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

Abstract

The present invention relates to a voltage-gated sodium channel Na V The present invention provides compounds useful for treating conditions associated with abnormal activity of 1.8, as well as methods of treating subjects with these compounds for conditions such as pain, itch, and cough. This application generally relates to sodium channel blocking compounds, their derivatives, and the use of such compounds as pharmacological agents. In another aspect, the present invention provides methods of treating a condition in a subject by providing a compound of the present invention, such as any of the compounds described above, to a subject having the condition.

Description

[Technical Field]

[0001] I. FIELD OF THE INVENTION TECHNICAL FIELD This application relates generally to sodium channel blocking compounds, their derivatives, and the use of such compounds as pharmacological agents. [Background technology]

[0002] II. Background Millions of people suffer from conditions related to pain, itching and / or cough.Pain can be the symptom or cause of conditions such as neuropathy, hyperalgesia and opioid use disorder.In many cases, the drugs used to treat these conditions do not provide relief or produce intolerable side effects.Therefore, existing treatments are inadequate for many patients suffering from these conditions. Summary of the Invention [Means for solving the problem]

[0003] III. Summary The present invention relates to a voltage-gated sodium channel Na V The present invention provides compounds useful for the treatment of conditions associated with the abnormal activity of 1.8, such as pain, itch, and cough.

[0004] (A) First set of compounds: In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein A is an aryl or heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of halo-C1-C4 alkyl, which may be unsubstituted or the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, which may be fully or partially deuterated, C3-C6 alkyl, and the like. 10substituted with one or more groups selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl, the haloalkoxy chain of which may be fully or partially halogenated, or arylalkoxyl; B is aryl or heteroaryl, where the aryl can have 1 to 4 substituents and the heteroaryl can have 1 to 3 substituents, which are independently selected from halogen, C1-C8 alkyl, haloalkyl, or alkoxy; R1, R2, R3 and R4 are independently H, halogen, -OH, C1-C6-alkyl, C1-C6 fluoroalkyl where the fluoroalkyl chain may be fully or partially fluorinated, C3-C8 branched alkyl, C3-C8 branched fluoroalkyl where the branched fluoroalkyl chain may be 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- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; R5 is H or C1-C3 alkyl; and R6 is -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R", or a group of formula (II): [ka] and in formula (II): Both X1 and X2 are O, NH, or NR'; or X1 is O and X2 is either NH or NR'; R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0005] In various embodiments, the compound of the present invention has formula (III): [ka] wherein in formula (III), R1, R2, R3, R4, R5, R6, and B are as described in formula (I); Q, T and W are independently N or CR9; R9 is 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; R8 is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which 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- to 6-membered cycloalkyl.

[0006] In another embodiment, B is [ka] where R6 is as described above; Z is CR 10 , N, or N + O - where R 10 is H, halo, -CD3, C1-C8 alkyl, haloalkyl, or alkoxy.

[0007] In another embodiment, R6 is [ka] where: Both X1 and X2 are O, NH, or NR'; or X1 is O and X2 is either NH or NR'; R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0008] In another embodiment, R6 is [ka] where: X1 is O, X2 is NH, and R7 is C1-C3 alkyl.

[0009] In another embodiment, R6 does not include -C(=O)NH2, -C(=O)NHR', or -C(=O)NR'R''.

[0010] In another embodiment, B is a phenyl ring.

[0011] In another embodiment, B is a pyridine ring.

[0012] In another embodiment, R1 is H, -CH3, or F.

[0013] In another embodiment, R2 is chloro, -CF3, H, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl.

[0014] In another embodiment, R3 is H, -CF3, or F.

[0015] In another embodiment, R4 is H.

[0016] In another embodiment, R8 is H, -CH3, or -O-CH3.

[0017] In another embodiment, R7 is -CH3.

[0018] In another embodiment, X is F or -CN.

[0019] In another embodiment, Q is N or CH.

[0020] In another embodiment, W is CH and T is CH.

[0021] In another embodiment, Z is CR 10 and R 10 is H or F. In another embodiment, the compound is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0022] (B) A second set of compounds In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or halo-C1-C4 alkyl, where the haloalkyl chain may be fully or partially halogenated; substituted or unsubstituted C1-C8 alkyl; deuterated C1-C4 alkyl, where the alkyl chain may be fully or partially deuterated; C3-C 10 substituted with one or more groups selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl, where the haloalkyoxy chain may be fully or partially halogenated, and arylalkoxyl; R1, R2, R3 and R4 are independently hydrogen, -OH, halogen, C1-C6-alkyl, C1-C6 fluoroalkyl where the fluoroalkyl chain may be fully or partially fluorinated, C3-C8 branched alkyl, C3-C8 branched fluoroalkyl where the branched fluoroalkyl chain may be fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R ’ )(R ”)-aryl, NR'R'', 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl; 3- to 6-membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N, a saturated or unsaturated 5-membered or larger ring, or an aryl ring optionally containing one or more heteroatoms independently selected from O, S, and N, wherein each 5-membered or larger ring is unsubstituted or substituted with 1 to 5 substituents selected from hydrogen, cyano, halo, or methyl; a fused ring formed by at least two of R1, R2, R3, and R4, wherein the fused ring is selected from the group consisting of: an optionally saturated carbocyclyl or heterocyclyl containing 5 to 6 ring members, wherein the heterocyclyl is selected from those containing one or more heteroatoms; R5 is H or substituted or unsubstituted C1-C3 alkyl; R6 is -(CH2) n R a , -(CR b R c ) n R a , -(CR b R c ) n -(OCH2CH2) n R a , -(CR b R c ) n -(NR'CH2CH2) n R a , -(CR b R c ) n -(NR'CH2CH2O) n R a , or -(CR b R c ) n -(NHCH2CH2NH) n R a and; where R ais H, C1-C6-alkyl, C2-C8 branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4- to 7-membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2) n R b , -NR'R", -COONR'R", -COOR', alkylsulfonyl, arylsulfonyl, or -SO2NR'R"; R b is independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl having one or more heteroatoms; R c is H, C1-C6 alkyl or F; R c and R b optionally forms a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one or more heteroatoms; R7 is NH2, -NHR', C1-C3 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0023] In various embodiments, the compound of the present invention has formula (II): [ka] wherein in formula (II), ring B and groups R1, R2, R3, R4, R5, R6, and R7 are as defined in claim 1; R8 is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, any of which may have one or more substituents, and wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; Q, T, and W are independently selected from N or CR9; R9 is 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.

[0024] In another embodiment, the compound of the present invention has formula (III): [ka] wherein in formula (III), R1, R2, R3, R4, R5, R6, and R7 are as 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 - is.

[0025] In another embodiment, X is F.

[0026] In another embodiment, R8 is -CH3.

[0027] In another embodiment, Q is N.

[0028] In another embodiment, Q is N, W is CH, and T is CH.

[0029] In another embodiment, R1 is H or F.

[0030] In another embodiment, R2 is H, chloro, or CF3.

[0031] In another embodiment, R3 is H or CF3.

[0032] In another embodiment, R4 is H.

[0033] In another embodiment, R5 is H.

[0034] In another embodiment, R7 is methyl.

[0035] In another embodiment, R6 is 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.

[0036] In another embodiment, R9 is H.

[0037] In another embodiment, the compound of formula (I) is: [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0038] (C) A third set of compounds In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A is a substituted or unsubstituted heteroaryl ring containing at least one heteroatom selected from the group consisting of O, S, or N; wherein one or more substituents on A are selected from H, —OH, halo, C1-C8-alkyl, C1-C8 fully or partially fluorinated fluoroalkyl, C2-C8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, —C(R′)(R″)-cycloalkyl, C(R′)(R″)-aryl, —NR′R″, substituted or unsubstituted 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; B is a substituted or unsubstituted aryl or heteroaryl, where the substitution can be substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, where the alkyl chain can be fully or partially deuterated, halo-C1-C4 alkyl, where the alkyl chain can be fully or partially halogenated, C3-C 10 selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl, where the haloalkoxyl chain may be fully or partially halogenated, or arylalkoxyl; C is a substituted or unsubstituted aryl or heteroaryl, where one or more substitutions are independently selected from the group consisting of halo, C1-C8 alkyl, haloalkyl, alkoxy; R1 is selected from the group consisting of: H and C1-C4 alkyl; R2 is of formula (II): [ka] , —C(═O)NH2, and —C(═O)NR′R″; In formula (II), m and n are independently 0 or 1; and X1 is O and X2 is either NH or NR'; or Both X1 and X2 are O, NH, or NR'; or X1 is O and X2 is NR3; where R3 is selected from the group consisting of: CD3, C1-C4 alkyl 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; R4 is selected from the group consisting of: -NH2, -NR'R", C1-C4 alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl.

[0039] In another embodiment, B is a 6-membered substituted or unsubstituted heteroaryl ring containing one or more N atoms. The N atoms in the heteroaryl ring may be in the form of an N-oxide. In certain embodiments, the N-oxide-containing B ring is selected from pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0040] In another embodiment, the compound has the formula (III): [ka] wherein Q, T and W are independently N or CR6; R6 is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy; R5 is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, any of which may carry one or more substituents; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, -OCF3.

[0041] In another embodiment, the compound has the formula (IV): [ka] and in formula (IV): Z is CR 10 , N, or N + O - where R 10 is H, halo, -CD3, C1-C8 alkyl, haloalkyl, or alkoxy.

[0042] In certain embodiments, ring A is a substituted or unsubstituted 6-membered or greater heteroaryl ring having at least one heteroatom independently selected from N, O, or S.

[0043] In certain embodiments, Ring A is a substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0044] In certain embodiments, ring A is a substituted or unsubstituted 6-membered heteroaryl having at least one heteroatom, where the heteroatom is N. In certain embodiments, ring A is a substituted or unsubstituted 6-membered heteroaryl having at least two N atoms.

[0045] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1, Q2, Q3 and Q4 are independently: N, N + O - or CR7; wherein at least two of Q1, Q2, Q3 and Q4 are CR7; R7 is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5- or 6-membered heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl.

[0046] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where: Q2 and Q4 are independently N or N + O - Is it; Q2 is N or N + O - and Q4 is CR7; or Q2 is CR7 and Q4 is N or N + O - and; R8 and R9 are independently selected from the 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;

[0047] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where: Q3 and Q4 are independently N or N + O - Is it; Q3 is N or N + O - and Q4 is CR7; or Q3 is CR7 and Q4 is N or N + O - where R7, R8 and R9 are defined above.

[0048] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where: Q1 and Q4 are independently N or N + O - Is it; Q1 is N or N + O - and Q4 is CR7; Q1 is CR7 and Q4 is N or N + O - or Q1 or Q4 is CR7; where R7, R8, and R9 are defined above.

[0049] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1 and Q2 are N; and where R8 and R9 are defined above.

[0050] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1 is CR7 and Q2 is N; R7, R8, and R9 are defined above.

[0051] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1 is N; Q2 is CR7; and R7, R8, and R9 are defined above.

[0052] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2 is: [ka] where m and n are independently 0 or 1; X1 is O, X2 is NH, and R4 is alkyl, such as methyl.

[0053] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2 is: [ka] where m and n are independently 0 or 1; X1 is O, X2 is O, and R4 is NH2 or alkyl, such as methyl.

[0054] In another embodiment, R2 is -S(=O)CH3. In another embodiment, in the compound of Formula (III) and / or Formula (IV), Q is N or CH; R5 is methyl or -OMe, and X is F or CN. In another embodiment, in the compound of Formula (III) and / or Formula (IV), Q is CF. In another embodiment, R7, R8, and R9 are independently selected from the group consisting of: H, methyl, fluoro, chloro, bromo, CF3, cyclopropyl, difluorophenyl, and dimethylpyrazole. In another embodiment, in the compound of Formula (III) and / or Formula (IV), R 10 is H or F. In other embodiments, in the compounds of Formula (III) and / or Formula (IV), Z is N or CH.

[0055] In certain embodiments of the invention, R2 does not include -C(=O)NH2 or -C(=O)NR'R''.

[0056] In certain embodiments, R2 is of formula (II): [ka] and in formula (II): m and n are independently 0 or 1; and X1 and X2 cannot both be O, NH, or NR'.

[0057] In other embodiments, the compounds of the invention are: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0058] (D) A fourth set of compounds In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A is a substituted or unsubstituted heteroaryl ring containing at least one heteroatom selected from the group consisting of O, S, or N; wherein one or more of the substituents on A are H, —OH, halo, C1-C8-alkyl, C1-C8 fully or partially fluorinated fluoroalkyl, C2-C8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, —C(R ’ )(R ” )-cycloalkyl, C(R ’ )(R ” )-aryl, -NR'R'', substituted or unsubstituted 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; B is a substituted or unsubstituted aryl or heteroaryl, where the substitution can be substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, where the alkyl chain can be fully or partially deuterated, haloC1-C4 alkyl, where the alkyl chain can be fully or partially halogenated, C3-C 10 selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl where the haloalkoxyl chain may be fully or partially halogenated, and arylalkoxyl; C is a substituted or unsubstituted aryl or heteroaryl, where one or more substitutions are independently selected from the group consisting of halo, C1-C8 alkyl, haloalkyl, alkoxy; R1 is selected from the group consisting of: H and C1-C4 alkyl; R2 is: -(CH2) n R a , -(CR b R c ) n R a , -(CR b R c ) n -(OCH2CH2) n R a , -(CR b R c ) n -(NR'CH2CH2)n R a , -(CR b R c ) n -(NR'CH2CH2O) n R a , and -(CR b R c ) n -(NHCH2CH2NH) n R a selected from the group consisting of: where R a is H, C1-C8 alkyl or branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4- to 7-membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2) n R b , -NR'R'', -COONR'R'', -COOR'R'', alkylsulfonyl, arylsulfonyl, or -SO2NR'R''; R b is H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3- to 7-membered, carbocyclyl, or heterocyclyl having one or more heteroatoms; Rc is H, C1-C6 alkyl, or F; R c and R b and together optionally form a 3- to 6-membered carbocyclic or heterocyclic ring; R3 is selected from the group consisting of C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl.

[0059] In another embodiment, the compound has the formula (II): [ka] wherein A, C, R1, R2, and R3 are as described above; Q, T, and W are independently N or CR5; R5 is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or cycloalkoxy; R4 is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, any of which may have one or more substituents, and wherein the 3- to 6-membered heterocycloalkyl contains 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.

[0060] In another embodiment, the compound has the formula (III): [ka] In the formula (III), Z is CH, N, CF, or N + O - and A, W, T, Q, X, R1, R2, R3, and R4 are described above.

[0061] In another embodiment, in the compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl having one or more heteroatoms. The 5- to 6-membered heteroaryl contains N as the one or more heteroatoms. The heteroatom N can be in the form of an N-oxide, wherein the N-oxide is selected from the group consisting of pyridyl N-oxide, pyrazinyl N-oxide, pyridazinyl N-oxide, and pyrimidinyl N-oxide.

[0062] In other embodiments, A is a 6-membered heteroaryl containing at least one heteroatom, where the heteroatom is N. In certain embodiments, A is a 6-membered heteroaryl containing two N atoms.

[0063] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), ring A can be a substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0064] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] where Q1, Q2, Q3 and Q4 are independently: N, N + O - or CR6; wherein at least two of Q1, Q2, Q3, and Q4 are CR6; and R6 is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5- or 6-membered heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl.

[0065] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] where: Q2 and Q4 are independently N or N + O - Is it; Q2 is N or N + O - and Q4 is CR6; or Q2 is CR6 and Q4 is N or N+ O - and; R7 and R8 are independently selected from the 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; R6 is described above.

[0066] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] where: Q3 and Q4 are N; Q3 is N, N + O - and Q4 is CR6; or Q3 is CR6 and Q4 is N or N + O - where R7 and R8 are defined above.

[0067] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] where Q1 and Q4 are independently N or N + O - Is it; Q1 is N or N + O - and Q4 is CR6; or Q1 is CR6 and Q4 is N or N + O - where R6, R7, and R8 are described above.

[0068] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] where Q1 and Q2 are N; and where R7 and R8 are described above.

[0069] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] wherein Q1 is CR6 and Q2 is N; R6, R7, and R8 are described above.

[0070] In other embodiments, in compounds of Formula (I), Formula (II), and / or Formula (III), Ring A is: [ka] wherein Q1 is N; Q2 is CR6; and R6, R7, and R8 are described above.

[0071] In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), R 1 is H.

[0072] In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), R3 is methyl.

[0073] In other embodiments, in the compounds of Formula (I), Formula (II), and / or Formula (III), R2 is H, methyl, -CH2-NH2, -CH2-NH-CH3, -CH2-OH, -CH(NH2)(CH3), -CH2-OH, -CH(OH)(CH3), -CH(CF3)(NH2), -CH2-O-CH3, amino-cyclopropyl, pyrrolidine, azetidine, oxetane, tetrahydrofuran, or hydroxypyrrolidone.

[0074] 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.

[0075] In another embodiment, in the compound of Formula (II) and / or Formula (III), R4 is methyl. In another embodiment, in the compound of Formula (II) and / or Formula (III), X is F.

[0076] In other embodiments, in the compounds of Formula (II) and / or Formula (III), Z is N or CH.

[0077] In other embodiments, the compounds of the invention are: [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0078] In another aspect, the present invention provides a method for treating a voltage-gated sodium channel, Na V 1.8. These inhibitors can have a defined chemical structure, such as the structure of any of the compounds described above.

[0079] In another aspect, the invention provides a method of treating a condition in a subject by providing to a subject having the condition a compound of the invention, such as any of the compounds described above.

[0080] This condition may be associated with abnormal activity of voltage-gated sodium channels. This condition is associated with abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma / injury, airway hyperresponsiveness, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burns, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache. 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 syndrome, constant unilateral facial pain with further attacks, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, pain due to disc degeneration, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry disease, facet joint syndrome, post-spinal surgery pain syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, pain from head and neck cancer, inflammatory bowel disease, inflammation Inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal injuries, myofascial orofacial pain, postischemic neurodegeneration, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, nociceptive pain, noncardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, overactive bladder, Pachyonychia congenita, pain, pain due to cancer, pain due to chemotherapy, pain due to diabetes, pain syndrome, painful arthroplasty, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic alveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, postmastectomy pain syndrome, postoperative pain, postictal pain, post-surgical painThe pain may be post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiation therapy-induced peripheral neuropathy, Raynaud's disease, 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 disorder, tension headache, trigeminal neuralgia, venous leg ulcers, vulvodynia, or whiplash-related disorder. In another aspect, the invention provides a method of making a medicament using a compound of the invention, such as any of the compounds described above.

[0081] In another aspect, the present invention provides an article of manufacture comprising a compound of the invention, such as any of the compounds described above, for treating a condition, such as any of the conditions described above, in a subject. DETAILED DESCRIPTION OF THE INVENTION

[0082] IV. Detailed Description definition 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 the subject matter described herein belongs. The definitions provided below are intended to supplement and illustrate, not preclude, definitions that would be apparent to one of ordinary skill in the art upon review of this disclosure.

[0083] Unless otherwise specified, the moieties described below are optionally substituted, i.e., they may be substituted in one or more positions. The terms substituted and substituent, whether preceded by the term "optionally" or not, as used herein, refer to the ability to replace one or more functional groups on a molecule with another functional group(s), provided that the valences of all atoms are maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at each position. Substituents may also be further substituted (e.g., an aryl group substituent may have another substituent, such as another aryl group, different from the aryl group, which is further substituted in one or more positions).

