to 80 °C and refluxed for 2 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 / EtOAc = 15 / 1 to 10 / 1) to give methyl 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoate (650 mg, 49.6%) as a black solid. LCMS (ESI) calcd. for C12H13FIO2[M + H]+m / z 334.99, found 334.60. Step 7. methyl 4-cyclopropyl-6-fluoro-2-methyl-3-(trifluoromethyl)benzoate: A solution of methyl 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoate (650 mg, 1.95 mmol) and CuI (741.0 mg, 3.89 mmol) in DMF (10 ml) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.87 g, 9.73 mmol) at room temperature. The reaction mixture was heated at 100 °C for 5 hours under N2. 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 / EtOAc = 10 / 1 to 5 / 1) to give methyl 4-cyclopropyl-6-fluoro-2- methyl-3-(trifluoromethyl)benzoate (500 mg, 83.7%) as yellow oil. LCMS (ESI) calcd. for C13H13F4O2[M + H]+m / z 277.08, found 277.10. Step 8. methyl 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate: A solution of methyl 4-cyclopropyl-6-fluoro-2-methyl-3- (trifluoromethyl)benzoate (500 mg, 1.81 mmol) and 6-fluoro-2-methylpyridin-3-ol (345.1 mg, 2.72 mmol) in MeCN (5 mL) was added Cs2CO3(1.75 g, 5.43 mmol) at room temperature. The reaction mixture was heated at 80 °C for 5 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (20 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 = 10 / 1 to 5 / 1) to give methyl 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate (200 mg, 25.9%) as a white solid. LCMS (ESI) calcd. for C19H18F4NO3[M + H]+m / z 384.12, found 384.10. Step 9. 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoic acid: A solution of methyl 4-cyclopropyl-6-((6-fluoro-2-methylpyridin- 3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoate (200 mg, 0.81 mmol) in t-BuOH / THF / H2O = 1 / 1 / 1 (5 mL) was added KOH (1.46 g, 26.09 mmol) at room temperature. The reaction mixture was heated to 80 °C and stirred for 8 hours After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum to obtain 4-cyclopropyl-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid (100 mg, 46.7%) as a yellow solid. LCMS (ESI) calcd. for C18H16F4NO3[M + H]+m / z 370.11, found 370.10. Intermediate 8

[0017] Reagents & conditions: a) K2CO3, MeI, DMF; b)H2SO4, fuming HNO3; c) Pd / C, H2, THF; d) NBS, MeCN; e) Trimethylboroxine, K2CO3, Pd(dppf)Cl2, 1,4-dioxane / H2O; f) CuCl2, t- BuONO, MeCN, 60˚C; g) Cs2CO3, MeCN, 80˚C; h) KOH, t-BuOH, THF / H2O, 80˚C Step 1. methyl 2-fluoro-4-(trifluoromethyl)benzoate: A solution of 2-fluoro-4- (trifluoromethyl)benzoic acid (8.5 g, 40.84 mmol) in DMF (100 mL) was added K2CO3(16.91 g, 122.53 mmol) and CH3I (8.6 g, 60.59 mmol). The mixture was stirred at room temperature for 16 hours. The filtrate was diluted with ice water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers 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 provide methyl 2-fluoro-4-(trifluoromethyl)benzoate (8 g, 85% yield) as white oil. LCMS (ESI) calcd. for C9H7F4O2[M + H]+m / z 223.04, found 223.04. Step 2. methyl 2-fluoro-5-nitro-4-(trifluoromethyl)benzoate: A stirred solution of H2SO4(80 mL) and fuming HNO3(6 mL) was added methyl 2-fluoro-4-(trifluoromethyl)benzoate 1 (8.0 g, 36.01 mmol) at 0 °C. The mixture was heated to 50 °C and stirred for 5 hours. The mixture was poured into ice water (500 mL) and filtered. The filter cake was dried to provide methyl 2- fluoro-5-nitro-4-(trifluoromethyl)benzoate (4 g, 40% yield) as a yellow solid.1H NMR (400 MHz, CDCl3, ppm) δ 8.58 (d, J = 6.1 Hz, 1 H), 7.65 (d, J = 9.7 Hz, 1 H), 4.02 (s, 3 H). Step 3. methyl 5-amino-2-fluoro-4-(trifluoromethyl)benzoate: A solution of methyl 2- fluoro-5-nitro-4-(trifluoromethyl)benzoate (4 g, 14.98 mmol) in THF (50 mL) was added Pd / C (600 mg) and stirred at room temperature for 16 hours under an atmosphere of H2. LCMS showed the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers 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 provide methyl 5- amino-2-fluoro-4-(trifluoromethyl)benzoate (2.9 g, 81.69% yield) as a yellow solid. LCMS (ESI) calcd. for C9H8F4NO2[M + H]+m / z 238.05, found 237.60. Step 4. methyl 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoate: A solution of methyl 5-amino-2-fluoro-4-(trifluoromethyl)benzoate (2.9 g, 12.23 mmol) in MeCN (40 mL) was added NBS (3.05 g, 17.13 mmol) and stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers 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 methyl 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (2.5 g, 64.94% yield) as light yellow oil. LCMS (ESI) calcd. for C9H7BrF4NO2[M + H]+m / z 315.96, found 315.90. Step 5. methyl 3-amino-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate: A solution of methyl 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (2.5 g, 7.94 mmol), Trimethylboroxine (4.98 g, 39.69 mmol), K2PO3(5.48 g, 39.69 mmol and Pd(dppf)Cl2(584 mg, 0.79 mmol) in dioxane (40 mL) and H2O (10 mL) was heated to 100 °C and refluxed for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers 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 methyl 3-amino-6-fluoro-2-methyl-4- (trifluoromethyl)benzoate (1.5 g, 75.38% yield) as light yellow oil. LCMS (ESI) calcd. for C10H10F4NO2[M + H]+m / z 252.07, found 252.00. Step 6. methyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate: To a flame-dried round-bottomed flask equipped with a magnetic stir bar and addition funnel under N2was added t-BuONO (1.22 g, 11.83 mmol), CuCl2(1.59 g, 11.83 mmol) and MeCN (20 mL). The solution was stirred at room temperature for 0.5 hour. A solution of methyl 3-amino-6-fluoro-2-methyl-4- (trifluoromethyl)benzoate (1.5 g, 5.74 mmol) in MeCN (10 mL) was added dropwise at 0 °C. The reaction mixture was heated to 60 °C and stirred for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers 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 methyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate (1.4 g, 87.50% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6, ppm) δ 7.88 (d, J = 9.3 Hz, 1 H), 3.96 (s, 3 H), 2.40 (s, 3 H). Step 7. methyl 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4- (trifluoromethyl)benzoate: A solution of methyl 3-chloro-6-fluoro-2-methyl-4- (trifluoromethyl)benzoate (1.4 g, 5.17 mmol) and 6-fluoro-2-methylpyridin-3-ol (0.99 g, 7.79 mmol) in MeCN (30 mL) was added Cs2CO3(6.78 g, 20.86 mmol) at room temperature. The mixture was heated to 80 °C and refluxed for 16 hours. After the reaction was completed, the mixture concentrated under vacuum and the residue was directly purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide methyl 3-chloro-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoate (1 g, 51.28% yield) as colorless oil. LCMS (ESI) calcd. for C16H13ClF4NO3[M + H]+m / z 378.05, found 377.95. Step 8. 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4- (trifluoromethyl)benzoic acid: A solution of methyl 3-chloro-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-2-methyl-4-(trifluoromethyl)benzoate (800 mg, 2.12 mmol) in THF / t-BuOH / H2O (1 / 1 / 1, 30 mL) was added KOH (1.54 g, 27.46 mmol) at 0 °C. The reaction mixture was heated to 70 °C and refluxed for 16 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)- 2-methyl-4-(trifluoromethyl)benzoic acid (700 mg, 90.91% yield) as a white solid. LCMS (ESI) calcd. for C15H11ClF4NO3[M + H]+m / z 364.04, found 363.60. Intermediate 9 Reagents & conditions: a) SOCl2, NH4OH, 80˚C; b) Cs2CO3, XantphosPd-G2, 1,4-dioxane, 100˚C Step 1.5-chloro-2-fluoro-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-fluoro- 4-(trifluoromethyl)benzoic acid (200 mg, 0.82 mmol) in SOCl2(5 mL) was heated to 80 °C and stirred for 0.5 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (5 mL) was added to a stirred solution of THF (5mL) in 28% NH3·H2O (5 mL) and at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then the mixture was quenched with water (20 mL) and 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 flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (180 mg, 90.36% yield) as yellow solid. LCMS (ESI) calcd. for C8H3ClF4NO [M - H]- m / z 239.98, found 240.1. Step 2. tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2- yl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of 5-chloro-2-fluoro-4- (trifluoromethyl)benzamide (500 mg, 2.07 mmol), tert-butyl (R)-((4-bromopyridin-2- yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (696 mg, 2.07 mmol), Cs2CO3(1.75 g, 5.38 mmol) and Xantphos-Pd-G2 (368 mg, 0.41 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide tert-butyl (R)-((4-(5-chloro-2-fluoro-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (400 mg, 38.89% yield) as a yellow solid. LCMS (ESI) calcd. for C19H17ClF4N3O4S [M - H]- m / z 494.05, found 494.0. Intermediate 10 Reagents & conditions: a) K2CO3, MeI, DMF, 70˚C; b) CD3MgI, Pd(dppf)Cl2, ZnCl2, DMF, 100˚C; c) BBr3, DCM Step 1.2-bromo-6-fluoro-3-methoxypyridine: A mixture of 2-bromo-6-fluoropyridin-3-ol 1 (1.5 g, 7.8 mmol), K2CO3(3.23 g, 23.3 mmol), MeI (2.22 g, 15.6 mmol) in DMF (40 mL) was heated at 70 °C and stirred for 3 hours. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 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 = 10 / 1) to give 2-bromo-6-fluoro-3-methoxypyridine (1.5 g, 93.3% yield) as a white solid. LCMS (ESI) calcd. for C6H6BrFNO [M + H]+m / z 205.96, found 206.0. Step 2. 6-fluoro-3-methoxy-2-(methyl-d3)pyridine: To a 250 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 2-bromo- 6-fluoro-3-methoxypyridine (500 mg, 2.43 mmol), ZnCl2(4.96 g, 36.4 mmol) and Pd(dppf)Cl2(178 mg, 0.24 mmol) in DMF (10 mL). This was followed by the addition of CD3MgI (1.0 M in diethyl ether, 36.4 mL) dropwise with stirring at room temperature. The solution was heated to 100 °C and stirred for 2 hours. The resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give 6-fluoro-3-methoxy-2-(methyl-d3)pyridine (250 mg, 70.9% yield) as a white solid. LCMS (ESI) calcd. for C7H6D3FNO [M + H]+m / z 145.09, found 145.0. Step 3. 6-fluoro-2-(methyl-d3)pyridin-3-ol: To a solution of 6-fluoro-3-methoxy-2- (methyl-d3)pyridine (250 mg, 1.73 mmol) in DCM (5 mL) was added BBr3 (1.0 M in DCM, 1 mL) at room temperature. The reaction mixture was heated to 40 °C and stirred for 6 hours. LCMS showed the rection was completed. The mixture was concentrated under vacuum and quenched with CH3OH (5mL). The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 6-fluoro-2-(methyl-d3)pyridin-3-ol 7 (60 mg, 26.7% yield) as a yellow solid. LCMS (ESI) calcd. for C6H4D3FNO [M + H]+m / z 131.07, found 131.0. Example 1A (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4- (trifluoromethyl)benzamide Reagents & conditions: a) (i) (COCl)2, DMF, DCM, (ii) DIEA, THF, tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (120 mg, 0.34 mmol) in DCM (3 mL) oxalyl chloride (78 mg , 0.62 mmol) and DMF (20 μL) was added. The mixture was stirred at room temperature for 0.5 hours. Then the mixture was concentrated under vacuum. The residue was dissolved in THF (5 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)λ6-sulfaneylidene)carbamate (102 mg, 0.38 mmol) and DIEA (178 mg, 1.38 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl (R)- ((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl) (methyl)(oxo)- λ6-sulfaneylidene)carbamate (110 mg, 53.4% ) as a yellow oil. LCMS (ESI) calcd. for C26H25ClF4N3O5S [M + H]+m / z 602.12, found 602.00. Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((3-(5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (110 mg, 0.18 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 (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN / H2O containing 0.1% NH3) to obtain (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (58.4 mg, 63.7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1 H), 8.29 (t, J = 1.8 Hz, 1 H), 8.10 (s, 1 H), 7.82 (d, J = 8.9 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.37 (s, 1 H), 7.04 (dd, J = 8.7, 3.4 Hz, 1 H), 4.22 (s, 1 H), 3.04 (s, 3 H), 2.34 (s, 3 H). LCMS (ESI) calcd. for C21H17ClF4N3O3S [M + H]+m / z 502.06, found 502.00. Example 2A (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4- (trifluoromethyl)benzamide

[0018] Reagents & conditions: a) (i) SOCl2, 80˚C; (ii) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate, DIEA, THF; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 0.95 mmol) in SOCl2(5 mL) was stirred at 80 °C for 0.5 hour. Then the solution was concentrated under vacuum to provide the chloride intermediate. The chloride intermediate was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (388 mg, 1.44 mmol) and DIEA (464.4 mg, 3.6 mmol) in THF (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 0.5 hour. Then the mixture was quenched with water (40 mL) and extracted with DCM (30 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 tert-butyl (R)-((3-(2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (400 mg, 74.3% ) as yellow solid. LCMS (ESI) calcd. for C26H26F4N3O5S [M + H]+m / z 568.16, found 568.10. Step 2: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((3-(2- ((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate (400 mg, 0.70 mmol) in DCM (5 mL) TFA (0.5 mL) was added 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 (30 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 prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 90% MeCN / H2O containing 0.1% NH3) to obtain (R)-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4- (trifluoromethyl)benzamide (125.4 mg, 42.5%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1 H), 8.34 (s, 1 H), 7.92-7.80 (m, 2 H), 7.68- 7.56 (m, 4 H), 7.24 (s, 1 H), 7.06 (dd, J = 8.7, 3.4 Hz, 1 H), 4.21 (s, 1 H), 3.04 (s, 3 H), 2.33 (s, 3 H). LCMS (ESI) calcd. for C21H18F4N3O3S [M + H]+m / z 468.10, found 468.00. Example 3A (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide Reagents & conditions: a) (i) (COCl)2, DMF, DCM; (ii) Et3N, THF; b) TFA, DCM Step 1: tert-butyl (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid (75 mg, 0.23 mmol) in DCM (3 mL), oxalyl chloride (289 mg , 2.28 mmol) and DMF (20 μL) was added. The mixture was stirred at room temperature for 0.5 hour. Then the mixture was concentrated under vacuum. The residue was dissolved in THF (5 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (74 mg, 0.27 mmol) and Et3N (115 mg, 1.14 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was 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-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (55 mg, 41.5%) as a yellow oil. LCMS (ESI) calcd. for C27H28F4N3O5S [M + H]+m / z 582.17, found 582.10. Step 2: (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((3-(6- ((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl) (oxo)- λ6-sulfaneylidene)carbamate (55 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. The residue was adjusted to pH of 8-9 with saturated aqueous NaHCO3. The resulting solution was extracted with DCM (10 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 C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% NH4OH) to obtain (R)-6- ((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide (15.6 mg, 34.3% ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.41 (s, 1 H), 7.86 (d, J = 7.7 Hz, 1 H), 7.79-7.65 (m, 3 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.12 (dd, J = 8.7, 3.4 Hz, 1 H), 6.74 (d, J = 8.8 Hz, 1 H), 4.22 (s, 1 H), 3.06 (s, 3 H), 2.45 (s, 3 H), 2.28 (s, 3 H). LCMS (ESI) calcd. for C22H20F4N3O3S [M + H]+m / z 482.12, found 482.05. Example 4A (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide

