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

Abstract

The present invention provides compounds useful in the treatment of conditions associated with aberrant activity of voltage gated sodium channel NaV1.8, and methods of using these compounds to treat conditions such as pain, pruritus, and cough in subjects.

Description

Technical Field

[0001] The present application relates generally to sodium channel blocking compounds, their derivatives, and the use of such compounds as pharmacological agents. Background Art

[0002] Millions of people suffer from conditions associated with pain, itching, and / or coughing. Pain can be a symptom or cause of conditions such as neuropathy, hyperalgesia, and opioid use disorder. In many cases, medications used to treat such conditions fail to provide relief or produce intolerable side effects. Consequently, existing treatments are insufficient to treat many patients suffering from these conditions. Summary of the Invention

[0003] The present invention provides a method for treating pain, itching and cough and other conditions related to voltage-gated sodium channels Na V 1.8. A compound having abnormal activity associated with a disease state.

[0004] (A) The first group of compounds:

[0005] In one aspect, the present invention provides a compound of formula (I):

[0006]

[0007] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein A is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted with one or more groups selected from the group consisting of: wherein the haloalkyl chain can be a fully or partially halogenated halo-C1-C4 alkyl, a substituted or unsubstituted C1-C8 alkyl, wherein the alkyl chain can be a fully or partially deuterated deuterated C1-C4 alkyl, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be a fully or partially halogenated haloalkoxy, or arylalkoxy;

[0008] B is aryl or heteroaryl, wherein the aryl may have 1 to 4 substituents, and the heteroaryl may have 1 to 3 substituents independently selected from halogen, C1-C8 alkyl, haloalkyl or alkoxy;

[0009] R1, R2, R3 and R4 are independently selected from H, halogen, -OH, C1-C6-alkyl, wherein the fluoroalkyl chain can be a fully or partially fluorinated C1-C6 fluoroalkyl, C3-C8 branched alkyl, wherein the branched fluoroalkyl chain can be a fully or partially fluorinated C3-C8 branched fluoroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0010] R5 is H or C1-C3 alkyl; and

[0011] R6 is -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R", or formula (II):

[0012]

[0013] in:

[0014] X1 and X2 are both O, NH or NR'; or

[0015] X1 is O, and X2 is NH or NR';

[0016] R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

[0017] In various embodiments, the compound of the present invention is a compound of formula (III):

[0018]

[0019] wherein R1, R2, R3, R4, R5, R6 and B are as described in formula (I);

[0020] Q, T and W are independently N or CR9;

[0021] R9 is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy;

[0022] X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3 or OCF3;

[0023] R8 is H, hydroxy, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, or substituted or unsubstituted 3-6 membered cycloalkyl.

[0024] In another embodiment, B is

[0025]

[0026] wherein R6 is as described above; Z is CR 10 , N or N - O - ; where R 10 It is H, halo, -CD3, C1-C8 alkyl, haloalkyl or alkoxy.

[0027] In another embodiment, R6 is

[0028]

[0029] in:

[0030] X1 and X2 are both O, NH or NR'; or

[0031] X1 is O, and X2 is NH or NR';

[0032] R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

[0033] In another embodiment, R6 is

[0034]

[0035] in:

[0036] X1 is O, X2 is NH, and R7 is C1-C3 alkyl.

[0037] In another embodiment, R6 does not include -C(=O)NH2, -C(=O)NHR' or -C(=O)NR'R".

[0038] In another embodiment, B is a phenyl ring.

[0039] In another embodiment, B is a pyridine ring.

[0040] In another embodiment, R1 is H, -CH3 or F.

[0041] In another embodiment, R2 is chloro, -CF3, H, 2-pyrazoline or 1-methyl-1H-pyrazol-4-yl. In another embodiment, R3 is H, -CF3 or F.

[0042] In another embodiment, R4 is H.

[0043] In another embodiment, R8 is H, -CH3 or -O-CH3.

[0044] In another embodiment, R7 is -CH3.

[0045] In another embodiment, X is F or -CN.

[0046] In another embodiment, Q is N or CH.

[0047] In another embodiment, W is CH and T is CH.

[0048] In another embodiment, Z is CR 10 , and R 10 It is H or F.

[0049] In another embodiment, the compound is selected from the group consisting of:

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] (B) The second group of compounds

[0062] In one aspect, the present invention provides a compound of formula (I):

[0063]

[0064] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

[0065] A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of: wherein the haloalkyl chain can be a fully or partially halogenated halo-C1-C4 alkyl, a substituted or unsubstituted C1-C8 alkyl, wherein the alkyl chain can be a fully or partially deuterated deuterated C1-C4 alkyl, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be fully or partially halogenated, and arylalkoxy;

[0066] R1, R2, R3 and R4 are independently selected from hydrogen, -OH, halogen, C1-C6-alkyl, wherein the fluoroalkyl chain can be a fully or partially fluorinated C1-C6 fluoroalkyl, C3-C8 branched alkyl, wherein the branched fluoroalkyl chain can be a fully or partially fluorinated C3-C8 branched fluoroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, NR'R", 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N, a saturated or unsaturated 5-membered or more ring or an aryl ring optionally containing 1 or more heteroatoms independently selected from O, S and N, wherein each 5-membered or more ring is unsubstituted or substituted with one to five substituents selected from the group consisting of 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 5-6 ring members, wherein the heterocyclyl includes one or more heteroatoms;

[0067] R5 is H or substituted or unsubstituted C1-C3 alkyl;

[0068] R6 is -(CH2) n R a 、-(CR b R c ) n R a 、-(CR b R c ) n -(OCH2CH2) n R a 、-(CR b Rc ) 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 ;

[0069] where R a is H, C1-C6-alkyl, C2-C8 branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2) n R b , -NR'R", -COONR'R", -COOR', alkylsulfonyl, arylsulfonyl or -SO2NR'R";

[0070] R b independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms;

[0071] R c is H, C1-C6 alkyl or F;

[0072] R c and R b Optionally forming a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms;

[0073] R7 is NH2, -NHR', C1-C3 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

[0074] In various embodiments, the compound of the present invention is a compound of formula (II):

[0075]

[0076] wherein Ring B and the groups R1, R2, R3, R4, R5, R6 and R7 are as described in claim 1;

[0077] R8 is H, hydroxy, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0078] Q, T and W are independently selected from N or CR9;

[0079] R9 is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3 or cycloalkoxy, each of which is optionally substituted;

[0080] X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3 or -OCF3.

[0081] In another embodiment, the compound of the present invention is a compound of formula (III):

[0082]

[0083] wherein R1, R2, R3, R4, R5, R6 and R7 are as described above in formula (I);

[0084] R8, W, T, Q and X are as described above in formula (II);

[0085] Z is CH, N, CF or N + -O - .

[0086] In another embodiment, X is F.

[0087] In another embodiment, R8 is -CH3.

[0088] In another embodiment, Q is N.

[0089] In another embodiment, Q is N, W is CH, and T is CH.

[0090] In another embodiment, R1 is H or F.

[0091] In another embodiment, R2 is H, chlorine or CF3.

[0092] In another embodiment, R3 is H or CF3.

[0093] In another embodiment, R4 is H.

[0094] In another embodiment, R5 is H.

[0095] In another embodiment, R7 is methyl.

[0096] 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.

[0097] In another embodiment, R9 is H.

[0098] In another embodiment, the compound of formula (I) is selected from the group consisting of:

[0099]

[0100]

[0101]

[0102]

[0103] (C) The third group of compounds

[0104] In one aspect, the present invention provides a compound of formula (I):

[0105]

[0106] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

[0107] A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from the group consisting of O, S or N;

[0108] wherein the one or more substitutions 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, cycloalkyloxy, haloalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0109] B is a substituted or unsubstituted aryl or heteroaryl group, wherein the substitutions are selected from the group consisting of: a substituted or unsubstituted C1-C8 alkyl group, a deuterated C1-C4 alkyl group in which the alkyl chain may be fully or partially deuterated, a halo-C1-C4 alkyl group in which the alkyl chain is fully or partially halogenated, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be a fully or partially halogenated haloalkoxy, or arylalkoxy;

[0110] C is a substituted or unsubstituted aryl or heteroaryl, wherein one or more substitutions are independently selected from the group consisting of halo, C1-C8 alkyl, haloalkyl, alkoxy;

[0111] R1 is selected from the group consisting of: H and C1-C4 alkyl;

[0112] R2 is selected from the group consisting of: Formula (II):

[0113] -C(=O)NH2 and -C(=O)NR'R";

[0114] in,

[0115] m and n are independently 0 or 1; and

[0116] X1 is O, and X2 is NH or NR'; or

[0117] X1 and X2 are both O, NH or NR'; or

[0118] X1 is O, and X2 is NR3; wherein 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;

[0119] R4 is selected from the group consisting of -NH2, -NR'R", C1-C4 alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl and heterocyclyl.

[0120] 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 can be in the form of an N-oxide. In certain embodiments, the N-oxide containing ring B is selected from pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0121] In another embodiment, the compound is a compound of formula (III):

[0122]

[0123] wherein Q, T and W are independently N or CR6;

[0124] R6 is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy;

[0125] R5 is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6 membered cycloalkyl, any of which may have one or more substituents;

[0126] X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, -OCF3.

[0127] In another embodiment, the compound is of formula (IV):

[0128]

[0129] in:

[0130] Z is CR 10 , N or N + O - ; where R 10 It is H, halo, -CD3, C1-C8 alkyl, haloalkyl or alkoxy.

[0131] In certain embodiments, Ring A is a substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S.

[0132] In certain embodiments, Ring A is a substituted or unsubstituted pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0133] In certain embodiments, Ring A is a substituted or unsubstituted 6-membered heteroaryl group having at least one heteroatom, wherein the heteroatom is N. In certain embodiments, Ring A is a substituted or unsubstituted 6-membered heteroaryl group having at least 2 N atoms.

[0134] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0135]

[0136] wherein Q1, Q2, Q3 and Q4 are independently selected from the group consisting of: N, N + O - or CR7; wherein at least two of Q1, Q2, Q3 and Q4 are CR7;

[0137] R7 is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5- or 6-membered ring heterocyclyl or heteroaryl, saturated heterocyclyl or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl or O-cycloheteroalkyl.

[0138] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0139]

[0140] in,

[0141] Q2 and Q4 are independently N or N + O - ;

[0142] Q2 is N or N + O - ; Q4 is CR7; or

[0143] Q2 is CR7, Q4 is N or N + O - ;

[0144] R8 and R9 are independently selected from the group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR', NR'R", aryl, heteroaryl, -CF2CH3 and -CF2CF3;

[0145] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0146]

[0147] in,

[0148] Q3 and Q4 are independently N or N + O - ;

[0149] Q3 is N or N + O - , and Q4 is CR7; or

[0150] Q3 is CR7, Q4 is N or N + O - ; wherein R7, R8 and R9 are defined above.

[0151] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0152]

[0153] in,

[0154] Q1 and Q4 are independently N or N + O - ;

[0155] Q1 is N or N + O - , and Q4 is CR7;

[0156] Q1 is CR7, and Q4 is N or N + O - ;or

[0157] Q1 or Q4 is CR7; wherein R7, R8 and R9 are defined above.

[0158] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0159]

[0160] wherein Q1 and Q2 are N; and wherein R8 and R9 are as defined above.

[0161] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0162]

[0163] wherein Q1 is CR7, Q2 is N; and R7, R8 and R9 are as defined above.

[0164] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0165]

[0166] wherein Q1 is N; Q2 is CR7; and R7, R8, and R9 are as defined above.

[0167] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), R2 is:

[0168]

[0169] wherein m and n are independently 0 or 1;

[0170] X1 is O, and X2 is NH, and R4 is an alkyl group, such as methyl.

[0171] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), R2 is:

[0172]

[0173] wherein m and n are independently 0 or 1;

[0174] X1 is O, and X2 is O, and R4 is NH2 or an alkyl group, such as methyl.

[0175] In other embodiments, R2 is -S(=O)CH3. In another embodiment, in these compounds of formula (III) and / or formula (IV), Q is N or CH; R5 is methyl or -OMe, and X is F or CN. In other embodiments, in these compounds of formula (III) and / or formula (IV), Q is CF. In other embodiments, R7, R8 and R9 are independently selected from the group consisting of H, methyl, fluorine, chlorine, bromine, CF3, cyclopropyl, difluorophenyl and dimethylpyrazole. In other embodiments, in these compounds 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.

[0176] In certain embodiments of the present invention, R2 does not comprise -C(=O)NH2 or -C(=O)NR'R".

[0177] In certain embodiments, R2 is of formula (II):

[0178]

[0179] in,

[0180] m and n are independently 0 or 1; and

[0181] X1 and X2 are not both O, NH or NR'.