[0084] When the term "independently selected" is used, the substituents being referenced (e.g., R groups such as groups R1, R2, or variables such as "m" and "n") can be the same or different. For example, both R1 and R2 can be substituted alkyl, or R1 can be hydrogen and R2 can be substituted alkyl, etc.

[0085] The terms "a," "an," or "a(n)," when used herein in reference to a group of substituents, mean at least one. For example, if a compound is substituted with "an" alkyl or aryl, then the compound is optionally substituted with at least one alkyl and / or at least one aryl. Furthermore, if a moiety is substituted with R substituents, then the group can be referred to as "R-substituted." When a moiety is R-substituted, then the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

[0086] A named "R" or group generally has the art-recognized structure corresponding to the group having that name, unless otherwise specified herein. For purposes of illustration, certain representative "R" groups set forth above are defined below.

[0087] The description of the compound of the present disclosure is limited by the principles of chemical bond formation known to those skilled in the art.Therefore, when group can be substituted by one or more of several substituents, this substitution is selected to be compatible with the principles of chemical bond formation, and to bring about a compound that is not inherently unstable, and / or is not known to those skilled in the art to be unstable under ambient conditions, such as aqueous conditions, neutral conditions and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bond formation known to those skilled in the art, thereby avoiding the compound from being inherently unstable.

[0088] Unless expressly defined otherwise, a "substituent group," as used herein, includes a functional group selected from one or more of the following moieties, as defined herein:

[0089] The term hydrocarbon, as used herein, refers to any chemical group containing hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As known to those skilled in the art, when any substitution is made, all valences must be satisfied. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Exemplary 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, etc.

[0090] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched-chain, acyclic or cyclic saturated hydrocarbon group, or combinations thereof, and can include divalent and polyvalent groups having the specified number of carbon atoms (e.g., C1-10 means 1 to 10 carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In certain embodiments, the term "alkyl" refers to a C1-C20 group, inclusive, derived by removing one hydrogen atom from a hydrocarbon moiety containing between 1 and 20 carbon atoms. 1~20 refers to linear (i.e., "straight chain"), branched, or cyclic saturated hydrocarbon radicals (containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons).

[0091] 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 homologs and isomers thereof.

[0092] "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, e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C 1~8 "Higher alkyl" refers to alkyl groups having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.

[0093] Alkyl groups can be optionally substituted with one or more alkyl group substituents, which can be the same or different ("substituted alkyl"). 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. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can be optionally inserted along the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0094] Thus, the term "substituted alkyl" includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group have been 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.

[0095] The term "heteroalkyl," alone or in combination with another term, means, unless otherwise specified, a stable linear or branched chain or cyclic hydrocarbon radical having 1 to 20 carbon atoms or heteroatoms, or 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, 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 located at any of the interior positions of the heteroalkyl group or at the position at which the 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)-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-OCH3 and -CH2-O-Si(CH3)3.

[0096] As noted above, heteroalkyl groups, as used herein, include groups 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'.

[0097] "Cycloalkyl" refers to a saturated monocyclic or polycyclic ring system of about 3 to about 15 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Cycloalkyl groups can also be optionally substituted with alkyl group substituents, oxo, and / or alkylene, as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can be optionally inserted along the cyclic alkyl chain, where the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus resulting in a heterocyclic group. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl.

[0098] The term "cycloalkylalkyl," as used herein, refers to an alkylene moiety also defined above, e.g., C 1~20

[0023] refers to a cycloalkyl group, as defined above, attached to the parent molecular moiety through an alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0099] The term "carbocyclyl" refers to a monocyclic or polycyclic ring system of about 3 to about 15 ring members, all of which are carbon atoms. Unless otherwise specified, a carbocyclyl can be saturated, partially saturated (i.e., having one or more double or triple bonds), or aromatic.

[0100] The term "heterocyclyl" refers to a monocyclic or polycyclic ring system of 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 can be saturated, partially saturated (i.e., having 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, isothiazolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl, and haloalkoxy substituted derivatives of any of the foregoing groups.

[0101] The terms "cycloheteroalkyl" and "heterocycloalkyl" refer to saturated ring systems, such as 3- to 10-membered cycloalkyl ring systems, containing one or more heteroatoms. These 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-tetrahydropyridyl), 1-piperidmyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, and 2-piperazinyl.

[0102] Cycloheteroalkyl rings may be optionally fused to or otherwise bonded to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having 1 to 3 heteroatoms, such as oxygen, sulfur, and nitrogen, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Examples include, but are not limited to, bicyclic or tricyclic groups containing fused 6-membered rings having between 1 and 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, where (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 optionally be 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.

[0103] The unsaturated hydrocarbon, carbocyclyl, or heterocyclyl has one or more double 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 higher homologs and isomers.

[0104] The term "alkenyl," as used herein, refers to a monovalent group derived by removing one hydrogen molecule from a C2-C20 straight-chain or branched hydrocarbon moiety, inclusive, having at least one carbon-carbon double bond. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0105] 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.

[0106] The term "alkynyl" as used herein refers to a straight or branched chain alkyl group having a specified number of carbon atoms. 2~20 "Alkynyl" refers to a monovalent group derived from a hydrocarbon and 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.

[0107] The term "alkylene," alone or as part of another substituent, refers to a straight-chain or branched divalent aliphatic hydrocarbon group derived from an alkyl group having 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-chain, branched, or cyclic. The alkylene group can also be optionally unsaturated and / or substituted with one or more "alkyl group substituents." Optionally inserted along the alkylene group can be one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl"), where the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (CH2)3, cyclohexylene (-CH6H 10 -), -CH=CH-CH=CH-, -CH=CH-CH-, -CHCHCHCHCHCH-, -CHCHCH(CHCHCHCH)CH-, -(CH)qN(R)-(CH)r- (where q and r are each 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-).

[0108] The term "heteroalkylene," by itself or as part of another substituent, means a divalent group derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, orientation of the linking group is not 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)-.

[0109] The term "spirocyclyl" refers to a polycyclic compound in which two rings have a single atom, such as carbon, as the only common member of the two rings. Thus, "spirocycloalkyl" refers to a cycloalkyl group in which the two rings have a single carbon in common, and "spiroheterocycloalkyl" or "spiroheterocycloalkyl" refers to a cycloheteroalkyl group in which the two rings have a single carbon or other atom, such as nitrogen, in common.

[0110] The term "aryl," unless otherwise specified, means an aromatic hydrocarbon substituent which may be monocyclic or polycyclic (such as 1 to 3 rings), which are fused together or covalently linked.

[0111] The term "heteroaryl" refers to a group (or ring) containing from 1 to 4 heteroatoms (in each separate ring, if polycyclic) selected from N, O, and S, where 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 ...

[0023] Examples of aryl and heteroaryl ring systems include azolyl, 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-quinolyl, and 6-quinolyl. Substituents for each of the above-defined 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.

[0112] When a heteroalkyl, heterocycloalkyl, or heteroaryl contains a specific number of members (eg, "3 to 7 members"), the term "member" refers to a carbon atom or a heteroatom.

[0113] Each of the above terms is intended to include both substituted and unsubstituted forms of the indicated radical. Optional substituents are provided below.

[0114] Substituents include, but are not limited to, the following: -OR', ═O, ═NR', ═N-OR', -NR'R"-SR', -halogen, -SiR'R"R", -OC(O)R, -C(O)R, -COR-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)R', -S(O)NR'R", -NRSOR', -CN, CF, fluorinated C(O) groups in a number ranging from 0 to (2m'+1) where m' is the total number of carbon atoms in such group. 1~4 R', R", R'", and R"" can each independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. 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-C 10 )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-C 10)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.

[0115] When a compound of the present disclosure includes more than one R group, for example, each R group is independently selected as are 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 is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those of skill in the art will understand that the term "alkyl" is meant to include groups that include carbon atoms bonded to groups other than hydrogen groups, for example, haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, and -C(O)CHOCH3, etc.).

[0116] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally form a ring of the formula -T-C(O)-(CRR')U-, where 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 the aryl or heteroaryl ring can optionally be replaced by a substituent of the formula -A-(CH)B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)-, -S(O)NR'-, or a single bond, and r is an integer from 1 to 4.

[0117] One of the single bonds in the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -(CRR')s-X'-(C"R''')d-, where s and d are independently integers 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.

[0118] As used herein, the term "acyl" refers to a radical of an organic acid in which the -OH of the carboxyl group has been replaced by another substituent and has the general formula RC(=O)-, where R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group, as defined herein. Thus, the term "acyl" specifically includes arylacyl groups such as a 2-(furan-2-yl)acetyl)- group and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, i.e., -RC(=O)NR, esters, i.e., -RC(=O)OR', ketones, i.e., -RC(=O)R', and aldehydes, i.e., -RC(=O)H.

[0119] 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, and the terms "alkyl," "alkenyl," and "alkynyl" are as previously described and can include C1-20 linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, inclusive, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like.

[0120] The term "alkoxyalkyl," as used herein, refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or ethoxymethyl group.

[0121] "Aryloxyl" refers to an aryl-O- group, where the aryl group is as previously described, including substituted aryl. As used herein, the term "aryloxyl" can refer to phenyloxyl or hexyloxyl, and phenyloxyl or hexyloxyl substituted with alkyl, substituted alkyl, halo, or alkoxyl.

[0122] "Aralkyl" refers to an aryl-alkyl group where the aryl and alkyl are as previously described, including substituted aryl and alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0123] "Aralkyloxyl" refers to an aralkyl-O- group, where aralkyl groups are as previously described. An exemplary aralkyloxyl group is benzyloxyl, i.e., C6H5CH2-O-. An aralkyloxyl group can be optionally substituted.

[0124] "Alkoxycarbonyl" refers to an alkyl-OC(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

[0125] "Aryloxycarbonyl" refers to the group aryl-OC(=O)-. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphthoxy-carbonyl.

[0126] "Aralkoxycarbonyl" refers to the group aralkyl-OC(=O)-. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

[0127] "Carbamoyl" refers to an amide group of the formula -C(=O)NH2.

[0128] "Alkylcarbamoyl" refers to the group R'RN-C(=O) where 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 the group R'RN-C(=O)- where each R and R' is independently alkyl and / or substituted alkyl as previously described.

[0129] The term "carbonyldioxyl," as used herein, refers to a carbonate group of formula -OC(=O)-OR.

[0130] "Acyloxyl" refers to an acyl-O- group, where acyl is as previously described.

[0131] The term "amino" refers to the -NH group and also to nitrogen-containing groups known in the art that are derived from ammonia by replacing one or more hydrogen radicals with an organic group. For example, the terms "acylamino" and "alkylamino" refer to specific N-substituted organic groups having acyl and alkyl substituents, respectively.

[0132] The term "aminoalkyl," as used herein, refers to an amino group covalently attached to an alkylene linker. More specifically, the terms alkylamino, dialkylamino, and trialkylamino, as used herein, refer to one, two, or three alkyl groups, respectively, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', where R' is an alkyl group, as previously defined, while the term dialkylamino refers to a group having the structure -NR'R", where 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''', where R', R", and R'" are each independently selected from the group consisting of alkyl groups. Additionally, R', R", and / or R''', taken together, optionally, form -(CH) k where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamine.

[0133] An amino group is -NR'R", where 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.

[0134] The terms alkylthioether and thioalkoxyl refer to saturated (i.e., alkyl-S—) or unsaturated (i.e., alkenyl-S— and alkynyl-S—) groups 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.

[0135] "Acylamino" refers to an acyl-NH- group in which acyl is as previously described. "Aroylamino" refers to an aroyl-NH- group in which aroyl is as previously described.

[0136] The term "carbonyl" refers to the group -C(=O)-, which can include aldehyde groups represented by the general formula RC(=O)H.

[0137] The term "carboxyl" refers to a COOH group. Such a group is also referred to herein as a "carboxylic acid" moiety.

[0138] The term "cyano" refers to the group --CN.

[0139] The terms "halo," "halide," and "halogen" refer to fluoro, chloro, bromo, and iodo groups.

[0140] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Furthermore, 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.

[0141] The terms "halocycloalkyl" and "cyclohaloalkyl" refer to a cycloalkly group having one or more halogens.

[0142] The term "hydroxyl" refers to the group --OH.

[0143] The term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0144] The term "mercapto" refers to the group --SH.

[0145] The term "oxo" refers to an oxygen atom that is double bonded to a carbon atom or another element.

[0146] The term "nitro" refers to the group --NO.sub.2.

[0147] The term "thio" refers to a compound previously described herein, in which a carbon or oxygen atom is replaced by a sulfur atom.

[0148] The term "sulfate" refers to the -SO4 group.

[0149] The term thiohydroxyl or thiol, as used herein, refers to a group of formula -SH.

[0150] More specifically, the term "sulfide" refers to a compound having a group of formula -SR.

[0151] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R'. The term "sulfoxide" refers to a compound with a sulfinyl group -S(O)R.

[0152] The term ureido refers to a urea group of formula -NH-CO-NH2.

[0153] Throughout this specification and the claims, a given chemical formula or name is intended to encompass all tautomers, congeners, and optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0154] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, as D- or L-, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-isomers or D- and L-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Where a compound described herein contains an olefinic bond or other center of geometric asymmetry, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0155] Unless otherwise specified, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0156] It will be apparent to one skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure. The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0157] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0158] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 The compounds may be radiolabeled with radioactive isotopes such as C. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0159] The compounds of the present disclosure can exist as salts, particularly as pharmaceutically acceptable salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphoric acids, and salts derived from organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, and methanesulfonic acids. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic or galactunoric acids. 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.

[0160] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0161] The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0162] Certain compounds of the present disclosure can exist in non-solvated form and solvated form, including hydrated form.Generally, solvated form is equivalent to non-solvated form and is included in the scope of the present disclosure.Specific compounds of the present disclosure can exist in multiple crystalline forms or amorphous forms.Generally, all physical forms are equivalent for the use envisioned by the present disclosure and are intended to be within the scope of the present disclosure.

[0163] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield compounds of the present disclosure. Furthermore, prodrugs can be converted to compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0164] The term "protecting group" refers to a chemical moiety that blocks some or all of the reactive moieties of a compound, preventing such moieties from participating in a chemical reaction until the protecting group is removed, such as those listed and described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). When different protecting groups are used, it can be advantageous for each (different) protecting group to be removable by a different means. Protecting groups that are cleaved under completely different reaction conditions allow for differential removal of such protecting groups.

[0165] For example, protecting groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected by hydrogenolysis-removable Cbz and base-labile Fmoc groups. Carboxylic acid and hydroxy reactive moieties can be blocked with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of acid-labile groups such as tert-butyl carbamate, or amines blocked with carbamates that are both acid- and base-stable but removable by hydrolysis.

[0166] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protecting groups such as benzyl groups, 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 protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride labile silyl carbamates.

[0167] Because allyl blocking groups are stable, they are useful in the presence of acid- and base-protecting groups and can be subsequently removed by metal or pi-acid catalysis. For example, an allyl-blocked carboxylic acid can be deprotected by palladium(O)-catalysis 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 can be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group is available for reaction.

[0168] Abbreviations and Acronyms When the following abbreviations are used herein, they have the following meanings: [Table 1-1] [Table 1-2] [Table 1-3] [Example]

[0169] Compound: The present invention provides compounds that modulate, e.g., inhibit, the activity of voltage-gated sodium channels. These compounds and methods for their preparation are provided in detail below.

[0170] (A) First set of compounds: In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein A is an aryl or heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of halo-C1-C4 alkyl, which may be unsubstituted or the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, which may be fully or partially deuterated, C3-C6 alkyl, and the like. 10 substituted with one or more groups selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl, the haloalkoxy chain of which may be fully or partially halogenated, or arylalkoxyl; B is aryl or heteroaryl, where the aryl can have 1 to 4 substituents and the heteroaryl can have 1 to 3 substituents, which are independently selected from halogen, C1-C8 alkyl, haloalkyl, or alkoxy; R1, R2, R3 and R4 are independently H, halogen, -OH, C1-C6-alkyl, C1-C6 fluoroalkyl where the fluoroalkyl chain may be fully or partially fluorinated, C3-C8 branched alkyl, C3-C8 branched fluoroalkyl where the branched fluoroalkyl chain may be 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- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; R5 is H or C1-C3 alkyl; and R6 is -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R", or a group of formula (II): [ka] and in formula (II): Both X1 and X2 are O, NH, or NR'; or X1 is O and X2 is either NH or NR'; R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0171] In various embodiments, the compound of the present invention has formula (III): [ka] wherein in formula (III), R1, R2, R3, R4, R5, R6, and B are as described in formula (I); Q, T and W are independently N or CR9; R9 is 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; R8 is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which 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- to 6-membered cycloalkyl.

[0172] In another embodiment, B is [ka] , where R6 is as described above; Z is CR 10 , N, or N + O - where R 10 is H, halo, -CD3, C1-C8 alkyl, haloalkyl, or alkoxy.

[0173] In another embodiment, R6 is [ka] where: Both X1 and X2 are O, NH, or NR'; or X1 is O and X2 is either NH or NR'; R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0174] In another embodiment, R6 is [ka] where: X1 is O, X2 is NH, and R7 is C1-C3 alkyl.

[0175] In another embodiment, R6 does not include -C(=O)NH2, -C(=O)NHR', or -C(=O)NR'R''.

[0176] In another embodiment, B is a phenyl ring.

[0177] In another embodiment, B is a pyridine ring.

[0178] In another embodiment, R1 is H, -CH3, or F.

[0179] In another embodiment, R2 is chloro, -CF3, H, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl.

[0180] In another embodiment, R3 is H, -CF3, or F.

[0181] In another embodiment, R4 is H.

[0182] In another embodiment, R8 is H, -CH3, or -O-CH3.

[0183] In another embodiment, R7 is -CH3.

[0184] In another embodiment, X is F or -CN.

[0185] In another embodiment, Q is N or CH.

[0186] In another embodiment, W is CH and T is CH.

[0187] In another embodiment, Z is CR 10 and R 10 is H or F.

[0188] In another embodiment, the compound is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0189] The first set of compounds provided herein are prepared by the methods and procedures described below. The intermediates described in this section are reliable for the preparation of the first set of compounds.

[0190] Chemicals were purchased from standard commercial suppliers and used as received unless otherwise noted. Otherwise, their preparation is straightforward and known to those skilled in the art, or is referenced or described herein. Abbreviations are consistent with those in the ACS style guide. "Dry" glassware means oven / dessicator dried. Solvents were ACS grade unless otherwise noted.

[0191] All reactions were performed in flame-dried glassware or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were magnetically stirred unless otherwise noted. Chemicals were purchased from standard commercial suppliers and used as received unless otherwise noted. Yields were not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.

[0192] Reactions, EMD MILLIPORE TM The purified product was monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from Biotage Inc. Purification was performed on a Biotage Isolera One Flash chromatography instrument or purified using one of the preparative HPLC methods specified below.

[0193] Preparative method 1 Instrument: Shimadzu LCMS 2020 mass-directed preparative HPLC system; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (containing 0.1% HCOOH), gradient can be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm;

[0194] Preparative method 2 Instrument: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5um C18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (containing 0.1% TFA), gradient may be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0195] Preparative method 3 Instrument: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (with 0.05% ammonia), gradient can be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0196] Analytical LCMCs were collected using one of the following methods. Method 1 Instrument: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 μm, 3.0 mm × 30 mm; Mobile phase: MeCN (0.05% HCOOH)-water (0.05% HCOOH); Gradient: 5% to 95% MeCN over 1.4 min with a 0.6 min hold, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.