[0019] Reagents & conditions: a) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6- sulfaneylidene)carbamate, Pyridine, POCl3; b) TFA, DCM Step 1: tert-butyl (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: A mixture of 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid (150 mg, 0.45 mmol), tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (146 mg, 0.54 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. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers 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 afford tert-butyl (R)- ((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 45.5%) as a yellow solid. LCMS (ESI) calcd. for C26H25F5N3O5S [M + H]+m / z 586.15, found 586.10. Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((3-(2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (120 mg, 0.20 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 (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 C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3) to provide (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (70.50 mg, 72.5%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1 H), 8.34 (d, J = 1.7 Hz, 1 H), 7.91- 7.77 (m, 3 H), 7.73-7.56 (m, 2 H), 7.15 (dd, J = 8.7, 3.4 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 4.25 (s, 1 H), 3.06 (s, 3 H), 2.30 (s, 3 H). LCMS (ESI) calcd. for C21H17F5N3O3S [M + H]+m / z 486.09, found 486.05. Example 5A and 6A (S)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)- 4-(trifluoromethyl)benzamide and (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (i) (COCl)2, DMF, DCM; (ii) NH3 / H2O, THF; b) Cs2CO3, Xantphos- Pd-G2, 4-bromo-2-(methylsulfinyl)pyridine, 1,4-dioxane, 100 °C; c) PhI(OAc)2, NH2CO2NH4, MeOH, 70 °C; d) chiral SFC separation Step 1: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (150 mg, 0.43 mmol) in DCM (5 mL) was added oxalyl chloride (0.3 mL) and DMF (2 drops) at room temperature. After addition, the reaction mixture 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 to a stirred solution of NH3-H2O (5 mL) dropwise. 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 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 5-chloro-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (120 mg, 80.0%) as a white solid. LCMS (ESI) calcd. for C14H10ClF4N2O2[M + H]+m / z 349.04, found 349.00. Step 2: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4- yl)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-(trifluoromethyl)benzamide (120 mg, 0.34 mmol) in 1,4-dioxane (8 mL) was added 4- bromo-2-(methylsulfinyl)pyridine (76 mg, 0.34 mmol), Cs2CO3(292 mg, 0.89 mmol) and Xantphos-Pd-G2 (61 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. After the reaction was completed, the filtrate 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 = 1 / 1) to give 5-chloro-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide (105 mg, 62.1%) as a white solid. LCMS (ESI) calcd. for C20H15ClF4N3O3S [M + H]+m / z 488.05, found 488.05. Step 3: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: To a solution of 5-chloro-2- ((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide (105 mg, 0.22 mmol) in MeOH (5 mL) was added PhI(OAc)2(173 mg, 0.54 mmol) and ammonium carbamate (50 mg, 0.65 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 (30 mL), and extracted with DCM (15 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 the crude, then the residue was repurified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% formic acid) to give 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (40.8 mg, 37.8%) as a white solid. LCMS (ESI) calcd. for C20H16ClF4N4O3S [M + H]+m / z 503.06, found 503.00. Step 4: (S)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide and (R)-5-chloro-2-((6-fluoro- 2-methylpyridin-3-yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide : 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide was purified by Chiral-Prep- HPLC (Chiralpak-IC, 4.6*250 mm, eluting with 35% CO2-MeOH containing 0.1% NH3). The first eluting isomer was lyophilized to afford (S)-5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (12.7 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1 H), 8.61 (d, J = 5.6 Hz, 1 H), 8.36 (s, 1 H), 8.15 (s, 1 H), 7.77-7.76 (m, 1 H), 7.71-7.67 (m, 1 H), 7.36 (s, 1 H), 7.07-7.04 (m, 1 H), 4.38 (s, 1 H), 3.14 (s, 3 H), 2.33 (s, 3 H). LCMS (ESI) calcd. for C20H16ClF4N4O3S [M + H]+m / z 503.06, found 503.05 and the second eluting (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (14.5 mg ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1 H), 8.61 (d, J = 5.6 Hz, 1 H), 8.36 (s, 1 H), 8.15 (s, 1 H), 7.77-7.76 (m, 1 H), 7.71-7.67 (m, 1 H), 7.36 (s, 1 H), 7.07-7.04 (m, 1 H), 4.38 (s, 1 H), 3.14 (s, 3 H), 2.33 (s, 3 H). LCMS (ESI) calcd. for C20H16ClF4N4O3S [M + H]+m / z 503.06, found 503.05. Example 7A (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N- (3-(S-methylsulfonimidoyl)phenyl)benzamide Reagents & conditions: a) (i) (COCl)2, DMF; DCM; (ii) tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate, Et3N, THF; b) TFA, DCM Step 1: tert-butyl (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl- 1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate: To a solution of 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid (90 mg, 0.26 mmol) in DCM (3 mL) was added oxalyl chloride (167 mg , 1.32 mmol) and DMF (20 μL). The mixture was stirred at room temperature for 0.5 hour. Then the mixture was concentrated under vacuum. The residue was dissolved in THF (5 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (86 mg, 0.32 mmol) and TEA (133 mg, 1.32 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was 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-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (75 mg, 47.9%) as a yellow oil. LCMS (ESI) calcd. for C30H33FN5O5S [M + H]+m / z 594.22, found 594.15. Step 2: (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)-N-(3-(S-methylsulfonimidoyl)phenyl)benzamide : A solution of tert-butyl (R)-((3-(6-((6- fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 0.13 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 combine organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% NH4OH) to obtain (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1- methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)benzamide (40.6 mg, 65.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1 H), 8.42 (t, J = 1.8 Hz, 1 H), 7.93 (s, 1 H), 7.85-7.80 (m, 1 H), 7.66-7.52 (m, 4 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.05 (dd, J = 8.7, 3.5 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 4.20 (s, 1 H), 3.89 (s, 3 H), 3.05 (s, 3 H), 2.35 (s, 3 H), 2.31 (s, 3 H). LCMS (ESI) calcd. for C25H25FN5O3S [M + H]+m / z 494.17, found 494.05. Example 8A Reagents & conditions: a) POCl3, pyridine; b) TFA, DCM Step 1. tert-butyl (R)-((5-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A solution of 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid (60 mg, 0.16 mmol) and tert-butyl (R)-((5-amino-2-fluorophenyl)(methyl)(oxo)-16- sulfaneylidene)carbamate (70 mg, 0.24 mmol) in Pyridine (3 mL) was added POCl3(0.09 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. 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 sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1:1 to 1 / 2) to provide to tert-butyl (R)-((5-(5-chloro-2-(4-cyano-2- methoxyphenoxy)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-16- sulfaneylidene)carbamate (60 mg, 57.8% yield) as yellow solid. LCMS (ESI) calcd. for C28H25ClF4N3O6S [M + H]+m / z 642.11, found 642.1. Step 2. (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(4-fluoro-3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((5-(5- chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)-2- fluorophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (60 mg, 0.09 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. 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 (15 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 C18 column, 150*21.2 mm, eluting with 20% to 65% MeCN / H2O containing 0.05% NH3.H2O) to provide (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(4-fluoro-3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (15 mg, 29.7% yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.91 (s, 1 H), 8.19 (dd, J = 6.5, 2.7 Hz, 1 H), 8.08 (s, 1 H), 7.90-7.82 (m, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.47-7.38 (m, 3 H), 7.17 (d, J = 8.3 Hz, 1 H), 4.68 (s, 1 H), 3.79 (s, 3 H), 3.18 (s, 3 H). LCMS (ESI) calcd. for C23H17ClF4N3O4S [M + H]+m / z 542.06, found 542.1. Example 9A Reagents & conditions: a) (i) SOCl2, 80˚C; (ii) DIEA, THF; b) TFA, DCM Step 1. tert-butyl (R)-((3-(4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A solution of 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoic acid (100 mg, 0.27 mmol in SOCl2(2 ml) was heated for 1 hour at 80 °C. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate in THF (5 mL) was added to tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (110.2 mg, 0.41 mmol) and DIEA (175.0 mg, 1.35 mmol) in THF (1 ml) at 0 °C and stirred for 2 hours at room temperature. After the reaction was completed, the mixture was 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-(4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (130 mg, 69.4%) as a yellow solid. LCMS (ESI) calcd. for C30H32F4N3O5S [M + H]+m / z 622.20, found 622.10. Step 2. (R)-4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((3-(4- cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (130 mg, 0.21 mmol) in DCM (2 mL) was added TFA (0.2 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 (10 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 C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3.H2O) to obtain (R)-4-cyclopropyl-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide (20 mg, 18.3% yield) as a white solid.1H NMR (400 MHz, DMSO- d6, ppm) δ 11.00 (s, 1 H), 8.39 (t, J = 1.8 Hz, 1 H), 7.86-7.78 (m, 1 H), 7.72-7.63 (m, 2 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.08 (dd, J = 8.7, 3.4 Hz, 1 H), 6.44 (s, 1 H), 4.21 (s, 1 H), 3.05 (d, J = 0.6 Hz, 3 H), 2.48-2.41 (m, 3 H), 2.28 (s, 3 H), 2.23-2.13 (m, 1 H), 0.98-0.87 (m, 2 H), 0.55 (m, 2 H). LCMS (ESI) calcd. for C25H24F4N3O3S [M + H]+m / z 522.15, found 522.20. Example 10A (R)-3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (i) SOCl2, 80˚C; (ii) DIEA, THF; b) TFA, DCM Step 1. tert-butyl (R)-((3-(3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A solution of 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoic acid (150 mg, 0.41 mmol) in SOCl2(3 mL) was heated to 80 °C and stirred for 0.5 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16- sulfaneylidene)carbamate (112 mg, 0.41 mmol), DIEA (159 mg, 1.23 mmol) in THF (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then the mixture was quenched with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers 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 / 2) to provide tert-butyl (R)-((3-(3- chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (180 mg, 70.82% yield) as light yellow oil. LCMS (ESI) calcd. for C27H26ClF4N3O5SNa [M + Na]+m / z 638.11, found 637.95. Step 2. (R)-3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((3-(3- chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (180 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 1 hour. 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 (15 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 C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3.H2O) to provide (R)-3-chloro-6-((6-fluoro-2-methylpyridin- 3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (74.70 mg, 99.8% purity, 49.54% yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.08 (s, 1 H), 8.31 (s, 1 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.69 (dd, J = 14.8, 7.9 Hz, 2 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.16 (s, 1 H), 7.06 (dd, J = 8.7, 3.4 Hz, 1 H), 4.20 (s, 1 H), 3.05 (s, 3 H), 2.45 (s, 3 H), 2.30 (s, 3 H). LCMS (ESI) calcd. for C22H19ClF4N3O3S [M + H]+m / z 516.08, found 516.00. Example 11A Reagents & conditions: a) Cs2CO3, MeCN, 80˚C; b) TFA, DCM Step 1. tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2- yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (200 mg, 0.40 mmol), 4-bromo-2-methoxyphenol (123 mg, 0.60 mmol), and Cs2CO3(393 mg, 1.21 mmol) in MeCN (5 mL) was heated to 80 °C and stirred for 2 hours. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 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 provide tert-butyl (R)-((4-(2-(4- bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)- l6-sulfaneylidene)carbamate (220 mg, 80.4% yield) as a yellow solid. LCMS (ESI) calcd. for C26H25BrClF3N3O6S [M + H]+m / z 678.03, found 680.1. Step 2. (R)-2-(4-bromo-2-methoxyphenoxy)-5-chloro-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)- ((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2- yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (70 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 1 hour. 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 (15 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 0.1% formic acid) to provide (R)-2-(4-bromo-2-methoxyphenoxy)-5-chloro-N-(2-(S-methylsulfonimidoyl)pyridin-4- yl)-4-(trifluoromethyl)benzamide (18 mg, 30.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.31 (s, 1 H), 8.62 (d, J = 5.5 Hz, 1 H), 8.39 (d, J = 1.6 Hz, 1 H), 8.08 (s, 1 H), 7.80 (dd, J = 5.4, 1.9 Hz, 1 H), 7.37 (d, J = 1.9 Hz, 1 H), 7.25-7.04 (m, 3 H), 4.37 (s, 1 H), 3.75 (s, 3 H), 3.14 (s, 3 H). LCMS (ESI) calcd. for C21H17BrClF3N4O4S [M + H]+m / z 577.98, found 579.9. Example 12A

[0020] Reagents & conditions: a) Zn(CN)2, Xbuxphos-Pd-G3, THF / H2O, 50˚C; b) TFA, DCM Step 1. tert-butyl (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (130 mg, 0.19 mmol), Zn(CN)2(34 mg, 0.29 mmol) and tBuXphos-Pd-G3(15 mg, 0.02 mmol) in THF / H2O = 4 / 1 (5 mL) was heated to 50 °C and stirred for 5 hours under a nitrogen atmosphere. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 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 provide tert-butyl (R)-((4-(5-chloro-2-(4- cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16- sulfaneylidene)carbamate (100 mg, 83.5% yield) as a yellow solid. LCMS (ESI) calcd. for C27H25ClF3N4O6S [M + H]+m / z 625.12, found 625.1. Step 2. (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)- ((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2- yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (100 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 1 hour. 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 (15 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 0.1% formic acid) to provide (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4- yl)-4-(trifluoromethyl)benzamide (18 mg, 21.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.34 (s, 1 H), 8.61 (d, J = 5.4 Hz, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 8.14 (s, 1 H), 7.75 (dd, J = 5.4, 2.0 Hz, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.52-7.38 (m, 2 H), 7.20 (d, J = 8.3 Hz, 1 H), 4.37 (s, 1 H), 3.78 (s, 3 H), 3.14 (s, 3 H). LCMS (ESI) calcd. for C22H17ClF3N4O4S [M + H]+m / z 525.06, found 525.0. Example 13A Reagents & conditions: a) Cs2CO3, MeCN, 80˚C; b) TFA, DCM Step 1. tert-butyl (R)-((4-(5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A solution of 6-fluoro-2-(methyl-d3)pyridin-3-ol (26.2 mg, 0.20 mmol), tert-butyl (R)-((4-(5-chloro-2- fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (100 mg, 0.20 mmol) and Cs2CO3(196.8 mg, 0.60 mmol) in MeCN (6 mL) was heated to 80 °C and stirred for 6 hours. The mixture was cooled to room temperature, filtered through celite. The filtrate was concentrated and purified by Flash chromatography (PE / EA=5:1) to afford tert-butyl (R)-((4-(5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (80 mg, 66.1% yield) as a white solid. LCMS (ESI) calcd. for C25H20D3ClF4N4O5SNa [M + Na]+m / z 628.12, found 628.0. Step 2. (R)-5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)- ((4-(5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (80 mg, 0.13 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 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 55% to 60% MeCN / H2O containing 0.05% NH3.H2O) to provide (R)-5-chloro-2-((6-fluoro-2-(methyl- d3)pyridin-3-yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (27.00 mg, 41.1% yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.38 (s, 1 H), 8.62 (d, J = 5.4 Hz, 1 H), 8.37 (d, J = 1.5 Hz, 1 H), 8.15 (s, 1 H), 7.81-7.65 (m, 2 H), 7.36 (s, 1 H), 7.06 (dd, J = 8.7, 3.4 Hz, 1 H), 4.39 (s, 1 H), 3.14 (s, 3 H). LCMS (ESI) calcd. for C20H13D3ClF4N4O3S [M + H]+m / z 506.08, found 506.0. Example 14 A

[0021] Reagents & conditions: a) HATU, DIEA, DMF; b) BH3•THF, THF; c) TFA, DCM Step 1. tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)-2- oxoethyl)carbamate: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (example 1) (120 mg, 0.24 mmol), (tert-butoxycarbonyl)glycine (83.8 mg, 0.48 mmol) and HATU (136.4 mg, 0.36 mmol) in DMF (5 mL) was added DIEA (92.7 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 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 provide tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)-2- oxoethyl)carbamate (100 mg, 63.5%yield) as a yellow solid. LCMS (ESI) calcd. for C28H28ClF4N4O6S [M + H]+m / z 659.14, found 659.10. Step 2. tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)ethyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)-2- oxoethyl)carbamate (700 mg, 1.06 mmol) in THF (10 mL) was added BH3-THF (0.7 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour 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 layers 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)-(2-(((3-(5-chloro- 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16- sulfaneylidene)amino)ethyl)carbamate (350 mg, 51.24% yield) as a white solid. LCMS (ESI) calcd. for C28H30ClF4N4O5S [M + H]+m / z 645.16, found 645.10. Step 3. (R)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-(2- (((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)ethyl)carbamate (350 mg, 0.54 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(20 mL) and extracted with DCM (20 mL x 3). The combined organic layers 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)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide formate (134.90 mg, 45.42% yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.06 (s, 1 H), 8.33 (s, 1 H), 8.25 (s, 1 H), 8.10 (s, 1 H), 7.83 (d, J = 3.8 Hz, 1 H), 7.67 (dd, J = 8.6, 6.7 Hz, 1 H), 7.64-7.60 (m, 2 H), 7.38 (s, 1 H), 7.04 (dd, J = 8.8, 3.3 Hz, 1 H), 3.17 (s, 3 H), 2.77 (d, J = 5.8 Hz, 4 H), 2.34 (s, 3 H). LCMS (ESI) calcd. for C23H22ClF4N4O3S [M + H]+m / z 545.11, found 545.00. The following compounds are prepared using the techniques of the intermediates and examples described above.

[0022]

[0023] Example 74A Compound profiling human NaV1.8 / β3 cell line – SyncroPatch384PE Assay Compounds were tested on recombinant human Nav1.8 / b3 stably transfected CHO cells using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2in Ham’s F-12 supplemented with 10% fetal bovine serum, 100 U / mL penicillin G sodium, 100 mg / mL streptomycin sulfate and selection antibiotics (0.01 mg / ml Blasticidin, 0.4 mg / ml Zeocin and 0.25 mg / ml Hygromycin). On the day of the recordings, cells in culture dishes were washed twice with Hank’s Balanced Salt Solution (HBSS) and treated with Accutase for approximately 20 minutes. Immediately before use in the SynchroPatch384PE using an 8-hole NPC-384 chip, the cells were washed in HBSS to remove the Accutase and re- suspended in extracellular solution. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl2, 5; EGTA, 1; HEPES, 10; pH adjusted to 7.2 with CsOH. Extracellular solution contained (mM): NaCl, 137; KCl, 4.0; CaCl2, 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents. Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic Acid. Compounds were diluted 1:3.33 in extracellular solution to create an 8-point concentration response curve. Each plate contained a historical positive control and up to ten compounds. 300 µM tetracaine and 0.3% DMSO + 0.03% pluronic acid were used as high and low controls respectively. Whole cell patch clamp recordings were conducted according to Nanion’s standard procedure for SyncroPatch384PE® Cells were held at a holding potential of 120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to -100 mV for 100 ms. An inactivation step at -35 mV for 10 sec was applied before stepping to -100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to -100 mV for 30 ms. Sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed in extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the SynchroPatch384 PE system into each well and the current was recorded for five minutes in extracellular solution, followed by application of tetracaine to achieve full block at the end of experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls. The table below shows the potency of compounds against human NaV1.8, where “A” represents an IC50less than or equal to 5 nM, “B” represents an IC50greater than 5 nM to less than or equal to 50 nM, “C” represents an IC50greater than 50 nM to less than or equal to 100 nM, “D” represents an IC50greater than 100 nM to less than or equal to 200 nM, “ E” represents an IC50 greater than 200 nM.