[0182] In other embodiments, the compound of the present invention is selected from the group consisting of:

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] (D) Group 4 compounds

[0198] In one aspect, the present invention provides a compound of formula (I):

[0199]

[0200] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

[0201] A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from the group consisting of O, S or N;

[0202] wherein the one or more substitutions 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, cycloalkyloxy, haloalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0203] B is a substituted or unsubstituted aryl or heteroaryl group, wherein the substitutions are selected from the group consisting of: a substituted or unsubstituted C1-C8 alkyl group, a deuterated C1-C4 alkyl group in which the alkyl chain may be fully or partially deuterated, a halo-C1-C4 alkyl group in which the alkyl chain is fully or partially halogenated, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be fully or partially halogenated, and arylalkoxy;

[0204] C is a substituted or unsubstituted aryl or heteroaryl, wherein one or more substitutions are independently selected from the group consisting of halo, C1-C8 alkyl, haloalkyl, alkoxy;

[0205] R1 is selected from the group consisting of: H and C1-C4 alkyl;

[0206] R2 is selected from the group consisting of: -(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;

[0207] where R a is H, C1-C8-alkyl or branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2) n R b , -NR'R", -COONR'R", -COOR'R", alkylsulfonyl, arylsulfonyl or -SO2NR'R";

[0208] R b is H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl or heterocyclyl having one or more heteroatoms;

[0209] Rc is H, C1-C6 alkyl or F;

[0210] R c and R b together optionally form a 3-6 membered carbocyclic or heterocyclic ring;

[0211] R3 is selected from the group consisting of C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl and heterocyclyl.

[0212] In another embodiment, the compound is a compound of formula (II):

[0213]

[0214] wherein: A, C, R1, R2 and R3 are as described above; Q, T and W are independently N or CR5;

[0215] R5 is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3 or cycloalkoxy;

[0216] R4 is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S, and N;

[0217] X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3 or -OCF3.

[0218] In another embodiment, the compound is a compound of formula (III):

[0219]

[0220] Wherein, Z is CH, N, CF or N + O - ; and A, W, T, Q, X, R1, R2, R3 and R4 are described above.

[0221] In other embodiments, in the compounds of Formula (I), (II) and / or (III), Ring A is a substituted or unsubstituted 5-6 membered heteroaryl group having one or more heteroatoms. The 5-6 membered heteroaryl group includes N as the one or more heteroatoms. The heteroatom N may 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.

[0222] In other embodiments, A is a 6-membered heteroaryl group containing at least one heteroatom, wherein the heteroatom is N. In certain embodiments, A is a 6-membered heteroaryl group containing 2 N atoms.

[0223] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A can be a substituted or unsubstituted pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0224] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0225]

[0226] wherein Q1, Q2, Q3 and Q4 are independently selected from the group consisting of: N, N + O - or CR6; wherein at least two of Q1, Q2, Q3 and Q4 are CR6; R6 is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5- or 6-membered ring heterocyclyl or heteroaryl, saturated heterocyclyl or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl or O-cycloheteroalkyl.

[0227] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0228]

[0229] in,

[0230] Q2 and Q4 are independently N or N + O - ;

[0231] Q2 is N or N + O - , and Q4 is CR6; or

[0232] Q2 is CR6, and Q4 is N or N + O - ;

[0233] R7 and R8 are independently selected from the group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR', NR'R", aryl, heteroaryl, -CF2CH3 and -CF2CF3;

[0234] R6 is described above.

[0235] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0236]

[0237] in,

[0238] Q3 and Q4 are N;

[0239] Q3 is N, N + O - ; Q4 is CR6; or

[0240] Q3 is CR6, Q4 is N or N + O - ; wherein R7 and R8 are defined above.

[0241] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0242]

[0243] in

[0244] Q1 and Q4 are independently N or N + O - ;

[0245] Q1 is N or N + O - , and Q4 is CR6; or

[0246] Q1 is CR6, and Q4 is N or N + O - ; wherein R6, R7 and R8 are described above.

[0247] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0248]

[0249] wherein Q1 and Q2 are N; and wherein R7 and R8 are as described above.

[0250] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0251]

[0252] wherein Q1 is CR6, and Q2 is N; R6, R7 and R8 are described above.

[0253] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), Ring A is:

[0254]

[0255] wherein Q1 is N; Q2 is CR6; and R6, R7, and R8 are as described above.

[0256] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), R1 is H.

[0257] In other embodiments, in the compounds of Formula (I), Formula (II) and / or Formula (III), R3 is methyl.

[0258] In other embodiments, in these 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.

[0259] 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.

[0260] In other embodiments, in the compounds of formula (II) and / or formula (III), R4 is methyl. In other embodiments, in the compounds of formula (II) and / or formula (III), X is F.

[0261] In other embodiments, in the compounds of Formula (II) and / or Formula (III), Z is N or CH.

[0262] In other embodiments, the compound of the present invention is selected from the group consisting of:

[0263]

[0264]

[0265]

[0266]

[0267] On the other hand, the present invention provides a voltage-gated sodium channel Na V 1.8 Inhibitors. The inhibitor may have a defined chemical structure, such as the structure of any of the compounds described above.

[0268] In another aspect, the invention provides methods of treating a condition in a subject by providing to the subject having the condition a compound of the invention, such as any of the compounds described above.

[0269] The condition may be related to abnormal activity of voltage-gated sodium channels.The condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain in major trauma / injury, airway hyperresponsiveness, atopic dermatitis, allergy, ankylosing spondylitis, asthma, atopy, Behcet's disease, painful bladder syndrome, bone cancer pain, brachial plexus injury, burns, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuroarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic pruritus, 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, persistent unilateral facial pain with another External attacks, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, intervertebral disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuralgia, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, pruritus, juvenile Idiopathic arthritis, mastocytosis, myelodysplastic disease, migraine, multiple sclerosis, musculoskeletal injury, myofascial orofacial pain, post-ischemic neuropathy, neurofibromatosis type II, neuropathic eye pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, congenital hyperonychia, pain, cancer-related pain, chemotherapy-related pain, diabetes-related pain, 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, post-stroke pain, postoperative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, peripheral neuropathy induced by radiation therapy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorder, tension-type headache, trigeminal neuralgia, vascular leg ulcer, vulvar pain, or whiplash-related conditions.In another aspect, the invention provides a method of using a compound of the invention, such as any of the compounds described above, for the preparation of a medicament.

[0270] In another aspect, the invention provides a product comprising a compound of the invention, such as any of the compounds described above, for use in treating a condition, such as any of the conditions described above, in a subject. DETAILED DESCRIPTION

[0271] definition:

[0272] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the presently disclosed subject matter belongs. The definitions provided below are intended to supplement and illustrate, but not to exclude, definitions that would be apparent to those of ordinary skill in the art upon reading this disclosure.

[0273] Unless otherwise indicated, the moieties described below are optionally substituted, i.e., they can be substituted at one or more positions. As used herein, the term substituted, whether or not preceded by the term "optionally" and substituents, refers to the ability to replace one or more functional groups on a molecule with another or more functional groups, provided that the valence of all atoms remains unchanged. When more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents can be the same or different at each position. Substituents can also be further substituted (e.g., an aryl group substituent can have another substituent away from it, such as another aryl group further substituted at one or more positions).

[0274] When the term "independently selected" is used, the substituents referred to (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.

[0275] The terms "a," "an," or "a(n)" when used herein with reference to a group of substituents means at least one. For example, when a compound is substituted with "an" alkyl or aryl group, the compound is optionally substituted with at least one alkyl group and / or at least one aryl group. In addition, where a moiety is substituted with R substituents, the group may be referred to as "R-substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

[0276] Unless otherwise indicated herein, a named "R" or group will generally have an art-recognized structure corresponding to the group having that name. For illustrative purposes, certain representative "R" groups listed above are defined below.

[0277] The description of the compounds of the present disclosure is subject to the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted with one or more of a plurality of substituents, such substitutions are selected so as to conform to the principles of chemical bonding and to yield compounds that are not inherently unstable and / or, as known to those skilled in the art, would likely be unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the remainder of the molecule via a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0278] Unless expressly defined otherwise, a "substituent" as used herein includes a functional group selected from one or more of the following moieties as defined herein.

[0279] As used herein, the term hydrocarbon refers to any chemical group comprising hydrogen and carbon. Hydrocarbons may be substituted or unsubstituted. As known to those skilled in the art, when any substitution is made, all valences must be satisfied. Hydrocarbons may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Illustrative hydrocarbons are further defined below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, etc.

[0280] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a linear (i.e., unbranched) or branched, acyclic or cyclic saturated hydrocarbon group, or combinations thereof, and may include divalent and multivalent groups, having the specified number of carbon atoms (e.g., C1-10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In specific embodiments, the term "alkyl" refers to a C 1-20 , inclusive of end values, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbon, straight chain (i.e., "straight chain"), branched or cyclic saturated hydrocarbon groups derived from a hydrocarbon moiety containing one to twenty carbon atoms by the removal of a single hydrogen atom.

[0281] 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.

[0282] "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms (i.e., C 1-8 "Higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0283] An alkyl group may be optionally substituted with one or more alkyl group substituents which may be the same or different ("substituted alkyl"). The term "alkyl group substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxy, aryloxy, alkoxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxy, and cycloalkyl. The alkyl chain may optionally be interrupted by one or more oxygen atoms, sulfur atoms, or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0284] Thus, the term "substituted alkyl" includes alkyl groups as defined herein in which one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0285] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain hydrocarbon radical having from 1 to 20 carbon atoms or heteroatoms, or a cyclic hydrocarbon radical having from 3 to 15 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom such as O, N, P, Si or S, and wherein the nitrogen, phosphorus and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0286] As described above, as used herein, heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)NR', ​​-NR'R", -OR', -SR, -S(O)R and / or -S(O2)R'.

[0287] "Cycloalkyl" refers to a saturated monocyclic or polycyclic ring system of about 3 to about 15 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group may also be optionally substituted with an alkyl group substituent, oxo, and / or alkylene as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the cyclic alkyl chain, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thereby providing a heterocyclic group. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.

[0288] The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group as defined above separated by an alkylene moiety also as defined above, e.g., C 1-20 The alkylene moiety is attached to the parent molecular moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0289] The term "carbocyclyl" refers to a monocyclic or polycyclic ring system of about 3 to about 15 ring members, wherein all ring members are carbon atoms. Unless otherwise indicated, a carbocyclyl can be saturated, partially saturated (i.e., having one or more double or triple bonds) or aromatic.

[0290] The term "heterocyclyl" refers to a monocyclic or polycyclic ring system of about 3 to about 15 ring members, at least one of which is a heteroatom, such as N, O or S. Unless otherwise specified, a heterocyclyl group 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-oxolanyl, azetidinyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyrinyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinyl, 1,3-thiazinyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiazolyl, triazolyl, azabicyclo-octyl, diazabicyclo-octyl, and all alkyl, alkoxy, haloalkyl, and haloalkoxy substituted derivatives of any of the foregoing groups.

[0291] The terms "cycloheteroalkyl" and "heterocycloalkyl" refer to saturated ring systems that include one or more heteroatoms, such as 3- to 10-membered cycloalkyl ring systems. The heteroatoms can be the same or different and can be nitrogen (N), oxygen (O), or sulfur (S). Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

[0292] Cycloheteroalkyl ring can be optionally fused or otherwise connected with other cycloheteroalkyl rings and / or aromatic hydrocarbon rings.Heterocycle includes heterocycles with one to three heteroatoms such as oxygen, sulphur and nitrogen, wherein nitrogen and sulphur heteroatoms can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.Example includes but is not limited to bicyclic or tricyclic groups, it comprises fused six-membered ring, these fused six-membered rings have one to three heteroatoms independently selected from oxygen, sulphur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 hydrogen bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) nitrogen and sulphur heteroatoms can be optionally oxidized, (iii) nitrogen heteroatom can be optionally quaternized, and (iv) any above-mentioned heterocycle can be fused with aryl or heteroaryl rings. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrofuranyl, and the like.

[0293] The unsaturated hydrocarbon, carbocyclic group or heterocyclic group has one or more double bonds or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl and higher homologues and isomers.

[0294] As used herein, the term "alkenyl" refers to a monovalent group derived from a C2-20, inclusive, straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by removing a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0295] As used herein, the term "cycloalkenyl" refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0296] As used herein, the term "alkynyl" refers to a straight or branched chain C-alkyl group derived from a designated number of carbon atoms containing at least one carbon-carbon triple bond. 2-20 Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl.

[0297] The term "alkylene" by itself or as part of another substituent refers to a straight or branched divalent aliphatic hydrocarbon radical derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. An alkylene group can be straight, branched, or cyclic. An alkylene group can also be optionally unsaturated and / or substituted with one or more "alkyl group substituents." One or more oxygen atoms, sulfur atoms, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") can be optionally inserted along the alkylene group, wherein the nitrogen substituent is an alkyl group as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (CH2)3, cyclohexylene (-CH6H 10 -), -CH=CH-CH=CH-, -CH=CH-CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)qN(R)-(CH2)r-, wherein 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; methylenedioxy (-O-CH2-O-); and ethylenedioxy (-O-(CH2)2-O-).

[0298] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply an orientation of the linking group. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0299] 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, a "spirocycloalkyl" refers to a cycloalkyl group having two rings with a single carbon in common, and a "spiroheterocycloalkyl" or "spiroheterocycloalkyl" refers to a cycloheteroalkyl group having two rings with a single carbon in common or other atom, such as nitrogen in common.

[0300] Unless otherwise indicated, the term "aryl" means an aromatic hydrocarbon substituent which can be a single ring or multiple rings (eg, 1 to 3 rings) which are fused together or linked covalently.

[0301] The term "heteroaryl" refers to and contains one to four heteroatoms (in the case of polycyclic, in each separate ring) selected from N, O and S (or ring), wherein nitrogen and sulphur atoms are optionally oxidized, and nitrogen-atoms are optionally quaternized. Heteroaryl groups can be connected to the rest of the molecule by carbon or heteroatoms. The limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above-noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl groups, respectively.