[0197] Method 2 Instrument: Shimadzu LCMS 2020 mass spectrometer; XBridge BEH C 18 2.5 μm, 3.0 mm x 30 mm Mobile phase: MeCN-water (0.1% NH4OH); Gradient: 5% to 95% MeCN over 1.8 min with a 0.7 min hold, total run time 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.

[0198] Method 3 Instrument: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 182.7 μm, 3.0 mm x 30 mm Mobile phase: MeCN (0.05% TFA)-water (0.05% TFA); Gradient: 5% to 95% MeCN over 1.4 min with a 0.6 min hold, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50°C; Wavelength: 214 and 254 nm PDA.

[0199] SFC chiral separation was performed using a Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD SF , SFC-30A) using the following method:

[0200] Method 1 Column: Daicel chiralpak-AS-H 5um 250 x 20mm; Mobile phase: CO2 / MeOH [0.1% NH3 (7M in MeOH)], CO2 / MeOH ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0201] Method 2 Column: Daicel chiralpak-OJ-H 5um 250x20mm; Mobile phase: CO2 / MeOH (0.1% HCOOH), CO2 / MeOH ratio changed for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0202] Method 3 Column: Daicel chiralpak-OD-H 5um 250x20mm; Mobile phase: CO2 / MeOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0203] Method 4 Column: Daicel chiralpak-AD-H 5um 250x20mm; Mobile phase: CO2 / i-PrOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0204] Method 5 Column: Daicel chiralpak-IC 5um 250x20mm; Mobile phase: CO2 / EtOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0205] Unless otherwise specified, 1 H nuclear magnetic resonance (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 were calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

[0206] General synthetic scheme Several methods for preparing the compounds of the present invention are illustrated in the following schemes and examples. The present invention further provides a process for preparing the compounds of formula I defined above. In some cases, the order of carrying out the above-described reaction schemes can be changed to facilitate the reaction or to avoid undesired reaction products. The following examples are provided for illustrative purposes only and should not be construed as limitations on the disclosed invention.

[0207] [ka] As illustrated in Scheme A, compounds of formula (I) can generally be synthesized starting from carboxylic acid A-1 by reacting it with a substituted aniline or heteroaryl aniline A-2 using a standard amide coupling reagent, including but not limited to HATU, TBTU, EDC, or T3P, and a base such as DIEA in an organic solvent to provide an intermediate of type A-3. Intermediate A-3 can contain a protecting group (PG), such as Boc, which can be removed by treatment with an acid such as TFA to provide a compound of formula (I) having structure A-4. Any suitable PG, such as Cbz or Fmoc, can be used and removed accordingly. Alternatively, carboxylic acid A-1 can 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 provide a carboxamide intermediate A-5, which can undergo metal-catalyzed coupling with a halogen-substituted aryl or heteroaryl compound of type A-6 to provide a compound of formula A-3. Compounds of formula (I) can then be obtained from A-3 as described.

[0208] [ka] As further illustrated in Scheme B, in general, compounds of the present invention can be prepared by reacting intermediate A-1 with amine B-1 using amide coupling conditions, or by activation of an appropriately functionalized carboxylic acid A-1 with (COCl) or POCl and an amine B-1 and a base such as DIEA or pyridine in DCM, DMF, or THF to give compounds of type B-2. 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. The R and S isomers can also be prepared by coupling the acid with an enantiomerically pure amine B-1 followed by deprotection.

[0209] [ka] As illustrated in Scheme C, compounds of the present invention can generally be prepared by activating an appropriately functionalized carboxylic acid A-1 with either (COCl) or SOCl in an organic solvent, followed by the addition of NHOH to yield C-1. Intermediate C-1 can then be combined with variously substituted Br compounds C-2 using Xantphos-Pd-G2 mediated coupling conditions to yield intermediate C-3. Compounds of formula C-3 can 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 into the corresponding R and S isomers using chiral HPLC conditions. Compounds of formula B-4 were obtained using standard amide coupling reagents, such as, but not limited to, HATU, a base, such as DIEA, and C-4.

[0210] The above schemes are intended to be illustrative and not limiting in any way. One skilled in the art can prepare compounds of formula (I) using these general schemes as a guide, but other methods are available to achieve the synthesis of compounds of the invention. Specific methods to further illustrate the synthesis of compounds of formula (I) are provided with each of the examples.

[0211] Intermediates Intermediate 1 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid [ka] Reagents and conditions: a) 2,2,6,6-tetramethylpiperidine, n-BuLi, THF, 0°C to -78°C, CO2; b) SOCl2, MeOH, 80°C; c) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, MeCN, 80°C; d) KOH, MeOH, HO, rt

[0212] 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. To the resulting solution was added dry ice (approximately 5 g). The reaction mixture was then slowly warmed to 0 °C and stirred at the same temperature for 1 hour. 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 NaSO, and concentrated under reduced pressure. 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.

[0213] 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 SOCl (20 mL) was heated at 80 °C for 1 h. The mixture was then concentrated in vacuo. The residue was added to MeOH (30 mL) and stirred at room temperature for 1 h. The final mixture was concentrated in vacuo to give crude methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (1.8 g), which was used directly in the next step without further purification.

[0214] 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 CsCO (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 reduced pressure. 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. forC 15 H 11 ClF4NO3[M + H] + m / z 364.04, found 363.70.

[0215] 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 / HO (1 / 1, 30 mL) was added KOH (907 mg 13.77 mmol). The mixture was stirred at room temperature for 2 hours. The organic solvent was then removed under reduced pressure. The aqueous solution was adjusted to pH=2-3 with 2 N HCl. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 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. forC 14 H9ClF4NO3[M + H] + m / z 350.02, found 349.65.

[0216] Intermediate 2 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid [ka] Reagents and conditions: a) MeI, K2CO3, DMF; b) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, DMF, 100 °C; c) LiOH.H2O, THF / H2O

[0217] Step 1: Methyl 2-fluoro-4-(trifluoromethyl)benzoate: To a solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (500 mg, 2.4 mmol) and KCO (993 mg, 7.2 mmol) in DMF (5 mL) was added CHCl (677 mg, 4.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 / z223.04, found 223.04.

[0218] Step 2: Methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate: To a solution of methyl 2-fluoro-4-(trifluoromethyl)benzoate (400 mg, 1.8 mmol) in 5 mL of DMF, CsCO (1.75 g, 5.4 mmol) and 6-fluoro-2-methylpyridin-3-ol (342 mg, 2.7 mmol) were added. The mixture was heated to 100° C. for 1 hour. After the reaction was complete, the mixture was filtered through celite. The solution was concentrated under reduced pressure and purified by flash column chromatography on silica gel (PE / EtOAc=4 / 1 to 3 / 1) to give methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate (350 mg, 86%) as a pale yellow solid. LCMS (ESI) calcd. for C 15 H 12 F4NO3[M + H] + m / z 330.08, found 330.00.

[0219] 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 HO (4 mL) was added LiOH.HO (267 mg, 6.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the residue was adjusted to pH=3-4 with HCl (1 M). The aqueous solution was then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 92%) as a white solid. LCMS (ESI) calcd. forC 14 H 10 F4NO3[M + H] + m / z 316.06, found 315.90.

[0220] Intermediate 3 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid [ka] Reagents and 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

[0221] 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 KCO (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 complete, the solution was diluted with DCM (100 mL) and washed with brine (100 mL × 3), dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1 to 1 / 3) to give methyl 6-fluoro-2-methyl-3-nitrobenzoate (2.00 g, 93.4%) as a white solid.

[0222] Step 2: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate: To 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 CsCO (3.31 g, 23.93 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete, the solution was diluted 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 / Et0Ac=5 / 1 to 3 / 1) to give 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 C 15 H 14 FN2O5[M + H] + m / z 321.09, found 321.05.

[0223] Step 3: Methyl 3-amino-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methylbenzoate: To 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), NH4Cl (1.99 g, 37.16 mmol), Fe (1.48 g, 26.54 mmol) were added. The mixture was heated to 60°C for 1 hour. After the reaction was complete, 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 and concentrated under reduced pressure to give 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 C 15 H 16FN2O3[M + H] + m / z 291.12, found 291.05.

[0224] Step 4: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate: TsOH . To a solution of HO (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 NaNO (713 mg, 10.33 mmol) and KI (2.14 g, 12.92 mmol) in HO (5 mL) at 0 °C. The mixture was stirred at room temperature for 2.5 h. After the reaction was complete, the mixture was quenched with water (100 mL) and adjusted to pH = 8-9 with saturated aqueous NaHCO. The solution was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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)-3-iodo-2-methylbenzoate (1.50 g, 72.4%) as a yellow solid. LCMS (ESI) calcd. for C 15 H 14 FINO3[M + H] + m / z 402.00, found 401.90.

[0225] Step 5: Methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoate: To 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 / HO (4 / 1, 10 mL), potassium carbonate (413 mg, 2.99 mmol) and Pd(dppf)Cl (146 mg, 0.20 mmol) were added. The mixture was heated at 100° C. under an atmosphere of N for 6 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 19 H 19 FN3O3[M + H] + m / z 356.14, found 356.10.

[0226] 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 / HO (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 complete, the mixture was concentrated. The residue was adjusted to pH=3-4 with aqueous HCl (1 M). The solution was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 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 C 18 H 17 FN3O3[M + H] + m / z 342.13, found 342.05.

[0227] Intermediate 4 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid [ka] Reagents and conditions: a) methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 120°C; b) LiOH, THF / MeO / HO, 60°C

[0228] 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), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.20 g, 6.23 mmol) was added dropwise at room temperature under an atmosphere of N. The mixture was heated at 120 °C for 6 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 C 16 H 14 F4NO3[M + H] + m / z 344.09, found 344.05.

[0229] 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 / HO (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 complete, the mixture was concentrated. The residue was adjusted to pH=3-4 with aqueous HCl (1 M). The solution was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 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 C 15 H 12 F4NO3[M + H] + m / z 330.08, found 330.05.

[0230] Intermediate 5 2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid [ka] Reagents and 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

[0231] 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), and MeI (988 mg, 6.96 mmol) in DMF (10 mL) was stirred at 25 °C for 16 h. The resulting solution was diluted with water (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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. 1 H NMR (400 MHz, CD3OD)δ 8.05-7.72 (m, 2H), 3.97 (s, 3H).

[0232] 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 under N2 for 16 h. LCMS showed the reaction was complete. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 15 H 11 F5NO3[M + H] + m / z 348.07, found 348.00.

[0233] 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 / HO (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 complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and 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 C 14 H9F5NO3[M + H] + m / z 334.05, found 334.00.

[0234] Intermediate 6 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid [ka] Reagents and conditions: a) Cs2CO3, MeCN, 80 °C; b) LiOH, THF / H2O

[0235] Step 1. 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 CsCO (838 mg, 2.57 mmol) in ACN (5 mL) was heated to 80 °C and stirred for 3 h. After the reaction was complete, the reaction was cooled to room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with water (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give methyl 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoate (120 mg, 36.2% yield) as a yellow solid. LCMS (ESI) calcd. for C 17 H 12 ClF3NO4[M + H] + m / z 386.14, found 386.0.

[0236] Step 2. 5-Chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid: To a mixture of methyl 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoate (120 mg, 0.31 mmol) in THF (2 mL) and HO (2 mL), LiOH (45 mg, 1.87 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH 3-4 with aqueous HCl (1 M). The solution was then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid (70 mg, 60.5% yield) as a colorless oil, which was used without further purification.

[0237] Intermediate 7 4-Cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid [ka] Reagents and 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℃;g)CuI, DMF, 100℃;h)Cs2CO3, MeCN, 80℃;i)KOH, t-BuOH, THF / H2O, 80℃

[0238] Step 1. 6-Fluoro-2-methyl-3-nitrobenzoic acid: To a solution of 2-fluoro-6-methylbenzoic acid (3 g, 19.5 mmol) in HSO (2 mL) was added HSO / fuming HNO (6 / 1, 7 mL) at 0 °C and stirred at room temperature for 5 h. The mixture was then added to ice-cold water. The precipitate was collected by filtration and dried under reduced pressure to give 6-fluoro-2-methyl-3-nitrobenzoic acid (2.5 g, 64.4%) as a yellow solid. 1 H 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).

[0239] Step 2. Methyl 6-fluoro-2-methyl-3-nitrobenzoate: To a solution of 6-fluoro-2-methyl-3-nitrobenzoic acid (2.5 g, 12.6 mmol) and CHCl (3.57 g, 25.1 mmol) in DMF (20 mL), KCO (5.22 g, 37.8 mmol) was added and stirred at room temperature for 18 hours. The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give methyl 6-fluoro-2-methyl-3-nitrobenzoate (1.5 g, 55.9%) as a yellow solid.

[0240] Step 3. Methyl 3-amino-6-fluoro-2-methylbenzoate: To a solution of methyl 6-fluoro-2-methyl-3-nitrobenzoate (2 g, 9.39 mmol) in MeOH / HO (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 at 65 °C for 5 h. The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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) calculation for C9H 11 FNO2[M + H] + m / z 184.08, found 183.90.

[0241] Step 4. Methyl 3-amino-4-bromo-6-fluoro-2-methylbenzoate: To 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 a yellow oil. LCMS (ESI) calcd. for C9H 10 BrFNO2[M + H] + m / z 261.99, found 216.95.

[0242] Step 5. Methyl 3-amino-4-cyclopropyl-6-fluoro-2-methylbenzoate: To a solution of cyclopropylboronic acid (590.0 mg, 6.87 mmol), Pd(dppf)Cl (251.3 mg, 0.34 mmol), and KCO (1.42 g, 10.3 mmol) in 1,4-dioxane / HO (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 under N for 16 h. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. 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 a yellow oil. LCMS (ESI) calcd. for C 12 H 15 FNO2[M + H] + m / z 224.11, found 223.90.

[0243] Step 6. Methyl 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoate: To 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 h. After the reaction was complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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) calculation for C 12 H 13 FiO2 [M + H] + m / z 334.99, found 334.60.

[0244] Step 7. Methyl 4-cyclopropyl-6-fluoro-2-methyl-3-(trifluoromethyl)benzoate: To 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), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.87 g, 9.73 mmol) was added at room temperature. The reaction mixture was heated at 100 °C under N for 5 hours. After the reaction was complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine, dried over Na SO , and concentrated under reduced pressure. 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 a yellow oil. LCMS (ESI) calcd. for C13 H 13 F4O2[M + H] + m / z 277.08, found 277.10.

[0245] Step 8. Methyl 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoate: To 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 CsCO (1.75 g, 5.43 mmol) at room temperature. The reaction mixture was heated at 80 °C for 5 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. 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 C 19 H 18 F4NO3[M + H] + m / z 384.12, found 384.10.

[0246] Step 9. 4-Cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid: To 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 / HO=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 complete, the mixture was concentrated. The residue was adjusted to pH 3-4 with aqueous HCl (1 M). The solution was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 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 C 18 H 16 F4NO3[M + H] + m / z 370.11, found 370.10.

[0247] Intermediate 8 [ka] Reagents and 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

[0248] Step 1. Methyl 2-fluoro-4-(trifluoromethyl)benzoate: To a solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (8.5 g, 40.84 mmol) in DMF (100 mL) was added KCO (16.91 g, 122.53 mmol) and CHI (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 × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give methyl 2-fluoro-4-(trifluoromethyl)benzoate (8 g, 85% yield) as a white oil. LCMS (ESI) calcd. for C9H7F4O2 [M + H] + m / z 223.04, found 223.04.

[0249] Step 2. Methyl 2-fluoro-5-nitro-4-(trifluoromethyl)benzoate: To a stirred solution of HSO (80 mL) and fuming HNO (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 h. The mixture was poured into ice water (500 mL) and filtered. The filter cake was dried to give methyl 2-fluoro-5-nitro-4-(trifluoromethyl)benzoate (4 g, 40% yield) as a yellow solid. 1 H 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).

[0250] Step 3. Methyl 5-amino-2-fluoro-4-(trifluoromethyl)benzoate: To 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 under an atmosphere of H for 16 hours. LCMS showed the reaction was complete. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give 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.

[0251] Step 4. Methyl 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoate: To 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 complete. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 20 / 1) to give methyl 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (2.5 g, 64.94% yield) as a pale yellow oil. LCMS (ESI) calcd. for C9H7BrF4NO2[M + H] + m / z 315.96, found 315.90.

[0252] 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 HO (10 mL) was heated to 100 °C and refluxed for 16 h. LCMS indicated the reaction was complete. 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, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 20 / 1) to give methyl 3-amino-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate (1.5 g, 75.38% yield) as a pale yellow oil. LCMS (ESI) calcd. for C 10 H 10 F4NO2[M + H] + m / z 252.07, found 252.00.

[0253] Step 6. Methyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate: To a flame-dried round-bottom flask equipped with a magnetic stir bar and an addition funnel under N was added t-BuONO (1.22 g, 11.83 mmol), CuCl (1.59 g, 11.83 mmol), and MeCN (20 mL). The solution was stirred at room temperature for 0.5 h. 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 h. LCMS indicated the reaction was complete. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=20 / 1) to give methyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate (1.4 g, 87.50% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 7.88 (d, J= 9.3 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H).

[0254] Step 7. Methyl 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoate: To 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 CsCO (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 was concentrated under reduced pressure, and the residue was directly purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to give methyl 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoate (1 g, 51.28% yield) as a colorless oil. LCMS (ESI) calcd. for C 16 H 13 ClF4NO3[M + H] + m / z 378.05, found 377.95.

[0255] Step 8. 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoic acid: To 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 / HO (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 h. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1 M). The solution was then extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 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 C 15 H 11 ClF4NO3[M + H] + m / z 364.04, found 363.60.

[0256] Intermediate 9 [ka] Reagents and conditions: a) SOCl2, NH4OH, 80°C; b) Cs2CO3, XantphosPd-G2, 1,4-dioxane, 100°C

[0257] 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 SOCl (5 mL) was heated to 80 °C and stirred for 0.5 h. The solution was concentrated under reduced pressure to give the chloride intermediate. This chloride intermediate, dissolved in THF (5 mL), was then added to a stirred solution of THF (5 mL) in 28% NH H O (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was then quenched with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (180 mg, 90.36% yield) as a yellow solid. LCMS (ESI) calculation for C8H3ClF4NO[M - H] - m / z 239.98, found 240.1.

[0258] Step 2. tert-Butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate: A mixture of 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (500 mg, 2.07 mmol), (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (696 mg, 2.07 mmol), CsCO (1.75 g, 5.38 mmol), and Xantphos-Pd-G (368 mg, 0.41 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. under nitrogen for 2 hours. After the reaction was complete, the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (400 mg, 38.89% yield) as a yellow solid. LCMS (ESI) calcd. for C 19 H 17 ClF4N3O4S[M - H] - m / z 494.05, found 494.0.

[0259] Intermediate 10 [ka] Reagents and conditions: a) K2CO3, MeI, DMF, 70 °C; b) CD3MgI, Pd(dppf)Cl2, ZnCl2, DMF, 100 °C; c) BBr3, DCM

[0260] 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), and MeI (2.22 g, 15.6 mmol) in DMF (40 mL) was heated at 70 °C and stirred for 3 h. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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.