[0024] Example 75A Compound profiling human NaV1.8 / β1 cell line – Sophion QPatch II Assay Compounds were tested on recombinant human NaV1.8 / β1 stably transfected HEK293 (Eurofins, CYL3025, St. Charles, MO) cells using the QPatch II system (Sophion Bioscience A / S, Ballerup – Denmark), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2in DMEM / F-12 supplemented with 10% fetal bovine serum, 1x Non-Essential Amino Acids, and selection antibiotics (0.625 µg / mL Puromycin, 400 µg / mL Geneticin, and 100 µg / mL Hygromycin). One or two days prior to recording, cells were moved to a lower temperature 30°C / 5% CO2incubator to increase surface expression of the channels. On the day of the recordings, cells in culture dishes were washed twice with Ca2+-Mg2+free DPBS and treated with Detachin (Genlantis, San Diego) for 3 minutes and then resuspended in Serum Free Medium (EX- CELL® ACF CHO Medium for Cell Culture (Sigma-Aldrich) supplemented with 0.04 mg / mL soybean trypsin Inhibitor and 25 mM HEPES (all components supplied by Sigma-Aldrich, St. Louis, MO) and allowed to recover for a minimum of 20 minutes in the onboard QStirrer. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl2, 2; EGTA, 5; HEPES, 10; pH adjusted to 7.2 with CsOH. Extracellular solution contained (mM): NaCl, 137; KCl, 4; CaCl2, 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. 500 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents. Compounds were tested in an interleaved manner across two cohorts of wells to develop an aggregate 8-point concentration response curve. Final concentrations include 0.1% DMSO and 0.03% pluronic Acid. In general, the concentration range spans a range from 0.01 – 300 nM. Compounds were diluted 1:10 with extracellular solution within their respective cohort. DMSO (0.1% by volume) served as a vehicle control to ascertain assay performance. Whole cell patch clamp recordings were conducted according to Sophion standard procedure for QPatch II®. Cells were held at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied to elicit inward Na+currents. Inter-sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed twice in extracellular solution containing 0.1% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the QPatch II system into each well in an ascending manner within cohort and the current was recorded for five minutes for each concentration. Percent of current remaining was determined by taking the average of the last 5 sweeps within each concentration and normalizing to the latest pre-compound saline period. The potency (IC50) values of the compounds were only assessed against resting state block. Wells whose initial sodium current magnitude were below 2 nA or whole cell resistance fell below 100 MΩ were excluded from analysis. The table below shows the potency of compounds against human NaV1.8, where “A” represents an IC50less than or equal to 5 nM, “B” represents an IC50greater than 5 nM to less than or equal to 50 nM, “C” represents an IC50greater than 50 nM to less than or equal to 100 nM, “D” represents an IC50greater than 100 nM to less than or equal to 200 nM, “ E” represents an IC50greater than 200 nM. (B) Second Set of Compounds In one aspect, the invention provides a compound of Formula (I):

[0025] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein: A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo- C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, aloalkoxyl wherein the haloalkyoxy chain may be fully or partially halogenated, and arylalkoxyl; R1, R2, R3and R4are independently selected from hydrogen, -OH, halogen, C1-C6-alkyl, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8branched alkyl, C3-C8branched fluoroalkyl wherein the branched fluoroalkyl chain maybe fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, NR’R’’, 3-8, membered cycloalkyl, 3-8- membered cycloalkenyl 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, a saturated or unsaturated 5 or more membered ring or an aryl ring optionally containing 1 or more heteroatoms independently selected from O, S, and N, wherein each 5 or more membered ring is unsubstituted or substituted with one to five substituents selected from hydrogen, cyano, halo, or methyl; a fused ring formed by at least two of R1, R2, R3and R4wherein the fused ring is selected from a group consisting of: optionally saturated carbocyclyl or heterocyclyl containing 5-6 ring members, wherein the heterocyclyl include one or more heteroatoms; R5is H, or substituted or unsubstituted C1-C3alkyl; R6is -(CH2)nRa, -(CRbRc)nRa, -(CRbRc)n-(OCH2CH2)nRa, -(CRbRc)n-(NR’CH2CH2)nRa, , - (CRbRc)n-(NR’CH2CH2O)nRa, or -(CRbRc)n-(NHCH2CH2NH)nRa; wherein Rais H, C1-C6-alkyl, C2-C8branched alkyl, C3-C8cycloalkyl, aryl, heteroaryl, 4-7 member heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2)nRb,- NR’R”, -COONR’R” , -COOR’, alkylsulfonyl, arylsulfonyl, or -SO2NR’R”; Rbis independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 member carbocyclyl, 4-7 member heterocyclyl with one or more heteroatoms; Rcis H, C1-C6alkyl or F; Rcand Rboptionally form a 3-6 member carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R7is NH2, -NHR’, C1-C3alkyl, substituted or unsubstituted C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl. In various embodiments, the compound of the invention is a compound of Formula (II): (Formula II) wherein ring B, and groups R1, R2, R3, R4, R5, R6, and R7, are described in claim 1; R8is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; Q, T, and W are independently selected from N or CR9; R9is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or cycloalkoxy, each of which is optionally substituted; X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, or -OCF3. In another embodiment, the compound of the invention is a compound of Formula (III): Formula (III) wherein, R1, R2, R3, R4, R5, R6, and R7are described above in Formula (I); R8, W, T, Q, and X are described above in Formula (II); Z is CH, N, CF, or N+-O- In another embodiment, X is F. In another embodiment, R8is -CH3. In another embodiment, Q is N. In another embodiment, Q is N, W is CH, and T is CH. In another embodiment, R1is H or F. In another embodiment R2is H chloro or CF3 In another embodiment, R3is H or CF3. In another embodiment, R4is H. In another embodiment, R5is H. In another embodiment, R7is methyl. In another embodiment, R6is azetidine, pyrrolidine, -CH2-OH, -CH-(CH3)-OH, -CH- CH2-NH-CH3, -CH2-NH2, CH-(CH3)-NH2, -CH2-NH2, -C-(CH3)2-NH2, or -cyclobutyl-NH2. In another embodiment, R9is H. In another embodiment, the compound of Formula (I) is selected from the group consisting of:

[0026] The second set of compounds, provided herein, are prepared by methods and procedures described below. The intermediates described in this section may be relied upon for preparation of second set of compounds. 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. 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 Formula (I) may be synthesized starting from carboxylic acids A-1 by reacting with a substituted aniline or heteroaryl aniline A-2 using standard amide coupling reagents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base such as DIEA to give intermediates of type A-3 Intermediates A-3 may contain a protecting group (PG) such as Boc which may be removed by treatment with an acid such as TFA to provide intermediates having structure A-4. Any suitable PG such as Cbz or Fmoc may be employed and can be removed accordingly. The NH group of A-4 may be acylated using standard amide coupling reagents such as HATU in conjunction with a carboxylic acid and a base such as DIEA or the NH group may be acylated with a reactive carboxylic acid ester such as an N- hydroxysuccinimide ester, to provide compounds of Formula (I) after removal of any protecting groups. There are numerous methods to acylate the NH group which can be affected by those skilled in the art. If desired, Compounds of Formula (I) may be further modified to provide additional Compounds of Formula (I). Alternatively, carboxylic acid A-1 may be treated with ammonia or a primary amine (R5NH2) in the presence of an amide coupling reagent such as HATU and a base such as DIEA to give carboxamide intermediate A-5 which can undergo metal-catalyzed coupling with a halogen-substituted aryl or heteroaryl compounds of type A-6 to give compounds of formula A-3. Compounds of Formula (I) can then be obtained from A-3 as described. Scheme B

[0027] As further illustrated in Scheme B, in general, compounds of the invention can be prepared by reacting intermediates A-1 with an amine B-1, utilizing amide coupling conditions or by activation of an appropriately functionalized carboxylic acid A-1 with (COCl)2or POCl3and with amine B-1 and base such as DIEA or pyridine in DCM, DMF or THF to give compounds of type B-2. The compounds of formula B-3 can be formed by removing a protecting group, such as Boc under acidic conditions. In some instances, B-3 can be separated into the corresponding R and S isomers using chiral HPLC. R- and S-isomers also can be prepared by coupling of the acid to enantiomerically pure amine B-1 followed by deprotection. The sulfoximine nitrogen of intermediate B-3 was acylated using standard amide coupling reagents such as, but not limited to, HATU, a base such as DIEA, and HO2C-R6-PG to give compounds of formula B-4. When B-4 contains a PG, as shown, it was removed to give a compound of formula B-5. For example, if a Boc group as used to protect the sulfoximine, it was removed by treatment with TFA to give compounds of formula B-5 Trialkylsilyl groups may be employed to protect hydroxyl groups and can be removed by treatment with aqueous acids such as acetic acid. B-3 may yield compound B- 5 directly if there is no need for a protecting group. Scheme C As illustrated in Scheme C, in general, compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-1 in organic solvent with either (COC1)2or SOCl2followed by addition of NH4OH to afford C-1. Intermediate C-1 can then be brought together with materials of variously substituted Br compounds C-2, utilizing Xantphos- Pd-G2 mediated coupling conditions to deliver intermediate C-3. The compounds of formula C-3 may be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to provide compounds of formula B-3. In some instances, B-3 was separated to the corresponding R and S isomers using chiral HPLC conditions. Compounds of formula B-4 were obtained using standard amide coupling reagents such as, not limited to, HATU, a base such as DIEA, and HO2C-R6-PG. When the protecting group PG was Boc, it was removed by treatment with TFA to give compounds of formula B-5. Trialkylsilyl groups may be employed to protect hydroxyl groups and can be removed by treatment with aqueous acids such as acetic acid. B-3 may yield compound B-5 directly if there is no need for a protecting group. The above schemes are intended to be illustrative and not limiting in any way. Those skilled in the art are able to prepare the Compounds of Formula (I) using these general schemes as a guideline but other methods are available to accomplish the synthesis of compounds of the invention. Specific methods are provided for each of the Examples to further illustrate the synthesis of Compounds of Formula (I). Intermediate 1 Methyl 2-chloro-4-methyl-5-nitronicotinate Reagents & conditions: a) phenyl dichlorophosphate, 160 °C A solution of methyl 2-hydroxy-4-methyl-5-nitronicotinate (4.0 g, 18.9 mmol) in phenyl dichlorophosphate (20 mL) was heated to 160°C for 3 h. The resulting solution was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (50 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 = 10 / 1) to provide methyl 2-chloro-4-methyl-5-nitronicotinate (3 g, 69%) as a light-yellow solid. LCMS (ESI) calcd. for C8H8ClN2O4[M+H]+m / z 231.02, found 230.85. Intermediate 2 (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid Reagents & conditions: TBSCl, imidazole, DCM To a solution of (S)-2-hydroxypropanoic acid (1 g, 11.11 mmol) and imidazole (2.27 g, 33.32 mmol) in DCM (15 mL) was added TBSCl (2.00 g, 13.33 mmol) at 0 °C. Then the mixture was heated at 25 °C for 16 hours. After the rection was completed, the mixture was diluted with water and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum to give crude (S)-2-((tert- butyldimethylsilyl)oxy)propanoic acid (1.4 g) which was used directly in next step without further purification. Intermediate 3 (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid Reagents & conditions: TBSCl, imidazole, DCM To a solution of (R)-2-hydroxypropanoic acid (1 g, 11.11 mmol) and imidazole (2.27 g, 33.32 mmol) in DCM (15 mL) was added TBSCl (2.00 g, 13.33 mmol) at 0 °C. Then the mixture was warmed to RT and stirred for 16 hours. After the rection was completed, the mixture was diluted with water and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum to give crude (R)-2-((tert- butyldimethylsilyl)oxy)propanoic acid (1.6 g) which was used directly in next step without further purification. Intermediate 4 2-((tert-butyldimethylsilyl)oxy)acetic acid: To a solution of 2-hydroxyacetic acid (1 g, 13.16 mmol) and imidazole (2.68 g, 39.47 mmol) in DCM (15 mL) was added TBSCl (2.38 g, 15.79 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 16 hours. After the rection was completed. The mixture was diluted with water and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum to give crude 2-((tert-butyldimethylsilyl)oxy)acetic acid (1.6 g) which was used directly in next step without further purification. Example 1B 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH / THF / H2O Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (160 mg, 0.32 mmol), (R)- 2-((tert-butyldimethylsilyl)oxy)propanoic acid (325.7 mg, 1.6 mmol) and HATU (181.8 mg, 0.48 mmol) in DMF (5 mL) was added DIEA (123.6 mg, 0.96 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 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 provide N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl) phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (140 mg, 63.8%) as a yellow solid. LCMS (ESI) calcd. for C30H35ClF4N3O5SSi [M + H]+m / z 688.17, found 688.15. Step 2: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (140 mg, 0.2 mmol) in THF / H2O / AcOH (1 / 3 / 3, 7 mL) 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 sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% formic acid) to provide 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (45.6 mg, 39.1%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.34 (s, 1 H), 8.12 (s, 1 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.73-7.61 (m, 3 H), 7.36 (s, 1 H), 7.05 (dd, J = 8.7, 3.3 Hz, 1 H), 4.71 (d, J = 5.3 Hz, 1 H), 4.02 (dd, J = 6.8, 5.4 Hz, 1 H), 3.46 (s, 3 H), 2.33 (s, 3 H), 1.26 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd. for C24H21ClF4N3O5S [M + H]+m / z 574.08, found 574.00. Example 2B (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid HATU, DIEA, DMF; b) AcOH / THF / H2O Step 1: (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.3 mmol), 2- ((tert-butyldimethylsilyl)oxy)acetic acid (170.6 mg, 0.9 mmol) and HATU (170.5 mg, 0.45 mmol) in DMF (5 mL) was added DIEA (115.9 mg, 0.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 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 provide (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (120 mg, 53.6%) as a yellow solid. LCMS (ESI) calcd. for C29H33ClF4N3O5SSi [M + H]+m / z 674.15, found 674.05. Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)- S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of (R)-N-(3-(N-(2- ((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF / H2O / AcOH (1 / 3 / 3, 7 mL) 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). Then the organic solution was washed with water (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 C18 column, 150*21.2 mm, eluting with 50% to 90% MeCN / H2O containing 0.1% FA) to provide (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4- (trifluoromethyl)benzamide (45.4 mg, 45.6% ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.32 (s, 1 H), 8.13 (s, 1 H), 7.91 (d, J = 6.8 Hz, 1 H), 7.75-7.60 (m, 3 H), 7.36 (s, 1 H), 7.10-7.01 (m, 1 H), 4.79 (d, J = 5.5 Hz, 1 H), 3.95 (d, J = 4.9 Hz, 2 H), 3.45 (s, 3 H), 2.34 (s, 3 H). LCMS (ESI) calcd. for C23H19ClF4N3O5S [M + H]+m / z 560.06, found 560.10. Example 3B 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH / THF / H2O Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide: A solution of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.30 mmol), (S)- 2-((tert-butyldimethylsilyl)oxy)propanoic acid (183 mg, 0.90 mmol), HATU (227 mg, 0.60 mmol) and DIEA (116 mg, 0.90 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers 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 N-(3-((R)-N-((S)-2-((tert- butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (180 mg, 87.55%) as colorless oil. LCMS (ESI) calcd. for C30H35ClF4N3O5SSi [M + H]+m / z 688.17, found 688.15. Step 2: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (180 mg, 0.26 mmol) in THF (2.2 mL) and H2O (6.5 mL) was added AcOH (8.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with EtOAc (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.H2O) to provide 5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (71.97 mg, 45.9%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.35 (s, 1 H), 8.12 (s, 1 H), 7.87 (d, J = 6.7 Hz, 1 H), 7.72-7.62 (m, 3 H), 7.36 (s, 1 H), 7.05 (dd, J = 8.7, 3.4 Hz, 1 H), 4.69 (d, J = 5.5 Hz, 1 H), 4.08-3.96 (m, 1 H), 3.44 (s, 3 H), 2.34 (s, 3 H), 1.24 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd. for C24H21ClF4N3O5S [M + H]+m / z 574.08, found 573.95. Example 4B (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2- oxoethyl)carbamate: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (120 mg, 0.24 mmol), (tert- butoxycarbonyl)glycine (83.8 mg, 0.48 mmol) and HATU (136.4 mg, 0.36 mmol) in DMF (5 mL) was added DIEA (92.7 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 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 provide tert-butyl (R)-(2-(((3-(5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl) (methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (100 mg, 63.5%) as a yellow solid. LCMS (ESI) calcd. for C28H28ClF4N4O6S [M + H]+m / z 659.14, found 659.10. Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-(2-(((3- (5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl) (oxo)- λ6-6-sulfaneylidene)amino)-2-oxoethyl)carbamate (100 mg, 0.15 mmol) in DCM (3 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-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (53.8 mg, 62.5%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1 H), 8.31 (s, 1 H), 8.13 (s, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.72-7.61 (m, 3 H), 7.36 (s, 1 H), 7.05 (dd, J = 8.7, 3.2 Hz, 1 H), 3.43 (s, 3 H), 3.23 (s, 2 H), 2.34 (s, 3 H), 1.69 (bs, 2 H). LCMS (ESI) calcd. for C23H20ClF4N4O4S [M + H]+m / z 559.09, found 559.05. Example 5B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin- 3-yl)oxy)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (120 mg, 0.24 mmol), (tert- butoxycarbonyl)-D-alanine (90.5 mg, 0.48 mmol) and HATU (136.4 mg, 0.36 mmol) in DMF (5 mL) was added DIEA (92.7 mg, 0.72 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 (60 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 provide tert-butyl ((R)-1-(((R)- (3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate (120 mg, 74.6%) as a yellow solid. LCMS (ESI) calcd. for C29H30ClF4N4O6S [M + H]+m / z 673.15, found 673.10. Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide : A solution of tert-butyl ((R)-1-(((R)-(3- (5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (120 mg, 0.18 mmol) in DCM (3 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 45% to 95% MeCN / H2O containing 0.05% NH3) to provide N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (73.9 mg, 72.4%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.33 (s, 1 H), 8.12 (s, 1 H), 7.88 (d, J = 7.7 Hz, 1 H), 7.73-7.61 (m, 3 H), 7.35 (s, 1 H), 7.05 (dd, J = 8.7, 3.4 Hz, 1 H), 3.43 (s, 3 H), 3.28 (d, J = 6.9 Hz, 1 H), 2.34 (s, 3 H), 2.04-1.31 (m, 2 H), 1.16 (d, J = 7.5 Hz, 3 H). LCMS (ESI) calcd. for C24H22ClF4N4O4S [M + H]+m / z 573.10, found 573.10. Example 6B (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide Reagents & conditions: a) 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl) carbamate: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (120 mg, 0.24 mmol), 1-((tert- butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (102.9 mg, 0.48 mmol) and HATU (136.4 mg, 0.36 mmol) in DMF (5 mL) was added DIEA (92.7 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred at 50°C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 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 provide tert-butyl(R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (120 mg, 71.8%) as a yellow solid. LCMS (ESI) calcd. for C31H32ClF4N4O6S [M + H]+m / z 699.17, found 699.15. Step 2: (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide : A solution of tert- butyl (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamoyl) cyclobutyl)carbamate (120 mg, 0.17 mmol) in DCM (3 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 C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide (R)-N-(3-(N-(1-aminocyclobutane-1- carbonyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (15.70 mg, 15.4%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.38 (s, 1 H), 8.12 (s, 1 H), 7.88 (d, J = 7.7 Hz, 1 H), 7.75-7.63 (m, 3 H), 7.37 (s, 1 H), 7.05 (dd, J = 8.7, 3.3 Hz, 1 H), 3.46 (s, 3 H), 2.46-2.37 (m, 2 H), 2.34 (s, 3 H), 2.14-1.91 (m, 2 H), 1.88-1.65 (m, 4 H). LCMS (ESI) calcd. for C26H24ClF4N4O4S [M + H]+m / z 599.12, found 599.05. Example 7B (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide

[0028] Reagents & conditions: a) 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-methyl-1- oxopropan-2-yl)carbamate: A mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N- (3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (120 mg, 0.24 mmol), 2-((tert- butoxycarbonyl)amino)-2-methylpropanoic acid (243 mg, 1.2 mmol) and HATU (181.8 mg, 0.48 mmol) in DMF (5 mL) was added DIEA (154.5 mg, 1.2 mmol) at room temperature. The reaction mixture was heated at 50°C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 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 provide tert-butyl (R)- (1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (100 mg, 60.9%) as a yellow solid. LCMS (ESI) calcd. for C30H32ClF4N4O6S [M + H]+m / z 687.17, found 687.10. Step 2: (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide : A solution of tert- butyl (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2- yl)carbamate (100 mg, 0.15 mmol) in DCM (3 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)-N-(3-(N-(2-amino-2- methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-(trifluoromethyl)benzamide (47.2 mg, 55.3%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1 H), 8.34 (s, 1 H), 8.11 (s, 1 H), 7.86 (d, J = 7.4 Hz, 1 H), 7.71-7.62 (m, 3 H), 7.37 (s, 1 H), 7.04 (dd, J = 8.7, 3.4 Hz, 1 H), 3.42 (s, 3 H), 2.34 (s, 3 H), 1.96-1.50 (m, 2 H), 1.19 (d, J = 3.3 Hz, 6 H). LCMS (ESI) calcd. for C25H24ClF4N4O4S [M + H]+m / z 587.12, found 587.10. Example 8B (S)-N-((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl) (methyl)(oxo)- λ6-sulfaneylidene)pyrrolidine-2-carboxamide formate Reagents & conditions: a) (tert-butoxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (tert- butoxycarbonyl)-L-proline (139 mg, 0.64 mmol) in DMF (5 mL) was added HATU (183 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 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-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)pyrrolidine-1-carboxylate (120 mg, 50.6%) as a yellow solid. LCMS (ESI) calcd. for C31H33F4N4O6S [M + H]+m / z 665.21, found 665.10. Step 2: A solution of tert-butyl (S)-2-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)carbamoyl)pyrrolidine-1- carboxylate (120 mg, 0.18 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 95% MeCN / H2O containing 0.05% NH3) to obtain (S)-N-((R)-(3-(2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl) (methyl)(oxo)- λ6- sulfaneylidene)pyrrolidine-2-carboxamide formate (75.6 mg, 72.8%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.43 (d, J = 1.8 Hz, 1 H), 8.23 (s, 1 H), 7.93-7.82 (m, 2 H), 7.72-7.64 (m, 4 H), 7.24 (s, 1 H), 7.07 (dd, J = 8.7, 3.3 Hz, 1 H), 3.86 (dd, J = 8.5, 6.5 Hz, 1 H), 3.49 (s, 3 H), 3.03-2.79 (m, 2 H), 2.33 (s, 3 H), 2.18-2.05 (m, 1 H), 1.95-1.82 (m, 1 H), 1.77-1.56 (m, 2 H). LCMS (ESI) calcd. for C26H25F4N4O4S [M + H]+m / z 565.16, found 565.05. Example 9B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)- 4-(trifluoromethyl)benzamide Reagents & conditions: a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (tert- butoxycarbonyl)-D-alanine (61 mg, 0.55 mmol) in DMF ( 5 mL) was added HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.02 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (40 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)-1-(((R)-(3-(2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16- sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (90 mg, 43.90%yield) as a white oil. LCMS (ESI) calcd. for C29H31F4N4O6S [M + H]+m / z 639.19, found 639.10. Step 2: A solution of tert-butyl ((R)-1-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate (90 mg, 0.15 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 (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 N-(3-((R)-N-(D-alanyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (40 mg, 53.3%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1 H), 8.37 (s, 1 H), 7.91-7.89 (d, J = 7.6 Hz, 2 H), 7.69-7.62 (m, 4 H), 7.24 (s, 1 H), 7.08- 7.05 (m, 1 H), 3.43 (s, 3 H), 2.33 (s, 3 H), 1.17 (d, J = 7.2 Hz, 3 H). LCMS (ESI) calcd. for C24H23F4N4O4S [M + H]+m / z 539.14, found 539.05. Example 10B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide

[0029] Reagents & conditions: a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and N-(tert- butoxycarbonyl)-N-methylglycine (104 mg, 0.55 mmol) in DMF ( 5 mL) was added HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.0 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 (40 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-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate (110 mg, 53.65%) as a white oil. LCMS (ESI) calcd. for C29H31F4N4O6S [M + H]+m / z 639.19, found 639.05. Step 2: A solution of tert-butyl (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate (110 mg, 0.17 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 (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 (R)-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-4- (trifluoromethyl)benzamide (68.9 mg, 67.2%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1 H), 8.38 (s, 1 H), 7.92-7.89 (m, 2 H), 7.69-7.65 (m, 4 H), 7.24 (s, 1 H), 7.08-7.05 (m, 1 H), 3.44 (s, 3 H), 3.20 (s, 2 H), 2.33 (s, 3 H), 2.23 (s, 3 H). LCMS (ESI) calcd. for C24H23F4N4O4S [M + H]+m / z 539.14, found 539.05. Example 11B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) TFA, DCM Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and 2-((tert- butyldimethylsilyl)oxy)acetic acid (105 mg, 0.55 mmol) in DMF ( 5 mL) was added HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.02 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 (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (100 mg, 49.02%) as a white oil. LCMS (ESI) calcd. for C29H34F4N3O5SSi [M + H]+m / z 640.19, found 640.05. Step 2: A solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (100 mg, 0.16 mmol) in THF (3 mL) was added AcOH (3 mL) and H2O (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 (20 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 (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (72.3 mg, 87 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1 H), 8.36 (s, 1 H), 7.93-7.90 (m, 2 H), 7.69-7.63 (m, 4 H), 7.23 (s, 1 H), 7.08-7.05 (m, 1 H), 4.80-4.78 (m, 1 H), 3.94 (d, J = 5.6 Hz, 2 H), 3.44 (s, 3 H), 2.33 (s, 3 H). LCMS (ESI) calcd. for C23H20F4N3O5S [M + H]+m / z 526.11, found 526.00. Example 12B 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide Reagents & conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF, H2O Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (S)-2- ((tert-butyldimethylsilyl)oxy)propanoic acid (112 mg, 0.55 mmol) in DMF (5 mL) was added HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.02 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 (40 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 N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl) phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (100 mg, 47.8%) as a white oil. LCMS (ESI) calcd. for C30H36F4N3O5SSi [M + H]+m / z 654.21, found 654.10. Step 2: A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (100 mg, 0.15 mmol) in THF (3 mL) was added AcOH (3 mL) and H2O (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 (30 mL) and extracted with DCM (20 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 C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.1% formic acid) to obtain 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (62.3 mg, 78%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1 H), 8.39 (s, 1 H), 7.91-7.87 (m, 2 H), 7.69-7.65 (m, 4 H), 7.23 (s, 1 H), 7.08-7.05 (m, 1 H), 4.68 (d, J = 5.6 Hz, 1 H), 4.04-4.01 (m, 1 H), 3.43 (s, 3 H), 2.33 (s, 3 H), 1.24 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd. for C24H22F4N3O5S [M + H]+m / z 540.12, found 540.05. Example 13B 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide

[0030] Reagents & conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (300 mg, 0.64 mmol) and (R)-2- ((tert-butyldimethylsilyl)oxy)propanoic acid ( 328 mg, 1.60 mmol) in DMF (4 mL) was added HATU (317 mg, 0.83 mmol) and DIEA (265 mg, 2.05 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, 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 = 2 / 1 to 1 / 1) to give N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (200 mg, 47.7%) as a yellow oil. LCMS (ESI) calcd. for C30H36F4N3O5SSi [M + H]+m / z 654.20, found 654.10. Step 2: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)- S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of N-(3-((R)-N-((R)-2- ((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (200 mg, 0.31 mmol) in THF (3 mL) was added CH3CO2H (3 mL) and H2O (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with EtOAc (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% TFA) to obtain 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (35 mg, 21.2%) as a white solid.1H NMR (400 MHz, CD3OD) δ 8.41 (dd, J = 4.0, 2.1 Hz, 1H), 7.91- 7.86(m, 2 H), 7.78-7.75 (m, 1 H), 7.67-7.60 (m, 2 H), 7.53 (dd, J = 8.7, 6.5 Hz, 1 H), 7.18 (s, 1 H), 6.92 (dd, J = 8.6, 3.1 Hz, 1 H), 4.21 (m, 1 H), 3.43 (s, 3 H), 2.39 (s, 3 H), 1.40 (dd, J = 6.9, 1.9 Hz, 3 H). LCMS (ESI) calcd. for C24H22F4N3O5S [M + H]+m / z 540.11, found 540.10. Example 14B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4- (trifluoromethyl)benzamide Reagents & conditions: a) (tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)carbamate: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (tert- butoxycarbonyl)glycine (96 mg, 0.55 mmol) in DMF (2 mL) was added HATU (159 mg, 0.42 mmol) and DIEA (133 mg, 1.03 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, 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 = 2 / 1 to 1 / 1) to give tert-butyl (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (150 mg, 74.9%) as a yellow oil. LCMS (ESI) calcd. for C28H29F4N4O6S [M + H]+m / z 625.17, found 625.05. Step 2: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-(2-(((3- (2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (150 mg, 0.24 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 NaHCO3solution (10 mL) and extracted with EA (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 C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3) to obtain (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide(50 mg, 39.7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1 H), 8.36 (s, 1 H), 7.91 (d, J = 7.7 Hz, 2 H), 7.69-7.62 (m, 4 H), 7.24 (s, 1 H), 7.07 (dd, J = 8.7, 3.4 Hz, 1 H), 3.44 (s, 3 H), 3.24 (s, 2 H), 2.33 (s, 3 H), 1.99 (bs, 2 H). LCMS (ESI) calcd. for C23H21F4N4O4S [M + H]+m / z 525.12, found 525.00. Example 15B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin- 3-yl)oxy)-3-(trifluoromethyl)benzamide Reagents & conditions: a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b)TFA, DCM Step 1: tert-butyl ((R)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (100 mg, 0.21 mmol) and (tert- butoxycarbonyl)-D-alanine (78 mg, 0.41 mmol) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol). The mixture was stirred at room temperature for 16 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)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (80 mg, 59.1%) as a yellow solid. LCMS (ESI) calcd. for C29H30F5N4O6S [M + H]+m / z 657.18, found 657.00. Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide: A solution of tert-butyl ((R)-1-(((R)-(3- (2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (80 mg, 0.12 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 layers 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 0.05% NH3) to obtain N-(3-((R)-N-(D-alanyl)-S- methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamide (30.5 mg, 44.3%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1 H), 8.39 (s, 1 H), 7.95-7.80 (m, 3 H), 7.74-7.64 (m, 2 H), 7.15 (dd, J = 8.6, 3.2 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 3.46 (s, 3 H), 3.32-3.27 (m, 1 H), 2.30 (s, 3 H), 1.71 (s, 2 H), 1.17 (d, J = 6.9 Hz, 3 H). LCMS (ESI) calcd. for C24H22F5N4O4S [M + H]+m / z 557.13, found 557.00. Example 16B (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide Reagents & conditions: a) (tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM Step1: tert-butyl (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2- oxoethyl)carbamate: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (100 mg, 0.21 mmol) and (tert- butoxycarbonyl)glycine (72 mg, 0.41 mmol) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol). The mixture was stirred at room temperature for 16 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 layers 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-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)carbamate (80 mg, 60.4%) as a yellow solid. LCMS (ESI) calcd. for C28H28F5N4O6S [M + H]+m / z 643.16, found 643.00. Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-(2-(((3- (2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (80 mg, 0.12 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 layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3) to obtain (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N- glycyl-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (22.5 mg, 32.9%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.37 (s, 1 H), 7.98-7.80 (m, 3 H), 7.73-7.63 (m, 2 H), 7.15 (dd, J = 8.7, 3.3 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 3.46 (s, 3 H), 3.24 (s, 2 H), 2.30 (s, 3 H), 2.01 (s, 2 H). LCMS (ESI) calcd. for C23H20F5N4O4S [M + H]+m / z 543.11, found 543.05. Example 17B (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide Reagents & conditions: a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (100 mg, 0.21 mmol) and N- (tert-butoxycarbonyl)-N-methylglycine (78 mg, 0.41 mmol) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol). The mixture was stirred at room temperature for 16 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-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2- oxoethyl)(methyl)carbamate (80 mg, 59.0%) as a yellow solid. LCMS (ESI) calcd. for C29H30F5N4O6S [M + H]+m / z 657.18, found 657.00. Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: A solution of tert-butyl (R)- (2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (80 mg, 0.12 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 layers 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 95% MeCN / H2O containing 0.05% NH3) to obtain (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (41.3 mg, 60.1%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.39 (s, 1 H), 7.96-7.80 (m, 3 H), 7.74-7.65 (m, 2 H), 7.15 (dd, J = 8.7, 3.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 3.46 (s, 3 H), 3.19 (s, 2 H), 2.30 (s, 3 H), 2.21 (s, 3 H). LCMS (ESI) calcd. for C24H22F5N4O4S [M + H]+m / z 557.13, found 557.05. Example 18B 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide

[0031] Reagents & conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamide: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.31 mmol) and (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (126 mg, 0.62 mmol) in DMF (5 mL) was added HATU (176 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (20 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 = 2 / 1 to 1 / 1) to give N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamide (120 mg, 57.8%) as a yellow solid. LCMS (ESI) calcd. for C30H35F5N3O5SSi [M + H]+m / z 672.20, found 672.05. Step 2: 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF (3 mL) and H2O (1 mL) was added AcOH (3 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 (30 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 95% MeCN / H2O containing 0.1% formic acid) to obtain 2-fluoro-6-((6-fluoro-2-methylpyridin- 3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide (41.2 mg, 41.2%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.40 (s, 1 H), 7.97-7.78 (m, 3 H), 7.74-7.65 (m, 2 H), 7.15 (dd, J = 8.7, 3.4 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 4.70 (d, J = 5.6 Hz, 1 H), 4.10-3.97 (m, 1 H), 3.45 (s, 3 H), 2.30 (s, 3 H), 1.24 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd. for C24H21F5N3O5S [M + H]+m / z 558.11, found 558.00. Example 19B 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide Reagents & conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamide: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.31 mmol) and (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (126 mg, 0.62 mmol) in DMF (5 mL) was added HATU (176 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (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 = 2 / 1 to 1 / 1) to give N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamide (120 mg, 57.8%) as a yellow solid. LCMS (ESI) calcd. for C30H35F5N3O5SSi [M + H]+m / z 672.20, found 672.05. Step 2: 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A mixture of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF (3 mL) and H2O (1 mL) was added AcOH (3 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 (30 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 95% MeCN / H2O containing 0.1% formic acid) to obtain 2-fluoro-6-((6-fluoro-2-methylpyridin- 3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide (40.5 mg, 40.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.39 (s, 1 H), 7.97-7.78 (m, 3 H), 7.76-7.64 (m, 2 H), 7.15 (dd, J = 8.6, 3.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 4.73 (d, J = 5.3 Hz, 1 H), 4.10-3.95 (m, 1 H), 3.48 (s, 3 H), 2.30 (s, 3 H), 1.27 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd. for C24H21F5N3O5S [M + H]+m / z 558.11, found 558.00. Example 20B (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide

[0032] Reagents & conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O Step 1: (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl) phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.309 mmol) and 2-((tert- butyldimethylsilyl)oxy)acetic acid (117.61 mg, 0.618 mmol) in DMF (5 mL) was added HATU (176.24 mg, 0.464 mmol) and DIEA (119.81 mg, 0.927 mmol). The mixture was stirred at room temperature for 8 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (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 = 2 / 1 to 1 / 1) to give (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 53.14 %) as a yellow solid. LCMS (ESI) calcd. for C29H33F5N3O5SSi [M + H]+m / z 658.19, found 658.10. Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of (R)-N-(3-(N-(2-((tert- butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.1824 mmol) in THF (1 mL) and H2O (3 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic layers 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 50% to 95% MeCN / H2O containing 0.1% FA) to afford (R)-2-fluoro-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-3- (trifluoromethyl)benzamide (27.2 mg, 26.32 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1 H), 8.36 (s, 1 H), 7.98-7.80 (m, 3 H), 7.74-7.65 (m, 2 H), 7.15 (dd, J = 8.7, 3.3 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 4.79 (t, J = 6.2 Hz, 1 H), 3.94 (d, J = 5.9 Hz, 2 H), 3.47 (s, 3 H), 2.30 (s, 3 H). LCMS (ESI) calcd. C23H19F5N3O5S [M + H]+m / z 544.10, found 543.80. Example 21B (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)pyrrolidine-2-carboxamide Reagents & conditions: a) (tert-butoxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)pyrrolidine-1- carboxylate: A mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.31 mmol) and (tert- butoxycarbonyl)-L-proline (133.39 mg, 0.62 mmol) in DMF (5 mL) was added HATU (175.89 mg, 0.46 mmol) and DIEA (119.57 mg, 0.93 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 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 = 2 / 1 to 1 / 1) to give tert-butyl (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)pyrrolidine-1- carboxylate (120 mg, 51.23%) as a yellow solid. LCMS (ESI) calcd. for C31H32F5N4O6S [M + H]+m / z 683.2, found 681.05. Step 2: (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)pyrrolidine-2- carboxamide: A solution of tert-butyl (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene) carbamoyl)pyrrolidine-1-carboxylate (120 mg, 0.17 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 (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 60 to 95% MeCN / H2O containing 0.05% NH3) to obtain (S)- N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- λ6-sulfaneylidene)pyrrolidine-2-carboxamide (41.3 mg, 38.8%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1 H), 8.42 (s, 1 H), 7.89-7.67 (m, 5 H), 7.15 (dd, J = 8.7, 3.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 3.51 (dd, J = 8.5, 5.8 Hz, 1 H), 3.45 (s, 3 H), 2.90-2.83 (m, 1 H), 2.61 (dt, J = 10.0, 6.8 Hz, 1 H), 2.30 (s, 3 H), 2.02- 1.93 (m, 1 H), 1.79-1.71 (m, 1 H), 1.61-1.43 (m, 2 H). LCMS (ESI) calcd. for C26H24F5N4O4S [M + H]+m / z 583.15, found 582.90. The following compounds are prepared using the techniques of the intermediates and examples described above.

[0033] Example 30B Compound profiling human NaV1.8 / β3 cell line – SyncroPatch384PE Assay Compounds were tested on recombinant human Nav1.8 / b3 stably transfected CHO cells using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2in Ham’s F-12 supplemented with 10% fetal bovine serum, 100 U / mL penicillin G sodium, 100 mg / mL streptomycin sulfate and selection antibiotics (0.01 mg / ml Blasticidin, 0.4 mg / ml Zeocin and 0.25 mg / ml Hygromycin). On the day of the recordings, cells in culture dishes were washed twice with Hank’s Balanced Salt Solution (HBSS) and treated with Accutase for approximately 20 minutes. Immediately before use in the SynchroPatch384PE using an 8-hole NPC-384 chip, the cells were washed in HBSS to remove the Accutase and re- suspended in extracellular solution. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl2, 5; EGTA, 1; HEPES, 10; pH adjusted to 7.2 with CsOH. Extracellular solution contained (mM): NaCl, 137; KCl, 4.0; CaCl2, 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents. Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic Acid. Compounds were diluted 1:3.33 in extracellular solution to create an 8-point concentration response curve. Each plate contained a historical positive control and up to ten compounds. 300 µM tetracaine and 0.3% DMSO + 0.03% pluronic acid were used as high and low controls respectively. Whole cell patch clamp recordings were conducted according to Nanion’s standard procedure for SyncroPatch384PE®. Cells were held at a holding potential of -120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to -100 mV for 100 ms. An inactivation step at -35 mV for 10 sec was applied before stepping to -100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to -100 mV for 30 ms. Sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed in extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the SynchroPatch384 PE system into each well and the current was recorded for five minutes in extracellular solution, followed by application of tetracaine to achieve full block at the end of experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls. The table below shows the potency of compounds against human NaV1.8, where “A” represents an IC50 less than or equal to 5 nM, “B” represents an IC50 greater than 5 nM to less than or equal to 50 nM, “C” represents an IC50 greater than 50 nM to less than or equal to 100 nM, “D” represents an IC50 greater than 100 nM to less than or equal to 200 nM, “ E” represents an IC50 greater than 200 nM.

[0034] (C) Third Set of Compounds In one aspect, the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C1-C8-alkyl, C1-C8fully or partially fluorinated fluoroalkyl, C2-C8branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R’’)-cycloalkyl, C(R’)(R’’)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; B is substituted or unsubstituted aryl or heteroaryl, wherein the substitutions are selected from the group consisting of substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, halo-C1-C4alkyl where the alkyl chain is fully or partially halogenated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl wherein the haloalkyoxyl chain may be fully or partially halogenated, or arylalkoxyl; C is substituted or unsubstituted aryl or heteroaryl, wherein the one or more substitutions are independently selected from a group consisting of halo, C1-C8alkyl, haloalkyl, alkoxy; R1is selected from a group consisting of: H and C1-C4alkyl; R2is selected from a group consisting of: Formula (II): (II), -C(=O)NH2, and -C(=O)NR’R”; wherein, m and n are independently 0 or 1; and X1is O and X2is either NH or NR’; or X1and X2are both O, NH, or NR’; or X1is O and X2is NR3; wherein R3is selected from a group consisting of: CD3, C1-C4alkyl or cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl, (C1-C6)alkyl- OH, (C1-C6)alkyl-NHR’, (C1-C6)alkyl-NR’R”, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-N-(C1- C6)alkyl ; R4is selected from a group consisting of: -NH2, -NR’R”, C1-C4alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl. In another embodiment, B is a 6 membered substituted or unsubstituted heteroaryl ring, comprising one or more N atoms. The N atoms in the heteroaryl ring may be in the form of a N- oxide. In certain embodiments, the N-oxide containing B-ring is selected from pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide. In another embodiment, the compound is a compound of Formula (III): Formula (III) wherein, Q, T and W are independently N or CR6; R6is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, - OCF3, or substituted or unsubstituted cycloalkoxy; R5is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2- cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6 membered cycloalkyl, any of which may have one or more substituents; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, -OCF3. In another embodiment, the compound is a compound of Formula (IV): Formula (IV), wherein: Z is CR10, N, or N+O-; wherein R10is H, halo, -CD3, C1-C8alkyl, haloalkyl, or alkoxy. In certain embodiments, ring A is substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S. In certain embodiments, ring A is substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In certain embodiments, ring A is substituted or unsubstituted 6 membered heteroaryl having at least one heteroatom, wherein the heteroatom is N. In certain embodiments, ring A is substituted or unsubstituted 6 membered heteroaryl having at least 2 N atoms. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein Q1, Q2, Q3and Q4are independently selected from a group consisting of: N, N+O-, or CR7; wherein at least two of Q1, Q2, Q3and Q4are CR7; R7is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O- cycloheteroalkyl. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q2and Q4are independently N or N+O- ; Q2is N or N+O- ; Q4is CR7; or Q2is CR7, Q4is N or N+O-; R8and R9are independently selected from a group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, aryl, heteroaryl, -CF2CH3, and -CF2CF3; In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q3and Q4are independently N or N+O- ; Q3is N or N+O- and Q4is CR7; or Q3is CR7, Q4is N or N+O-; wherein R7, R8and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q1and Q4are independently N or N+O-; Q1is N or N+O-, and Q4is CR7; Q1is CR7and Q4is N or N+O-; or Q1or Q4is CR7; wherein R7, R8, and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein Q1and Q2are N; wherein R8and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein Q1is CR7, Q2is N; R7, R8, and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: wherein, Q1is N; Q2is CR7; R7, R8, and R9are defined above. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2is: wherein m and n are independently 0 or 1; X1is O and X2is NH, and R4is alkyl, for example, methyl. In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2is: wherein m and n are independently 0 or 1; X1is O and X2is O, and R4is NH2or alkyl, for example, methyl. In other embodiments, R2is -S(=O)CH3. In another embodiments, in the compound of Formula (III) and / or Formula (IV), Q is N or CH; R5is methyl or -OMe, X is F or CN. In other embodiments, in the compound of Formula (III) and / or Formula (IV), Q is CF. In other embodiments, R7, R8, and R9are independently selected from a group consisting of: H, methyl, fluoro, chloro, bromo, CF3, cyclopropyl, difluorophenyl, and dimethylpyrazole. In other embodiments, in the compound of Formula (III) and / or Formula (IV), R10is H or F. In other embodiments, in the compound of Formula (III) and / or Formula (IV), Z is N or CH. In certain embodiments of the invention, R2does not comprise -C(=O)NH2or - C(=O)NR’R”. In certain embodiments, R2is Formula (II): wherein, m and n are independently 0 or 1; and X1and X2are not both O, NH, or NR’. In other embodiments, the compound of the invention is selected from a group consisting of:

[0035] The third set of compounds, provided herein, are prepared by methods and procedures described below. The intermediates described in this section may be relied upon for preparation of third set of compounds. 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. Analytical 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. Analytical 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. Analytical 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: Analytical Method 4 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. Analytical Method 5 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. Analytical Method 6 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. Analytical Method 7 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. Analytical Method 8 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. 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. Compounds of Formula (I) may be prepared from A-1 starting materials or intermediates but not limited to methyl 4,6-dichloropyridazine-3-carboxylate, 2,6-dichloro-3- (trifluoromethyl)pyridine, 2,4-dichloro-5-nitropyridine, methyl 2-hydroxy-4-methylnicotinate, 2- bromo-3,5-dichloroisonicotinic acid, methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate, methyl 5-bromo-2-chloro-4-methylnicotinate, ethyl 5-bromo-3-fluoro-2-iodoisonicotinate, 2,6- dichloro-4-methylnicotinic acid, ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate, methyl 2- chloro-5-nitronicotinate, 2-chloro-4,6-dimethylnicotinic acid, that are commercially available, synthesized using published procedures, or synthesized by methods known to those skilled in the art. Modifications may be made to the starting materials and intermediates to prepare still other intermediates that possess alternate or additional groups such as alkyl, fluoroalkyl, trifluoromethyl, cyano, halogen, chloro, bromo, iodo, amino, nitro, aryl, heteroaryl, carboalkoxy, alkoxy, aryloxy, heteroaryloxy, and the like. Methodology used to convert above starting materials into Compounds of Formula (I) are shown for each of the Examples. Scheme A As illustrated in Scheme A, in general, compounds of Formula (I) may be synthesized from an A-1 starting material or intermediate. Ring A and X of A-1 may first be modified to give an intermediate A-1 suitable for subsequent modification. Modifications can include, but are not limited to, exchange of a halogen for trifluoromethyl, metal-catalyzed coupling to introduce an alkyl, aromatic, or heteroaromatic group, treatment with nitric acid to introduce a nitro group, reduction of a nitro group to an amino group, or other transformations known to those skilled in the art. The X group of A-1 may be displaced by various substituted phenols or heteroaromatic alcohols in the presence of base, such as K2CO3, Cs2CO3, NaH, KH or other organic bases to provide intermediates of type A-2. Intermediates of type A-2 may or may not be further modified on Ring A and the carboxylate ester is subsequently hydrolyzed with KOH or LiOH in an aqueous solvent, to give the carboxylic acid intermediate A-3. Intermediates A-3 may be reacted with a substituted aniline or heteroaryl aniline using standard amide coupling reagents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base, such as DIEA, to give Compounds of Formula (I). If desired, Compounds of Formula (I) may be further modified to provide additional Compounds of Formula (I). Alternatively, Intermediate A-2 may be treated with ammonia, a primary amine (R1NH2), or a dialkylaluminum amide to give carboxamide A-4 which can undergo metal-catalyzed coupling with a halo-substituted aniline or heteroaryl aniline to give Compounds of Formula (I). Scheme B

[0036] As illustrated in Scheme B, in general, compounds of the invention can be prepared by reacting substituted compound A-1 with an aryl- or heteroaryl-alcohol B using a base such as DIEA or inorganic base such as K2CO3or Cs2CO3to afford intermediate A-2. Intermediate A-2 can be converted to corresponding acid A-3 by treating A-2 with base such as KOH or LiOH or NaOH in aqueous EtOH or MeOH or a mixture of MeOH / THF / H2O. Intermediates A-5 can be formed either by treating A-3 and amine C, utilizing amide coupling conditions or by activationof appropriately functionalized carboxylic acid A-4with (COCl)2or POCl3and with amine C basesuch as DIEA or pyridine in DCM, DMF or THF. The compounds of formula A-6 can be formed by removing a protecting group, such as Boc under acidic conditions. In some instances, A-6 can be separated to the corresponding R and S isomers using chiral HPLC. R- and S-isomers also can be prepared by coupling of the acid to enantiomerically pure amine C followed deprotection. Scheme C

[0037] As illustrated in Scheme C, in general, compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-3 in organic solvent with either (COC1)2or SOCl2followed 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 B-2. The compounds of formula B-2 treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to deliver compound of formula B-3. In some instances, B-3 was separated corresponding R and S isomers using chiral HPLC conditions. Intermediate 1 2-((6-Fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid

[0038] Reagents & conditions: a) fuming HNO3, H2SO4, 0 to 50 °C; b) PhOPOCl2, 160 °C; c) Cs2CO3, MeCN, 50 °C; d) Fe, NH4Cl, MeOH / H2O, 50 °C; e) p-TsOH•H2O, NaNO2, KI, MeCN / H2O, rt; f) CuI, DMF, N2, 120 °C; g) LiOH, THF / MeOH / H2O, rt Step1. methyl 2-hydroxy-4-methyl-5-nitronicotinate: To a stirred solution of methyl 2- hydroxy-4-methylnicotinate (40 g, 0.24 mol) in H2SO4(200 mL) was added fuming HNO3(13 mL) dropwise at 0 °C. The mixture was heated to 50 °C for 5 hours. The resulting mixture was poured into ice water (3 L). The precipitate was collected by filtration, washed with water, and dried under vacuum to give crude methyl 2-hydroxy-4-methyl-5-nitronicotinate (26 g, 51% yield) as a yellow solid. LCMS (ESI) calcd. for C8H9N2O5[M + H]+m / z 213.05, found 212.90. Step 2. methyl 2-chloro-4-methyl-5-nitronicotinate: A solution of methyl 2-hydroxy-4- methyl-5-nitronicotinate 5 (8.0 g, 37.8 mmol) in phenyl dichlorophosphate (40 mL) was heated to 160 °C for 2 hours. The resulting solution was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers 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 provide methyl 2-chloro-4-methyl-5- nitronicotinate (6 g, 69% yield) as a light-yellow solid. LCMS (ESI) calcd. for C8H8ClN2O4[M + H]+m / z 231.02, found 231.00. Step 3. methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate: To a solution of methyl 2-chloro-4-methyl-5-nitronicotinate (4 g, 17 mmol) and 6-fluoro-2- methylpyridin-3-ol (2.31 g, 18 mmol) in MeCN (30 mL) was added Cs2CO3(8.46 g, 26 mmol). The mixture was heated at 50 °C for 1 hours. After the reaction was completed, the mixture concentrated under vacuum and the residue was directly purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1 to 3 / 1) to provide methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)- 4-methyl-5-nitronicotinate (4.2 g, 77% yield) as a light-yellow solid. LCMS (ESI) calcd. for C14H13FN3O5[M + H]+m / z 322.09, found 322.00. Step 4. methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: A solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate 9 (4.2 g, 13.1 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (4.91 g, 91.7 mmol), Fe (3.66 g, 65.5 mmol). The mixture was heated at 60 °C for 2 hours. After the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 5-amino-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-methylnicotinate (3.7 g, 97% yield) as a yellow solid. LCMS (ESI) calcd. for C14H15FN3O3[M + H]+m / z 292.11, found 291.95. Step 5. methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate: To a solution of TsOH.H2O (3.94 g, 20.7 mmol) and methyl 5-amino-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-methylnicotinate (2 g, 6.9 mmol) in MeCN (60 mL) was added a solution of NaNO2(950 mg, 13.8 mmol) and KI (2.86 g, 17.3 mmol) in H2O (10 mL) at 0 °C. The mixture was stirred at room temperature for 2.5 h. After the reaction was completed, the mixture was quenched with water (100 mL), adjusted to pH = 8-9 with saturated aqueous NaHCO3. The solution was extracted with EtOAc (200 mL x 3). The combined organic layers 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 1 / 1) to provide methyl 2-((6-fluoro-2- methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate (2.2 g, 78% yield) as yellow solid. LCMS (ESI) calcd. for C14H13FIN2O3[M + H]+m / z 403.00, found 402.90. Step 6. methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinate: To a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5- iodo-4-methylnicotinate (1.2 g, 3 mmol) and CuI (1.14 g, 6 mmol) in DMF (30 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (2.88 g, 15 mmol) dropwise at room temperature under an atmosphere of N2. The mixture was heated at 120 °C for 6 hours. After the reaction was completed, the resulting solution was diluted with water (100 mL) and extracted with EtOAc (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 = 10 / 1 to 1 / 1) to give methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinate (1 g, 93.3% yield). LCMS (ESI) calcd. for C15H13F4N2O3[M + H]+m / z 345.09, found 344.95. Step 7. 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinate 12 (1 g, 2.9 mmol) in THF / MeOH / H2O (1 / 1 / 1, 30 mL) was added LiOH.H2O (730 mg, 17.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl- 5-(trifluoromethyl)nicotinic acid (900 mg, 94% yield) as a white solid. LCMS (ESI) calcd. for C14H11F4N2O3[M + H]+m / z 331.07, found 330.90. Intermediate 2 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid

[0039] Reagents & conditions: a) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, MeCN, 50˚C; b) Fe, NH4Cl, MeOH / H2O, 60˚C; c) t-BuoNO, CuBr, MeCN, 50˚C; d) LiOH, THF / H2O, rt Step 1: methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate: To a solution of methyl 2-chloro-4-methyl-5-nitronicotinate (3.6 g, 15.7 mmol) and 6-fluoro-2- methylpyridin-3-ol (2.0 g, 15.7 mmol) in MeCN (60 mL) was added Cs2CO3(10.0 g, 31.5 mmol). The mixture was heated at 50 °C for 1 hour. After the reaction was completed, the mixture concentrated under vacuum and directly purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to provide methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl- 5-nitronicotinate (2.7 g, 53.6%) as a light-yellow solid. LCMS (ESI) calcd. for C14H13FN3O5[M + H]+m / z 322.09, found 321.95. Step 2: methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: A solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate (2.5 g, 7.8 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 5-amino-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-methylnicotinate (1.4 g, 61.9%) as a yellow solid. LCMS (ESI) calcd. for C14H15FN3O3[M + H]+m / z 292.11, found 292.00. Step 3: methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To a solution of methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (1.3 g, 4.46 mmol) and CuBr (638 mg, 4.46 mmol) in MeCN (30 mL) was added t-BuONO (459 mg, 4.46 mmol) dropwise at room temperature. The reaction solution was heated at 50 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (80 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 = 10 / 1 to 5 / 1) to give methyl 5-bromo-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-methylnicotinate (620 mg, 39%) as a yellow solid. LCMS (ESI) calcd. for C14H13BrFN2O3[M + H]+m / z 357.01, found 356.85. Step 4: 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid: A solution of methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (620 mg, 1.75 mmol) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was added LiOH.H2O (483 mg, 10.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with 1N HCl. Then the aqueous solution was extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid (490 mg, 82% ) as a brown solid. LCMS (ESI) calcd. for C13H11BrFN2O3[M + H]+m / z 341.00, found 340.85. Intermediate 3 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid

[0040] Reagents & conditions: a) 6-fluoro-2-methylpyridin-3-ol, DIEA, DMF, 100˚C; b) LiOH, THF, H2O, rt Step 1: methyl 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylate: A mixture of methyl 3-chloro-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylate (500 mg, 1.97 mmol), 6-fluoro-2-methylpyridin-3-ol (375 mg, 2.95 mmol), DIEA (381 mg, 2.95 mmol), in DMF (10 mL) was heated at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (80 mL) and extracted with EtOAc (50 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 = 3 / 1) to give methyl 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxylate (420 mg, 61.6%) as a yellow solid. LCMS (ESI) calcd. for C14H12F4N3O3[M + H]+m / z 346.08, found 345.90. Step 2: 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine- 4-carboxylic acid : To a solution of methyl 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylate (350 mg, 1.01 mmol) in THF / H2O (1 / 1, 10 mL) was added LiOH (242 mg, 10.11 mmol) at room temperature. The mixture was stirred at room temperature 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 (30 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated under reduced pressure to give 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylic acid (270 mg, 80.5%) as a yellow solid. LCMS (ESI) calcd. for C13H10F4N3O3[M + H]+m / z 332.07, found 331.90. Intermediate 4 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid Reagents & conditions: a) 4-hydroxy-3-methoxybenzonitrile, Cs2CO3, MeCN, 50˚C; b) Fe, NH4Cl, MeOH / H2O, 60˚C; c) t-BuONO, CuBr, MeCN, 50˚C; d) LiOH, THF / MeOH / H2O, rt Step 1: methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinate: To a solution of methyl 2-chloro-4-methyl-5-nitronicotinate (3 g, 13 mmol) and 4-hydroxy-3- methoxybenzonitrile (2.04 g, 13.7 mmol) in MeCN (30 mL) was added Cs2CO3(6.36 g, 19.5 mmol). The mixture was heated at 50 °C for 1 hour. After the reaction was completed, the mixture concentrated under vacuum and directly purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1 to 3 / 1) to provide methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5- nitronicotinate (2.5 g, 56%) as a light-yellow solid. LCMS (ESI) calcd. for C16H14N3O6[M + H]+m / z 344.09, found 343.95. Step 2: methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: A solution of methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinate (2.5 g, 7.3 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (2 g, 87.7% ) as a yellow solid.LCMS (ESI) calcd. for C16H16N3O4[M + H]+m / z 314.11, found 313.90. Step 3: methyl 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: To a solution of methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (1 g, 3.2 mmol) and CuBr (458 mg, 3.2 mmol) in MeCN (20 mL) was added t-BuONO (391 mg, 3.8 mmol) dropwise at room temperature. The reaction solution was heated at 50 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (30 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 = 10 / 1) to give methyl 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4- methylnicotinate (500 mg, 41%) as a yellow solid. LCMS (ESI) calcd. for C16H14BrN2O4[M + H]+m / z 377.01, found 377.05. Step 4: 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid: A solution of methyl 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (500 mg, 1.33 mmol) in THF (3 mL), MeOH (3 mL) and H2O (3 mL) was added LiOH.H2O (336 mg, 8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with 1N HCl. Then the aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 5- bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid (420 mg, 61%) as a brown solid. LCMS (ESI) calcd. for C15H12BrN2O4[M + H]+m / z 363.00, found 362.85. Intermediate 5 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid

[0041] Reagents & conditions: a) TsOH.H2O, Acetonitrile, 0 °C, NaNO2, KI, 0 °C; b) added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, DMF, 100 °C; c) LiOH.H2O, THF / MeOH / H2O, rt Step 1: methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate: To a solution of TsOH.H2O (691mg, 3.64 mmol) and methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4- methylnicotinate (380 mg, 1.21 mmol) in acetonitrile (12 mL) stirred air at 0 °C was added a solution of NaNO2(167 mg, 2.43 mmol) and potassium iodide (503 mg, 3.03 mmol) in H2O (1.8 mL). The reaction mixture was stirred at room temperature for 2.5 h. After the reaction was completed. The mixture was quenched with water (10 mL), adjust pH (9~10) with sodium bicarbonate (20 mL) and sodium thiosulfate (20 mL). The aqueous solution was extracted with EtOAc (30 mL x 3). The combined organic layers 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 1 / 1) to provide methyl 2-(4-cyano-2-methoxyphenoxy)-5- iodo-4-methylnicotinate (400 mg, 74.01%) as colorless oil. LCMS (ESI) calcd. for C16H14IN2O4[M + H]+m / z 425.00, found 424.95. Step 2: methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate: To a stirred solution of methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate (380 mg, 0.89 mmol) and copper(I) iodide (341 mg, 1.79 mmol) in DMF (40 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (860 mg, 4.48 mmol) dropwise at room temperature under an atmosphere of N2. The mixture was heated at 120 °C for 6 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (30 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 = 10 / 1 to 1 / 1) to give methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5- (trifluoromethyl)nicotinate (300 mg, 91.46%). LCMS (ESI) calcd. for C17H14F3N2O4[M + H]+m / z 367.09, found 367.05. Step 3: 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: A solution of methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate (300 mg, 0.82 mmol) in THF (2 mL), MeOH (2 mL) and H2O (2 mL) was added LiOH.H2O (207 mg, 4.93 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5- (trifluoromethyl)nicotinic acid (140 mg, 48.53%) as a white solid. LCMS (ESI) calcd. for C16H12F3N2O4[M + H]+m / z 353.08, found 353.05. Intermediate 6 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid Reagents & conditions: a) 4-hydroxy-3-methylbenzonitrile, NaH, DMF; b) NaI, ACN; AcCl; c) [Ph2SCF3] [OTf]-, Cu, DMF, 60°C; d) LiOH, THF, H2O, rt Step 1: To a solution of 4-hydroxy-3-methylbenzonitrile (1.28 g, 9.66 mmol) in DMF (10 mL) was added NaH (348 mg, 14.49 mmol, 60%). The mixture was stirred at room temperature for 30 minutes then added dropwise to a solution of methyl 4,6-dichloropyridazine-3-carboxylate (2.0 g, 9.66 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 1 hour. 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 = 2 / 1) to provide methyl 6-chloro-4-(4-cyano-2-methylphenoxy)pyridazine-3-carboxylate (1850 mg, 63.05%) as a yellow solid. LCMS (ESI) calcd. for C14H11ClN3O3[M + H]+m / z 304.05, found 304.10. Step 2: To a solution of methyl 6-chloro-4-(4-cyano-2-methylphenoxy)pyridazine-3- carboxylate (1000 mg, 3.29 mmol) in MeCN (10 mL) was added NaI (4939 mg , 32.92 mmol) at 0 °C. Then a solution of AcCl (568 mg, 7.24 mmol) in MeCN (5 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 6 hours. 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 = 2 / 1) to give methyl 4-(4- cyano-2-methylphenoxy)-6-iodopyridazine-3-carboxylate (800 mg, 61.48%) as a yellow solid. LCMS (ESI) calcd. for C14H11IN3O3[M + H]+m / z 395.98, found 396.15. Step 3: To a solution of methyl 4-(4-cyano-2-methylphenoxy)-6-iodopyridazine-3- carboxylate (800 mg, 2.02 mmol) and Cu (386 mg, 6.07 mmol) in DMF (10 mL) was added [Ph2SCF3] [OTf]- (1473 mg ,3.64 mmol). The mixture was heated at 60 °C for 16 hours. Then the mixture was filtered through celite. The filtrate was diluted 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 = 5 / 1) to provide methyl 4-(4-cyano-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-3-carboxylate (420 mg, 55.36%) as a yellow solid. LCMS (ESI) calcd. for C15H11F3N3O3[M + H]+m / z 338.07, found 338.15. Step 4: To a solution of methyl 4-(4-cyano-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-3-carboxylate (420 mg, 1.25 mmol) in THF / H2O (1 / 1, 10 mL) was added LiOH (522 mg, 12.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. 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 4-(4-cyano-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-3-carboxylic acid (380 mg, 94.40% yield) as a yellow solid. LCMS (ESI) calcd. for C14H9F3N3O3[M + H]+m / z 324.06, found 324.10. Intermediate 7 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid Reagents & conditions: a) NaOH, H2O2, H2O, 0 °C; b) methyl 4,6-dichloropyridazine-3- carboxylate, NaH, DMF; c) NaI, ACN; AcCl; d) methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 120 °C; e) LiOH, THF, H2O, rt Step 1: To a solution of (3,4-difluoro-2-methoxyphenyl)boronic acid (2 g, 10.64 mmol) in THF (20 mL) was added NaOH (850 mg , 21.28 mmol), H2O (5 mL) and H2O2(1 mL, 30%) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH = 3-4 with 1N HCl 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 = 3 / 1) to provide 3,4-difluoro-2- methoxyphenol (1.2 g, 70.59%) as a yellow solid.1H NMR (400 MHz, CDCl3-d6, ppm) δ 6.74- 6.61 (m, 2 H), 4.81 (s, 1 H), 3.85 (s, 3 H). Step 2: To a solution of 3,4-difluoro-2-methoxyphenol (1.2 g, 7.49 mmol) in DMF (10 mL) was added NaH (0.36 g, 8.99 mmol, 60%). The mixture was stirred at room temperature for 30 minutes. Then the mixture was added dropwise to a solution of methyl 4,6-dichloropyridazine- 3-carboxylate (1.54 g, 7.49 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 1h. 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 (eluting with PE / EtOAc = 2 / 1) to provide methyl 6-chloro-4-(3,4- difluoro-2-methoxyphenoxy)pyridazine-3-carboxylate (0.8 g, 32.3%) as yellow solid. LCMS (ESI) calcd. for C13H10ClF2N2O4[M + H]+m / z 331.03, found 330.90. Step 3: To a solution of methyl 6-chloro-4-(3,4-difluoro-2-methoxyphenoxy)pyridazine- 3-carboxylate (800 mg, 2.42 mmol) in MeCN (10 mL) was added NaI (3640 mg , 24.24 mmol) at 0 °C. Then a solution of AcCl (415 mg, 5.32 mmol) in MeCN (5 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 3 h. 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 (eluting PE / EtOAc = 2 / 1) to provide methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-iodopyridazine-3- carboxylate (800 mg, 78.43% ) as a yellow solid. LCMS (ESI) calcd. for C13H10F2IN2O4[M + H]+m / z 422.97, found 422.85. Step 4: To a solution of methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-iodopyridazine-3- carboxylate (800 mg, 1.89 mmol) and CuI (720 mg, 3.79 mmol) in DMF (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2912 mg ,15.17 mmol). The mixture was heated at 120 °C for 2 hours. LCMS showed the rection was completed. Then the mixture was filtered through celite. The filtrate was diluted 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 = 5 / 1) to provide methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3- carboxylate (360 mg, 52.17%) as a yellow solid. LCMS (ESI) calcd. for C14H10F5N2O4[M + H]+m / z 365.06, found 365.15. Step 5: To a solution of methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-3-carboxylate (310 mg, 0.85 mmol) in THF / H2O (1 / 1, 8 mL) was added LiOH (204 mg, 8.52 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hours. After the reaction was completed, the mixture was concentrated to remove the THF. 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 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid (220 mg, 73.83%) as a yellow solid. LCMS (ESI) calcd. for C13H8F5N2O4[M + H]+m / z 351.04, found 350.90. Intermediate 8 3-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide Reagents & conditions: a) Et3N, DCM, rt A solution of bis(2,4-dimethoxybenzyl)amine (1.00 g, 3.20 mmol), 3- bromobenzenesulfonyl chloride (0.86 g, 3.36 mmol) and triethylamine (0.97 g, 9.60 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with DCM (100 mL x 3). The combined organic layers 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 5 / 1) to provide 3-bromo-N,N-bis(2,4-dimethoxybenzyl) benzenesulfonamide (1.4 g, 83.33% ) as colorless oil. LCMS (ESI) calcd. for C24H26BrNO6SNa [M + Na] m / z 560.06, found 560.05. Intermediate 9 tert-butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16- sulfaneylidene)carbamate Reagents & conditions: a) added acrylonitrile, TEA2, DCM; b) EtMgBr, Ti(Oi-Pr)4, Et2O, rt; c) TEA, Boc2O, DCM, 0 °C to rt; d) PhI(OAc)2, AcONH4, EtOH, rt; e) DMAP, Boc2O, TEA, DCM, rt Step1: 3-((3-bromophenyl)thio)propanenitrile: A mixture of 3-bromobenzenethiol (4 g, 0.021 mol), acrylonitrile (1.24 g, 0.023 mol) and TEA (6.44 g, 0.063 mol) in DCM (40 mL) was stirred at room temperature for 3 hours. After the reaction was completed, the resulting solution was diluted with water (25 mL) and extracted with EtOAc (25 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 = 20 / 1) to provide 3-((3- bromophenyl)thio)propanenitrile (4.6 g, 84.91% yield) as a colorless oil. NMR (400 MHz, CDCl3, ppm) δ 7.55 (t, J = 1.8 Hz, 1 H), 7.42 (dd, J = 7.9, 0.8 Hz, 1 H), 7.36-7.31 (m, 1 H), 7.21 (t, J = 7.9 Hz, 1 H), 3.15 (t, J = 7.2 Hz, 2 H), 2.62 (t, J = 7.3 Hz, 2 H). Step2: 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine: A mixture of 3-((3- bromophenyl)thio)propanenitrile (3 g, 0.012 mol) in Et2O (100 mL) under N2at room temperature was added Titanium tetraisopropanolate (3.88 g, 0.014 mol) and ethylmagnesium bromide (5 mL, 1 mol / L in THF). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with 10% hydroxide sodium solution (100 mL) and extracted with DCM (50 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 (DCM / MeOH = 10 / 1) to provide 1-((3-bromophenyl)thio)-3- ethylpentan-3-amine (1.9 g, 50.81% yield) as a colorless oil. LCMS (ESI) calcd. for C13H21BrNS [M + H]+m / z 302.06, found 302.0. Step3: tert-butyl (1-((3-bromophenyl)thio)-3-ethylpentan-3-yl)carbamate: A mixture of 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine (1.9 g, 6.3 mmol) and Boc2O (4.12 g, 0.019 mol) in DCM (50 mL) was added TEA (1.91 g, 0.019 mol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (25 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 = 10 / 1) to provide tert-butyl (1-((3- bromophenyl)thio)-3-ethylpentan-3-yl)carbamate (1.5 g, 58.73% yield) as a colorless oil. LCMS (ESI) calcd. for C18H29BrNO2[M + H]+m / z 402.11, found 402.1. Step4: tert-butyl (1-(3-bromophenylsulfonimidoyl)-3-ethylpentan-3-yl)carbamate: A mixture of tert-butyl (1-((3-bromophenyl)thio)-3-ethylpentan-3-yl)carbamate (1.5 g, 3.7 mmol), PhI(OAc)2(3.58 g, 0.011 mol) and NH4OAc (0.57 g, 0.0074 mol) in EtOH (30 mL) was stirred at room temperature for 6 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (25 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 provide tert-butyl (1-(3- bromophenylsulfonimidoyl)-3-ethylpentan-3-yl)carbamate (0.95 g, 59.46% yield) as a white solid. LCMS (ESI) calcd. for C18H30BrN2O3S [M + H]+m / z 435.12, found 435.0. Step5: tert-butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)- l6-sulfaneylidene)carbamate: A mixture of tert-butyl (1-(3-bromophenylsulfonimidoyl)-3- ethylpentan-3-yl)carbamate (0.95 g, 2.19 mmol), Boc2O (2.39 g, 0.0109 mol), TEA (1.11 g, 0.0109 mol) and DMAP (26.78 mg, 0.22 mmol) in DCM (20 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (100 mL) and extracted with DCM (25 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 (100% DCM) to provide tert-butyl ((3-bromophenyl)(3-((tert- butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfaneylidene)carbamate (720 mg, 61.45% yield) as a yellow oil. LCMS (ESI) calcd. for C23H38BrN2O5S [M + H]+m / z 533.17, found 533.1. Intermediate 10 tert-butyl((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16- sulfaneylidene)carbamate Reagents & conditions: a) t-BuOK, DMF, rt; b) PhI(OAc)2, NH4OAc, 50 °C; c) DMAP, Boc2O, THF, 50 °C; d) Fe, NH4Cl, EtOH / H2O, 70 °C Step 1. 2-methyl-4-((3-nitrophenyl)thio)butan-2-ol : A mixture of 3-nitrobenzenethiol (600.00 mg, 3.87 mmol), 4-bromo-2-methylbutan-2-ol (775.07 mg, 4.64 mmol), t-BuOK (650.81 mg, 5.80 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 (DCM / MeOH = 10 / 1) to provide 2-methyl-4-((3-nitrophenyl)thio)butan-2-ol (800 mg, 77.17% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08-7.94 (m, 2 H), 7.77-7.71 (m, 1 H), 7.60 (t, J = 8.0 Hz, 1 H), 4.42 (s, 1 H), 3.17-3.05 (m, 2 H), 1.75-1.62 (m, 2 H), 1.15 (s, 6 H). Step 2. (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16-sulfanone: A mixture of 2- methyl-4-((3-nitrophenyl)thio)butan-2-ol (800 mg, 3.32 mmol), PhI(OAc)2(3.20 g, 9.9 mmol), NH4OAc (766.63 mg, 9.95 mol) in EtOH (20 mL) was stirred at 50 °C for 3 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (60 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 provide (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16-sulfanone (640 mg, 63.80% yield) as a yellow oil. LCMS (ESI) calcd. for C11H17N2O4S [M + H]+m / z 273.09, found 273.0. Step 3. tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(3-nitrophenyl)(oxo)-16- sulfaneylidene)carbamate : A mixture of (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16- sulfanone (500 mg, 1.84 m mol), (Boc)2O (1.60 g, 0.0073 mol) in THF (10 mL) was added DMAP (560.79 mg, 4.59 mmol) at 25 °C. The reaction mixture was stirred at 50 °C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 = 5 / 1) to provide tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3- methylbutyl)(3-nitrophenyl)(oxo)-16-sulfaneylidene)carbamate (320 mg, 25.46% yield) as a yellow oil. LCMS (ESI) calcd. for C21H33N2O8S [M + H]+m / z 473.20, found 473.2. Step 4. tert-butyl ((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16- sulfaneylidene)carbamate : A mixture of tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3- methylbutyl)(3-nitrophenyl)(oxo)-16-sulfaneylidene)carbamate (320 mg, 0.67 mmol), NH4Cl (108.20 mg, 2.02 mmol) in EtOH / H2O (4 / 1, 10 mL) was added Fe (263.62 mg, 4.72 mmol) at 70 °C. The reaction mixture was stirred at 70 °C for 2 hours. After the reaction was completed, the resulting mixture was filtrated through celite. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 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 provide tert-butyl ((3-aminophenyl)(3-((tert- butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16-sulfaneylidene)carbamate 5 (300 mg, 90.06% yield) as a yellow oil. LCMS (ESI) calcd. for C21H35N2O6S [M + H]+m / z 443.22, found 443.2. Intermediate 11 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-(trifluoromethyl)isonicotinic acid Reagents & conditions: a) MeI, K2CO3, DMF; b) CuI, DMF, 80 °C; c) Cs2CO3, MeCN, 80 °C; d) LiOH, THF / H2O, 60 °C Step 1: A mixture of 2-bromo-3,5-dichloroisonicotinic acid 1 (3 g, 11.1 mmol), K2CO3(4.6 g, 33.3 mmol), MeI (3.15 g, 22.2 mmol) in DMF (40 mL) was heated at 70 °C for 2 hours. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 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 = 10 / 1 to 5 / 1) to give methyl 2-bromo-3,5-dichloroisonicotinate 2 (3 g, 95.5% yield) as a white solid. LCMS (ESI) calcd. for C7H5BrCl2NO2[M + H]+m / z 283.89, found 283.70. Step 2: A solution of methyl 2-bromo-3,5-dichloroisonicotinate 2 (2 g, 7 mmol), CuI (2.76 g, 14 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (6.72 g, 35 mmol) in DMF (25 mL) was heated at 100 °C for 5 hours under N2. LCMS showed the rection was completed. The mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1 to 5 / 1) to give methyl 3,5-dichloro-2-(trifluoromethyl)isonicotinate 3 (1.2 g, 63% yield) as a yellow oil. LCMS (ESI) calcd. for C8H5Cl2F3NO2[M + H]+m / z 273.97, found 273.95. Step 3: A mixture of methyl 3,5-dichloro-2-(trifluoromethyl)isonicotinate (1.5 g, 5.5 mmol), 6-fluoro-2-methylpyridin-3-ol (420 mg, 3.3 mmol) and Cs2CO3(5.38 g, 16.5 mmol) in MeCN (30 mL) was heated 80 °C for 2 hours. The mixture was cooled to room temperature, filtered through celite. The filtrate was concentrated and purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1 to 3 / 1) to afford methyl 3-chloro-5-((6-fluoro-2-methylpyridin-3- yl)oxy)-2-(trifluoromethyl)isonicotinate (1.2 g, 59.9% yield) as a white oil. LCMS (ESI) calcd. for C14H10ClF4N2O3[M + H]+m / z 365.03, found 364.95. Step 4: To a solution of methyl 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinate 7 (290 mg, 0.80 mmol) in THF / H2O (1 / 1, 10 mL) was added LiOH (200 mg, 7.95 mmol) at 25 °C. Then the mixture was heated at 60 °C for 5 hours. After the reaction was completed, the mixture was quenched by 2N HCl and adjusted pH to 3-4. Then the solution was concentrated to remove most THF. The residue was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinic acid (190 mg, 68.1% yield) as a yellow solid. LCMS (ESI) calcd. for C13H8ClF4N2O3[M + H]+m / z 351.01, found 350.95. Intermediate 12 5-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-methyl-2-(trifluoromethyl)isonicotinic acid Reagents & conditions: a) K3PO4, Pd(dppf)Cl2DCM, MeCN,100 °C; b) LiOH, THF / H2O, 60°C Step 1: A mixture of methyl 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinate (400mg, 1.1 mmol), methylboronic acid (656.6 mg, 10.1 mmol), K3PO4(1.16 g, 5.5 mmol) and Pd(dppf)Cl2DCM (89.6 mg, 0.11 mmol) in CH3CN (15 mL) was heated at 100 °C for 16 hours in a sealed tube under N2. The mixture was cooled to room temperature, filtered through celite. The filtrate was concentrated and purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1 to 3 / 1) to afford methyl 5-((6-fluoro-2- methylpyridin-3-yl)oxy)-3-methyl-2-(trifluoromethyl)isonicotinate (140 mg, 37% yield) as a white oil. LCMS (ESI) calcd. for C15H13F4N2O3[M + H]+m / z 345.09, found 345.05. Step 2: To a solution of methyl 5-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-methyl-2- (trifluoromethyl)isonicotinate 5 (140 mg, 0.39 mmol) in THF / H2O (1 / 1, 10 mL) was added LiOH (93 mg, 3.9 mmol) at 25 °C. 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 layers were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5- ((6-fluoro-2-methylpyridin-3-yl)oxy)-3-methyl-2-(trifluoromethyl)isonicotinic acid (110 mg, 85.2% yield) as a yellow solid. LCMS (ESI) calcd. for C14H11F4N2O3[M + H]+m / z 331.07, found 331.00. Intermediate 13 tert-butyl (R)-((3-aminophenyl)(ethyl)(oxo)-16-sulfaneylidene)carbamate Reagents & conditions: a) NaH, MeI, DMF A mixture of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (See: WO2022 / 192487; 550 mg, 2.03 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 89 mg, 2.23 mmol) 0 °C. Iodomethane (346 mg, 2.23 mmol) was then added to the reaction at 0 °C. The mixture was warmed to 25°C and stirred for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (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 = 2 / 1 to 1 / 1) to provide tert-butyl (R)-((3- aminophenyl)(ethyl)(oxo)-16-sulfaneylidene)carbamate (270 mg, 46.71% yield) as yellow oil. LCMS (ESI) calcd. for C13H21N2O3S [M + H]+m / z 285.13, found 285.00. Intermediate 14 tert-butyl ((3-aminophenyl)(3-((tert-butyldimethylsilyl)oxy)propyl)(oxo)-16- sulfaneylidene)carbamate