[0302] When a heteroalkyl, heterocycloalkyl, or heteroaryl group includes a specific number of members (eg, "3- to 7-membered"), the term "member" refers to a carbon atom or a heteroatom.

[0303] Each of the above terms is intended to include both substituted and unsubstituted forms of the indicated radical. Optional substituents are provided below.

[0304] The substituents may be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R", SR', -halogen, -SiR'R"R", -OC(O)R, -C02R, -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R, -NR'-C(O)NR"R"', -NR"C(O)OR', -NR-C(NR'R")=NR"', -S(O)R, -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN, CF3, fluorinated C 1-4alkyl and -NO2, the number of which ranges from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R", R'' and R"" can each independently refer to hydrogen, halogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups or aralkyl groups. Other non-limiting examples of substituents include (C1-C6)alkyl, (C2-C8)alkenyl, (C3-C8)alkynyl, halogen, halo(C1-C6)alkyl, hydroxyl, -O(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C8)cycloalkyl, (C6-C8) 10 )aryl, heterocyclic, 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 group attached to the rest of the molecule through a divalent oxygen.

[0305] When a compound of the present disclosure includes more than one R group, for example, each R group in the R group is independently selected as each R', R", R"' and R"" group is independently selected 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-membered, 5-membered, 6-membered, or 7-membered ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl groups (e.g., -CF3 and -CH2CF3) and acyl groups (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0306] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -TC(O)-(CRR')qU-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A-(CH2)rB-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4.

[0307] One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by substituents of the formula -(CRR')s-X'-(C"R"')d-, wherein 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.

[0308] As used herein, the term "acyl" refers to an organic acid group in which the -OH of the carboxyl group is replaced by another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic or aromatic heterocyclic group as defined herein. Thus, the term "acyl" specifically includes aryl acyl groups such as 2-(furan-2-yl)acetyl)- and 2-phenylacetyl groups. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC(=O)NR, esters, -RC(=O)OR', ketones, -RC(=O)R' and aldehydes, -RC(=O)H.

[0309] The terms "alkoxy" or "alkoxyl" are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms "alkyl," "alkenyl," and "alkynyl" are as previously described and can include C1-20, inclusive, linear, branched, or cyclic saturated or unsaturated oxy-hydrocarbon chains including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and n-pentoxy, neopentoxy, n-hexoxy, and the like.

[0310] The term "alkoxyalkyl" as used herein refers to an alkyl-O-alkyl ether, such as a methoxyethyl or ethoxymethyl group.

[0311] "Aryloxy" refers to an aryl-O- group, wherein the aryl group is as previously described, including substituted aryl groups. As used herein, the term "aryloxy" may refer to phenoxy or hexyloxy, as well as alkyl, substituted alkyl, halo or alkoxy substituted phenoxy or hexyloxy.

[0312] "Aralkyl" refers to an aryl-alkyl group in which the aryl and alkyl are as previously described and include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenethyl, and naphthylmethyl.

[0313] "Aralkyloxy" refers to an aralkyl-O- group, wherein the aralkyl group is as previously described. An exemplary aralkyloxy group is benzyloxy, i.e., C6H5CH2-O-. An aralkyloxy group may be optionally substituted.

[0314] "Alkoxycarbonyl" refers to an alkyl-OC(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl.

[0315] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

[0316] "Aralkyloxycarbonyl" refers to an aralkyl-OC(=O)- group. An exemplary aralkyloxycarbonyl group is benzyloxycarbonyl.

[0317] "Carbamoyl" refers to an amide group of formula -C(=O)NH2.

[0318] "Alkylcarbamoyl" refers to an R'RN-C(=O) group, wherein one of R and R' is hydrogen and the other of R and R' is alkyl and / or substituted alkyl as previously described. "Dialkylcarbamoyl" refers to an R'RN-C(=O)- group, wherein each of R and R' is independently alkyl and / or substituted alkyl as previously described.

[0319] As used herein, the term "carbonyldioxy" refers to a carbonate group of formula -OC(=O)-OR.

[0320] "Acyloxy" means an acyl-O- group in which the acyl group is as previously described.

[0321] The term "amino" refers to an -NH2 group and refers to nitrogen-containing groups known in the art that are derived from ammonia by replacement of one or more hydrogen groups with an organic group. For example, the terms "acylamino" and "alkylamino" refer to specific N-substituted organic groups having acyl and alkyl substituent groups, respectively.

[0322] As used herein, "aminoalkyl" refers to an amino group covalently bound 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 via a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', wherein R' is an alkyl group as previously defined; while the term dialkylamino refers to a group having the structure -NR'R", wherein R' and R" are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R"R"', wherein R', R" and R'"' are each independently selected from the group consisting of alkyl groups. Additionally, R', R" and / or R'"' taken together may optionally be -(CH2) k , wherein 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.

[0323] 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.

[0324] The terms alkylthioether and thioalkoxy 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 thioalkoxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0325] "Acylamino" means an acyl-NH- group in which the acyl group is as previously described. "Aroylamino" means an aroyl-NH- group in which the aroyl group is as previously described.

[0326] The term "carbonyl" refers to a -C(=O)- group and may include an aldehyde group represented by the general formula RC(=O)H.

[0327] The term "carboxyl" refers to a COOH group. Such groups are also referred to herein as "carboxylic acid" moieties.

[0328] The term "cyano" refers to a -CN group.

[0329] The terms "halo," "halide," and "halogen" refer to fluoro, chloro, bromo, and iodo groups.

[0330] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Additionally, the term "haloalkyl" includes monohaloalkyl and polyhaloalkyl. For example, the term "halo (C1-4) alkyl" includes but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0331] The terms "halocycloalkyl" and "cyclohaloalkyl" refer to a cycloalkyl group having one or more halogens.

[0332] The term "hydroxy" refers to an -OH group.

[0333] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0334] The term "mercapto" refers to a -SH group.

[0335] The term "oxo" refers to an oxygen atom double-bonded to a carbon atom or another element.

[0336] The term "nitro" refers to a -NO2 group.

[0337] The term "thio" refers to compounds previously described herein wherein a carbon or oxygen atom is replaced by a sulfur atom.

[0338] The term "sulfate" refers to a -SO4 group.

[0339] As used herein, the term thiol or thiol refers to a group of formula -SH.

[0340] More specifically, the term "sulfide" refers to a compound having a group of formula -SR.

[0341] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R'.

[0342] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R.

[0343] The term urea refers to a urea group of the formula -NH-CO-NH2.

[0344] Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, homologs, optical and stereoisomers, as well as the racemic mixtures where such isomers and mixtures exist.

[0345] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical centers or chiral centers) or double bonds; in terms of absolute stereochemistry, enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined as (R)- or (S)- or D- or L- of amino acids and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds that are too unstable to be synthesized and / or separated as known in the art. The present disclosure is intended to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)- or D- and L- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometric asymmetric centers, and unless otherwise indicated, it is contemplated that the compounds include both E and Z geometric isomers.

[0346] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric mixtures and diastereomeric mixtures of the present compounds are within the scope of the present disclosure.

[0347] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of these compounds are within the scope of the present disclosure. As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0348] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, structures having a structure containing a hydrogen replaced by a deuterium or tritium, or a structure having ... 13 C or 14 Compounds of the present structures in which a C-enriched carbon replaces a carbon are within the scope of this disclosure.

[0349] 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 be treated with tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or non-radioactive, are encompassed within the scope of the present disclosure.

[0350] The compounds of the present disclosure may exist in the form of salts, and specifically in the form of pharmaceutically acceptable salts. The present disclosure includes such salts. Examples of suitable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts or similar salts. When the compounds of the present disclosure contain relatively alkaline functional groups, acid addition salts can be obtained by contacting such compounds in a neutral form with a sufficient amount of the desired acid (pure 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 acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

[0351] 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.

[0352] The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0353] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0354] In addition to salt forms, the present disclosure also provides compounds in the form of prodrugs. The prodrugs of the compounds described herein are those compounds that are easily subjected to chemical changes under physiological conditions to provide compounds of the present disclosure. Additionally, prodrugs can be converted into compounds of the present disclosure by chemical or biochemical methods in an isolated environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into a compound of the present disclosure.

[0355] The term "blocking group" refers to a chemical moiety that blocks some or all reactive moieties of a compound and prevents such moieties from participating in a chemical reaction until the blocking group is removed, such as TW Greene, PGM Wuts, " Blocking Groups in Organic Synthesis ", those parts listed and described in the 3rd edition John Wiley & Sons (1999). When different blocking groups are employed, it may be advantageous that each (different) blocking group can be removed by different methods. The blocking group cut under completely different reaction conditions allows for the different removal of such blocking groups.

[0356] For example, protecting groups can be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid unstable and can be used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected by Cbz groups that can be removed by hydrogenolysis and alkali unstable Fmoc groups. In the presence of acid unstable groups such as t-butyl carbamate or carbamate-terminated amines that are stable but hydrolytically removable with acid and base, alkali unstable groups can be used, such as but not limited to methyl, ethyl and acetyl-terminated carboxylic acid and hydroxyl reactive moieties.

[0357] Carboxylic acid and hydroxyl reactive moieties can also be capped with hydrolytically removable protecting groups such as benzyl, while amine groups capable of hydrogen bonding with acids can be capped with base-labile groups such as Fmoc. Carboxylic acid reactive moieties can be capped with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups can be capped with fluorine-labile silylcarbamates.

[0358] Allyl end-blocking group is useful in the presence of acid blocking group and base blocking group, because the former is stable, and can be removed by metal or π acid catalyst subsequently.For example, in the presence of acid-unstable t-butyl carbamate or base-unstable acetamide blocking group, the carboxylic acid of allyl end-blocking can be deprotected with the reaction catalyzed by palladium (0).Another kind of blocking group form is the resin that can be connected with compound or intermediate.As long as residue is connected with resin, this functional group will be end-blocked, and can not react.In case, discharge from resin, functional group just can react.

[0359] Abbreviations and acronyms

[0360] When used herein, the following abbreviations have the following meanings:

[0361]

[0362]

[0363]

[0364] Compound:

[0365] The present invention provides compounds that modulate, for example, inhibit the activity of voltage-gated sodium channels. These compounds and methods for their preparation are provided in detail below.

[0366] (A) The first group of compounds

[0367] In one aspect, the present invention provides a compound of formula (I):

[0368]

[0369] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein A is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted with one or more groups selected from the group consisting of: wherein the haloalkyl chain can be a fully or partially halogenated halo-C1-C4 alkyl, a substituted or unsubstituted C1-C8 alkyl, wherein the alkyl chain can be a fully or partially deuterated deuterated C1-C4 alkyl, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be a fully or partially halogenated haloalkoxy, or arylalkoxy;

[0370] B is aryl or heteroaryl, wherein the aryl may have 1 to 4 substituents, and the heteroaryl may have 1 to 3 substituents independently selected from halogen, C1-C8 alkyl, haloalkyl or alkoxy;

[0371] R1, R2, R3 and R4 are independently selected from H, halogen, -OH, C1-C6-alkyl, wherein the fluoroalkyl chain can be a fully or partially fluorinated C1-C6 fluoroalkyl, C3-C8 branched alkyl, wherein the branched fluoroalkyl chain can be a fully or partially fluorinated C3-C8 branched fluoroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0372] R5 is H or C1-C3 alkyl; and

[0373] R6 is -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R", or formula (II):

[0374]

[0375] in:

[0376] X1 and X2 are both O, NH or NR'; or

[0377] X1 is O, and X2 is NH or NR';

[0378] R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

[0379] In various embodiments, the compound of the present invention is a compound of formula (III):

[0380]

[0381] wherein R1, R2, R3, R4, R5, R6 and B are as described in formula (I);

[0382] Q, T and W are independently N or CR9;

[0383] R9 is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy;

[0384] X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3 or OCF3;

[0385] R8 is H, hydroxy, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, or substituted or unsubstituted 3-6 membered cycloalkyl.

[0386] In another embodiment, B is

[0387]

[0388] wherein R6 is as described above; Z is CR 10 , N or N + O - ; where R 10 It is H, halo, -CD3, C1-C8 alkyl, haloalkyl or alkoxy.

[0389] In another embodiment, R6 is

[0390]

[0391] in:

[0392] X1 and X2 are both O, NH or NR'; or

[0393] X1 is O, and X2 is NH or NR';

[0394] R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

[0395] In another embodiment, R6 is

[0396]

[0397] in:

[0398] X1 is O, X2 is NH, and R7 is C1-C3 alkyl.

[0399] In another embodiment, R6 does not include -C(=O)NH2, -C(=O)NHR' or -C(=O)NR'R".

[0400] In another embodiment, B is a phenyl ring.

[0401] In another embodiment, B is a pyridine ring.

[0402] In another embodiment, R1 is H, -CH3 or F.

[0403] In another embodiment, R2 is chloro, -CF3, H, 2-pyrazoline or 1-methyl-1H-pyrazol-4-yl. In another embodiment, R3 is H, -CF3 or F.

[0404] In another embodiment, R4 is H.

[0405] In another embodiment, R8 is H, -CH3 or -O-CH3.

[0406] In another embodiment, R7 is -CH3.

[0407] In another embodiment, X is F or -CN.

[0408] In another embodiment, Q is N or CH.

[0409] In another embodiment, W is CH and T is CH.

[0410] In another embodiment, Z is CR 10 , and R 10 It is H or F.