[0261] Step 2. 6-Fluoro-3-methoxy-2-(methyl-d3)pyridine: To a 250 mL three-necked round-bottom flask purged with nitrogen and maintained under an inert atmosphere of nitrogen, 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) was added. Then, CD3MgI (1.0 M in diethyl ether, 36.4 mL) was added dropwise with stirring at room temperature. The solution was heated to 100 °C and stirred for 2 h. The resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to give 6-fluoro-3-methoxy-2-(methyl-d)pyridine (250 mg, 70.9% yield) as a white solid. LCMS (ESI) calculation for C7H6D3FNO[M + H] + m / z 145.09, found 145.0.

[0262] Step 3. 6-Fluoro-2-(methyl-d)pyridin-3-ol: To a solution of 6-fluoro-3-methoxy-2-(methyl-d)pyridine (250 mg, 1.73 mmol) in DCM (5 mL) was added BBr (1.0 M in DCM, 1 mL) at room temperature. The reaction mixture was heated to 40 °C and stirred for 6 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure and quenched with CHOH (5 mL). The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 6-fluoro-2-(methyl-d)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.

[0263] Example 1A (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (i) (COCl)2, DMF, DCM, (ii) DIEA, THF, (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfanylidene) tert-butyl carbamate; b) TFA, DCM, rt

[0264] Step 1: (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (R)-sulfanylidene)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) was added oxalyl chloride (78 mg, 0.62 mmol) and DMF (20 μL). The mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and (R)-((3-aminophenyl)(methyl)(oxo)λ 6 To a solution of tert-butyl (-sulfanylidene)carbamate (102 mg, 0.38 mmol) and DIEA (178 mg, 1.38 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (-sulfanylidene)carbamate (110 mg, 53.4%) was obtained as a yellow oil. LCMS (ESI) calcd. for C 26 H 25 ClF4N3O5S [M + H] + m / z 602.12, found 602.00.

[0265] Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 45% to 95% MeCN / HO (with 0.1% NH) gave (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. 1 H 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 = 8.9Hz, 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 C 21 H 17 ClF4N3O3S[M + H] + m / z 502.06, found 502.00.

[0266] Example 2A (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (i) SOCl2, 80°C; (ii) (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfanylidene) tert-butyl carbamate, DIEA, THF; b) TFA, DCM, rt

[0267] Step 1: (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 0.95 mmol) in SOCl (5 mL) was stirred at 80° C. for 0.5 h. The solution was then concentrated under reduced pressure to give the chloride intermediate. This chloride intermediate was converted to (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (R)-sulfanylidene)carbamate (388 mg, 1.44 mmol) and DIEA (464.4 mg, 3.6 mmol) in THF (5 mL) was added at 0° C. The resulting mixture was stirred at 25° C. for 0.5 h. The mixture was then quenched with water (40 mL) and extracted with DCM (30 mL×2). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=3 / 1) to give (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (-sulfanylidene)carbamate (400 mg, 74.3%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 26 H 26 F4N3O5S [M + H] + m / z 568.16, found 568.10.

[0268] Step 2: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)carbamate (400 mg, 0.70 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 complete, the solution was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 35% to 90% MeCN / HO (with 0.1% NH) gave (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. 1 H 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. forC 21 H 18 F4N3O3S [M + H] + m / z 468.10, found 468.00.

[0269] Example 3A (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (i) (COCl)2, DMF, DCM; (ii) Et3N, THF; b) TFA, DCM

[0270] Step 1: (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid (75 mg, 0.23 mmol) in DCM (3 mL) was added oxalyl chloride (289 mg, 2.28 mmol) and DMF (20 μL). The mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (6-sulfanylidene)carbamate (74 mg, 0.27 mmol) and EtN (115 mg, 1.14 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (-sulfanylidene)carbamate (55 mg, 41.5%) was obtained as a yellow oil. LCMS (ESI) calcd. for C 27 H 28 F4N3O5S [M + H] +m / z 582.17, found 582.10.

[0271] Step 2: (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to a 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, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% NHOH) gave (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. forC 22 H 20 F4N3O3S [M + H] +m / z 482.12, found 482.05.

[0272] Example 4A (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfanylidene) tert-butyl carbamate, pyridine, POCl3; b) TFA, DCM

[0273] Step 1: (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfanylidene) tert-butyl carbamate: 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid (150 mg, 0.45 mmol), (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 To a mixture of tert-butyl 2-sulfanylidene)carbamate (146 mg, 0.54 mmol) in pyridine (5 mL) was added POCl (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 × 2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (-sulfanylidene)carbamate (120 mg, 45.5%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 26 H 25 F5N3O5S [M + H] + m / z 586.15, found 586.10.

[0274] Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (30 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 95% MeCN / HO (containing 0.05% NH) gave (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, 1H), 4.25 (s, 1H), 3.06 (s, 3H), 2.30 (s, 3H). LCMS(ESI) calcd. for C 21 H 17 F5N3O3S[M + H] + m / z 486.09, found 486.05.

[0275] Examples 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 [ka] Reagents and 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

[0276] Step 1: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: To 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 the addition, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated. The residue was diluted with THF and added dropwise to a stirred solution of NH3-H2O (5 mL). Then, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 C 14 H 10 ClF4N2O2[M + H] + m / z 349.04, found 349.00.

[0277] Step 2: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: To 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), CsCO (292 mg, 0.89 mmol), and Xantphos-Pd-G (61 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at 100° C. under nitrogen for 16 hours. After the reaction was complete, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 C 20 H 15 ClF4N3O3S [M + H] + m / z 488.05, found 488.05.

[0278] 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) (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 complete, the reaction was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (15 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / Et0Ac=1 / 1) to give the crude product, which was then purified by prep-HPLC (Gemini 5um C 18 Purification again on a column, 150 x 21.2 mm, eluting with 30% to 90% MeCN / HO (containing 0.1% formic acid) gave 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 C 20 H 16 ClF4N4O3S [M + H] + m / z 503.06, found 503.00.

[0279] 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 x 250 mm, eluted with 35% CO-MeOH (with 0.1% NH). The first eluting isomer was lyophilized to give (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. 1 H 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 C 20 H 16 ClF4N4O3S[M + H] + m / z 503.06, found 503.05. The second elution was (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 C 20 H 16 ClF4N4O3S[M + H] + m / z 503.06, found 503.05.

[0280] 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 [ka] Reagents and conditions: a) (i) (COCl)2, DMF; DCM; (ii) (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfanylidene) tert-butyl carbamate, Et3N, THF; b) TFA, DCM

[0281] Step 1: (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl 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 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl 2-sulfanylidene)carbamate (86 mg, 0.32 mmol) and TEA (133 mg, 1.32 mmol) in THF (5 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (-sulfanylidene)carbamate (75 mg, 47.9%) was obtained as a yellow oil. LCMS (ESI) calcd. for C 30 H 33 FN5O5S [M + H] + m / z 594.22, found 594.15.

[0282] 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: (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamide)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% NHOH) gave (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. 1 H 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. forC 25 H 25 FN5O3S [M + H] + m / z 494.17, found 494.05.

[0283] Example 8A [ka] Reagents and conditions: a) POCl3, pyridine; b) TFA, DCM

[0284] Step 1. tert-Butyl (R)-((5-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-16-sulfanylidene)carbamate: To 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-sulfanylidene)carbamate (70 mg, 0.24 mmol) in pyridine (3 mL), POCl (0.09 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. After the reaction was complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1:1 to 1 / 2) to give tert-butyl (R)-((5-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-16-sulfanylidene)carbamate (60 mg, 57.8% yield) as a yellow solid. LCMS (ESI) calcd. for C 28 H 25 ClF4N3O6S[M + H] + m / z 642.11, found 642.1.

[0285] Step 2. (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: To a solution of tert-butyl (R)-((5-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-16-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (15 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by prep-HPLC (Gemini 5um C 18 Column, 150 × 21.2 mm, 20% to 65% MeCN / HO (0.05% NH 3. Purification by chromatography (elution with HO) gave (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. 1 H 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, 3H), 7.17 (d, J = 8.3 Hz, 1H), 4.68 (s, 1H), 3.79 (s, 3H), 3.18 (s, 3H). LCMS (ESI) calcd. for C 23 H 17 ClF4N3O4S[M + H] + m / z 542.06, found 542.1.

[0286] Example 9A [ka] Reagents and conditions: a) (i) SOCl2, 80 °C; (ii) DIEA, THF; b) TFA, DCM

[0287] 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-sulfanylidene)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 SOCl (2 mL) was heated at 80 °C for 1 h. The solution was concentrated under reduced pressure to give the chloride intermediate. This chloride intermediate in THF (5 mL) was then diluted with tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfanylidene)carbamate (110.2 mg, 0.41 mmol) and DIEA (175.0 mg, 1.3 mmol) in THF (1 mL). 5 mmol) at 0° C. and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. 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-sulfanylidene)carbamate (130 mg, 69.4%) as a yellow solid. LCMS (ESI) calcd. for C 30 H 32 F4N3O5S[M + H] + m / z 622.20, found 622.10.

[0288] Step 2. (R)-4-Cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: To 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-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Column, 150 × 21.2 mm, 40% to 95% MeCN / HO (0.05% NH 3. Purification by chromatography (elution with HO) gave (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. 1 H 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, 2H). LCMS (ESI) calcd. for C25 H 24 F4N3O3S[M + H] + m / z 522.15, found 522.20.

[0289] Example 10A (R)-3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (i) SOCl2, 80 °C; (ii) DIEA, THF; b) TFA, DCM

[0290] 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-sulfanylidene)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 SOCl (3 mL) was heated to 80 °C and stirred for 0.5 h. The solution was concentrated under reduced pressure to give the chloride intermediate. This chloride intermediate was then added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfanylidene)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 h. The mixture was then quenched with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=3 / 2) to give tert-butyl (R)-((3-(3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)carbamate (180 mg, 70.82% yield) as a pale yellow oil. LCMS (ESI) calcd. for C 27 H 26 ClF4N3O5SNa[M + Na] + m / z 638.11, found 637.95.

[0291] Step 2. (R)-3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: To 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-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (15 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Column, 150 × 21.2 mm, 40% to 95% MeCN / HO (0.05% NH 3. Purification by chromatography (elution with HO) to afford (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. 1 H 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, 2H), 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 C 22 H 19 ClF4N3O3S[M + H] +m / z 516.08, found 516.00.

[0292] Example 11A [ka] Reagents and conditions: a) Cs2CO3, MeCN, 80 °C; b) TFA, DCM

[0293] Step 1. tert-Butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate: A mixture of tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (200 mg, 0.40 mmol), 4-bromo-2-methoxyphenol (123 mg, 0.60 mmol), and CsCO (393 mg, 1.21 mmol) in MeCN (5 mL) was heated to 80° C. and stirred for 2 h. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (220 mg, 80.4% yield) as a yellow solid. LCMS (ESI) calcd. for C 26 H 25 BrClF3N3O6S[M + H] + m / z 678.03, found 680.1.

[0294] Step 2. (R)-2-(4-Bromo-2-methoxyphenoxy)-5-chloro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: To a solution of tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (15 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 50% to 95% MeCN / HO (with 0.1% formic acid) gave (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. 1 H 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 C 21 H 17 BrClF3N4O4S[M + H] + m / z 577.98, found 579.9.

[0295] Example 12A [ka] Reagents and conditions: a) Zn(CN)2, Xbuxphos-Pd-G3, THF / H2O, 50 °C; b) TFA, DCM

[0296] Step 1. tert-Butyl (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate: A mixture of tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (130 mg, 0.19 mmol), Zn(CN) (34 mg, 0.29 mmol), and tBuXphos-Pd-G (15 mg, 0.02 mmol) in 5 mL of THF / HO=4 / 1 was heated to 50° C. and stirred under a nitrogen atmosphere for 5 hours. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give tert-butyl (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (100 mg, 83.5% yield) as a yellow solid. LCMS (ESI) calcd. for C 27 H 25 ClF3N4O6S[M + H] + m / z 625.12, found 625.1.

[0297] Step 2. (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: To a solution of tert-butyl (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (15 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 50% to 95% MeCN / HO (with 0.1% formic acid) gave (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. 1 H 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 C 22 H 17 ClF3N4O4S[M + H] + m / z 525.06, found 525.0.

[0298] Example 13A [ka] Reagents and conditions: a) Cs2CO3, MeCN, 80 °C; b) TFA, DCM

[0299] 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)-l6-sulfanylidene)carbamate: A solution of 6-fluoro-2-(methyl-d3)pyridin-3-ol (26.2 mg, 0.20 mmol), (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-l6-sulfanylidene)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 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by flash chromatography (PE / EA=5:1) to give 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-sulfanylidene)carbamate (80 mg, 66.1% yield) as a white solid. LCMS (ESI) calcd. for C 25 H 20 D3ClF4N4O5SNa[M + Na] + m / z 628.12, found 628.0.

[0300] 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: To 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-sulfanylidene)carbamate (80 mg, 0.13 mmol) in DCM (5 mL), TFA (1 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH 8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Column, 150 × 21.2 mm, 55% to 60% MeCN / HO (0.05% NH 3. Purification by chromatography (elution with HO) to afford (R)-5-chloro-2-((6-fluoro-2-(methyl-d)pyridin-3-yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (27.00 mg, 41.1% yield) as a white solid. 1 H 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, 1H), 7.06 (dd, J = 8.7, 3.4Hz, 1H), 4.39 (s, 1H), 3.14 (s, 3H). LCMS (ESI)calcd. for C 20 H 13 D3ClF4N4O3S[M + H] + m / z 506.08, found 506.0.

[0301] Example 14A [ka] Reagents and conditions: a) HATU, DIEA, DMF; b) BH3·THF, THF; c) TFA, DCM

[0302] Step 1. tert-Butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)amino)-2-oxoethyl)carbamate: To 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 complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 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-sulfanylidene)amino)-2-oxoethyl)carbamate (100 mg, 63.5% yield) as a yellow solid. LCMS (ESI) calcd. for C 28 H 28 ClF4N4O6S[M + H] + m / z 659.14, found 659.10.

[0303] Step 2. tert-Butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)amino)ethyl)carbamate: To 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-sulfanylidene)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. under nitrogen for 1 hour. 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, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)amino)ethyl)tert-butylcarbamate (350 mg, 51.24% yield) as a white solid. LCMS (ESI) calcd. for C 28 H 30 ClF4N4O5S[M + H] + m / z 645.16, found 645.10.

[0304] Step 3. (R)—N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: To a solution of (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)amino)ethyl)tert-butyl carbamate (350 mg, 0.54 mmol) in DCM (10 mL), TFA (1 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was quenched with saturated aqueous NaHCO (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% formic acid) gave (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. 1 H 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 C 23 H 22 ClF4N4O3S[M + H] +m / z 545.11, found 545.00.

[0305] The following compounds were prepared using the techniques of the Intermediates and Examples described above. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0306] Example 74A Compound Profiling Human NaV1.8 / β3 Cell Line - SyncroPatch384PE Assay Compounds were tested on CHO cells stably transfected with recombinant human Nav1.8 / b3 using the SynchroPatch384PE system (Nanion Technologies), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2 in Ham's F-12 medium 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 recording, cells in the culture dish 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-well NPC-384 chip, cells were washed in HBSS to remove Accutase and resuspended in extracellular solution. All experiments were performed at ambient temperature. The intracellular solution contained (mM): CsCl 50; CsF 90; MgCl2 5; EGTA 1; HEPES 10, pH adjusted to 7.2 with CsOH. The 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.

[0307] Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3.33 with extracellular solution to generate eight-point concentration-response curves. Each plate included a historical positive control and up to 10 compounds. 300 μM tetracaine and 0.3% DMSO + 0.03% pluronic acid were used as high and low controls, respectively.

[0308] Whole-cell patch-clamp recordings were performed according to Nanion's standard procedure for SyncroPatch384PE®. Cells were held at a holding potential of -120 mV. A 30 ms depolarizing step to 10 mV was applied (P1 measurement), followed by a 100 ms hyperpolarizing step to -100 mV. A 10 s inactivating step at -35 mV was applied, followed by a 20 ms step to -100 mV, followed by a 30 ms step to 10 mV (P2 measurement), followed by a 30 ms return to -100 mV. The sweep interval was 15 s. After establishing the whole-cell configuration in the extracellular solution, cells were washed in an extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize baseline currents. Compounds were then applied to each well using the SynchroPatch384 PE system, and currents were recorded in the extracellular solution for 5 minutes, after which tetracaine was applied at the end of the experiment to achieve complete blockade. Compound efficacy was assessed using two readings: resting-state block (P1 measurement) or inactivation-state block (P2 measurement), to obtain IC50 values. Values ​​were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.

[0309] The table below shows the human Na V 1.8, and "A" indicates the potency of the compound against IC 50 "B" indicates an IC of greater than 5 nM but less than 50 nM or equal to 50 nM. 50 "C" represents an IC greater than 50 nM but less than 100 nM or equal to 100 nM 50"D" represents an IC of greater than 100 nM but less than 200 nM or equal to 200 nM 50 and "E" represents an IC50 greater than 200 nM. [Table 2-1] [Table 2-2]

[0310] Example 75A Compound Profiling Human NaV1.8 / β1 Cell Line - Sophion QPatch II Assay Compounds were applied to recombinant human NaCl using an automated patch clamp device, the QPatch II system (Sophion Bioscience A / S, Ballerup - Denmark). V The study was performed on HEK293 (Eurofins, CYL3025, St. Charles, MO) cells stably transfected with 1.8 / β1. Cells were cultured at 37°C / 5% CO2 in 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 before recording, cells were transferred to a cooler incubator at 30°C / 5% CO2 to increase channel surface expression. On the day of recording, cells in the culture dish were incubated with Ca 2+ -Mg 2+Cells were washed twice with free DPBS and treated with Detachin (Genlantis, San Diego) for 3 minutes, then resuspended in serum-free medium (EX-CELL® ACF CHO medium (Sigma-Aldrich) for cell culture 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 an on-board QStirrer. All experiments were performed at ambient temperature. The intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl2, 2; EGTA, 5; HEPES, 10, and the pH was adjusted to 7.2 with CsOH. The extracellular solution contained (mM): NaCl, 137; KCl, 4; CaCl, 3.8; MgCl, 1; HEPES, 10; glucose, 10, and the pH was adjusted to 7.4 with NaOH. 500 nM tetrodotoxin (TTX) was added to this extracellular solution to block endogenous TTX-sensitive sodium currents.

[0311] Compounds were tested in two cohorts of wells in an interleaved fashion to generate a total of eight concentration-response curves. The final concentration contained 0.1% DMSO and 0.03% pluronic acid. The concentration range generally ranged from 0.01 to 300 nM. Compounds were diluted 1:10 with extracellular solution within each cohort. DMSO (0.1% by volume) served as a vehicle control to verify assay performance.

[0312] Whole-cell patch-clamp recordings were performed according to Sophion standard procedures on a QPatch II®. Cells were held at a holding potential of -120 mV. A 30 ms depolarizing step to 10 mV was applied to measure inward Na +Currents were elicited. The interval between sweeps was 15 seconds. After establishing the whole-cell configuration in the extracellular solution, cells were washed twice in an extracellular solution containing 0.1% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied to each well in an ascending fashion within a cohort using the QPatch II system, and currents were recorded for 5 minutes for each concentration. The percentage of remaining current was determined by averaging at least five sweeps within each concentration and normalizing to the most recent pre-compound saline period. Compound potency (IC 50 ) values ​​were assessed for resting-state block only. Wells in which the initial sodium current magnitude was less than 2 nA or the whole-cell resistance fell below 100 MΩ were excluded from analysis.