[0042] Reagents & conditions: a) Cs2CO3, DMF, rt; b) PhI(OAc)2, AcONH4, EtOH; c) (Boc)2O, DMAP; d) Fe, NH4Cl Step 1: A mixture of 3-nitrobenzenethiol (1 g, 6.4 mmol), (3-bromopropoxy)(tert- butyl)dimethylsilane (1.78 g, 7 mmol), Cs2CO3(6.26 g, 19.3 mmol) in DMF (20 mL) was stirred at room temperature for 3 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum to provide tert- butyldimethyl(3-((3-nitrophenyl)thio)propoxy)silane 3 (2 g, 95.31% yield) as a yellow oil which was used directly in next step without further purification.1H NMR (400 MHz, CDCl3, ppm) δ 8.12 (t, J = 1.8 Hz, 1 H), 7.98 (dd, J = 8.1, 1.5 Hz, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 3.74 (t, J = 5.8 Hz, 2 H), 3.10 (t, J = 7.2 Hz, 2 H), 1.91-1.84 (m, 2 H), 0.90 (s, 9 H), 0.06 (s, 6 H). Step 2: A mixture of tert-butyldimethyl(3-((3-nitrophenyl)thio)propoxy)silane (2 g, 6.1 mmol), PhI(OAc)2(5.89 g, 18.3 mmol), NH4OAc (0.94 g, 12.2 mmol) in EtOH (20 mL) was stirred at 50 °C for 6 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to provide (3-((tert-butyldimethylsilyl)oxy)propyl)(imino)(3-nitrophenyl)-16-sulfanone (1.8 g, 81.97% yield) as a yellow oil. LCMS (ESI) calcd. for C15H27N2O4SSi [M + H]+m / z 359.15, found 359.1. Step 3: A mixture of (3-((tert-butyldimethylsilyl)oxy)propyl)(imino)(3-nitrophenyl)-16- sulfanone (1.68 g, 4.7 mmol), (Boc)2O (1.03 g, 4.7 mmol) in THF (10 mL) was added DMAP (0.57 g, 4.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 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 = 5 / 1) to provide tert-butyl ((3-((tert- butyldimethylsilyl)oxy)propyl)(3-nitrophenyl)(oxo)-16-sulfaneylidene)carbamate (0.55 g, 25.46% yield) as a yellow oil. LCMS (ESI) calcd. for C20H35N2O6SSi [M + H]+m / z 459.20, found 459.1. Step 4: A mixture of tert-butyl ((3-((tert-butyldimethylsilyl)oxy)propyl)(3- nitrophenyl)(oxo)-16-sulfaneylidene)carbamate (550 mg, 1.19 mmol), NH4Cl (320.03 mg, 5.98 mmol) in MeOH / H2O (4 / 1, 30 mL) was added Fe power (400.98 mg, 7.18 mmol). The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, the resulting mixture was filtrated through celite. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 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 provide tert-butyl ((3-aminophenyl)(3-((tert- butyldimethylsilyl)oxy)propyl)(oxo)-16-sulfaneylidene)carbamate (350 mg, 68.08% yield) as a yellow oil. LCMS (ESI) calcd. for C20H37N2O4SSi [M + H]+m / z 429.2, found 429.2. Intermediate 15 di-tert-butyl ((3-bromophenyl)(methyl)-16-sulfanediylidene)dicarbamate Reagents & conditions: a) (i) 70% HClO4, dioxane, 0 °C; (ii) DCM, 0 °C; b) (i) NCS, Na2CO3, DMF; (ii) (Me3Si)2NH; c) t-BuOK, (Boc)2OTHF, rt Step 1: To a solution of ethyl (Z)-N-((mesitylsulfonyl)oxy)acetimidate (4.4 g, 15.4 mmol) in dioxane (15 mL) was added HClO4(70%, 15 mL) dropwise at 0 °C. The mixture was stirred 0 °C for 15 minutes. The mixture was quenched with cold water (30 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate. Then a solution of (3-bromophenyl)(methyl)sulfane (2 g, 9.85 mmol) in DCM (15 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 2h. After the reaction was completed, ~1 / 2 of the DCM was evaporated, and diethyl ether (50 mL) was added to the mixture. After storing at 0 °C overnight, the crystal precipitation was collected and dried under vacuum to provide (3-bromophenyl)(methyl)-14-sulfanimine (1.5 g, 70% yield) was crystallized upon storage at 0 °C overnight. LCMS (ESI) calcd. for C7H9BrNS [M + H]+m / z 219.96, found 219.90. Step 2: To a solution of (3-bromophenyl)(methyl)-14-sulfanimine 2 (1.5 g, 6.88 mmol) in DMF (15 mL) was added NCS (1.1 g, 0.008 mol) and Na2CO3(4.3 g, 0.041 mol) at 0 °C under N2. The mixture was stirred at 0 °C for 15 minutes. Then (Me3Si)2NH (3.3 g, 0.021 mol) was added to the mixture at 0 °C. The mixture was stirred at room temperature for 16 hours. The resulting solution was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 5% to 30% MeCN / H2O containing 0.05% NH3) to provide (3-bromophenyl)(methyl)-16-sulfanediimine (200 mg, 12.48% yield) as a white solid. LCMS (ESI) calcd. for C7H10BrN2S [M + H]+m / z 232.98, found 232.85. Step 3: (3-bromophenyl)(methyl)-16-sulfanediimine (200 mg, 0.862 mmol), t-BuOK (241 mg, 2.155 mmol) and Boc2O (563 mg, 2.586 mmol) in THF (10 mL) was stirred at room temperature for 16 h. 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 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 di-tert-butyl ((3-bromophenyl)(methyl)-16-sulfanediylidene)dicarbamate (80 mg, 21.51%yield) as a yellow solid. LCMS (ESI) calcd. for C17H26BrN2O4S [M + H]+m / z 433.08, found 433.00. Intermediate 16 5-cyclobutyl-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid Reagents & conditions: a) Mg, I2, Pd(dppf)Cl2, ZnCl2, THF, 70 °C; b) KOH, THF / H2O / t- BuOH, 80 °C Step 1: A mixture of Mg power (3 g, 123.43 mmol) and I2 (250 mg, 0.99 mmol) in a 250 mL three-necked flask was evacuated and backfilled with N2three times and then charged with N2. The flask was heated carefully with a hot air blower until I2 was sublimated. Then a solution of bromocyclobutane (2.25 g, 16.67 mmol) in THF (5 mL) was added intermediately via a syringe. The mixture was stirred for 10 minutes at room temperature. Then the heater and stirrer were removed. The upper layer clear solution was added dropwise into a stirred solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate (1.5 g, 3.73 mmol), ZnCl2(300 mg, 1.57 mmol) and Pd(dppf)Cl2(300 mg, 0.43 mmol) in THF (4 mL) under an atmosphere of N2. The mixture was heated to 50 °C and stirred for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combine organic layers 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 5-cyclobutyl-2-((6- fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (510 mg, 39.23% yield) as white oil. LCMS (ESI) calcd. for C18H20FN2O3[M+H]+m / z 331.15, found 330.80. Step 2: To a solution of methyl 5-cyclobutyl-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methylnicotinate (510 mg, 1.54 mmol) in t-BuOH / THF / H2O (v / v / v = 1 / 1 / 1, 20 mL) was added potassium hydroxide (1.29 g, 23.11 mmol) at room temperature. The mixture was heated at 80 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature, the reaction was extracted with DCM (20 mL), then the aqueous phase was adjusted to pH =3 with 1 N HCl and extracted with DCM (20 mL x 3). The organic phase was dried with Na2SO4and concentrated under vacuum to give 5-cyclobutyl-2-((6- fluoro-2-methylpyridi...