[0411] In another embodiment, the compound is selected from the group consisting of:

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423] The first group of compounds provided herein are prepared by the methods and procedures described below.The intermediates described in this section can be used to prepare the first group of compounds.

[0424] Unless otherwise noted, chemicals were purchased from standard commercial suppliers and used as received. Otherwise, their preparation is readily available and known to those of ordinary skill in the art, or 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.

[0425] Unless otherwise stated, all reactions were performed under a positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware with magnetic stirring. Unless otherwise stated, chemicals were purchased from standard commercial suppliers and used as received. Yields were not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.

[0426] Use purchased from EMD MILLIPORETM The reaction was monitored by thin layer chromatography (TLC) on 0.25 mm silica gel 60 F254 plates. Purification was performed using Biotage Isolera One flash chromatography or using one of the preparative HPLC methods mentioned below.

[0427] Preparation method 1

[0428] Equipment: Shimadzu LCMS2020 mass-directed preparative HPLC system; column: Gemini 5um C 18 Column, 150*21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.1% HCOOH, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0429] Preparation method 2

[0430] Equipment: Shimadzu LC-20AP preparative HPLC system; column: Gemini 5um C 18 Column, 150*21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.1% TFA, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0431] Preparation method 3

[0432] Equipment: 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 0.05% ammonia, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0433] Collect and analyze LCMC using one of the following methods:

[0434] Method 1

[0435] Equipment: Shimadzu LCMS2020 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 in 1.4 minutes, held for 0.6 minutes, with a total run time of 2.5 minutes; flow rate: 1.8 ml / min; column temperature: 50°C; wavelengths: 214 and 254 nm PDA.

[0436] Method 2

[0437] Equipment: Shimadzu LCMS2020 spectrometer; XBridge BEH C 18 2.5 μm, 3.0 mm × 30 mm mobile phase: MeCN-water (0.1% NH4OH); gradient: 5% to 95% MeCN in 1.8 minutes, hold for 0.7 minutes, total run time of 3.0 minutes; flow rate: 1.0 ml / min; column temperature: 50°C; wavelength: 214 and 254 nm PDA.

[0438] Method 3

[0439] Equipment: Shimadzu LCMS2020 spectrometer; column: HALO C 18 2.7 μm, 3.0 mm × 30 mm mobile phase: MeCN (0.05% TFA)-water (0.05% TFA); gradient: 5% to 95% MeCN in 1.4 minutes, hold for 0.6 minutes, total run time of 2.5 minutes; flow rate: 1.8 ml / min; column temperature: 50°C; wavelength: 214 and 254 nm PDA.

[0440] The following method was used to analyze the Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD SF , SFC-30A) for SFC chiral separation:

[0441] Method 1

[0442] Column: Daicel chiralpak-AS-H 5 μm 250 x 20 mm; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M in MeOH)], with different CO 2 / MeOH ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0443] Method 2

[0444] Column: Chiralpak-OJ-H, 5 μm, 250×20 mm; mobile phase: CO 2 / MeOH (0.1% HCOOH), with different CO 2 / MeOH ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0445] Method 3

[0446] Column: Chiralpak-OD-H 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / MeOH, with different ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0447] Method 4

[0448] Column: Chiralpak-AD-H 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / i-PrOH, with different ratios for different compounds; oven temperature: 40°C; flow rate: 38 ml / min.

[0449] Method 5

[0450] Column: Chiralpak-IC 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / EtOH, with different ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0451] Unless otherwise stated, 1 H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz digital NMR spectrometer. Chemical shifts δ are quoted in parts per million (ppm) relative to TMS and are calibrated using residual undeuterated solvent as an internal reference. The following abbreviations are used to indicate multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet), dq (doublet of quadruplet), hep (septet), m (multiplet), pent (quintet), td (triplet of doublet), qd (quadruple of doublet), app. (apparent), and br. (broad). Coupling constants J are quoted to the nearest 0.1 Hz.

[0452] General synthetic scheme

[0453] Several methods for preparing the compounds of the present invention are described in the following schemes and examples. The present invention further provides methods for preparing compounds of formula I as defined above. In some cases, the order in which the preceding reaction schemes are performed may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

[0454] Plan A

[0455]

[0456] As shown in Scheme A, compounds of formula (I) can generally be synthesized starting from formic acid A-1 by reacting a substituted aniline or heteroaryl aniline A-2 using a standard amide coupling agent, not limited to HATU, TBTU, EDC, or T3P, such as DIEA, in an organic solvent and base to obtain an intermediate of type A-3. Intermediate A-3 may 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, formic acid A-1 can be treated with ammonia or a primary amine (R5NH2) in the presence of an amide coupling agent such as HATU and a base such as DIEA to obtain a carboxamide intermediate A-5, which can be metal-catalyzed coupled with a halogen-substituted aryl or heteroaryl compound of type A-6 to obtain a compound of formula A-3. Compounds of formula (I) can then be obtained from A-3 as described.

[0457] Plan B

[0458]

[0459] As further illustrated in Scheme B, generally, compounds of the present invention can be prepared by reacting intermediate A-1 with amine B-1, utilizing amide coupling conditions or by activating appropriately functionalized formic acid A-1 with amine B-1 and bases such as DIEA or pyridine in DCM, DMF or THF to obtain B-2 type compounds. Formula B-3 compounds can be formed by removing protecting groups such as Boc under acidic conditions. In some cases, chiral HPLC can be used to separate B-3 into corresponding R and S isomers. R- and S-isomers can also be prepared by coupling acid with enantiomerically pure amine B-1 and then deprotecting.

[0460] Plan C

[0461]

[0462] As further illustrated in Scheme B, generally, the compounds of the present invention can be prepared by activating appropriately functionalized formic acid A-1 with (COCl) or SOCl in an organic solvent, followed by the addition of NH4OH to obtain C-1. Intermediate C-1 is then combined with various substituted Br compound C-2 materials using Xantphos-Pd-G2-mediated coupling conditions to deliver intermediate C-3. Compounds of formula C-3 can be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodine) benzene (PIDA) in methanol to provide compounds of formula B-3. In some cases, B-3 is separated into corresponding R and S isomers using chiral HPLC conditions. Compounds of formula B-4 are obtained using standard amide coupling agents, such as, but not limited to, HATU, bases such as DIEA, and C-4.

[0463] The above schemes are intended to illustrate and are not intended to be limiting in any way. Those skilled in the art can use these general schemes as a guide to prepare compounds of formula (I), but other methods can also be used to complete the synthesis of compounds of the present invention. Specific methods are provided for each example in the examples to further illustrate the synthesis of compounds of formula (I).

[0464] intermediates

[0465] Intermediate 1

[0466] 5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid

[0467]

[0468] 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, H2O, room temperature

[0469] Step 1: 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid: Under an atmosphere of N2, n-BuLi (2.4M in hexane, 9.58mL, 23mmol) was added dropwise to a solution of Me4-piperidine (3.2g, 23mmol) in THF (30mL) at 0°C. The mixture was stirred at 0°C for 1 hour. Then, a solution of 1-chloro-4-fluoro-2-(trifluoromethyl)benzene (3g, 15mmol) in THF (30mL) was added dropwise at -78°C. The mixture was stirred at -78°C for 2 hours. Dry ice (about 5g) was added to the resulting solution. 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 NH4Cl aqueous solution (100mL) and extracted with EtOAc (100mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=20 / 1) to give 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (2 g, 54.6%) as a yellow solid. LCMS (ESI): [MH] - m / z calculated value 240.97, found value 240.85.

[0470] Step 2: 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester: 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (2g, 8.30mmol) was added to SOCl2(20mL) and heated at 80 DEG C for 1 hour.Then the mixture was concentrated in vacuo. Residue was added to MeOH (30mL) and stirred at room temperature for 1 hour. The final mixture was concentrated in vacuo to obtain crude 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (1.8g), which was directly used in the next step without further purification.

[0471] Step 3: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid methyl ester: A solution of 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. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was directly purified by silica gel flash column chromatography (PE / EtAOc=3 / 1) to give 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid methyl ester (2.4 g, 93.93%) as a yellow solid. LCMS (ESI): C15 H 11 [M+H] of ClF4NO3 - m / z calculated value 364.04, found value 363.70.

[0472] 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 2N HCl. The precipitate was collected by filtration, washed with water and dried under vacuum to afford 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (900 mg, 93.65%) as a yellow solid. LCMS (ESI): C 14 [M+H] of H9ClF4NO3 + m / z calculated value 350.02, found value 349.65.

[0473] Intermediate 2

[0474] 2-((6-Fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid

[0475]

[0476] Reagents and conditions: a) MeI, K2CO3, DMF; b) 6-fluoro-2-methylpyridin-3-ol, Cs2CO3, DMF, 100°C; c) LiOH.H2O, THF / H2O

[0477] Step 1: 2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester: To a solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (500 mg, 2.4 mmol) and K2CO3 (993 mg, 7.2 mmol) in DMF (5 mL) was added CH3I (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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1 to 5 / 1) to obtain 2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (490 mg, 81.7%) as a white oil. LCMS (ESI): [M+H] + m / z calcd. 223.04, found 223.04.

[0478] Step 2: Methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate: A solution of methyl 2-fluoro-4-(trifluoromethyl)benzoate (400 mg, 1.8 mmol) in DMF (5 mL) Cs2CO3 (1.75 g, 5.4 mmol), 6-fluoro-2-methylpyridin-3-ol (342 mg, 2.7 mmol) was added. The mixture was heated to 100° C. for 1 hour. After the reaction was complete, the mixture was filtered through celite. The solution was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (PE / EtOAc=4 / 1 to 3 / 1) to provide methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate (350 mg, 86%) as a light yellow solid. LCMS (ESI): C 15 H 12 [M+H] of F4NO3 + m / z calcd. 330.08, found 330.00.

[0479] Step 3: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid: To a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate (350 mg, 1.06 mmol) in THF (4 mL) and H2O (4 mL) was added LiOH.H2O (267 mg, 6.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the residue was adjusted to pH = 3-4 with HCl (1 M). The aqueous solution was then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 92%) as a white solid. LCMS (ESI): C 14 H 10 [M+H] of F4NO3 + m / z calculated value 316.06, found value 315.90.

[0480] Intermediate 3

[0481] 6-((6-Fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid

[0482]

[0483] 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

[0484] Step 1: 6-fluoro-2-methyl-3-nitrobenzoic acid methyl ester: 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 x 3), dried over sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1 to 1 / 3) to provide 6-fluoro-2-methyl-3-nitrobenzoic acid methyl ester (2.00 g, 93.4%) as a white solid.

[0485] 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 completed, the solution was diluted with DCM (150 mL) and washed with brine (150 mL), dried over sodium sulfate, then concentrated and purified by silica gel flash column chromatography (Pe / EtOAc=5 / 1 to 3 / 1) to provide methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate (1.80 g, 70.5%) as a white solid. LCMS (ESI): C 15 H 14 [M+H] of FN2O5 + m / z calculated value 321.09, found value 321.05.

[0486] Step 3: 3-amino-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methylbenzoic acid methyl ester: To a solution of 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoic acid methyl ester (1.70 g, 5.31 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (1.99 g, 37.16 mmol), Fe (1.48 g, 26.54 mmol). The mixture was heated to 60 ° C for 1 hour. After the reaction was 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 in vacuo to provide methyl 3-amino-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methylbenzoate (1.50 g, 97.3%) as a red oil. LCMS (ESI): C 15 H 16 [M+H] of FN2O3 + m / z calculated value 291.12, found value 291.05.

[0487] Step 4: Methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate: To a solution of TsOH·H2O (2.95 g, 15.50 mmol) and methyl 3-amino-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methylbenzoate (1.50 g, 5.17 mmol) in MeCN (30 mL) was added a solution of NaNO2 (713 mg, 10.33 mmol) and KI (2.14 g, 12.92 mmol) in H2O (5 mL) at 0°C. The mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, the mixture was quenched with water (100 mL) and adjusted to pH = 8-9 with saturated NaHCO3 aqueous solution. The solution was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1 to 1 / 1) to provide methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate (1.50 g, 72.4%) as a yellow solid. LCMS (ESI): C 15 H 14 FINO3's [M+H] + m / z calcd. 402.00, found 401.90.

[0488] Step 5: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoate: A mixture of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate (400 mg, 1.00 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (188 mg, 1.50 mmol) in 1,4-dioxane / HO (4 / 1, 10 mL) was added potassium carbonate (413 mg, 2.99 mmol) and Pd(dppf)Cl (146 mg, 0.20 mmol). Under an atmosphere of N, the mixture was heated at 100 ° C for 6 hours. The reaction was monitored by LCMS. After completion of the reaction, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to 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): C 19 H 19 [M+H] of FN3O3 + m / z calculated value 356.14, found value 356.10.

[0489] 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid (90 mg, 37.5%) as a white solid. LCMS (ESI): C 18 H 17 [M+H] of FN3O3 + m / z calculated value 342.13, found value 342.05.

[0490] Intermediate 4

[0491] 6-((6-Fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid

[0492]

[0493] Reagents and conditions: a) methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 120°C; b) LiOH,

[0494] THF / MeO / H2O, 60℃

[0495] Step 1: 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoate: Under an atmosphere of N2, to a solution of 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2-methylbenzoate (500 mg, 1.25 mmol) and CuI (475 mg, 2.49 mmol) in DMF (10 mL) was added dropwise 2,2-difluoro-2-(fluorosulfonyl)acetate (1.20 g, 6.23 mmol). 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 x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 16 H 14 [M+H] of F4NO3 + m / z calculated value 344.09, found value 344.05.