[0313] The table below shows the human Na V 1.8, and "A" indicates the potency of the compound against IC 50 "B" indicates an IC of greater than 5 nM but less than 50 nM or equal to 50 nM. 50 "C" represents an IC greater than 50 nM but less than 100 nM or equal to 100 nM 50 "D" represents an IC of greater than 100 nM but less than 200 nM or equal to 200 nM 50 "E" represents an IC greater than 200 nM 50 Represents. [Table 3]

[0314] (B) A second set of compounds In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or halo-C1-C4 alkyl, where the haloalkyl chain may be fully or partially halogenated; substituted or unsubstituted C1-C8 alkyl; deuterated C1-C4 alkyl, where the alkyl chain may be fully or partially deuterated; C3-C 10 substituted with one or more groups selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl, in which the haloalkoxy chain may be fully or partially halogenated, and arylalkoxyl; R1, R2, R3 and R4 are independently hydrogen, -OH, halogen, C1-C6-alkyl, C1-C6 fluoroalkyl where the fluoroalkyl chain may be fully or partially fluorinated, C3-C8 branched alkyl, C3-C8 branched fluoroalkyl where the branched fluoroalkyl chain may be fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R ’ )(R ” )-aryl, NR'R'', 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl; 3- to 6-membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N, a saturated or unsaturated 5-membered or larger ring, or an aryl ring optionally containing one or more heteroatoms independently selected from O, S, and N, wherein each 5-membered or larger ring is unsubstituted or substituted with 1 to 5 substituents selected from hydrogen, cyano, halo, or methyl; a fused ring formed by at least two of R1, R2, R3, and R4, wherein the fused ring is selected from the group consisting of: an optionally saturated carbocyclyl or heterocyclyl containing 5 to 6 ring members, wherein the heterocyclyl is selected from those containing one or more heteroatoms; R5 is H or substituted or unsubstituted C1-C3 alkyl; R6 is -(CH2) n R a , -(CR b R c ) n R a , -(CR b R c ) n -(OCH2CH2) n R a , -(CR b R c ) n -(NR'CH2CH2) n R a , -(CR b R c ) n -(NR'CH2CH2O) n R a , or -(CR b R c ) n -(NHCH2CH2NH) n R a and; where R a is H, C1-C6-alkyl, C2-C8 branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4- to 7-membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2) n R b , -NR'R", -COONR'R", -COOR', alkylsulfonyl, arylsulfonyl, or -SO2NR'R"; R b is independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl having one or more heteroatoms; R c is H, C1-C6 alkyl or F; R c and R boptionally forms a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one or more heteroatoms; R7 is NH2, -NHR', C1-C3 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0315] In various embodiments, the compound of the present invention has formula (II): [ka] wherein in formula (II), ring B and groups R1, R2, R3, R4, R5, R6, and R7 are as defined in claim 1; R8 is H, hydroxyl, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, any of which may have one or more substituents, and wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; Q, T, and W are independently selected from N or CR9; R9 is 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.

[0316] In another embodiment, the compound of the present invention has formula (III): [ka] wherein in formula (III), R1, R2, R3, R4, R5, R6, and R7 are as 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 - is.

[0317] In another embodiment, X is F.

[0318] In another embodiment, R8 is -CH3.

[0319] In another embodiment, Q is N.

[0320] In another embodiment, Q is N, W is CH, and T is CH.

[0321] In another embodiment, R1 is H or F.

[0322] In another embodiment, R2 is H, chloro, or CF3.

[0323] In another embodiment, R3 is H or CF3.

[0324] In another embodiment, R4 is H.

[0325] In another embodiment, R5 is H.

[0326] In another embodiment, R7 is methyl.

[0327] In another embodiment, R6 is 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.

[0328] In another embodiment, R9 is H.

[0329] In another embodiment, the compound of formula (I) is: [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0330] The second set of compounds provided herein are prepared by the methods and procedures described below. The intermediates described in this section are reliable for the preparation of the second set of compounds.

[0331] Chemicals were purchased from standard commercial suppliers and used as received unless otherwise noted. Otherwise, their preparation is straightforward and known to those skilled in the art, or is referenced or described herein. Abbreviations are consistent with those in the ACS style guide. "Dry" glassware means oven / dessicator dried. Solvents were ACS grade unless otherwise noted.

[0332] All reactions were performed in flame-dried glassware or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were magnetically stirred unless otherwise noted. Chemicals were purchased from standard commercial suppliers and used as received unless otherwise noted. Yields were not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.

[0333] Reactions, EMD MILLIPORE TM The purified product was monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from Biotage Inc. Purification was performed on a Biotage Isolera One Flash chromatography instrument or purified using one of the preparative HPLC methods specified below.

[0334] Preparative method 1 Equipment: Shimadzu LCMS 2020 Mass Directed Preparative HPLC System; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (containing 0.1% HCOOH), gradient can be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm;

[0335] Preparative method 2 Instrument: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (containing 0.1% TFA), gradient may be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0336] Preparative method 3 Instrument: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (with 0.05% ammonia), gradient can be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0337] Analytical LCMCs were collected using one of the following methods. Method 1 Instrument: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 μm, 3.0 mm × 30 mm; Mobile phase: MeCN (0.05% HCOOH)-water (0.05% HCOOH); Gradient: 5% to 95% MeCN over 1.4 min with a 0.6 min hold, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.

[0338] Method 2 Instrument: Shimadzu LCMS 2020 mass spectrometer; XBridge BEH C 18 2.5 μm, 3.0 mm x 30 mm Mobile phase: MeCN-water (0.1% NH4OH); Gradient: 5% to 95% MeCN over 1.8 min with a 0.7 min hold, total run time 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.

[0339] Method 3 Instrument: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 μm, 3.0 mm x 30 mm Mobile phase: MeCN (0.05% TFA)-water (0.05% TFA); Gradient: 5% to 95% MeCN over 1.4 min with a 0.6 min hold, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50°C; Wavelength: 214 and 254 nm PDA.

[0340] SFC chiral separation was performed using a Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD SF , SFC-30A) using the following method: Method 1 Column: Daicel chiralpak-AS-H 5um 250 x 20mm; Mobile phase: CO2 / MeOH [0.1% NH3 (7M in MeOH)], CO2 / MeOH ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0341] Method 2 Column: Daicel chiralpak-OJ-H 5um 250x20mm; Mobile phase: CO2 / MeOH (0.1% HCOOH), CO2 / MeOH ratio changed for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0342] Method 3 Column: Daicel chiralpak-OD-H 5um 250x20mm; Mobile phase: CO2 / MeOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0343] Method 4 Column: Daicel chiralpak-AD-H 5um 250x20mm; Mobile phase: CO2 / i-PrOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0344] Method 5 Column: Daicel chiralpak-IC 5um 250x20mm; Mobile phase: CO2 / EtOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0345] Unless otherwise specified, 1 H nuclear magnetic resonance (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 were calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

[0346] General synthetic scheme Several methods for preparing the compounds of the present invention are illustrated in the following schemes and examples. The present invention further provides a process for preparing the compounds of formula I defined above. In some cases, the order of carrying out the above-described reaction schemes can be changed to facilitate the reaction or to avoid undesired reaction products. The following examples are provided for illustrative purposes only and should not be construed as limitations on the disclosed invention.

[0347] [ka] As illustrated in Scheme A, compounds of formula (I) can generally be synthesized by starting with carboxylic acid A-1 and reacting it with a substituted aniline or heteroaryl aniline A-2 using a standard amide coupling reagent, including but not limited to HATU, TBTU, EDC, or T3P, and a base such as DIEA in an organic solvent to provide an intermediate of type A-3. Intermediate A-3 can contain a protecting group (PG), such as Boc, which can be removed by treatment with an acid such as TFA to provide an intermediate having structure A-4. Any suitable PG, such as Cbz or Fmoc, can be used and removed accordingly. The NH group of A-4 can be acylated using a standard amide coupling reagent, such as HATU, in combination with a carboxylic acid and a base such as DIEA, or the NH group can be acylated with a reactive carboxylic acid ester, such as an N-hydroxysuccinimide ester, to provide a compound of formula (I) after removal of the protecting group, if present. Numerous methods exist for acylating the NH group, which can be performed by one skilled in the art. If desired, the compound of formula (I) can be further modified to obtain additional compounds of formula (I). Alternatively, the carboxylic acid A-1 can 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 the carboxamide intermediate A-5, which can undergo metal-catalyzed coupling with a halogen-substituted aryl or heteroaryl compound of the type A-6 to give a compound of formula A-3. The compound of formula (I) can then be obtained from A-3 as described.

[0348] [ka] As further illustrated in Scheme B, in general, compounds of the present invention can be prepared by reacting intermediate A-1 with amine B-1 using amide coupling conditions, or by activation of an appropriately functionalized carboxylic acid A-1 with (COCl) or POCl and an amine B-1 and a base such as DIEA or pyridine in DCM, DMF, or THF to give compounds of type B-2. 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. The R- and S-isomers can also be prepared by coupling the acid with enantiomerically pure amine B-1 followed by deprotection. The sulfoximine nitrogen of intermediate B-3 is acylated using a standard amide coupling reagent, such as, but not limited to, HATU, a base such as DIEA, and HO2C-R6-PG to give compounds of formula B-4. As shown, if B-4 contains PG, it can be removed to give a compound of formula B-5. For example, if a Boc group was used to protect the sulfoximine, it can be removed by treatment with TFA to give a compound of formula B-5. A trialkylsilyl group can be used to protect the hydroxyl group and can be removed by treatment with an aqueous acid such as acetic acid. If no protecting group is required, B-3 can directly give compound B-5.

[0349] [ka] As illustrated in Scheme C, compounds of the present invention can generally be prepared by activating an appropriately functionalized carboxylic acid A-1 with either (COCl) or SOCl in an organic solvent, followed by the addition of NHOH to give C-1. Intermediate C-1 can then be combined with variously substituted Br compounds C-2 using Xantphos-Pd-G2-mediated coupling conditions to give intermediate C-3. Compounds of formula C-3 can 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 into the corresponding R and S isomers using chiral HPLC conditions. Compounds of formula B-4 were obtained using standard amide coupling reagents, such as, but 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. A trialkylsilyl group can be used to protect the hydroxyl group and can be removed by treatment with an aqueous acid such as acetic acid. If no protecting group is needed, B-3 can directly give compound B-5.

[0350] The above schemes are intended to be illustrative and not limiting in any way. One skilled in the art can prepare compounds of formula (I) using these general schemes as a guide, but other methods are available to achieve the synthesis of compounds of the invention. Specific methods to further illustrate the synthesis of compounds of formula (I) are provided with each of the examples.

[0351] Intermediate 1 2-chloro-4-methyl-5-nitronicotinic acid methyl ester [ka] Reagents and conditions: a) Phenyl dichlorophosphate, 160°C

[0352] 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 × 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give methyl 2-chloro-4-methyl-5-nitronicotinate (3 g, 69%) as a pale yellow solid. LCMS (ESI) calcd. for C8H8ClN2O4 [M+H] + m / z 231.02, found 230.85.

[0353] Intermediate 2 (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid [ka] Reagents and conditions: TBSCl, imidazole, DCM

[0354] 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. The mixture was then heated at 25 °C for 16 h. After the reaction was complete, the mixture was diluted with water and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give crude (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (1.4 g), which was used directly in the next step without further purification.

[0355] Intermediate 3 (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid [ka] Reagents and conditions: TBSCl, imidazole, DCM

[0356] 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. The mixture was then warmed to room temperature and stirred for 16 h. After the reaction was complete, the mixture was diluted with water and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give crude (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (1.6 g), which was used directly in the next step without further purification.

[0357] Intermediate 4 [ka]

[0358] 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. The mixture was then stirred at 25 °C for 16 h. After the reaction was complete, the mixture was diluted with water and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give crude 2-((tert-butyldimethylsilyl)oxy)acetic acid (1.6 g), which was used directly in the next step without further purification.

[0359] 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 [ka] Reagents and conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH / THF / HO

[0360] 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: To 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 complete, 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, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give 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 C 30 H 35 ClF4N3O5SSi [M +H] + m / z 688.17, found 688.15.

[0361] 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 / HO / AcOH (1 / 3 / 3, 7 mL) was stirred at room temperature for 4 hours. After the reaction was complete, 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 reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% formic acid) gave 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. 1 H 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. forC 24 H 21 ClF4N3O5S [M + H] +m / z 574.08, found 574.00.

[0362] Example 2B (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid HATU, DIEA, DMF; b) AcOH / THF / HO

[0363] 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: To 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), DIEA (115.9 mg, 0.9 mmol) was added 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 × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc = 1 / 1) to give (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 C 29 H 33 ClF4N3O5SSi [M +H] + m / z 674.15, found 674.05.

[0364] 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 / HO / AcOH (1 / 3 / 3, 7 mL) was stirred at room temperature for 4 hours. After the reaction was complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The organic solution was then washed with water (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 50% to 90% MeCN / HO (containing 0.1% FA) gave (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. 1 H 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, 1H), 3.95 (d, J = 4.9 Hz, 2 H), 3.45 (s, 3 H), 2.34 (s, 3 H). LCMS (ESI) calcd. for C 23 H 19 ClF4N3O5S[M + H] + m / z 560.06, found 560.10.

[0365] 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 [ka] Reagents and conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH / THF / HO

[0366] 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 complete. 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, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give 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 a colorless oil. LCMS (ESI) calcd. for C 30 H 35 ClF4N3O5SSi [M +H] + m / z 688.17, found 688.15.

[0367] 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: To 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 HO (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, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Column, 150 × 21.2 mm, 50% to 95% MeCN / HO (0.05% NH 3. Purification by chromatography (elution with HCl) to afford 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. 1 H 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. forC 24 H 21ClF4N3O5S [M + H] + m / z 574.08, found 573.95.

[0368] Example 4B (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM

[0369] Step 1: (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (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 complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to give (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (2-sulfanylidene)amino)-2-oxoethyl)carbamate (100 mg, 63.5%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 28 H 28 ClF4N4O6S [M + H] + m / z 659.14, found 659.10.

[0370] Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (6-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 50% to 95% MeCN / HO (containing 0.05% NH) gave (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, 1H), 3.43 (s, 3H), 3.23 (s, 2H), 2.34 (s, 3H), 1.69 (bs, 2H). LCMS (ESI) calcd. for C 23 H 20 ClF4N4O4S[M + H] + m / z 559.09, found 559.05.

[0371] Example 5B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM

[0372] Step 1: ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (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 complete, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to give ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (1-sulfanylidene)amino)-1-oxopropan-2-yl)carbamate (120 mg, 74.6%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 29 H 30 ClF4N4O6S [M + H] + m / z 673.15, found 673.10.

[0373] Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 45% to 95% MeCN / HO (with 0.05% NH) gave 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. 1 H 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, 3H), 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. forC 24 H 22 ClF4N4O4S [M + H] + m / z 573.10, found 573.10.

[0374] 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 [ka] Reagents and conditions: a) 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid, HATU, DIEA, DMF; b) TFA, DCM

[0375] Step 1: (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (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 complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to give (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (-sulfanylidene)carbamoyl)cyclobutyl)carbamate (120 mg, 71.8%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 31 H 32 ClF4N4O6S [M + H] + m / z 699.17, found 699.15.

[0376] 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: (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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. The aqueous solution was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 50% to 95% MeCN / HO (with 0.05% NH) gave (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, 3H), 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 C 26 H 24 ClF4N4O4S[M + H] + m / z 599.12, found 599.05.

[0377] 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 [ka] Reagents and conditions: a) 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid, HATU, DIEA, DMF; b) TFA, DCM

[0378] Step 1: (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (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 complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to give (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (2-methyl-1-oxopropan-2-yl)-1-sulfanylideneamino)carbamate (100 mg, 60.9%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 30 H 32 ClF4N4O6S [M + H] + m / z 687.17, found 687.10.

[0379] 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: (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 50% to 95% MeCN / HO (with 0.05% NH) gave (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. 1 H 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, 3H), 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 C 25 H 24 ClF4N4O4S[M + H] + m / z 587.12, found 587.10.

[0380] Example 8B (S)—N—((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6-sulfanylidene)pyrrolidine-2-carboxamide formate [ka] Reagents and conditions: a) (tert-butoxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM

[0381] Step 1: To 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), HATU (183 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give (S)-2-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (-sulfanylidene)carbamoyl)pyrrolidine-1-carboxylate (120 mg, 50.6%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 31 H 33 F4N4O6S [M + H] + m / z 665.21, found 665.10.

[0382] Step 2: (S)-2-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 column, 150 × 21.2 mm, eluted with 40% to 95% MeCN / HO (containing 0.05% NH) to give (S)—N—((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfanylidene)pyrrolidine-2-carboxamide formate (75.6 mg, 72.8%) was obtained as a white solid. 1 H 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, 3.3Hz, 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, 2H). LCMS (ESI) calculation for C 26 H 25 F4N4O4S[M + H] + m / z 565.16, found 565.05.

[0383] Example 9B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM

[0384] Step 1: To 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 complete, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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-sulfanylidene)amino)-1-oxopropan-2-yl)carbamate (90 mg, 43.90% yield) as a white oil. LCMS (ESI) calcd. for C 29 H 31 F4N4O6S [M + H] + m / z 639.19, found 639.10.

[0385] Step 2: ((R)-1-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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. The aqueous solution was then extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% formic acid) gave 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. 1 H 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. forC 24 H 23 F4N4O4S [M + H] + m / z 539.14, found 539.05.

[0386] Example 10B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM

[0387] Step 1: To 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 complete, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (2-sulfanylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 53.65%) was obtained as a white oil. LCMS (ESI) calcd. for C 29 H 31 F4N4O6S [M + H] + m / z 639.19, found 639.05.

[0388] Step 2: (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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 complete, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% formic acid) gave (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. 1 H 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. forC 24 H 23 F4N4O4S [M + H] + m / z 539.14, found 539.05.

[0389] Example 11B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) TFA, DCM

[0390] Step 1: To 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 complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 29 H 34 F4N3O5SSi [M + H] + m / z 640.19, found 640.05.

[0391] Step 2: To 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 HO (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% formic acid) gave (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. 1 H 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. forC 23 H 20 F4N3O5S [M + H] + m / z 526.11, found 526.00.

[0392] Example 12B 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF, HO

[0393] Step 1: To 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), HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.02 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 30 H 36 F4N3O5SSi [M + H] + m / z 654.21, found 654.10.

[0394] Step 2: To 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 HO (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (with 0.1% formic acid) gave 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. 1 H 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 C 24 H 22 F4N3O5S[M + H] + m / z 540.12, found 540.05.

[0395] Example 13B 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / HO

[0396] 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: To 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 × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 30 H 36F4N3O5SSi [M + H] + m / z 654.20, found 654.10.

[0397] Step 2: 2-((6-Fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: To 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 CHCOH (3 mL) and HO (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, 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 reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (containing 0.1% TFA) gave 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. forC 24 H 22 F4N3O5S [M + H] + m / z 540.11, found 540.10.