Claims

CLAIMS:

1. A compound of formula (I):and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C1-C8-alkyl, C1-C8fully or partially fluorinated fluoroalkyl, C2-C8branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R’’)-cycloalkyl, C(R’)(R’’)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; B is substituted or unsubstituted aryl or heteroaryl, wherein the substitutions are selected from the group consisting of substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, halo-C1-C4alkyl where the alkyl chain is fully or partially halogenated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl wherein the haloalkyoxyl chain may be fully or partially halogenated, or arylalkoxyl; C is substituted or unsubstituted aryl or heteroaryl, wherein the one or more substitutions are independently selected from a group consisting of halo, C1-C8alkyl, haloalkyl, alkoxy; R1is selected from a group consisting of: H and C1-C4alkyl;R2is selected from a group consisting of: Formula (II): (II), -C(=O)NH2, and -C(=O)NR’R”;wherein, m and n are independently 0 or 1; and X1is O and X2is either NH or NR’; or X1and X2are both O, NH, or NR’; or X1is O and X2is NR3; wherein R3is selected from a group consisting of: CD3, C1-C4alkyl or cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl, (C1-C6)alkyl- OH, (C1-C6)alkyl-NHR’, (C1-C6)alkyl-NR’R”, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-N-(C1- C6)alkyl ; R4is selected from a group consisting of: -NH2, -NR’R”, C1-C4alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl.

2. The compound of claim 1, wherein B is a 6 membered substituted or unsubstituted heteroaryl ring, comprising one or more N atoms.

3. The compound of claim 2, wherein the one or more N atoms in the heteroaryl ring are in form of a N-oxide.

4. The compound of claim 2, wherein the B ring including the N-oxide is selected from group consisting of: pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

5. The compound of claim 1, wherein the compound is a compound of formula (III):Formula (III) wherein: Q, T and W are independently N or CR6; R6is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, - OCF3, or substituted or unsubstituted cycloalkoxy; R5is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2- cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6 membered cycloalkyl, any of which may have one or more substituents; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, - OCF3.

6. The compound of claim 1, wherein the compound is a compound of Formula (IV):Formula (IV), wherein:Z is CR10, N, or N+O-; wherein R10is H, halo, -CD3, C1-C8alkyl, haloalkyl, or alkoxy.

7. The compound of claim 1, wherein A is substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S.

8. The compound of claim 1, wherein A is substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

9. The compound of claim 1, wherein A is substituted or unsubstituted 6 membered heteroaryl having at least one heteroatom, wherein the heteroatom is N.

10. The compound of claim 1, wherein A iswherein Q1, Q2, Q3and Q4are independently selected from a group consisting of: N, N+O-, or CR7; wherein at least two of Q1, Q2, Q3and Q4are CR7; R7is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O- cycloheteroalkyl.

11. The compound of claim 1, wherein A iswherein,Q2and Q4are independently N or N+O- ; Q2is N or N+O- ; Q4is CR7; or Q2is CR7, Q4is N or N+O-; R8and R9are independently selected from a group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, aryl, heteroaryl, -CF2CH3, and -CF2CF3; R7is described in claim 10.

12. The compound of claim 1, wherein A iswherein, Q3and Q4are independently N or N+O- ; Q3is N or N+O- and Q4is CR7; or Q3is CR7, Q4is N or N+O-; wherein R7, R8and R9are defined above.

13. The compound of claim 1, wherein A iswherein, Q1and Q4are independently N or N+O-; Q1is N or N+O-, and Q4is CR7; Q1is CR7and Q4is N or N+O-; orQ1or Q4is CR7; wherein R7, R8, and R9are defined above.

14. The compound of claim 1, wherein A iswherein Q1and Q2are N; wherein R8and R9are defined above.

15. The compound of claim 1, wherein A iswherein Q1is CR7, Q2is N; R7, R8, and R9are defined above.

16. The compound of claim 1, wherein A iswherein, Q1is N; Q2is CR7; R7, R8, and R9are defined above.

17. The compound of claim 1, wherein R1is H.

18. The compound of claim 1, wherein R2is:wherein m and n are independently 0 or 1; X1is O and X2is NH, and R4is alkyl.

19. The compound of claim 1, wherein R2is:wherein m and n are independently 0 or 1; X1is O and X2is O, and R4is NH2or alkyl, for example, methyl.

20. The compound of claim 1, wherein R2is -S(=O)CH3.

21. The compound of claim 5, wherein, Q is N or CH; R5is methyl or -OMe, X is F or CN.

22. The compound of claim 5, wherein Q is CF.

23. The compound of claim 6, wherein R10is H or F.

24. The compound of claim 6, wherein Z is N or CH.

25. The compound of claim 6, wherein Z is CF.

26. The compound of any one of claims 11-16, wherein R7, R8, and R9are independently selected from a group consisting of: H, methyl, fluoro, chloro, bromo, CF3, cyclopropyl, difluorophenyl, and dimethylpyrazole.

27. The compound of claim 1, wherein R2does not comprise -C(=O)NH2or -C(=O)NR’R”.

28. The compound of claim 1, wherein the compound is selected from a group consisting of:

29. The compound of claim 1, wherein R2is Formula (II):wherein, m and n are independently 0 or 1; and X1and X2are not both O, NH, or NR’.

30. A method of treating a condition in a subject, the method comprising providing to a subject having a condition, a compound selected from the compounds recited in claims 1 – 29.

31. A compound of Formula (I):and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein, A is aryl or heteroaryl wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo-C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl, wherein the haloalkoxy chain may be fully or partially halogenated, or arylalkoxyl;B is aryl or heteroaryl wherein the aryl may have 1 to 4 substituents and heteroaryl may have 1 to 3 substituents, these substituents are independently selected from halogen, C1-C8alkyl, haloalkyl, or alkoxy; R1, R2, R3and R4are independently selected from H, halogen, -OH, C1-C6-alkyl, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8branched alkyl, C3-C8branched fluoroalkyl wherein the branched fluoroalkyl chain maybe fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, - NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; R5is H or C1-C3alkyl; and R6-C(=O)NH2, -C(=O)NHR’, -C(=O)NR’R”, or Formula (II):wherein: X1and X2are both O, NH, or NR’; or X1is O and X2is either NH or NR’; R7is NH2, NHR’, NR’R”, C1-C3alkyl, C3-C8cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl.

32. The compound of claim 31, wherein the compound is a compound of Formula (III):Formula (III) wherein, R1, R2, R3, R4, R5, R6, and B are described in claim 1; Q, T and W is independently N or CR9; R9is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy; X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, - or OCF3; R8is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, or substituted or unsubstituted 3-6 membered cycloalkyl.

33. The compound of claim 31, wherein B is:, wherein R6is described above; Z is CR10, N, or N+O-; wherein R10is H, halo, -CD3, C1- C8alkyl, haloalkyl, or alkoxy.

34. The compound of claim 33, wherein R6is, wherein: X1and X2are both O, NH, or NR’; or X1is O and X2is either NH or NR’; R7is NH2, NHR’, NR’R”, C1-C3alkyl, C3-C8cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl.

35. The compound of claim 33, wherein R6is, wherein: X1is O, X2is NH, and R7is C1-C3alkyl.

36. The compound of claim 31, wherein R6does not include -C(=O)NH2, -C(=O)NHR’, or - C(=O)NR’R”.

37. The compound of claim 31, wherein B is a phenyl ring.

38. The compound of claim 31, wherein B is a pyridine ring.

39. The compound of claim 31, wherein R1is H, -CH3, or F.

40. The compound of claim 31, wherein R2is chloro, -CF3, H, 2-pyrazoline, or 1-methyl-1H- pyrazol-4-yl.

41. The compound of claim 31, wherein R3is H, -CF3, or F.

42. The compound of claim 31, wherein R4is H.

43. The compound of claim 32, wherein R8is H, -CH3, or -O-CH3..

44. The compound of claim 32, wherein R7is -CH3.

45. The compound of claim 32, wherein X is F or -CN.

46. The compound of claim 32, wherein Q is N or CH.

47. The compound of claim 32, wherein W is CH and T is CH.

48. The compound of claim 33, wherein Z is CR10, and R10is H or F.

49. The compound of claim 31, wherein the compound is selected from a group consisting of:

50. A method of treating a condition in a subject, the method comprising providing to a subject having a condition, a compound selected from the compounds recited in claims 31 – 49.

51. A compound of Formula (I):and pharmaceutically acceptable salts, hydrates, and solvates thereof,, wherein: A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo- C1-C4alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted orunsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, aloalkoxyl wherein the haloalkyoxy chain may be fully or partially halogenated, and arylalkoxyl; R1, R2, R3and R4are independently selected from hydrogen, -OH, halogen, C1-C6-alkyl, C1-C6fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8branched alkyl, C3-C8branched fluoroalkyl wherein the branched fluoroalkyl chain maybe fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, NR’R’’, 3-8, membered cycloalkyl, 3-8- membered cycloalkenyl 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, a saturated or unsaturated 5 or more membered ring or an aryl ring optionally containing 1 or more heteroatoms independently selected from O, S, and N, wherein each 5 or more membered ring is unsubstituted or substituted with one to five substituents selected from hydrogen, cyano, halo, or methyl; a fused ring formed by at least two of R1, R2, R3and R4wherein the fused ring is selected from a group consisting of: optionally saturated carbocyclyl or heterocyclyl containing 5-6 ring members, wherein the heterocyclyl include one or more heteroatoms; R5is H, or substituted or unsubstituted C1-C3alkyl; R6is -(CH2)nRa, -(CRbRc)nRa, -(CRbRc)n-(OCH2CH2)nRa, -(CRbRc)n-(NR’CH2CH2)nRa, , - (CRbRc)n-(NR’CH2CH2O)nRa, or -(CRbRc)n-(NHCH2CH2NH)nRa; wherein Rais H, C1-C6-alkyl, C2-C8branched alkyl, C3-C8cycloalkyl, aryl, heteroaryl, 4-7 member heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2)nRb,- NR’R”, -COONR’R” , -COOR’, alkylsulfonyl, arylsulfonyl, or -SO2NR’R”; Rbis independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 member carbocyclyl, 4-7 member heterocyclyl with one or more heteroatoms; Rcis H, C1-C6alkyl or F;Rcand Rboptionally form a 3-6 member carbocyclic ring or 4-6 member heterocyclic ring with one or more hetero atoms; R7is NH2, -NHR’, C1-C3alkyl, substituted or unsubstituted C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl.

52. The compound of claim 51, wherein the compound is a compound of Formula (II):(Formula II) wherein ring B, and groups R1, R2, R3, R4, R5, R6, and R7, are described in claim 1; R8is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; Q, T, and W are independently selected from N or CR9; R9is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or cycloalkoxy, each of which is optionally substituted, X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, or -OCF3.

53. The compound of claim 51, wherein the compound is a compound of Formula (III):Formula (III) wherein, R1, R2, R3, R4, R5, R6, and R7are described in claim 1; R8, W, T, Q, and X are described in claim 52; Z is CH, N, CF, or N+-O- 54. The compound of claim 52, wherein X is F.

55. The compound of claim 52, wherein R8is -CH3.

56. The compound of claim 52, wherein Q is N.

57. The compound of claim 52, wherein Q is N, W is CH, and T is CH.

58. The compound of claim 51, wherein R1is H or F.

59. The compound of claim 51, wherein R2is H, chloro, or CF3.

60. The compound of claim 51, wherein R3is H or CF3.

61. The compound of claim 51, wherein R4is H.

62. The compound of claim 51, wherein R5is H.

63. The compound of claim 51, wherein R7is methyl.

64. The compound of claim 51, wherein R6is azetidine, pyrrolidine, -CH2-OH, -CH-(CH3)- OH, -CH-CH2-NH-CH3, -CH2-NH2, CH-(CH3)-NH2, -CH2-NH2, -C-(CH3)2-NH2, or - cyclobutyl-NH2.

65. The compound of claim 52, wherein R9is H.

66. The compound of claim 51, wherein the compound of Formula (I) is selected from the group consisting of:

67. A method of treating a condition in a subject, the method comprising providing to a subject having a condition, a compound selected from the compounds recited in claims 51 – 66.

68. A compound of Formula (I):and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C1-C8-alkyl, C1-C8fully or partially fluorinated fluoroalkyl, C2-C8branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R”)-cycloalkyl, C(R’)(R”)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; B is substituted or unsubstituted aryl or heteroaryl, wherein the substitutions are selected from the group consisting of substituted or unsubstituted C1-C8alkyl, deuterated C1-C4alkyl wherein the alkyl chain may be fully or partially deuterated, halo C1-C4alkyl where the alkyl chain is fully or partially halogenated, C3-C10cycloalkyl, halogen, cyano, nitro, C1-C8alkoxyl, haloalkoxyl wherein the haloalkyoxyl chain may be fully or partially halogenated, and arylalkoxyl; C is substituted or unsubstituted aryl or heteroaryl, wherein the one or more substitutions are independently selected from a group consisting of halo, C1-C8alkyl, haloalkyl, alkoxy;R1is selected from a group consisting of: H and C1-C4alkyl; R2is selected from a group consisting of: -(CH2)nRa, -(CRbRc)nRa, -(CRbRc)n- (OCH2CH2)nRa, -(CRbRc)n-(NR’CH2CH2)nRa, , -(CRbRc)n-(NR’CH2CH2O)nRa, and -(CRbRc)n- (NHCH2CH2NH)nRa; wherein Rais H, C1-C8-alkyl or branched alkyl, C3-C8cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2)nRb, -NR’R’’, -COONR’R’’ , -COOR’R’’, alkylsulfonyl, arylsulfonyl, or -SO2NR’R”; Rbis H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 memebered carbocyclyl or heterocyclyl with one or more heteroatoms; Rcis H, C1-C6alkyl, or F; Rcand Rbtogether optionally form a 3-6 member carbocyclic or heterocyclic ring; R3is selected from a group consisting of C1-C3alkyl, C3-C4cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl.

69. The compound of claim 68, wherein the compound is a compound of Formula (II):Formula (II) wherein: A, C, R1, R2, and R3are described above; Q, T and W are independently N or CR5;R5is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, - OCF3, or cycloalkoxy; R4is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2- cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, or - OCF3; A, C, R1, R2, and R3are described in claim 68.

70. The compound of claim 69, wherein the compound is a compound of Formula (III):Formula (III) wherein, Z is CH, N, CF, or N+O-; A, W, T, Q, X, R1, R2, R3, and R4, are described in claims 68 and 69.

71. The compound of claim 68, wherein A is substituted or unsubstituted 5-6 membered heteroaryl with one or more heteroatom.

72. The compound of claim 71, wherein the heteroaryl includes a N as the one or more heteroatom.

73. The compound of claim 72, wherein the heteroatom N is 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.

74. The compound of claim 68, wherein A is substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

75. The compound of claim 68, wherein A is a 6-membered heteroaryl comprising at least one heteroatom selected from N.

76. The compound of claim 68, wherein A iswherein Q1, Q2, Q3and Q4are independently selected from a group consisting of: N,N+O-, or CR6;wherein at least two of Q1, Q2, Q3and Q4are CR6; R6is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O- aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl.

77. The compound of claim 68, wherein A iswherein, Q2and Q4are independently N or N+O- ; Q2is N or N+O- and Q4is CR6; or Q2is CR6and Q4is N or N+O-; R7and R8 are independently selected from the group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR’, NR’R”, aryl, Heteroaryl, -CF2CH3, and -CF2CF3; R6is described in claim 76.

78. The compound of claim 69, wherein A iswherein, Q3and Q4are N; Q3is N, N+O-; Q4is CR6; or Q3is CR6, Q4is N or N+O-; wherein R7and R8are defined in claim 77.

79. The compound of claim 67, wherein A iswherein Q1and Q4are independently N or N+O-; Q1is N or N+O- and Q4is CR6; orQ1is CR6and Q4is N or N+O-; wherein R6, R7, and R8are defined in claim 77.

80. The compound of claim 68, wherein A is:wherein Q1and Q2is N; wherein R7and R8are defined in claim 77.

81. The compound of claim 68, wherein A iswherein Q1is CR6, and Q2is N; R6is defined in claim 76, and R7and R8are defined above in claim 77.

82. The compound of claim 68, wherein A iswherein, Q1is N; Q2is CR6; R6is defined in claim 9, and R7and R8are defined above in claim 77.

83. The compound of claim 68, wherein R1is H.

84. The compound of claim 69, wherein T is N.

85. The compound of claim 69, wherein T is N, W is CH, and Q is CH.

86. The compound of claim 69, wherein R4is methyl.

87. The compound of claim 69, wherein X is F.

88. The compound of claim 68, wherein R3is methyl.

89. The compound of claim 68, wherein R2is H, methyl, -CH2-NH2, -CH2-NH-CH3, -CH2- OH, -CH(NH2)(CH3), -CH2-OH, -CH(OH)(CH3), -CH(CF3)(NH2), -CH2-O-CH3, amino- cycopropyl, pyrrolidine, azetidine, oxetane, tetrahydrofuran, or hydroxypyrrolidone.

90. The compound of claim 70, wherein Z is N or CH.

91. The compound of claim 68, wherein the compound is selected from a group consisting of:

92. A method of treating a condition in a subject, the method comprising providing to a subject having a condition, a compound selected from the compounds recited in claims 68 – 91.

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