[0496] 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid (75 mg, 22.3%) as a white solid. LCMS (ESI): C 15 H 12 [M+H] of F4NO3 + m / z calculated value 330.08, found value 330.05.

[0497] Intermediate 5

[0498] 2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoic acid

[0499]

[0500] 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

[0501] Step 1: 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid methyl ester: A mixture of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1 g, 3.48 mmol), K CO (1.44 g, 10.44 mmol), MeI (988 mg, 6.96 mmol) in DMF (10 mL) was stirred at 25 ° C for 16 hours. The resulting solution was diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na SO and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=3 / 1) to obtain 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid methyl ester (950 mg, 90.9%) as a yellow solid. 1H NMR (400MHz, CD3OD) δ8.05-7.72 (m, 2H), 3.97 (s, 3H).

[0502] 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 hours. 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 vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=3 / 1) to obtain methyl 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzoate (250 mg, 72.5%) as a yellow oil. LCMS (ESI): C 15 H 11 [M+H] of F5NO3 + m / z calcd. 348.07, found 348.00.

[0503] 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 1N 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): C 14 [M+H] of H9F5NO3 +m / z calcd. 334.05, found 334.00.

[0504] Intermediate 6

[0505] 5-Chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid

[0506]

[0507] Reagents and conditions: a) Cs2CO3, MeCN, 80°C; b) LiOH, THF / H2O

[0508] Step 1.5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoate: A solution of 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 hours. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with water (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to afford methyl 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoate (120 mg, 36.2% yield) as a yellow solid. LCMS (ESI): C 17 H 12 [M+H] of ClF3NO4 - m / z calculated 386.14, found 386.0.

[0509] 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 H2O (2 mL) was added LiOH (45 mg, 1.87 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After completion of the reaction, 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 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.

[0510] Intermediate 7

[0511] 4-Cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid

[0512]

[0513] 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°C; g) CuI, DMF, 100°C; h) Cs2CO3, MeCN, 80°C; i) KOH, t-BuOH, THF / H2O, 80°C

[0514] 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 hours. The mixture was then added to ice-cold water. The precipitate was collected by filtration and dried under vacuum to afford 6-fluoro-2-methyl-3-nitrobenzoic acid (2.5 g, 64.4%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm) δ8.12 (dd, J=9.1, 5.2Hz, 1H), 7.46 (t, J=8.8Hz, 1H), 2.45 (s, 3H).

[0515] Step 2.6-fluoro-2-methyl-3-nitrobenzoic acid methyl ester: To a solution of 6-fluoro-2-methyl-3-nitrobenzoic acid (2.5 g, 12.6 mmol) and CH3I (3.57 g, 25.1 mmol) in DMF (20 mL) was added K2CO3 (5.22 g, 37.8 mmol) and stirred at room temperature for 18 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give 6-fluoro-2-methyl-3-nitrobenzoic acid methyl ester (1.5 g, 55.9%) as a yellow solid.

[0516] Step 3.3-amino-6-fluoro-2-methylbenzoic acid methyl ester: At room temperature, Fe powder (3.68g, 65.7mmol) and NH4Cl (3.52g, 65.7mmol) were added to a solution of 6-fluoro-2-methyl-3-nitrobenzoic acid methyl ester (2g, 9.39mmol) in MeOH / H2O (3:1, 8mL). The mixture was stirred at 65°C for 5 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50mL) and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1 to 1 / 3) to obtain 3-amino-6-fluoro-2-methylbenzoic acid methyl ester (1.5g, 87.2%) as a yellow solid. LCMS (ESI): C9H 11 [M+H] of FNO2 + m / z calculated value 184.08, found value 183.90.

[0517] Step 4.3-amino-4-bromo-6-fluoro-2-methylbenzoic acid methyl ester: At 0 ° C, to a solution of NBS (1.75g, 9.8mmol) in DMF (10mL) was added 3-amino-6-fluoro-2-methylbenzoic acid methyl ester (1.5g, 8.2mmol). 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 silica gel flash column chromatography (PE / EtOAc=15 / 1 to 10 / 1) to obtain 3-amino-4-bromo-6-fluoro-2-methylbenzoate (900mg, 37.8%) as a yellow oil. LCMS (ESI): C9H 10 [M+H] of BrFNO2 +m / z calculated value 261.99, found value 216.95.

[0518] Step 5.3-amino-4-cyclopropyl-6-fluoro-2-methylbenzoic acid methyl ester: To a solution of cyclopropylboronic acid (590.0 mg, 6.87 mmol), Pd(dppf)Cl2 (251.3 mg, 0.34 mmol) and K2CO3 (1.42 g, 10.3 mmol) in 1,4-dioxane / HO (4:1, 10 mL) was added 3-amino-4-bromo-6-fluoro-2-methylbenzoic acid methyl ester (900 mg, 3.43 mmol) at room temperature. Under N2, the reaction mixture was heated at 100 ° C for 16 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 12 H 15 [M+H] of FNO2 + m / z calculated value 224.11, found value 223.90.

[0519] Step 6.4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoic acid methyl ester: To a solution of 3-amino-4-cyclopropyl-6-fluoro-2-methylbenzoic acid methyl ester 6 (700 mg, 3.14 mmol) and I (1.19 g, 4.70 mmol) in THF (10 ml) was added t-BuONO (485.0 mg, 4.70 mmol) at room temperature. The reaction mixture was heated to 80 ° C and refluxed for 2 hours. After the reaction was complete, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over Na SO and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=15 / 1 to 10 / 1) to obtain 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoic acid methyl ester (650 mg, 49.6%) as a black solid. LCMS (ESI): C 12 H 13 [M+H] of FIO2 + m / z calculated value 334.99, found value 334.60.

[0520] Step 7.4-cyclopropyl-6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid methyl ester: To a solution of 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoic acid methyl ester (650 mg, 1.95 mmol) and CuI (741.0 mg, 3.89 mmol) in DMF (10 ml) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (1.87 g, 9.73 mmol) at room temperature. The reaction mixture was heated at 100 ° C for 5 hours under N2. After the reaction was 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 vacuum. The residue was purified by silica gel flash column chromatography (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): C 13 H 13 [M+H] of F4O2 + m / z calculated value 277.08, found value 277.10.

[0521] Step 8. 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoate: To a solution of 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 completion of the reaction, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 19 H 18 [M+H] of F4NO3 + m / z calculated: 384.12, found: 384.10.

[0522] 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 completion of the reaction, 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 x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford 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): C 18 H 16 [M+H] of F4NO3 + m / z calculated value 370.11, found value 370.10.

[0523] Intermediate 8

[0524]

[0525] Reagents and conditions: a) K2CO3, MeI, DMF; b) H2SO4, fuming HNO3; c) Pd / C, H2, THF; d) NBS, MeCN; e) trimethylboroxane, 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

[0526] Step 1.2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester: 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to provide 2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (8 g, 85% yield) as a white oil. LCMS (ESI): [M+H] + m / z calcd. 223.04, found 223.04.

[0527] Step 2.2-Fluoro-5-nitro-4-(trifluoromethyl)benzoic acid methyl ester: At 0 ° C, to a stirred solution of H SO (80 mL) and fuming HNO (6 mL) was added 2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester 1 (8.0 g, 36.01 mmol). The mixture was heated to 50 ° C and stirred for 5 hours. The mixture was poured into ice water (500 mL) and filtered. The filter cake was dried to provide 2-fluoro-5-nitro-4-(trifluoromethyl)benzoic acid methyl ester (4 g, 40% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3, ppm) δ8.58 (d, J = 6.1 Hz, 1H), 7.65 (d, J = 9.7 Hz, 1H), 4.02 (s, 3H).

[0528] Step 3: 5-amino-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester: Pd / C (600 mg) was added to a solution of 2-fluoro-5-nitro-4-(trifluoromethyl)benzoic acid methyl ester (4 g, 14.98 mmol) in THF (50 mL) and stirred at room temperature for 16 hours under an atmosphere of H2. LCMS showed that 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 vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to provide 5-amino-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (2.9 g, 81.69% yield) as a yellow solid. LCMS (ESI): [M+H] + m / z calculated value 238.05, found value 237.60.

[0529] Step 4.3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester: To a solution of 5-amino-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (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 that the reaction was complete. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=20 / 1) to provide 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (2.5 g, 64.94% yield) as a light yellow oil. LCMS (ESI): [M+H] + m / z calculated value 315.96, found value 315.90.

[0530] Step 5.3-amino-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid methyl ester: A solution of 3-amino-2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (2.5 g, 7.94 mmol), trimethylboroxane (4.98 g, 39.69 mmol), K PO (5.48 g, 39.69 mmol) and Pd(dppf)Cl (584 mg, 0.79 mmol) in dioxane (40 mL) and H O (10 mL) was heated to 100 ° C and refluxed for 16 hours. LCMS showed that 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 vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=20 / 1) to afford methyl 3-amino-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate (1.5 g, 75.38% yield) as a pale yellow oil. LCMS (ESI): C 10 H 10 [M+H] of F4NO2 + m / z calcd. 252.07, found 252.00.

[0531] Step 6.3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid methyl ester: Under N2, t-BuONO (1.22 g, 11.83 mmol), CuCl2 (1.59 g, 11.83 mmol) and MeCN (20 mL) were added to a flame-dried round-bottom flask equipped with a magnetic stirring bar and an addition funnel. The solution was stirred at room temperature for 0.5 hours. A solution of 3-amino-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid methyl ester (1.5 g, 5.74 mmol) in MeCN (10 mL) was added dropwise at 0°C. The reaction mixture was heated to 60°C and stirred for 1 hour. LCMS showed that the reaction was complete. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL x3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 20 / 1) to afford methyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate (1.4 g, 87.50% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6, ppm) δ7.88 (d, J = 9.3Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H).

[0532] 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 h. After the reaction was completed, the mixture was concentrated under vacuum and the residue was directly purified by silica gel flash column chromatography (PE / EtOAc=10 / 1) to provide methyl 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoate (1 g, 51.28% yield) as a colorless oil. LCMS (ESI): C 16 H 13 [M+H] of ClF4NO3 + m / z calculated value 378.05, found value 377.95.

[0533] 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 hours. After completion of the reaction, 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzoic acid (700 mg, 90.91% yield) as a white solid. LCMS (ESI): C 15 H 11 [M+H] of ClF4NO3 + m / z calculated value 364.04, found value 363.60.

[0534] Intermediate 9

[0535]

[0536] Reagents and conditions: a) SOCl2, NH4OH, 80℃; b) Cs2CO3, XantphosPd-G2, 1,4-dioxane, 100℃

[0537] Step 1.5-chloro-2-fluoro-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (200 mg, 0.82 mmol) in SOCl2 (5 mL) was heated to 80 ° C and stirred for 0.5 hours. The solution was concentrated under vacuum to provide a chloride intermediate. The chloride intermediate dissolved in THF (5 mL) was then added to a stirred solution of THF (5 mL) in 28% NH3·H2O (5 mL) and at 0 ° C. The resulting mixture was stirred at 25 ° C for 1 hour. The mixture was then quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to provide 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (180 mg, 90.36% yield) as a yellow solid. LCMS (ESI): [MH] -m / z calculated value 239.98, found value 240.1.

[0538] Step 2. tert-Butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate: A mixture of tert-butyl 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. for 2 h under nitrogen. After completion of the reaction, the mixture was filtered through celite. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to provide 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): C 19 H 17 [MH] of ClF4N3O4S - m / z calcd. 494.05, found 494.0.

[0539] Intermediate 10

[0540]

[0541] Reagents and conditions: a) K2CO3, MeI, DMF, 70°C; b) CD3MgI, Pd(dppf)Cl2, ZnCl2, DMF, 100°C; c) BBr3, DCM

[0542] Step 1.2-bromo-6-fluoro-3-methoxypyridine: A mixture of 2-bromo-6-fluoropyridine-3-ol 1 (1.5 g, 7.8 mmol), K2CO3 (3.23 g, 23.3 mmol), MeI (2.22 g, 15.6 mmol) in DMF (40 mL) was heated at 70 ° C and stirred for 3 hours. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to give 2-bromo-6-fluoro-3-methoxypyridine (1.5 g, 93.3% yield) as a white solid. LCMS (ESI): [M+H] + m / z calculated: 205.96, found: 206.0.

[0543] Step 2.6-Fluoro-3-methoxy-2-(methyl-d3)pyridine: To a 250 mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 2-bromo-6-fluoro-3-methoxypyridine (500 mg, 2.43 mmol), ZnCl2 (4.96 g, 36.4 mmol) and Pd(dppf)Cl2 (178 mg, 0.24 mmol) in DMF (10 mL). CD3MgI (1.0 M in diethyl ether, 36.4 mL) was then added dropwise at room temperature with stirring. The solution was heated to 100°C and stirred for 2 hours. The resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1) to give 6-fluoro-3-methoxy-2-(methyl-d3)pyridine (250 mg, 70.9% yield) as a white solid. LCMS (ESI): [M+H] + m / z calcd. 145.09, found 145.0.