[0398] Example 14B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM

[0399] Step 1: (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (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) were 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 complete, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (2-sulfanylidene)amino)-2-oxoethyl)carbamate (150 mg, 74.9%) was obtained as a yellow oil. LCMS (ESI) calcd. for C 28 H 29 F4N4O6S [M + H] + m / z 625.17, found 625.05.

[0400] Step 2: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 complete, the solution was diluted with NaHCO3 solution (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 reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 95% MeCN / HO (containing 0.05% NH) gave (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. 1 H 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, 3H), 3.24 (s, 2H), 2.33 (s, 3H), 1.99 (bs, 2H). LCMS (ESI) calcd. for C 23 H 21 F4N4O4S[M + H] + m / z 525.12, found 525.00.

[0401] Example 15B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM

[0402] Step 1: ((R)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (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) were 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 complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give ((R)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (1-sulfanylidene)amino)-1-oxopropan-2-yl)carbamate (80 mg, 59.1%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 29 H 30 F5N4O6S [M + H] + m / z 657.18, found 657.00.

[0403] Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide: ((R)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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 layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 90% MeCN / HO (containing 0.05% NH) gave 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. 1 H 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 C 24 H 22 F5N4O4S[M + H] + m / z 557.13, found 557.00.

[0404] Example 16B (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM

[0405] Step 1: (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (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) were 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 complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (2-sulfanylidene)amino)-2-oxoethyl)carbamate (80 mg, 60.4%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 28 H 28 F5N4O6S [M + H] + m / z 643.16, found 643.00.

[0406] Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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 layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 95% MeCN / HO (with 0.05% NH) gave (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 C 23 H 20 F5N4O4S[M + H] + m / z 543.11, found 543.05.

[0407] Example 17B (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM

[0408] Step 1: (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (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) were 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 complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (2-sulfanylidene)amino)-2-oxoethyl)(methyl)carbamate (80 mg, 59.0%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 29 H 30 F5N4O6S [M + H] + m / z 657.18, found 657.00.

[0409] Step 2: (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (-sulfanylidene)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 complete, 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 reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 95% MeCN / HO (containing 0.05% NH) gave (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. 1 H 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 C 24 H 22 F5N4O4S[M + H] + m / z 557.13, found 557.05.

[0410] 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 [ka] Reagents and conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / HO

[0411] 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: To 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), HATU (176 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol) were added. 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 × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 30 H 35 F5N3O5SSi [M + H] + m / z 672.20, found 672.05.

[0412] 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: To 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 HO (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 complete, the solution was diluted with water (30 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 95% MeCN / HO (with 0.1% formic acid) gave 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. 1 H 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, 1H), 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) calculation for C 24 H 21 F5N3O5S[M + H]+ m / z 558.11, found 558.00.

[0413] 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 [ka] Reagents and conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / HO

[0414] 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: To 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), HATU (176 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol) were added. 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 × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 30 H 35 F5N3O5SSi [M + H] + m / z 672.20, found 672.05.

[0415] 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: To 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 HO (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 complete, 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 reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 95% MeCN / HO (with 0.1% formic acid) gave 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. 1 H 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, 1H), 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 C 24 H 21 F5N3O5S[M + H] +m / z 558.11, found 558.00.

[0416] Example 20B (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide [ka] Reagents and conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) AcOH, THF / HO

[0417] 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: To 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), HATU (176.24 mg, 0.464 mmol) and DIEA (119.81 mg, 0.927 mmol) were added. 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 × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. 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 C 29 H 33 F5N3O5SSi [M + H] + m / z 658.19, found 658.10.

[0418] Step 2: (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: To 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 HO (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 NaHCO. The aqueous solution was then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C 18 Purification by column, 150 × 21.2 mm, eluting with 40% to 50% to 95% MeCN / HO (containing 0.1% FA) gave (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. 1 H 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, 1H), 3.94 (d, J = 5.9 Hz, 2 H), 3.47 (s, 3 H), 2.30 (s, 3 H). LCMS (ESI) calcd.C 23 H 19 F5N3O5S[M + H] + m / z 544.10, found 543.80.

[0419] Example 21B (S)—N—((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfanylidene)pyrrolidine-2-carboxamide [ka] Reagents and conditions: a) (tert-butoxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM

[0420] Step 1: (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 tert-Butyl (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) were 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 complete, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to give (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (-sulfanylidene)carbamoyl)pyrrolidine-1-carboxylate (120 mg, 51.23%) was obtained as a yellow solid. LCMS (ESI) calcd. for C 31 H 32 F5N4O6S [M + H] + m / z 683.2, found 681.05.

[0421] Step 2: (S)—N—((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfanylidene)pyrrolidine-2-carboxamide: (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (-sulfanylidene)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. The aqueous solution was then extracted with DCM (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 um C 18 column, 150 × 21.2 mm, eluted with 50% to 60 to 95% MeCN / HO (containing 0.05% NH) to give (S)—N—((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfanylidene)pyrrolidine-2-carboxamide (41.3 mg, 38.8%) was obtained as a white solid. 1 H 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, 3H), 2.02-1.93 (m, 1 H), 1.79-1.71 (m, 1 H), 1.61-1.43 (m, 2H). LCMS (ESI) calculation for C 26 H 24 F5N4O4S[M + H] + m / z 583.15, found 582.90.

[0422] The following compounds were prepared using the techniques of the Intermediates and Examples described above. [ka] [ka] [ka]

[0423] Example 30B Compound Profiling Human NaV1.8 / β3 Cell Line - SyncroPatch384PE Assay Compounds were tested on CHO cells stably transfected with recombinant human Nav1.8 / b3 using the SynchroPatch384PE system (Nanion Technologies), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2 in Ham's F-12 medium 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 recording, cells in the culture dish 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-well NPC-384 chip, cells were washed in HBSS to remove Accutase and resuspended in extracellular solution. All experiments were performed at ambient temperature. The intracellular solution contained (mM): CsCl 50; CsF 90; MgCl2 5; EGTA 1; HEPES 10, pH adjusted to 7.2 with CsOH. The 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.

[0424] Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3.33 with extracellular solution to generate eight-point concentration-response curves. Each plate included a historical positive control and up to 10 compounds. 300 μM tetracaine and 0.3% DMSO + 0.03% pluronic acid were used as high and low controls, respectively.

[0425] Whole-cell patch-clamp recordings were performed according to Nanion's standard procedure for SyncroPatch384PE®. Cells were held at a holding potential of -120 mV. A 30 ms depolarizing step to 10 mV was applied (P1 measurement), followed by a 100 ms hyperpolarizing step to -100 mV. A 10 s inactivating step at -35 mV was applied, followed by a 20 ms step to -100 mV, followed by a 30 ms step to 10 mV (P2 measurement), followed by a 30 ms return to -100 mV. The sweep interval was 15 s. After establishing the whole-cell configuration in the extracellular solution, cells were washed in an extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize baseline currents. Compounds were then applied to each well using the SynchroPatch384 PE system, and currents were recorded in the extracellular solution for 5 minutes, after which tetracaine was applied at the end of the experiment to achieve complete blockade. Compound efficacy was assessed using two readings: resting-state block (P1 measurement) or inactivation-state block (P2 measurement), to obtain IC50 values. Values ​​were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.

[0426] The table below shows the human Na V 1.8, where "A" represents an IC50 of less than or equal to 5 nM, "B" represents an IC50 of greater than 5 nM but less than or equal to 50 nM, "C" represents an IC50 of greater than 50 nM but less than or equal to 100 nM, "D" represents an IC50 of greater than 100 nM but less than or equal to 200 nM, and "E" represents an IC50 of greater than 200 nM. [Table 4-1] [Table 4-2]

[0427] (C) A third set of compounds In one aspect, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A is a substituted or unsubstituted heteroaryl ring containing at least one heteroatom selected from the group consisting of O, S, or N; wherein one or more substituents on A are selected from H, —OH, halo, C1-C8-alkyl, C1-C8 fully or partially fluorinated fluoroalkyl, C2-C8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, —C(R′)(R″)-cycloalkyl, C(R′)(R″)-aryl, —NR′R″, substituted or unsubstituted 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; B is a substituted or unsubstituted aryl or heteroaryl, where the substitution can be substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, where the alkyl chain can be fully or partially deuterated, halo-C1-C4 alkyl, where the alkyl chain can be fully or partially halogenated, C3-C 10 selected from the group consisting of cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxyl, haloalkoxyl, where the haloalkoxyl chain may be fully or partially halogenated, or arylalkoxyl; C is a substituted or unsubstituted aryl or heteroaryl, where one or more substitutions are independently selected from the group consisting of halo, C1-C8 alkyl, haloalkyl, alkoxy; R1 is selected from the group consisting of: H and C1-C4 alkyl; R2 is of formula (II): [ka] , —C(═O)NH2, and —C(═O)NR′R″; In formula (II), m and n are independently 0 or 1; and X1 is O and X2 is either NH or NR'; or Both X1 and X2 are O, NH, or NR'; or X1 is O and X2 is NR3; where R3 is selected from the group consisting of: CD3, C1-C4 alkyl 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; R4 is selected from the group consisting of: -NH2, -NR'R", C1-C4 alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl.

[0428] In another embodiment, B is a 6-membered substituted or unsubstituted heteroaryl ring containing one or more N atoms. The N atoms in the heteroaryl ring may be in the form of an N-oxide. In certain embodiments, the N-oxide-containing B ring is selected from pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0429] In another embodiment, the compound has the formula (III): [ka] wherein Q, T and W are independently N or CR6; R6 is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy; R5 is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl in which the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, any of which may carry one or more substituents; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, -OCF3.

[0430] In another embodiment, the compound has the formula (IV): [ka] and in formula (IV): Z is CR 10 , N, or N + O - where R 10 is H, halo, -CD3, C1-C8 alkyl, haloalkyl, or alkoxy.

[0431] In certain embodiments, ring A is a substituted or unsubstituted 6-membered or greater heteroaryl ring having at least one heteroatom independently selected from N, O, or S.

[0432] In certain embodiments, Ring A is a substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0433] In certain embodiments, ring A is a substituted or unsubstituted 6-membered heteroaryl having at least one heteroatom, where the heteroatom is N. In certain embodiments, ring A is a substituted or unsubstituted 6-membered heteroaryl having at least two N atoms.

[0434] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1, Q2, Q3 and Q4 are independently: N, N + O - or CR7; wherein at least two of Q1, Q2, Q3 and Q4 are CR7; R7 is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5- or 6-membered heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl.

[0435] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where: Q2 and Q4 are independently N or N + O - Is it; Q2 is N or N + O - and Q4 is CR7; or Q2 is CR7 and Q4 is N or N + O - and; R8 and R9 are independently selected from the 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;

[0436] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where: Q3 and Q4 are independently N or N + O - Is it; Q3 is N or N + O - and Q4 is CR7; or Q3 is CR7 and Q4 is N or N + O - where R7, R8 and R9 are defined above.

[0437] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where: Q1 and Q4 are independently N or N + O - Is it; Q1 is N or N + O - and Q4 is CR7; Q1 is CR7 and Q4 is N or N + O - or Q1 or Q4 is CR7; where R7, R8, and R9 are defined above.

[0438] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1 and Q2 are N; and where R8 and R9 are defined above.

[0439] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1 is CR7 and Q2 is N; R7, R8, and R9 are defined above.

[0440] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), A is: [ka] where Q1 is N; Q2 is CR7; and R7, R8, and R9 are defined above.

[0441] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2 is: [ka] where m and n are independently 0 or 1; X1 is O, X2 is NH, and R4 is alkyl, such as methyl.

[0442] In other embodiments, in the compounds of Formula (I), Formula (III), and / or Formula (IV), R2 is: [ka] where m and n are independently 0 or 1; X1 is O, X2 is O, and R4 is NH2 or alkyl, such as methyl.

[0443] In another embodiment, R2 is -S(=O)CH3. In another embodiment, in the compound of Formula (III) and / or Formula (IV), Q is N or CH; R5 is methyl or -OMe, and X is F or CN. In another embodiment, in the compound of Formula (III) and / or Formula (IV), Q is CF. In another embodiment, R7, R8, and R9 are independently selected from the group consisting of: H, methyl, fluoro, chloro, bromo, CF3, cyclopropyl, difluorophenyl, and dimethylpyrazole. In another embodiment, in the compound of Formula (III) and / or Formula (IV), R 10 is H or F. In other embodiments, in the compounds of Formula (III) and / or Formula (IV), Z is N or CH.

[0444] In certain embodiments of the invention, R2 does not include -C(=O)NH2 or -C(=O)NR'R''.

[0445] In certain embodiments, R2 is of formula (II): [ka] and in formula (II): m and n are independently 0 or 1; and X1 and X2 cannot both be O, NH, or NR'.

[0446] In other embodiments, the compounds of the invention are: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0447] The third set of compounds provided herein are prepared by the methods and procedures described below. The intermediates described in this section are reliable for the preparation of the third set of compounds.

[0448] Methods for making the compounds of the present invention, and intermediates used in their synthesis, are provided in the following general synthetic schemes and specific synthetic procedures. Chemicals were purchased from standard commercial suppliers and used as received unless otherwise noted. Otherwise, their preparation is straightforward and known to those skilled in the art, or is referenced or described herein. Abbreviations are consistent with those in the ACS style guide. "Dry" glassware means oven / dessicator dried. Solvents were ACS grade unless otherwise noted.

[0449] All reactions were performed in flame-dried glassware or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were magnetically stirred unless otherwise noted. Chemicals were purchased from standard commercial suppliers and used as received unless otherwise noted. Yields were not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.

[0450] Reactions, EMD MILLIPORE TM The purified product was monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from Biotage Inc. Purification was performed on a Biotage Isolera One Flash chromatography instrument or purified using one of the preparative HPLC methods specified below.

[0451] Preparative method 1 Equipment: Shimadzu LCMS 2020 Mass Directed Preparative HPLC System; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (containing 0.1% HCOOH), gradient can be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm;

[0452] Preparative method 2 Instrument: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (containing 0.1% TFA), gradient may be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0453] Preparative method 3 Instrument: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5um C 18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O (with 0.05% ammonia), gradient can be adjusted slightly for specific compounds; flow rate: 20 mL / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0454] Analytical LCMCs were collected using one of the following methods. Analysis method 1 Instrument: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 μm, 3.0 mm × 30 mm; Mobile phase: MeCN (0.05% HCOOH)-water (0.05% HCOOH); Gradient: 5% to 95% MeCN over 1.4 min with a 0.6 min hold, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.

[0455] Analysis method 2 Instrument: Shimadzu LCMS 2020 mass spectrometer; XBridge BEH C 18 2.5 μm, 3.0 mm x 30 mm Mobile phase: MeCN-water (0.1% NH4OH); Gradient: 5% to 95% MeCN over 1.8 min with a 0.7 min hold, total run time 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.

[0456] Analysis method 3 Instrument: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 μm, 3.0 mm x 30 mm Mobile phase: MeCN (0.05% TFA)-water (0.05% TFA); Gradient: 5% to 95% MeCN over 1.4 min with a 0.6 min hold, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50°C; Wavelength: 214 and 254 nm PDA.

[0457] SFC chiral separation was performed using a Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD SF , SFC-30A) using the following method: Analysis method 4 Column: Daicel chiralpak-AS-H 5um 250 x 20mm; Mobile phase: CO2 / MeOH [0.1% NH3 (7M in MeOH)], CO2 / MeOH ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0458] Analysis method 5 Column: Daicel chiralpak-OJ-H 5um 250x20mm; Mobile phase: CO2 / MeOH (0.1% HCOOH), CO2 / MeOH ratio changed for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0459] Analysis method 6 Column: Daicel chiralpak-OD-H 5um 250x20mm; Mobile phase: CO2 / MeOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0460] Analysis method 7 Column: Daicel chiralpak-AD-H 5um 250x20mm; Mobile phase: CO2 / i-PrOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0461] Analysis method 8 Column: Daicel chiralpak-IC 5um 250x20mm; Mobile phase: CO2 / EtOH, ratio varied for different compounds; Oven temperature: 40°C; Flow rate: 38mL / min.

[0462] Unless otherwise specified, 1 H nuclear magnetic resonance (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 were calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

[0463] General synthetic scheme Several methods for preparing the compounds of the present invention are illustrated in the following schemes and examples. The present invention further provides a process for preparing the compounds of formula I defined above. In some cases, the order of carrying out the above-described reaction schemes can be changed to facilitate the reaction or to avoid undesired reaction products. The following examples are provided for illustrative purposes only and should not be construed as limitations on the disclosed invention.

[0464] Compounds of formula (I) can be prepared from A-1 starting materials or intermediates, including 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-diiodoisonicotinate, 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, which are commercially available, synthesized using published procedures, or by methods known to those skilled in the art. Modifications can be made to the starting materials and intermediates to prepare still other intermediates, having alternative or additional groups such as alkyl, fluoroalkyl, trifluoromethyl, cyano, halogen, chloro, bromo, iodo, amino, nitro, aryl, heteroaryl, carboalkoxy, alkoxy, aryloxy, and heteroaryloxy. The methods used to convert the starting materials to compounds of formula (I) are provided for each of the examples.

[0465] [ka] As illustrated in Scheme A, compounds of Formula (I) can generally be synthesized from a starting material or intermediate of type A-1. Rings A and X of A-1 can be first modified to provide intermediate A-1, suitable for subsequent modification. Modifications can include, but are not limited to, exchange of trifluoromethyl with halogen, metal-catalyzed coupling to introduce alkyl, aromatic, or heteroaromatic groups, treatment with nitric acid to introduce a nitro group, reduction of the nitro group to an amino group, or other transformations known to those skilled in the art. The X group of A-1 can be displaced with various substituted phenols or heteroaromatic alcohols in the presence of a base such as KCO, CsCO, 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 at ring A, and the carboxylic acid ester is then hydrolyzed with KOH or LiOH in aqueous solvent to provide carboxylic acid intermediate A-3. Intermediate A-3 can be reacted with a substituted aniline or heteroaryl aniline using standard amide coupling reagents, including but not limited to HATU, TBTU, EDC, or T3P, in an organic solvent, and a base, such as DIEA, to provide a compound of formula (I). If desired, the compound of formula (I) can be further modified to provide additional compounds of formula (I). Alternatively, intermediate A-2 can be treated with ammonia, a primary amine (R1NH2), or a dialkylaluminum amide to provide carboxamide A-4, which can undergo metal-catalyzed coupling with a halo-substituted aniline or heteroaryl aniline to provide a compound of formula (I).

[0466] [ka] As illustrated in Scheme B, compounds of the present invention can generally be prepared by reacting a substituted compound A-1 with an aryl- or heteroaryl-alcohol B using a base such as DIEA or an inorganic base such as KCO or CsCO to yield intermediate A-2. Intermediate A-2 can be converted to the corresponding acid A-3 by treating A-2 with a base such as KOH, LiOH, or NaOH in aqueous EtOH or MeOH or a mixture of MeOH / THF / HO. Intermediate A-5 can be formed either by treating A-3 and an amine C using amide coupling conditions or by activation of an appropriately functionalized carboxylic acid A-4 with (COCl) or POCl and an amine C and a base such as DIEA or pyridine in DCM, DMF, or THF. 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 into the corresponding R and S isomers using chiral HPLC. The R- and S-isomers can also be prepared by coupling the acid with an enantiomerically pure amine C followed by deprotection.

[0467] [ka] As illustrated in Scheme C, in general, compounds of the present invention can be prepared by activating an appropriately functionalized carboxylic acid A-3 with either (COCl) or SOCl in an organic solvent, followed by the addition of NHOH to give B-1. Intermediate B-1 can then be combined with variously substituted Br compounds using Xantphos-Pd-G2-mediated coupling conditions to give intermediate B-2. Compounds of formula B-2 can be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to give compounds of formula B-3. In some instances, B-3 was separated into the corresponding R and S isomers using chiral HPLC conditions.

[0468] Intermediate 1 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid [ka] Reagents and conditions: a) Fuming HNO3, H2SO4, 0-50℃; b) PhOPOCl2, 160℃; c) Cs2CO3, MeCN, 50℃; d) Fe, NH4Cl, MeOH / H 2O, 50℃; e) p-TsOH·H2O, NaNO2, KI, MeCN / H2O, rt; f) CuI, DMF, N2, 120℃; g) LiOH, THF / MeOH / H2O, rt

[0469] Step 1. Methyl 2-hydroxy-4-methyl-5-nitronicotinate: To a stirred solution of methyl 2-hydroxy-4-methylnicotinate (40 g, 0.24 mol) in HSO (200 mL) was added fuming HNO (13 mL) dropwise at 0 °C. The mixture was heated to 50 °C for 5 h. The resulting mixture was poured into ice water (3 L). The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give crude methyl 2-hydroxy-4-methyl-5-nitronicotinate (26 g, 51% yield) as a yellow solid. LCMS (ESI) calcd. for CHNO [M + H] + m / z 213.05, found 212.90.

[0470] 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 h. The resulting solution was cooled to room temperature, quenched with water (100 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give methyl 2-chloro-4-methyl-5-nitronicotinate (6 g, 69% yield) as a pale yellow solid. LCMS (ESI) calcd. for C8H8ClN2O4 [M + H] + m / z 231.02, found 231.00.

[0471] 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 CsCO (8.46 g, 26 mmol). The mixture was heated at 50 °C for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was directly purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1 to 3 / 1) to give methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate (4.2 g, 77% yield) as a pale yellow solid. LCMS (ESI) calcd. for C 14 H 13 FN3O5[M + H] + m / z 322.09, found 322.00.

[0472] Step 4. Methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To 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 h. After the reaction was complete, 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, and concentrated under reduced pressure to give 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 C 14 H 15 FN3O3[M + H] + m / z 292.11, found 291.95.

[0473] Step 5. Methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate: TsOH .To a solution of HO (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 NaNO (950 mg, 13.8 mmol) and KI (2.86 g, 17.3 mmol) in HO (10 mL) at 0 °C. The mixture was stirred at room temperature for 2.5 h. After the reaction was complete, the mixture was quenched with water (100 mL) and adjusted to pH = 8-9 with saturated aqueous NaHCO. The solution was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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)-5-iodo-4-methylnicotinate (2.2 g, 78% yield) as a yellow solid. LCMS (ESI) calcd. for C 14 H 13 FIN2O3[M + H] + m / z 403.00, found 402.90.

[0474] 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), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.88 g, 15 mmol) was added dropwise at room temperature under an atmosphere of N. The mixture was heated at 120 °C for 6 hours. After the reaction was complete, the resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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) calculation for C 15 H 13 F4N2O3[M + H] + m / z 345.09, found 344.95.

[0475] 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 / HO (1 / 1 / 1, 30 mL) was added LiOH.HO (730 mg, 17.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH 3-4 with aqueous HCl (1 M). The solution was then extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 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 C 14 H 11 F4N2O3[M + H] + m / z 331.07, found 330.90.

[0476] Intermediate 2 5-Bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid [ka] Reagents and 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

[0477] 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 CsCO (10.0 g, 31.5 mmol). The mixture was heated at 50° C. for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure and directly purified by flash column chromatography on silica gel (PE / EtOAc=3 / 1) to give methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate (2.7 g, 53.6%) as a pale yellow solid. LCMS (ESI) calcd. for C 14 H 13 FN3O5[M + H] + m / z 322.09, found 321.95.

[0478] Step 2: Methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To 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), NH4Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol) were added. The mixture was heated to 60°C for 1 hour. After the reaction was complete, 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 and concentrated under reduced pressure to give 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 C 14 H 15 FN3O3[M + H] + m / z 292.11, found 292.00.

[0479] 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×3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 C 14 H 13 BrFN2O3[M + H] + m / z 357.01, found 356.85.

[0480] Step 4: 5-Bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid: To 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 HO (5 mL) was added LiOH.HO (483 mg, 10.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH=3-4 with 1N HCl. The aqueous solution was then extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid (490 mg, 82%) as a brown solid. LCMS (ESI) calcd. for C 13 H 11 BrFN2O3[M + H] + m / z 341.00, found 340.85.

[0481] Intermediate 3 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid [ka] Reagents and conditions: a) 6-fluoro-2-methylpyridin-3-ol, DIEA, DMF, 100 °C; b) LiOH, THF, HO, rt

[0482] 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 complete, the reaction was cooled to room temperature. The resulting solution was diluted with water (80 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. 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 C 14 H 12 F4N3O3[M + H] + m / z 346.08, found 345.90.

[0483] 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 / HO (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 complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and 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 C 13 H 10 F4N3O3[M + H] + m / z 332.07, found 331.90.

[0484] Intermediate 4 5-Bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid [ka] Reagents and 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

[0485] 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 CsCO (6.36 g, 19.5 mmol). The mixture was heated at 50 °C for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and directly purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1 to 3 / 1) to give methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinate (2.5 g, 56%) as a pale yellow solid. LCMS (ESI) calcd. for C 16 H 14 N3O6[M + H] + m / z 344.09, found 343.95.

[0486] Step 2: Methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: To 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) and Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 °C for 1 h. After the reaction was complete, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (2 g, 87.7%) as a yellow solid. LCMS (ESI) calculation for C 16 H 16 N3O4[M + H] + m / z 314.11, found 313.90.

[0487] 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 complete, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 C 16 H 14 BrN2O4[M + H] + m / z 377.01, found 377.05.

[0488] Step 4: 5-Bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid: To 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 HO (3 mL) was added LiOH.HO (336 mg, 8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH 3-4 with 1N HCl. The aqueous solution was then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid (420 mg, 61%) as a brown solid. LCMS (ESI) calculation for C 15 H 12 BrN2O4[M + H] +m / z 363.00, found 362.85.

[0489] Intermediate 5 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid [ka] Reagents and conditions: a) TsOH . H2O, acetonitrile, 0 °C, NaNO2, KI, 0 °C; b) additional methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 100 °C; c) LiOH.H2O, THF / MeOH / H2O, rt

[0490] Step 1: Methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate: Stirring at 0° C., TsOH . To a solution of HO (691 mg, 3.64 mmol) and methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (380 mg, 1.21 mmol) in acetonitrile (12 mL) was added a solution of NaNO (167 mg, 2.43 mmol) and potassium iodide (503 mg, 3.03 mmol) in HO (1.8 mL). The reaction mixture was stirred at room temperature for 2.5 h. After the reaction was complete, the mixture was quenched with water (10 mL), and the pH was adjusted to 9-10 with sodium bicarbonate (20 mL) and sodium thiosulfate (20 mL). The aqueous solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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)-5-iodo-4-methylnicotinate (400 mg, 74.01%) as a colorless oil. LCMS (ESI) calcd. for C 16 H 14 IN2O4[M + H] + m / z 425.00, found 424.95.

[0491] 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), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (860 mg, 4.48 mmol) was added dropwise at room temperature under an atmosphere of N. The mixture was heated at 120 °C for 6 hours. After the reaction was complete, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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 C 17 H 14 F3N2O4[M + H] + m / z 367.09, found 367.05.

[0492] Step 3: 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: To 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 HO (2 mL) was added LiOH.HO (207 mg, 4.93 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was concentrated. The residue was adjusted to pH 3-4 with aqueous HCl (1 M). The aqueous solution was then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (140 mg, 48.53%) as a white solid. LCMS (ESI) calcd. for C 16 H 12 F3N2O4[M + H] + m / z 353.08, found 353.05.

[0493] Intermediate 6 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid [ka] Reagents and conditions: a) 4-hydroxy-3-methylbenzonitrile, NaH, DMF; b) NaI, ACN; AcCl; c) [PhSCF][OTf] - , Cu, DMF, 60℃; d) LiOH, THF, H2O, rt

[0494] 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 and 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 × 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give methyl 6-chloro-4-(4-cyano-2-methylphenoxy)pyridazine-3-carboxylate (1850 mg, 63.05%) as a yellow solid. LCMS (ESI) calculation for C 14 H 11 ClN3O3[M + H] + m / z 304.05, found 304.10.

[0495] 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×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. 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) calculation for C 14 H 11 IN3O3[M + H] +m / z 395.98, found 396.15.

[0496] 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 [PhSCF][OTf] - (1473 mg, 3.64 mmol) was added. 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×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=5 / 1) to give methyl 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylate (420 mg, 55.36%) as a yellow solid. LCMS (ESI) calcd. for C 15 H 11 F3N3O3[M + H] + m / z 338.07, found 338.15.

[0497] Step 4: To a solution of methyl 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylate (420 mg, 1.25 mmol) in THF / HO (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 over NaSO, 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 C 14 H9F3N3O3[M + H] + m / z 324.06, found 324.10.

[0498] Intermediate 7 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid [ka] Reagents and conditions: a) NaOH, HO, HO, 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, HO, rt

[0499] 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), HO (5 mL), and HO (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 1 N HCl and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to give 3,4-difluoro-2-methoxyphenol (1.2 g, 70.59%) as a yellow solid. 1 H NMR (400 MHz, CDCl3-d6, ppm) δ6.74-6.61 (m, 2H), 4.81 (s, 1H), 3.85 (s, 3H).

[0500] 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 1 hour. LCMS showed that the reaction was complete. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc=2 / 1) to give methyl 6-chloro-4-(3,4-difluoro-2-methoxyphenoxy)pyridazine-3-carboxylate (0.8 g, 32.3%) as a yellow solid. LCMS (ESI) calcd. for C 13 H 10 ClF2N2O4[M + H] + m / z 331.03, found 330.90.

[0501] 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 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc=2 / 1) to give methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-iodopyridazine-3-carboxylate (800 mg, 78.43%) as a yellow solid. LCMS (ESI) calcd. for C 13 H 10 F2IN2O4[M + H] + m / z 422.97, found 422.85.

[0502] 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 reaction was complete. The mixture was then filtered through celite. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=5 / 1) to give methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylate (360 mg, 52.17%) as a yellow solid. LCMS (ESI) calcd. for C 14 H 10 F5N2O4[M + H] + m / z 365.06, found 365.15.

[0503] 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 / HO (1 / 1, 8 mL) was added LiOH (204 mg, 8.52 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the mixture was concentrated to remove the THF. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over NaSO, 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 C 13 H8F5N2O4[M + H] + m / z 351.04, found 350.90.

[0504] Intermediate 8 3-Bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [ka] Reagents and conditions: a) Et3N, DCM, rt

[0505] 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 complete. The mixture was diluted with water (30 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1 to 5 / 1) to give 3-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (1.4 g, 83.33%) as a colorless oil. LCMS (ESI) calcd. for C 24 H 26 BrNO6SNa[M + Na] m / z 560.06, found 560.05.

[0506] Intermediate 9 tert-Butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfanylidene)carbamate [ka] Reagents and conditions: a) additional 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

[0507] Step 1: 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 h. After the reaction was complete, the resulting solution was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic phases were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 20 / 1) to give 3-((3-bromophenyl)thio)propanenitrile (4.6 g, 84.91% yield) as a colorless oil. 1 H 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).

[0508] Step 2: 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine: To a mixture of 3-((3-bromophenyl)thio)propanenitrile (3 g, 0.012 mol) in EtO (100 mL) under N at room temperature, titanium tetraisopropanolate (3.88 g, 0.014 mol) and ethylmagnesium bromide (5 mL, 1 mol / L in THF) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting solution was diluted with 10% sodium hydroxide solution (100 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to give 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine (1.9 g, 50.81% yield) as a colorless oil. LCMS (ESI) calcd. for C 13 H 21 BrNS[M + H] + m / z 302.06, found 302.0.

[0509] Step 3: tert-Butyl (1-((3-bromophenyl)thio)-3-ethylpentan-3-yl)carbamate: To a mixture of 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine (1.9 g, 6.3 mmol) and BocO (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 h. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with DCM (25 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to give 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 C 18 H29 BrNO2[M + H] + m / z 402.11, found 402.1.

[0510] Step 4: 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) (3.58 g, 0.011 mol) and NHOAc (0.57 g, 0.0074 mol) in EtOH (30 mL) was stirred at room temperature for 6 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (25 mL × 3). The combined organic phase was washed with brine, dried over NaSO and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give tert-butyl (1-(3-bromophenylsulfonimidoyl)-3-ethylpentan-3-yl)carbamate (0.95 g, 59.46% yield) as a white solid. LCMS (ESI) calcd. for C 18 H 30 BrN2O3S[M + H] + m / z 435.12, found 435.0.

[0511] Step 5: tert-Butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfanylidene)carbamate: A mixture of tert-butyl (1-(3-bromophenylsulfonimidoyl)-3-ethylpentan-3-yl)carbamate (0.95 g, 2.19 mmol), BocO (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 complete, the resulting solution was diluted with water (100 mL) and extracted with DCM (25 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% DCM) to give tert-butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfanylidene)carbamate (720 mg, 61.45% yield) as a yellow oil. LCMS (ESI) calcd. for C 23 H 38 BrNOS[M + H] + m / z 533.17, found 533.1.

[0512] Intermediate 10 tert-Butyl ((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16-sulfanylidene)carbamate [ka] Reagents and 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

[0513] 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), and t-BuOK (650.81 mg, 5.80 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give 2-methyl-4-((3-nitrophenyl)thio)butan-2-ol (800 mg, 77.17% yield) as a yellow oil. 1 H 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, 2H), 1.15 (s, 6H).

[0514] 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) (3.20 g, 9.9 mmol), and NHOAc (766.63 mg, 9.95 mol) in EtOH (20 mL) was stirred at 50 °C for 3 h. After the reaction was complete, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1) to give (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16-sulfanone (640 mg, 63.80% yield) as a yellow oil. LCMS (ESI) calcd. for C11 H 17 N2O4S[M + H] + m / z 273.09, found 273.0.

[0515] Step 3. tert-Butyl ((3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(3-nitrophenyl)(oxo)-l6-sulfanylidene)carbamate: To a mixture of (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-l6-sulfanone (500 mg, 1.84 mmol), (Boc)O (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 h. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=5 / 1) to give tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(3-nitrophenyl)(oxo)-16-sulfanylidene)carbamate (320 mg, 25.46% yield) as a yellow oil. LCMS (ESI) calcd. for C 21 H 33 N2O8S[M + H] + m / z 473.20, found 473.2.

[0516] Step 4. tert-Butyl ((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16-sulfanylidene)carbamate: To a mixture of tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(3-nitrophenyl)(oxo)-16-sulfanylidene)carbamate (320 mg, 0.67 mmol), NHCl (108.20 mg, 2.02 mmol) in EtOH / HO (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 h. After the reaction was complete, the resulting mixture was filtered through celite. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 2 / 1) to give tert-butyl ((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16-sulfanylidene)carbamate 5 (300 mg, 90.06% yield) as a yellow oil. LCMS (ESI) calcd. for C 21 H 35 N2O6S[M + H] + m / z 443.22, found 443.2.

[0517] Intermediate 11 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-(trifluoromethyl)isonicotinic acid [ka] Reagents and conditions: a) MeI, K2CO3, DMF; b) CuI, DMF, 80°C; c) Cs2CO3, MeCN, 80°C; d) LiOH, THF / H2O, 60°C

[0518] Step 1: A mixture of 2-bromo-3,5-dichloroisonicotinic acid 1 (3 g, 11.1 mmol), K2CO3 (4.6 g, 33.3 mmol), and MeI (3.15 g, 22.2 mmol) in DMF (40 mL) was heated at 70 °C for 2 h. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated u...

Claims

1. Formula (I): 【Chemical 339】 and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A is a substituted or unsubstituted heteroaryl ring containing at least one heteroatom selected from the group consisting of O, S, or N; wherein one or more substituents on A are H, —OH, halo, C １ ~C ８ -Alkyl, C １ ~C ８ fully or partially fluorinated fluoroalkyl of C ２ ~C ８ branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R')(R'')-cycloalkyl, C(R')(R'')-aryl, -NR'R'', substituted or unsubstituted 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein said 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; B is a substituted or unsubstituted aryl or heteroaryl, where the substitution is substituted or unsubstituted C １ ~C ８ Alkyl, deuterated C, where the alkyl chain can be fully or partially deuterated １ ~C ４ Alkyl, halo-C, where the alkyl chain may be fully or partially halogenated １ ~C ４ Alkyl, C ３ ~C １０ Cycloalkyl, halogen, cyano, nitro, C １ ~C ８ selected from the group consisting of alkoxyl, haloalkoxyl, where the haloalkoxyl chain may be fully or partially halogenated, or arylalkoxyl; C is a substituted or unsubstituted aryl or heteroaryl, where one or more substitutions are independently halo, C １ ~C ８ selected from the group consisting of alkyl, haloalkyl, and alkoxy; R １ are: H and C １ ~C ４ selected from the group consisting of alkyl; R ２ is: Formula (II): 【Hua340】 , —C(═O)NH ２ and —C(═O)NR′R″; In formula (II), m and n are independently 0 or 1; and X １ is O and X ２ is either NH or NR'; or X １ and X ２ and both are O, NH, or NR'; or X １ is O and X ２ NR ３ where R ３ Ha: CD ３ , C １ ~C ４ Alkyl or cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl, (C １ ~C ６ ) alkyl-OH, (C １ ~C ６ ) alkyl-NHR′, (C １ ~C ６ ) alkyl-NR'R", (C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkyl-N—(C １ ~C ６ ) alkyl; R ４ Is: -NH ２ , -NR'R", C １ ~C ４ Alkyl, C ３ ~C ８ - selected from the group consisting of cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl; compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof.

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

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

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

5. The compound has the formula (III): 【Chemical 341】 and in formula (III): Q, T and W are independently N or CR ６ and R ６ is H, halogen, -CD ３ , alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ or substituted or unsubstituted cycloalkoxy; R ５ is H, -OH, halo, -CD ３ , C １ ~C ６ -Alkyl, branched alkyl, haloalkyl in which the alkyl chain is completely or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH ２ -cycloalkyl, -CH(CH ３ )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3- to 6-membered cycloalkyl, any of which may have one or more substituents; X is H, halo, -CD ３ , alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ That is, The compound of claim 1.

6. The compound has the formula (IV): 【Chemical 342】 and in formula (IV): Z is CR １０ , N, or N ＋ O － where R １０ is H, halo, -CD ３ , C １ ~C ８ alkyl, haloalkyl, or alkoxy; The compound of claim 1.

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

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

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

10. A is, 【Chemical 343】 where Q １ , Q ２ , Q ３ and Q ４ are independently: N, N ＋ O － , or CR ７ wherein Q is selected from the group consisting of １ , Q ２ , Q ３ and Q ４ At least two of them are CR ７ and R ７ is H, -OH, halo, -CD ３ , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ , a substituted or unsubstituted 5- or 6-membered heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl; The compound of claim 1.