[0544] Step 3.6-fluoro-2-(methyl-d3)pyridine-3-ol: To a solution of 6-fluoro-3-methoxy-2-(methyl-d3)pyridine (250 mg, 1.73 mmol) in DCM (5 mL) was added BBr3 (1.0 M in DCM, 1 mL) at room temperature. The reaction mixture was heated to 40 ° C and stirred for 6 hours. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum and quenched with CH3OH (5 mL). The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give 6-fluoro-2-(methyl-d3)pyridine-3-ol 7 (60 mg, 26.7% yield) as a yellow solid. LCMS (ESI): [M + H] for CH4D3FNO + m / z calculated: 131.07, found: 131.0.

[0545] Example 1A

[0546] (R)-5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0547]

[0548] Reagents and conditions: a) (i) (COCl) 2, DMF, DCM, (ii) DIEA, THF, (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfylidene) tert-butyl carbamate; b) TFA, DCM, room temperature

[0549] Step 1: (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 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 vacuum. The residue was dissolved in THF (5 mL) and added to (R)-((3-aminophenyl)(methyl)(oxo)-λ 6To the mixture of tert-butyl methyl ester (102 mg, 0.38 mmol) and DIEA (178 mg, 1.38 mmol) in THF (5 mL) was added 4-(trifluoromethyl)benzamido)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)methyl)-1-(2-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-1-(trifluoromethyl)benzamido)phenyl)methyl)-1-(2-(5-chloro ... 6 -sulfylidene)carbamic acid tert-butyl ester (110 mg, 53.4%). LCMS (ESI): C 26 H 25 [M+H] of ClF4N3O5S + m / z calculated 602.12, found 602.00.

[0550] Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-1-thiosulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (1-thio) carbamate (110 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water (40 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with salt water, dried over sodium sulfate, and concentrated under vacuum. By preparative HPLC (Gemini 5 μm C 18 The residue was purified by using a 4% to 95% MeCN / H2O column (HPLC-MS / MS: 500 nm, eluted with 0.1% NH3) to obtain (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (58.4 mg, 63.7%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.29(t,J=1.8Hz,1H),8.10(s,1H),7.82(d,J=8.9Hz,1H),7.71-7.63(m ,2H),7.58(t,J=7.9Hz,1H),7.37(s,1H),7.04(dd,J=8.7,3.4Hz,1H),4.22(s,1H),3.04(s,3H),2.34(s,3H). LCMS(ESI):C 21 H 17 [M+H] of ClF4N3O3S + m / z calculated 502.06, found 502.00.

[0551] Example 2A

[0552] (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminoimidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0553]

[0554] Reagents and conditions: a) (i) SOCl2, 80°C; (ii) (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfylidene) tert-butyl carbamate, DIEA, THF; b) TFA, DCM, room temperature

[0555] Step 1: (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene) carbamic acid tert-butyl ester: A solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 0.95 mmol) in SOCl2 (5 mL) was stirred at 80 ° C for 0.5 hours. The solution was then concentrated under vacuum to provide the chloride intermediate. The chloride intermediate was added to (R)-((3-aminophenyl)(methyl)(oxo)-λ at 0 ° C. 6-sulfydene) tert-butyl carbamate (388mg, 1.44mmol) and DIEA (464.4mg, 3.6mmol) in THF (5mL) solution. The resulting mixture was stirred at 25 ° C for 0.5 hours. The mixture was then quenched with water (40mL) and extracted with DCM (30mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=3 / 1) to provide (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl) (methyl) (oxo)-λ 6 -sulfylidene)carbamic acid tert-butyl ester (400 mg, 74.3%). LCMS (ESI): C 26 H 26 [M+H] of F4N3O5S + m / z calculated value 568.16, found value 568.10.

[0556] Step 2: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (400mg, 0.70mmol) of t-butyl carbamate (400mg, 0.70mmol) in DCM (5mL) was added TFA (0.5mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water (30mL) and extracted with DCM (20mL x 3). The combined organic phases were washed with salt water, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5um C 18 The residue was purified by using a 5-[4-nitro-4-ol (4-[4-nitro-2-ol)-4-ol)-4-nitro-3-ol (5-nitro-4-ol)-2-ol)-4-[4-nitro-2-ol)-4-nitro-3-ol (5-nitro-4-ol)-2-ol)-4-nitro-3-ol (6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (125.4 mg, 42.5%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.34(s,1H),7.92-7.80(m,2H),7.68-7.56(m, 4H), 7.24 (s, 1H), 7.06 (dd, J = 8.7, 3.4Hz, 1H), 4.21 (s, 1H), 3.04 (s, 3H), 2.33 (s, 3H). LCMS(ESI):C 21 H 18 [M+H] of F4N3O3S + m / z calcd. 468.10, found 468.00.

[0557] Example 3A

[0558] (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0559]

[0560] Reagents and conditions: a) (i) (COCl)2, DMF, DCM; (ii) Et3N, THF; b) TFA, DCM

[0561] Step 1: (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene) carbamic acid tert-butyl ester: To a solution of 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid (75 mg, 0.23 mmol) in DCM (3 mL) was added oxalyl chloride (289 mg, 2.28 mmol) and DMF (20 μL). The mixture was stirred at room temperature for 0.5 hours. The mixture was then concentrated under vacuum. The residue was dissolved in THF (5 mL) and added to (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 To the mixture of tert-butyl methyl ester (74 mg, 0.27 mmol) and EtN (115 mg, 1.14 mmol) in THF (5 mL) was added 4-nitro-2-nitropropane (4-nitro-2-nitropropane) (74 mg, 0.27 mmol) and EtN (115 mg, 1.14 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum. 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-sulfylidene)carbamic acid tert-butyl ester (55 mg, 41.5%). LCMS (ESI): C 27 H 28 [M+H] of F4N3O5S + m / z calculated value 582.17, found value 582.10.

[0562] Step 2: (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To (R)-((3-(6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl (55mg, 0.09mmol) of t-butyl (-sulfylidene) carbamate in DCM (3mL) was added TFA (0.3mL). 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 NaHCO3 aqueous solution. The resulting solution was extracted with DCM (10mL x 3). The combined organic layer was washed with salt water, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5um C 18 The residue was purified by using a 4% to 90% MeCN / H2O column (HPLC-MS / MS: 500 nm, eluted with 0.1% NH4OH in 40% to 90% MeCN) to obtain (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide (15.6 mg, 34.3%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.41(s,1H),7.86(d,J=7.7Hz,1H),7.79-7.65(m,3H),7.58(t,J=7.9Hz ,1H),7.12(dd,J=8.7,3.4Hz,1H),6.74(d,J=8.8Hz,1H),4.22(s,1H),3.06(s,3H),2.45(s,3H),2.28(s,3H). LCMS(ESI):C 22 H 20 [M+H] of F4N3O3S + m / z calculated: 482.12, found: 482.05.

[0563] Example 4A

[0564] (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0565]

[0566] Reagents and conditions: a) (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfylidene) tert-butyl carbamate, pyridine, POCl3; b) TFA, DCM

[0567] Step 1: (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene) carbamic acid tert-butyl ester: 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) carbamate (146 mg, 0.54 mmol) in pyridine (5 mL) was added POCl3 (150 μL) dropwise. The reaction solution was stirred at room temperature for 1 hour. The mixture was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to obtain (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid tert-butyl ester (120 mg, 45.5%). LCMS (ESI): C 26 H 25 [M+H] of F5N3O5S + m / z calculated value 586.15, found value 586.10.

[0568] Step 2: (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminoimidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To (R)-((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl (1-thio) carbamate (120 mg, 0.20 mmol) in DCM (3 mL) was added TFA (0.3 mL). 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 NaHCO3 aqueous solution. The aqueous solution was then extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a Celite® 5-[4-nitro-2-methylpyridin-3-yl) column, 150*21.2 mm, eluted with 40% to 95% MeCN / H2O containing 0.05% NH3 to provide (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide (70.50 mg, 72.5%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ11.27(s,1H),8.34(d,J=1.7Hz,1H),7.91-7.77(m,3H),7.73-7.56(m, 2H), 7.15 (dd, J=8.7, 3.4Hz, 1H), 6.79 (d, J=8.9Hz, 1H), 4.25 (s, 1H), 3.06 (s, 3H), 2.30 (s, 3H). LCMS(ESI):C 21 H 17 [M+H] of F5N3O3S + m / z calculated: 486.09, found: 486.05.

[0569] Examples 5A and 6A

[0570] (S)-5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide and (R)-5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide

[0571]

[0572] 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

[0573] 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 addition, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated. The residue was diluted with THF and added dropwise to a stirred solution of NH3-HO (5 mL). The mixture was then stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 14 H 10 [M+H] of ClF4N2O2 + m / z calcd. 349.04, found 349.00.

[0574] 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 completion of the reaction, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (105 mg, 62.1%) as a white solid. LCMS (ESI): C 20 H 15[M+H] of ClF4N3O3S + m / z calcd. 488.05, found 488.05.

[0575] Step 3: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminosulfonyl)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 mixture was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to give a crude product, and then purified by preparative HPLC (Gemini 5um C18 column, 150*21.2mm, eluted with 30% to 90% MeCN / H2O containing 0.1% formic acid) to give 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (40.8mg, 37.8%) as a white solid. LCMS (ESI): C 20 H 16 [M+H] of ClF4N4O3S + m / z calculated 503.06, found 503.00.

[0576] Step 4: (S)-5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide and (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: 5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide was purified by chiral preparative HPLC (Chiralpak-IC, 4.6*250mm, eluted with 35% CO2-MeOH containing 0.1% NH3). The first eluting isomer was lyophilized to give (S)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (12.7 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.61(d,J=5.6Hz,1H),8.36(s,1H),8.15(s,1H),7.77-7.76 (m,1H),7.71-7.67(m,1H),7.36(s,1H),7.07-7.04(m,1H),4.38(s,1H),3.14(s,3H),2.33(s,3H). LCMS(ESI):C 20 H 16 [M+H] of ClF4N4O3S + m / z 503.06, observed 503.05 and second eluting (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S-methylaminoylidenesulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (14.5 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.61(d,J=5.6Hz,1H),8.36(s,1H),8.15(s,1H),7.77-7.76 (m,1H),7.71-7.67(m,1H),7.36(s,1H),7.07-7.04(m,1H),4.38(s,1H),3.14(s,3H),2.33(s,3H). LCMS(ESI):C 20 H 16 [M+H] of ClF4N4O3S + m / z calculated value 503.06, found value 503.05.

[0577] Example 7A

[0578] (R)-6-((6-Fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylaminoylidenesulfonyl)phenyl)benzamide

[0579]

[0580] Reagents and conditions: a) (i) (COCl) 2, DMF; DCM; (ii) (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 -sulfylidene) tert-butyl carbamate, Et3N, THF; b) TFA, DCM

[0581] 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 6 -sulfylidene) carbamic acid tert-butyl ester: To a solution of 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid (90 mg, 0.26 mmol) in DCM (3 mL) was added oxalyl chloride (167 mg, 1.32 mmol) and DMF (20 μL). The mixture was stirred at room temperature for 0.5 hours. The mixture was then concentrated under vacuum. The residue was dissolved in THF (5 mL) and added to (R)-((3-aminophenyl)(methyl)(oxo)-λ 6 To the mixture of tert-butyl methyl ester (86 mg, 0.32 mmol) and TEA (133 mg, 1.32 mmol) in THF (5 mL) was added 4-thiophene-2-yl)thiazolin-2-yl (R)-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)methyl)(oxo)-λ-pyrrolidone (R)-((3-(6 ... 6 -sulfylidene)carbamic acid tert-butyl ester (75 mg, 47.9%). LCMS (ESI): C 30 H 33 [M+H] of FN5O5S + m / z calculated value 594.22, found value 594.15.

[0582] Step 2: (R)-6-((6-Fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylamino-1H-sulfonyl)phenyl)benzamide: To (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 To a solution of tert-butyl (-sulfydene) carbamate (75 mg, 0.13 mmol) in DCM (5 mL) was added TFA (0.5 mL). 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 phases were washed with salt water, dried over sodium sulfate, and concentrated under vacuum. The column chromatography was performed by preparative HPLC (Gemini 5 μm C 18 The residue was purified by using a Strand-4 column (150*21.2 mm, eluted with 40% to 90% MeCN / H2O containing 0.1% NH4OH) to obtain (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylaminosulfonyl)phenyl)benzamide (40.6 mg, 65.2% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.42(t,J=1.8Hz,1H),7.93(s,1H),7.85-7.80(m,1H),7.66-7.52(m,4H),7.36(d,J=8. 6Hz, 1H), 7.05 (dd, J = 8.7, 3.5Hz, 1H), 6.68 (d, J = 8.6Hz, 1H), 4.20 (s, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H). LCMS(ESI):C 25 H 25 [M+H] of FN5O3S + m / z calculated: 494.17, found: 494.05.

[0583] Example 8A

[0584]

[0585] Reagents and conditions: a) POCl3, pyridine; b) TFA, DCM

[0586] 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) was added POCl (0.09 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. After completion of the reaction, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1:1 to 1 / 2) to provide 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): C 28 H 25 [M+H] of ClF4N3O6S + m / z calculated 642.11, found 642.1.

[0587] Step 2. (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(4-fluoro-3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To a solution of (R)-tert-butyl((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 completion of the reaction, 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 5-[4-nitro-2-methoxy-4-[4-(4-fluoro-3-(S-methylaminosulfonyl)phenyl]-4-(trifluoromethyl)benzamide (50 mg, 29.7% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm) δ10.91 (s, 1H), 8.19 (dd, J = 6.5, 2.7Hz, 1H), 8.08 (s, 1H), 7.90-7.82 (m, 1H), 7.63(d,J=1.8Hz,1H),7.47-7.38(m,3H),7.17(d,J=8.3Hz,1H),4.68(s,1H),3.79(s,3H),3.18(s,3H). LCMS(ESI):C 23 H 17 [M+H] of ClF4N3O4S + m / z calculated value 542.06, found value 542.1.

[0588] Example 9A

[0589]

[0590] Reagents and conditions: a) (i) SOCl2, 80°C; (ii) DIEA, THF; b) TFA, DCM

[0591] Step 1. (R)-tert-Butyl((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 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then at 0 ° C, THF (5 mL) containing the chloride intermediate was added to THF (1 ml) containing (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfylidene)carbamic acid tert-butyl ester (110.2 mg, 0.41 mmol) and DIEA (175.0 mg, 1.35 mmol), and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1 to 1 / 2) to obtain (R)-((3-(4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfylidene)carbamic acid tert-butyl ester (130 mg, 69.4%) as a yellow solid. LCMS (ESI): C 30 H 32 [M+H] of F4N3O5S + m / z calculated 622.20, found 622.10.

[0592] Step 2. (R)-4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminosulfonyl)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 completion of the reaction, 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 layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The results were analyzed by preparative HPLC (Gemini 5 μm C 18 Column, 150*21.2mm, using 0.05% NH 3.The residue was purified by eluting with 40% to 95% MeCN / H2O in HO to afford (R)-4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide as a white solid (20 mg, 18.3% yield). 1 H NMR (400MHz, DMSO-d6, ppm) δ11.00(s,1H),8.39(t,J=1.8Hz,1H),7.86-7.78(m,1H),7.72-7.63(m,2H),7.57(t,J=7.9Hz,1H),7.08(dd,J=8.7, 3.4Hz,1H),6.44(s,1H),4.21(s,1H),3.05(d,J=0.6Hz,3H),2.48-2.41 (m,3H),2.28(s,3H),2.23-2.13(m,1H),0.98-0.87(m,2H),0.55(m,2H). LCMS(ESI):C 25 H 24 [M+H] of F4N3O3S + m / z calculated value 522.15, found value 522.20.

[0593] Example 10A

[0594] (R)-3-Chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0595]

[0596] Reagents and conditions: a) (i) SOCl2, 80°C; (ii) DIEA, THF; b) TFA, DCM

[0597] Step 1. (R)-tert-Butyl((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 SOCl2 (3 mL) was heated to 80°C and stirred for 0.5 h. The solution was concentrated under vacuum to provide the chloride intermediate. The chloride intermediate was then added to a 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 obtained mixture was stirred at 25 DEG C for 1 hour.Then the mixture was quenched with water (15mL) and extracted with DCM (15mL x 3).The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum.The residue was purified by flash column chromatography on silica gel (PE / EtOAc=3 / 2) to provide (R)-((3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)carbamic acid tert-butyl ester (180mg, 70.82% yield) as a light yellow oil.LCMS(ESI):C 27 H 26 [M+Na] of ClF4N3O5SNa + m / z calculated value 638.11, found value 637.95.

[0598] Step 2. (R)-3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminosulfonyl)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 completion of the reaction, 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The results were analyzed by preparative HPLC (Gemini 5 μm C 18Column, 150*21.2mm, using 0.05% NH 3. The residue was purified by eluting with 40% to 95% MeCN / H2O in H2O to afford (R)-3-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (74.70 mg, 99.8% purity, 49.54% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm) δ11.08(s,1H),8.31(s,1H),7.80(d,J=7.6Hz,1H),7.69(dd,J=14.8,7.9Hz,2H),7.5 7(t,J=7.9Hz,1H),7.16(s,1H),7.06(dd,J=8.7,3.4Hz,1H),4.20(s,1H),3.05(s,3H),2.45(s,3H),2.30(s,3H). LCMS(ESI):C 22 H 19 [M+H] of ClF4N3O3S + m / z calculated 516.08, found 516.00.

[0599] Example 11A

[0600]

[0601] Reagents and conditions: a) Cs2CO3, MeCN, 80°C; b) TFA, DCM

[0602] 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 hours. After completion of the reaction, 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 vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to provide (R)-tert-butyl((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): C 26 H 25 [M+H] of BrClF3N3O6S + m / z calculated value 678.03, found value 680.1.

[0603] Step 2. (R)-2-(4-bromo-2-methoxyphenoxy)-5-chloro-N-(2-(S-methylaminosulfonyl)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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 50% to 95% MeCN / H2O column (column, 150*21.2 mm, eluted with 0.1% formic acid in 50% to 95% MeCN to afford (R)-2-(4-bromo-2-methoxyphenoxy)-5-chloro-N-(2-(S-methylaminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (18 mg, 30.2% yield) as a white solid. 1 HNMR(400MHz,DMSO-d6,ppm)δ11.31(s,1H),8.62(d,J=5.5Hz,1H),8.39(d,J=1.6Hz,1H),8.08(s,1H),7.8 0(dd,J=5.4,1.9Hz,1H),7.37(d,J=1.9Hz,1H),7.25-7.04(m,3H),4.37(s,1H),3.75(s,3H),3.14(s,3H). LCMS(ESI):C 21 H 17 [M+H] of BrClF3N4O4S + m / z calculated value 577.98, found value 579.9.

[0604] Example 12A

[0605]

[0606] Reagents and conditions: a) Zn(CN)2, Xbuxphos-Pd-G3, THF / H2O, 50°C; b) TFA, DCM

[0607] Step 1. tert-Butyl (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylide)carbamate: A mixture of tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylide)carbamate (130 mg, 0.19 mmol), Zn(CN)2 (34 mg, 0.29 mmol) and tBuXphos-Pd-G3 (15 mg, 0.02 mmol) in THF / H2O=4 / 1 (5 mL) was heated to 50°C and stirred under nitrogen atmosphere for 5 hours. At 4 DEG C, 8 hours evaporation, 1 hour evaporation, 1 hour evaporation, 2 hours evaporation, 3 hours evaporation, 4 hours evaporation, 8 hours evaporation.After the reaction is complete, gained solution is diluted with water (20mL) and extracted with EtOAc (20mL x 3).By the organic layer washed with salt water, through Na2SO4 drying, concentrate under vacuum.By silica gel flash column chromatography (PE / EtOAc=1 / 1), residue is carried out to purification, to provide (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl) (methyl) (oxo)-16-sulfydene) tert-butyl carbamate (100mg, 83.5% yield) as yellow solid.LCMS(ESI):C 27 H 25 [M+H] of ClF3N4O6S + m / z calculated 625.12, found 625.1.

[0608] Step 2. (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(2-(S-methylaminosulfonyl)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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 50% to 95% MeCN / H2O column (column, 150*21.2 mm, eluted with 0.1% formic acid in 50% to 95% MeCN to afford (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-N-(2-(S-methylaminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (18 mg, 21.4% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm) δ11.34(s,1H),8.61(d,J=5.4Hz,1H),8.33(d,J=1.8Hz,1H),8.14(s,1H),7.75(dd,J=5.4 ,2.0Hz,1H),7.63(d,J=1.8Hz,1H),7.52-7.38(m,2H),7.20(d,J=8.3Hz,1H),4.37(s,1H),3.78(s,3H),3.14(s,3H). LCMS(ESI):C 22 H 17 [M+H] of ClF3N4O4S + m / z calculated 525.06, found 525.0.

[0609] Example 13A

[0610]

[0611] Reagents and conditions: a) Cs2CO3, MeCN, 80°C; b) TFA, DCM

[0612] Step 1. tert-Butyl (R)-((4-(5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate: A solution of tert-butyl 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)-16-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 mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by flash chromatography (PE / EA=5:1) to afford tert-butyl (R)-((4-(5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (80 mg, 66.1% yield) as a white solid. LCMS (ESI): C 25 H 20 [M+Na] of D3ClF4N4O5SNa + m / z calculated 628.12, found 628.0.

[0613] Step 2. (R)-5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-N-(2-(S-methylamino-2-sulfonyl)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) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by using a 5-nitro-2-nitro-5-nitro-2-propenetrafluoroethylene (5-nitro-4-nitro-2-propenetrafluoroethylene) column, 150*21.2 mm, eluted with 55% to 60% MeCN / H2O containing 0.05% NH3·H2O) to provide (R)-5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-N-(2-(S-methylaminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (27.00 mg, 41.1% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm) δ11.38(s,1H),8.62(d,J=5.4Hz,1H),8.37(d,J=1.5Hz,1H),8.15( s,1H),7.81-7.65(m,2H),7.36(s,1H),7.06(dd,J=8.7,3.4Hz,1H),4.39(s,1H),3.14(s,3H). LCMS(ESI):C 20 H 13 [M+H] of D3ClF4N4O3S + m / z calculated value 506.08, found value 506.0.

[0614] Example 14A

[0615]

[0616] Reagents and conditions: a) HATU, DIEA, DMF; b) BH3·THF, THF; c) TFA, DCM

[0617] 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-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide (Example 1) (120 mg, 0.24 mmol), (tert-butyloxycarbonyl)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. To 4- (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)amino)-2-oxoethyl)carbamic acid tert-butyl ester (100mg, 63.5% yield) is provided as a yellow solid. LCMS (ESI): C 28 H 28 [M+H] of ClF4N4O6S + m / z calculated: 659.14, found: 659.10.

[0618] Step 2. tert-Butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylide)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-sulfanylide)amino)-2-oxoethyl)carbamate (700 mg, 1.06 mmol) in THF (10 mL) at 0° C. was added BH3-THF (0.7 mL). The reaction mixture was stirred under nitrogen at 0° C. for 1 hour. The reaction was monitored by LCMS. At 4 DEG C, 8 hours filtration, 1 hour filtration, 1 hour filtration, 2 hours filtration.After the reaction is complete, the filtrate is diluted with water (20mL) and extracted with DCM (20mL x 3).The organic layer merged is washed with brine, dried over sodium sulfate, concentrated under vacuum.By silica gel flash column chromatography (PE / EtOAc=1 / 1), the residue is purified to obtain (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfanylidene)amino)ethyl)t-butylcarbamate (350mg, 51.24% yield) as a white solid.LCMS(ESI):C 28 H 30 [M+H] of ClF4N4O5S + m / z calculated 645.16, found 645.10.

[0619] Step 3. (R)-N-(3-(N-(2-aminoethyl)-5-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: 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)ethyl)carbamate (350 mg, 0.54 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The results were analyzed by preparative HPLC (Gemini 5 μm C 18The residue was purified by using a 4% to 90% MeCN / H2O column (HPLC-MS / MS, 150*21.2 mm, eluted with 0.1% formic acid in 40% to 90% MeCN / H2O) to obtain (R)-N-(3-(N-(2-aminoethyl)-S-methylaminosulfonyl)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 (400MHz, DMSO-d6, ppm) δ11.06(s,1H),8.33(s,1H),8.25(s,1H),8.10(s,1H),7.83(d,J=3.8Hz,1H),7.67(dd,J=8.6, 6.7Hz,1H),7.64-7.60(m,2H),7.38(s,1H),7.04(dd,J=8.8,3.3Hz,1H),3.17(s,3H),2.77(d,J=5.8Hz,4H),2.34(s,3H). LCMS(ESI):C 23 H 22 [M+H] of ClF4N4O3S + m / z calculated 545.11, found 545.00.

[0620] The following compounds were prepared using the techniques of the intermediates and examples described above.

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637] Example 74A

[0638] Compound Profiling Human NaV1.8 / β3 Cell Line - SyncroPatch384PE Assay

[0639] Compounds were tested on CHO cells stably transfected with recombinant human Nav1.8 / b3 using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2 in Ham's F-12 supplemented with 10% fetal bovine serum, 100 U / mL penicillin G sodium, 100 mg / mL streptomycin sulfate, and selective 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. Cells were washed in HBSS to remove Accutase and resuspended in extracellular solution and then immediately used in SynchroPatch384PE using an 8-well NPC-384 chip. All experiments were performed at ambient temperature. The intracellular solution contained (mM): CsCl 50; CsF 90; MgCl 5; EGTA 1; HEPES 10; and the pH was adjusted to 7.2 with CsOH. The extracellular solution contained (mM): NaCl 137; KCl 4.0; CaCl 3.8; MgCl 1; HEPES 10; and glucose 10; and the pH was adjusted to 7.4 with NaOH. 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.

[0640] Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3.33 in extracellular solution to generate an 8-point concentration-response curve. Each plate contained a historical positive control and up to ten compounds. 300 μM tetracaine and 0.3% DMSO + 0.03% pluronic acid were used as high and low controls, respectively.

[0641] According to Nanion Standard procedure carries out whole-cell patch clamp recording.Cell is maintained at the holding potential of-120mV.The depolarization step of applying 10mV continues 30 milliseconds (P1 measurement), is followed by the hyperpolarization step of-100mV and continues 100 milliseconds.The inactivation step of being applied in-35mV continues 10 seconds, then steps into-100mV and continues 20 milliseconds, then steps into 10mV and continues 30 milliseconds (P2 measurement), and then returns to-100mV and continues 30 milliseconds.The sweep interval is 15 seconds.After setting up the whole-cell configuration in extracellular solution, cell is washed with stable baseline current in the extracellular solution containing 0.3%DMSO and 0.03% pluronic acid.Then by SynchroPatch384 PE system, compound is applied in each hole, and electric current is recorded five minutes in extracellular solution, applies tetracaine subsequently to realize complete blocking at the end of experiment. The potency of compounds was assessed on two readouts, resting state blockade (P1 measurement) or inactivated state blockade (P2 measurement) to obtain IC50 values. Values ​​were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.