11. A is, 【Chemical 344】 where Q ２ and Q ４ are independently N or N ＋ O － Is it; Q ２ is N or N ＋ O － and Q ４ is CR ７ or Q ２ is CR ７ and Q ４ is N or N ＋ O － and R ８ and R ９ are independently H, —OH, halo, or —CD ３ , substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH ２ , NHR′, NR′R″, aryl, heteroaryl, —CF ２ CH ３ , and -CF ２ CF ３ selected from the group consisting of: R ７ is as claimed in claim 10, The compound of claim 1.

12. A is, 【Chemical 345】 where Q ３ and Q ４ are independently N or N ＋ O － Is it; Q ３ is N or N ＋ O － And Q ４ is CR ７ or Q ３ is CR ７ and Q ４ is N or N ＋ O － where R ７ , R ８ and R ９ is defined above, The compound of claim 1.

13. A is, 【Chemical 346】 where Q １ and Q ４ are independently N or N ＋ O － Is it; Q １ is N or N ＋ O － and Q ４ is CR ７ Is it; Q １ is CR ７ And Q ４ is N or N ＋ O － or Q １ Or Q ４ is CR ７ where R ７ , R ８ , and R ９ is defined above, The compound of claim 1.

14. A is, 【Chemical 347】 where Q １ and Q ２ is N; where R ８ and R ９ 2. The compound of claim 1, wherein:

15. A is, 【Chemical 348】 where Q １ is CR ７ and Q ２ is N; R ７ , R ８ , and R ９ 2. The compound of claim 1, wherein:

16. A is, 【Chemical 349】 where Q １ is N; Q ２ is CR ７ and R ７ , R ８ , and R ９ 2. The compound of claim 1, wherein:

17. R １ The compound of claim 1 , wherein is H.

18. R ２ but: 【Hua350】 wherein m and n are independently 0 or 1; X １ is O and X ２ is NH, and R ４ is alkyl, The compound of claim 1.

19. R ２ but: 【Chemistry 351】 wherein m and n are independently 0 or 1; X １ is O and X ２ is O and R ４ is NH ２ or alkyl, e.g., methyl; The compound of claim 1.

20. R ２ -S(=O)CH ３ 2. The compound of claim 1, wherein:

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

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

23. R １０ The compound of claim 6, wherein is H or F.

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

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

26. R ７ , R ８ , and R ９ are independently: H, methyl, fluoro, chloro, bromo, CF ３ 17. The compound of any one of claims 11 to 16, wherein the compound is selected from the group consisting of cyclopropyl, difluorophenyl, and dimethylpyrazole.

27. R ２ -C(=O)NH ２ 2. The compound of claim 1, wherein the compound does not contain any of -C(=O)NR'R" and -C(=O)NR'R".

28. The compound is: 【Chemical 352】 【Chemical 353】 【Chemical 354】 【Chemical 355】 【Chemical Formula 356】 【Chemical 357】 【Chemical 358】 【Chemical 359】 【Hua360】 【Hua 361】 【Chemical 362】 【Hua 363】 【Chemical 364】 【Hua365】 【Hua366】 【Hua 367】 2. The compound of claim 1 selected from the group consisting of:

29. R ２ is of formula (II): 【Hua368】 and in formula (II): m and n are independently 0 or 1; and X １ and X ２ and cannot both be O, NH, or NR'; The compound of claim 1.

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

31. Formula (I): 【Chemical 369】 and pharmaceutically acceptable salts, hydrates, and solvates thereof, In formula (I), A is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or a halo-C, wherein the haloalkyl chain may be fully or partially halogenated. １ ~C ４ Alkyl, substituted or unsubstituted C １ ~C ８ Alkyl, deuterated C, where the alkyl chain can be fully or partially deuterated １ ~C ４ Alkyl, C ３ ~C １０ Cycloalkyl, halogen, cyano, nitro, C １ ~C ８ alkoxyl, haloalkoxyl, which haloalkoxy chains may be fully or partially halogenated, or arylalkoxyl, substituted with one or more groups selected from the group consisting of; B is aryl or heteroaryl, wherein the aryl can have 1 to 4 substituents and the heteroaryl can have 1 to 3 substituents, which are independently selected from halogen, C １ ~C ８ selected from alkyl, haloalkyl, or alkoxy; R １ , R ２ , R ３ and R ４ are independently H, halogen, —OH, C １ ~C ６ - alkyl, fluoroalkyl chains may be fully or partially fluorinated C １ ~C ６ Fluoroalkyl, C ３ ~C ８ C, in which the branched alkyl, branched fluoroalkyl chain may be fully or partially fluorinated ３ ~C ８ branched fluoroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R ’ ) (R ” )-cycloalkyl, C(R ’ ) (R ” )-aryl, -NR'R'', substituted or unsubstituted 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein said 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; R ５ is H or C １ ~C ３ is alkyl; and R ６ is -C(=O)NH ２ , —C(═O)NHR′, —C(═O)NR′R″, or formula (II): 【Hua370】 and in formula (II): X １ and X ２ and both are O, NH, or NR'; or X １ is O and X ２ is either NH or NR'; R ７ is NH ２ , NHR', NR'R'', C １ ~C ３ Alkyl, C ３ ~C ８ cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl; compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof.

32. The compound has the formula (III): 【Chemical 371】 wherein in formula (III), R １ , R ２ , R ３ , R ４ , R ５ , R ６ and B is as defined in claim 1; Q, T and W are independently N or CR ９ and R ９ is H, halogen, -CD ３ , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ or substituted or unsubstituted cycloalkoxy; X is H, halogen, -CD ３ , alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF ３ , or -OCF ３ and R ８ is H, hydroxyl, halogen, -CD ３ , C １ ~C ６ -Alkyl, branched alkyl, haloalkyl in which the alkyl chain is completely or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH ２ -cycloalkyl, -CH(CH ３ )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, or substituted or unsubstituted 3- to 6-membered cycloalkyl; 32. The compound of claim 31.

33. B: 【Chemical 372】 where R ６ is described above; Z is CR １０ , N, or N ＋ O － where R １０ is H, halo, -CD ３ , C １ ~C ８ 32. The compound of claim 31, which is alkyl, haloalkyl, or alkoxy.

34. R ６ but, 【Chemical 373】 and where: X １ and X ２ and both are O, NH, or NR'; or X １ is O and X ２ is either NH or NR'; R ７ is NH ２ , NHR', NR'R'', C １ ~C ３ Alkyl, C ３ ~C ８ cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl; 34. The compound of claim 33.

35. R ６ but, 【Chemical 374】 and where: X １ is O and X ２ is NH, and R ７ is C １ ~C ３ is alkyl, 34. The compound of claim 33.

36. R ６ is -C(=O)NH ２ , -C(=O)NHR', or -C(=O)NR'R" .

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

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

39. R １ is H, -CH ３ or F.

40. R ２ But chloro, -CF ３ 32. The compound of claim 31, wherein the compound is 1-methyl-1H-pyrazol-4-yl, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl.

41. R ３ H, -CF ３ or F.

42. R ４ 32. The compound of claim 31 , wherein is H.

43. R ８ is H, -CH ３ , or —O—CH ３ 33. The compound of claim 32, wherein:

44. R ７ Ga-CH ３ 33. The compound of claim 32, wherein:

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

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

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

48. Z is CR １０ and R １０ is H or F.

49. The compound is: 【Chemical 375】 【Chemical 376】 【Chemical 377】 【Chemical 378】 【Chemical 379】 【Hua380】 【Chemical 381】 【Chemical 382】 【Chemical 383】 【Chemical 384】 【Chemistry 385】 【Hua 386】 32. The compound of claim 31 selected from the group consisting of:

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

51. Formula (I): 【Chemical 387】 and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or halo-C, where the haloalkyl chain may be fully or partially halogenated. １ ~C ４ Alkyl, substituted or unsubstituted C １ ~C ８ Alkyl, deuterated C, where the alkyl chain can be fully or partially deuterated １ ~C ４ Alkyl, C ３ ~C １０ Cycloalkyl, halogen, cyano, nitro, C １ ~C ８ alkoxyl, haloalkoxyl, which haloalkoxy chain may be fully or partially halogenated, and arylalkoxyl, which are substituted with one or more groups selected from the group consisting of; R １ , R ２ , R ３ and R ４ are independently hydrogen, —OH, halogen, C １ ~C ６ - alkyl, fluoroalkyl chains may be fully or partially fluorinated C １ ~C ６ Fluoroalkyl, C ３ ~C ８ C, in which the branched alkyl, branched fluoroalkyl chain may be fully or partially fluorinated ３ ~C ８ branched fluoroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkoxy, nitro, cyano, —C(R′)(R″)-cycloalkyl, C(R ’ ) (R ” )-aryl, NR'R'', 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 6-membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N, saturated or unsaturated 5-membered or larger rings, or aryl rings optionally containing one or more heteroatoms independently selected from O, S, and N, wherein each 5-membered or larger ring is unsubstituted or substituted with 1 to 5 substituents selected from hydrogen, cyano, halo, or methyl; R １ , R ２ , R ３ and R ４ a fused ring formed by at least two of the following, wherein the fused ring is selected from the group consisting of: an optionally saturated carbocyclyl or heterocyclyl containing 5 to 6 ring members, wherein the heterocyclyl is selected from those containing one or more heteroatoms; R ５ is H or substituted or unsubstituted C １ ~C ３ is alkyl; R ６ is -(CH ２ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ -(OCH ２ CH ２ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ -(NR'CH ２ CH ２ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ -(NR'CH ２ CH ２ O) ｎ R ａ , or -(CR ｂ R ｃ ) ｎ -(NHCH ２ CH ２ NH) ｎ R ａ and Here, R ａ is H, C １ ~C ６ -Alkyl, C ２ ~C ８ Branched alkyl of C ３ ~C ８ Cycloalkyl, aryl, heteroaryl, 4- to 7-membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH ２ CH ２ ) ｎ R ｂ , —NR′R″, —COONR′R″, —COOR′, alkylsulfonyl, arylsulfonyl, or —SO ２ NR'R"; R ｂ are independently H, F, C １ ~C ６ - selected from alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl having one or more heteroatoms; R ｃ is H, C １ ~C ６ alkyl or F; R ｃ and R ｂ optionally forms a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one or more heteroatoms; R ７ is NH ２ , -NHR', C １ ~C ３ Alkyl, substituted or unsubstituted C ３ ~C ４ cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl; compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof.

52. The compound has the formula (II): 【Hua 388】 In the formula (II), the ring B and the group R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ is as claimed in claim 1; R ８ is H, hydroxyl, halogen, -CD ３ , C １ ~C ６ -Alkyl, branched alkyl, haloalkyl in which the alkyl chain is completely or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH ２ -cycloalkyl, -CH(CH ３ )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, any of which can have one or more substituents, and wherein said 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; Q, T, and W are independently N or CR ９ Selected from: R ９ is H, halogen, -CD ３ , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ or cycloalkoxy, each of which is optionally substituted; X is H, halogen, -CD ３ , alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF ３ , or -OCF ３ That is, 52. The compound of claim 51.

53. The compound has the formula (III): 【Chemical 389】 wherein in formula (III), R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ is as claimed in claim 1; R ８ , W, T, Q, and X are as set forth in claim 52; Z is CH, N, CF, or N ＋ -O － That is, 52. The compound of claim 51.

54. 53. The compound of claim 52, wherein X is F.

55. R ８ Ga-CH ３ 53. The compound of claim 52, wherein:

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

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

58. R １ is H or F.

59. R ２ is H, chloro, or CF ３ 52. The compound of claim 51, wherein:

60. R ３ is H or CF ３ 52. The compound of claim 51, wherein:

61. R ４ 52. The compound of claim 51 , wherein

62. R ５ 52. The compound of claim 51 , wherein

63. R ７ 52. The compound of claim 51, wherein is methyl.

64. R ６ Azetidine, pyrrolidine, -CH ２ -OH, -CH-(CH ３ )-OH, -CH-CH ２ -NH-CH ３ , -CH ２ -NH ２ , CH-(CH ３ )-NH ２ , -CH ２ -NH ２ , —C—(CH ３ ) ２ -NH ２ or -cyclobutyl-NH ２ 52. The compound of claim 51, wherein:

65. R ９ 53. The compound of claim 52, wherein is H.

66. The compound of formula (I) is: 【Chemical Formula 390】 【Chemical 391】 【Chemical 392】 【Chemical Formula 393】 52. The compound of claim 51 selected from the group consisting of:

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

68. Formula (I): 【Chemical 394】 and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein the compound is represented by formula (I): A is a substituted or unsubstituted heteroaryl ring containing at least one heteroatom selected from the group consisting of O, S, or N; wherein one or more substituents on A are H, —OH, halo, C １ ~C ８ -Alkyl, C １ ~C ８ fully or partially fluorinated fluoroalkyl of C ２ ~C ８ branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R ’ ) (R ” )-cycloalkyl, C(R ’ ) (R ” )-aryl, —NR′R″, substituted or unsubstituted 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, or 3- to 6-membered heterocycloalkyl, wherein said 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; B is a substituted or unsubstituted aryl or heteroaryl, where the substitution is substituted or unsubstituted C １ ~C ８ Alkyl, deuterated C, where the alkyl chain can be fully or partially deuterated １ ~C ４ Alkyl, halo C, where the alkyl chain can be fully or partially halogenated １ ~C ４ Alkyl, C ３ ~C １０ Cycloalkyl, halogen, cyano, nitro, C １ ~C ８ selected from the group consisting of alkoxyl, haloalkoxyl, where the haloalkoxyl chain may be fully or partially halogenated, and arylalkoxyl; C is a substituted or unsubstituted aryl or heteroaryl, where one or more substitutions are independently halo, C １ ~C ８ selected from the group consisting of alkyl, haloalkyl, and alkoxy; R １ are: H and C １ ~C ４ selected from the group consisting of alkyl; R ２ Is:-(CH ２ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ -(OCH ２ CH ２ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ -(NR'CH ２ CH ２ ) ｎ R ａ , -(CR ｂ R ｃ ) ｎ -(NR'CH ２ CH ２ O) ｎ R ａ , and -(CR ｂ R ｃ ) ｎ -(NHCH ２ CH ２ NH) ｎ R ａ selected from the group consisting of: Here, R ａ is H, C １ ~C ８ - alkyl or branched alkyl, C ３ ~C ８ Cycloalkyl, aryl, heteroaryl, 4- to 7-membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH ２ CH ２ ) ｎ R ｂ , —NR′R″, —COONR′R″, —COOR′R″, alkylsulfonyl, arylsulfonyl, or —SO ２ NR'R"; R ｂ is H, F, C １ ~C ６ - alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3- to 7-membered, carbocyclyl, or heterocyclyl having one or more heteroatoms; Rc is H, C １ ~C ６ alkyl, or F; R ｃ and R ｂ and together optionally form a 3- to 6-membered carbocyclic or heterocyclic ring; R ３ is C １ ~C ３ Alkyl, C ３ ~C ４ selected from the group consisting of cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, and heterocyclyl; compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof.

69. The compound has the formula (II): 【Chemical 395】 wherein in formula (II): A, C, R １ , R ２ , and R ３ are described above; Q, T and W are independently N or CR ５ and R ５ is H, halogen, -CD ３ , alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ or cycloalkoxy; R ４ is H, -OH, halo, -CD ３ , C １ ~C ６ -Alkyl, branched alkyl, haloalkyl in which the alkyl chain is completely or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH ２ -cycloalkyl, -CH(CH ３ )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, any of which can have one or more substituents, and wherein said 3- to 6-membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N; X is H, halo, -CD ３ , alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF ３ , or -OCF ３ and A, C, R １ , R ２ , and R ３ is as claimed in claim 68, 69. The compound of claim 68.

70. The compound has the formula (III): 【Chemical 396】 In formula (III), Z is CH, N, CF, or N ＋ O － and A, W, T, Q, X, R １ , R ２ , R ３ , and R ４ is as claimed in claims 68 and 69.

70. The compound of claim 69.

71. 69. The compound of claim 68, wherein A is a substituted or unsubstituted 5- to 6-membered heteroaryl having one or more heteroatoms.

72. 72. The compound of claim 71, wherein said heteroaryl comprises N as said one or more heteroatoms.

73. 73. The compound of claim 72, wherein said heteroatom N is in the form of an N-oxide, wherein said N-oxide is selected from the group consisting of: pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

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

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

76. A is, 【Chemical 397】 where Q １ , Q ２ , Q ３ and Q ４ are independently: N, N ＋ O － , or CR ６ selected from the group consisting of: Here, Q １ , Q ２ , Q ３ and Q ４ At least two of them are CR ６ and R ６ is H, -OH, halo, -CD ３ , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF ３ , -OCF ３ , a substituted or unsubstituted 5- or 6-membered heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl; 69. The compound of claim 68.

77. A is, 【Chemical 398】 where Q ２ and Q ４ are independently N or N ＋ O － Is it; Q ２ is N or N ＋ O － And Q ４ is CR ６ or Q ２ is CR ６ And Q ４ is N or N ＋ O － and R ７ and R8 is independently H, —OH, halo, —CD ３ , substituted or unsubstituted C １ ~C ６ Alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH ２ , NHR′, NR′R″, aryl, heteroaryl, —CF ２ CH ３ , and -CF ２ CF ３ selected from the group consisting of: R ６ is as claimed in claim 76, 69. The compound of claim 68.

78. A is, 【Chemical 399】 where Q ３ and Q ４ is N; Q ３ is N, N ＋ O － and Q ４ is CR ６ or Q ３ is CR ６ and Q ４ is N or N ＋ O － where R ７ and R ８ is defined in claim 77, 70. The compound of claim 69.

79. A is, 【Chemistry 400】 where Q １ and Q ４ are independently N or N ＋ O － Is it; Q １ is N or N ＋ O － And Q ４ is CR ６ or Q １ is CR ６ And Q ４ is N or N ＋ O － where R ６ , R ７ , and R ８ is defined in claim 77, 68. The compound of claim 67.

80. A: 【Chemistry 401】 where Q １ and Q ２ is N; where R ７ and R ８ The compound of claim 68, wherein:

81. A is, 【Chemistry 402】 where Q １ is CR ６ and Q ２ is N; R ６ is defined in claim 76, and R ７ and R ８ 77. The compound of claim 68, wherein:

82. A is, 【Chemistry 403】 where Q １ is N; Q ２ is CR ６ and R ６ is defined in claim 9, and R ７ and R ８ 77. The compound of claim 68, wherein:

83. R １ 69. The compound of claim 68, wherein is H.

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

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

86. R ４ 70. The compound of claim 69, wherein is methyl.

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

88. R ３ 69. The compound of claim 68, wherein is methyl.

89. R ２ is H, methyl, -CH ２ -NH ２ , -CH ２ -NH-CH ３ , -CH ２ -OH, -CH(NH ２ ) (CH ３ ), -CH ２ -OH, -CH(OH)(CH ３ ), —CH(CF ３ ) (NH ２ ), -CH ２ -O-CH ３ , amino-cyclopropyl, pyrrolidine, azetidine, oxetane, tetrahydrofuran, or hydroxypyrrolidone.

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

91. The compound is: 【404】 【Chemistry 405】 【Chemistry 406】 【Chemistry 407】 【Chemistry 408】 69. The compound of claim 68, selected from the group consisting of:

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

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