[0642] The following table shows the effects of the compounds on human Na V 1.8 potency, where "A" represents IC 50 Less than or equal to 5 nM, "B" indicates IC 50 Greater than 5nM to less than or equal to 50nM, "C" represents IC 50 Greater than 50nM to less than or equal to 100nM, "D" represents IC 50 Greater than 100 nM to less than or equal to 200 nM, "E" indicates IC50 greater than 200 nM.

[0643]

[0644]

[0645] Example 75A

[0646] Compound Profiling Human NaV1.8 / β1 Cell Line - Sophion QPatch II Assay

[0647] The QPatch II system (Sophion Bioscience A / S, Ballerup-Denmark), an automated patch clamp device, was used to generate recombinant human Na VCompounds were tested on HEK293 cells (Eurofins, CYL3025, St. Charles, MO) 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 selective antibiotics (0.625 μg / mL puromycin, 400 μg / mL geneticin, and 100 μg / mL hygromycin). One or two days before recording, cells were moved to a lower temperature 30°C / 5% CO2 incubator to increase surface expression of the channel. On the day of recording, cells in the culture dish were incubated with CaCl2. 2+ -Mg 2+ The cells were washed twice with DPBS and treated with Detachin (Genlantis, San Diego) for 3 minutes and then resuspended in serum-free medium (for cell culture). Cells were cultured in ACF CHO medium (Sigma-Aldrich) supplemented with 0.04 mg / mL soybean trypsin inhibitor and 25 mM HEPES (all components provided by Sigma-Aldrich, St. Louis, MO) and allowed to recover in an onboard QStirrer for a minimum of 20 minutes. All experiments were performed at ambient temperature. The intracellular solution contained (mM): CsCl 50; CsF 90; MgCl 2 2; EGTA 5; HEPES 10; pH was adjusted to 7.2 with CsOH. The extracellular solution contained (mM): NaCl, 137; KCl, 4; CaCl2, 3.8; MgCl2, 1; HEPES, 10; glucose, 10; and the pH was adjusted to 7.4 with NaOH. 500 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.

[0648] Compounds were tested in a staggered manner across two well groups to obtain a total of 8-point concentration-response curves. Final concentrations included 0.1% DMSO and 0.03% pluronic acid. Typically, the concentration range spanned 0.01-300 nM. In their respective groups, compounds were diluted 1:10 with extracellular solution. DMSO (0.1% by volume) was used as a vehicle control to determine assay performance.

[0649] According to QPatch Whole-cell patch clamp recordings were performed using the Sophion standard procedure. Cells were held at a holding potential of -120 mV. Depolarization steps of 10 mV were applied for 30 ms to elicit Na inward. +Current. The internal sweep interval was 15 seconds. After establishing the whole-cell configuration in the extracellular solution, the cells were washed twice in an extracellular solution containing 0.1% DMSO and 0.03% pluronic acid to stabilize the baseline current. The compound was then applied to each well within the group in an incremental manner via the QPatch II system, and the current for each concentration was recorded for five minutes. The percentage of residual current was determined by taking the average of the last 5 sweeps within each concentration and normalizing it to the latest pre-compound saline period. The potency of the compound (IC 50 ) values ​​were evaluated only for resting-state blockade. Wells with initial sodium current amplitudes below 2 nA or whole-cell resistance falling below 100 MΩ were excluded from analysis.

[0650] The following table shows the effects of the compounds on human Na V 1.8 potency, where "A" represents IC 50 Less than or equal to 5 nM, "B" indicates IC 50 Greater than 5nM to less than or equal to 50nM, "C" represents IC 50 Greater than 50nM to less than or equal to 100nM, "D" represents IC 50 Greater than 100nM to less than or equal to 200nM, "E" represents IC 50 Greater than 200nM.

[0651]

[0652]

[0653] (B) The second group of compounds

[0654] In one aspect, the present invention provides a compound of formula (I):

[0655]

[0656] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

[0657] A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of: wherein the haloalkyl chain can be a fully or partially halogenated halo-C1-C4 alkyl, a substituted or unsubstituted C1-C8 alkyl, wherein the alkyl chain can be a fully or partially deuterated deuterated C1-C4 alkyl, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be fully or partially halogenated, and arylalkoxy;

[0658] R1, R2, R3 and R4 are independently selected from hydrogen, -OH, halogen, C1-C6-alkyl, wherein the fluoroalkyl chain can be a fully or partially fluorinated C1-C6 fluoroalkyl, C3-C8 branched alkyl, wherein the branched fluoroalkyl chain can be a fully or partially fluorinated C3-C8 branched fluoroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, NR'R", 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N, a saturated or unsaturated 5-membered or more ring or an aryl ring optionally containing 1 or more heteroatoms independently selected from O, S and N, wherein each 5-membered or more ring is unsubstituted or substituted with one to five substituents selected from the group consisting of 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 5-6 ring members, wherein the heterocyclyl includes one or more heteroatoms;

[0659] R5 is H or substituted or unsubstituted C1-C3 alkyl;

[0660] 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 ;

[0661] where R ais H, C1-C6-alkyl, C2-C8 branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4-7 membered heterocyclyl, alkenyl, alkynyl, haloalkyl, OH, alkoxy, cycloalkoxy, haloalkoxy, -(OCH2CH2) n R b , -NR'R", -COONR'R", -COOR', alkylsulfonyl, arylsulfonyl or -SO2NR'R";

[0662] R b independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms;

[0663] R c is H, C1-C6 alkyl or F;

[0664] R c and R b Optionally forming a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms;

[0665] R7 is NH2, -NHR', C1-C3 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

[0666] In various embodiments, the compound of the present invention is a compound of formula (II):

[0667]

[0668] wherein Ring B and the groups R1, R2, R3, R4, R5, R6 and R7 are as described in claim 1;

[0669] R8 is H, hydroxy, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0670] Q, T and W are independently selected from N or CR9;

[0671] R9 is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3 or cycloalkoxy, each of which is optionally substituted;

[0672] X is H, halogen, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3 or -OCF3.

[0673] In another embodiment, the compound of the present invention is a compound of formula (III):

[0674]

[0675] wherein R1, R2, R3, R4, R5, R6 and R7 are as described above in formula (I);

[0676] R8, W, T, Q and X are as described above in formula (II);

[0677] Z is CH, N, CF or N + -O - .

[0678] In another embodiment, X is F.

[0679] In another embodiment, R8 is -CH3.

[0680] In another embodiment, Q is N.

[0681] In another embodiment, Q is N, W is CH, and T is CH.

[0682] In another embodiment, R1 is H or F.

[0683] In another embodiment, R2 is H, chlorine or CF3.

[0684] In another embodiment, R3 is H or CF3.

[0685] In another embodiment, R4 is H.

[0686] In another embodiment, R5 is H.

[0687] In another embodiment, R7 is methyl.

[0688] 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.

[0689] In another embodiment, R9 is H.

[0690] In another embodiment, the compound of formula (I) is selected from the group consisting of:

[0691]

[0692]

[0693]

[0694]

[0695] The second group of compounds provided herein are prepared by the methods and procedures described below.The intermediates described in this section can be used to prepare the second group of compounds.

[0696] Unless otherwise noted, chemicals were purchased from standard commercial suppliers and used as received. Otherwise, their preparation is readily available and known to those of ordinary skill in the art, or 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.

[0697] Unless otherwise noted, all reactions were performed under a positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware with magnetic stirring. 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.

[0698] Use purchased from EMD MILLIPORE TM The reaction was monitored by thin layer chromatography (TLC) on 0.25 mm silica gel 60 F254 plates. Purification was performed using Biotage Isolera One flash chromatography or using one of the preparative HPLC methods mentioned below.

[0699] Preparation method 1

[0700] Equipment: Shimadzu LCMS2020 mass-directed preparative HPLC system; column: Gemini 5um C 18 Column, 150*21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.1% HCOOH, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0701] Preparation method 2

[0702] Equipment: Shimadzu LC-20AP preparative HPLC system; column: Gemini 5um C 18Column, 150*21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.1% TFA, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0703] Preparation method 3

[0704] Equipment: 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 0.05% ammonia, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0705] Collect and analyze LCMC using one of the following methods:

[0706] Method 1

[0707] Equipment: Shimadzu LCMS2020 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 in 1.4 minutes, held for 0.6 minutes, with a total run time of 2.5 minutes; flow rate: 1.8 ml / min; column temperature: 50°C; wavelengths: 214 and 254 nm PDA.

[0708] Method 2

[0709] Equipment: Shimadzu LCMS2020 spectrometer; XBridge BEH C 18 2.5 μm, 3.0 mm × 30 mm mobile phase: MeCN-water (0.1% NH4OH); gradient: 5% to 95% MeCN in 1.8 minutes, hold for 0.7 minutes, total run time of 3.0 minutes; flow rate: 1.0 ml / min; column temperature: 50°C; wavelength: 214 and 254 nm PDA.

[0710] Method 3

[0711] Equipment: Shimadzu LCMS2020 spectrometer; column: HALO C 182.7 μm, 3.0 mm × 30 mm mobile phase: MeCN (0.05% TFA)-water (0.05% TFA); gradient: 5% to 95% MeCN in 1.4 minutes, hold for 0.6 minutes, total run time of 2.5 minutes; flow rate: 1.8 ml / min; column temperature: 50°C; wavelength: 214 and 254 nm PDA.

[0712] The following method was used to analyze the Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD SF , SFC-30A) for SFC chiral separation:

[0713] Method 1

[0714] Column: Chiralpak-AS-H (5 μm, 250 x 20 mm) from Daicel; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M in MeOH)], with different CO 2 / MeOH ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0715] Method 2

[0716] Column: Chiralpak-OJ-H, 5 μm, 250×20 mm; mobile phase: CO 2 / MeOH (0.1% HCOOH), with different CO 2 / MeOH ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0717] Method 3

[0718] Column: Chiralpak-OD-H 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / MeOH, with different ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0719] Method 4

[0720] Column: Chiralpak-AD-H 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / i-PrOH, with different ratios for different compounds; oven temperature: 40°C; flow rate: 38 ml / min.

[0721] Method 5

[0722] Column: Chiralpak-IC 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / EtOH, with different ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[0723] Unless otherwise stated, 1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz digital NMR spectrometer. Chemical shifts δ are quoted in parts per million (ppm) relative to TMS and are calibrated using residual undeuterated solvent as an internal reference. The following abbreviations are used to indicate multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet), dq (doublet of quadruplet), hep (septet), m (multiplet), pent (quintet), td (triplet of doublet), qd (quadruple of doublet), app. (apparent), and br. (broad). Coupling constants J are quoted to the nearest 0.1 Hz.

[0724] General synthetic scheme

[0725] Several methods for preparing the compounds of the present invention are described in the following schemes and examples. The present invention further provides methods for preparing compounds of formula I as defined above. In some cases, the order in which the preceding reaction schemes are performed may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

[0726] Plan A

[0727]

[0728] As shown in Scheme A, compounds of Formula (I) can generally be synthesized starting from formic acid A-1 by reacting a substituted aniline or heteroaryl aniline A-2 using a standard amide coupling agent, not limited to HATU, TBTU, EDC, or T3P, such as DIEA, in an organic solvent and base to yield an intermediate of type A-3. Intermediate A-3 may 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 agent such as HATU in combination with formic acid and a base such as DIEA, or the NH group can be acylated with a reactive formic ester such as N-hydroxysuccinimide ester to provide compounds of Formula (I) after removal of any protecting groups. Numerous methods exist for acylating NH groups, which are readily apparent to those skilled in the art. If desired, compounds of Formula (I) can be further modified to provide additional compounds of Formula (I). Alternatively, formic acid A-1 can be treated with ammonia or a primary amine (R5NH2) in the presence of an amide coupling agent such as HATU and a base such as DIEA to provide the carboxamide intermediate A-5, which can be metal-catalyzed coupled with a halogen-substituted aryl or heteroaryl compound of the type A-6 to provide a compound of formula A-3. Compounds of formula (I) can then be obtained from A-3 as described.

[0729] Plan B

[0730]

[0731] As further illustrated in Scheme B, compounds of the present invention can generally be prepared by reacting intermediate A-1 with amine B-1 using amide coupling conditions or by activating a suitably functionalized formic acid A-1 with amine B-1 and a base such as DIEA or pyridine in DCM, DMF, or THF to obtain a compound of type B-2. Compounds of formula B-3 can be formed by removing protecting groups such as Boc under acidic conditions. In some cases, chiral HPLC can be used to separate B-3 into corresponding R and S isomers. R- and S-isomers can also be prepared by coupling an acid with an enantiomerically pure amine B-1 and then deprotecting it. The sulfoximine nitrogen of intermediate B-3 can be acylated using standard amide coupling agents, such as, but not limited to, HATU, a base such as DIEA, and HO2C-R6-PG to obtain a compound of formula B-4. As shown, when B-4 contains PG, it is removed to obtain a compound of formula B-5. For example, if the Boc group is used to protect the sulfoximine, it can be removed by treating with TFA to obtain a compound of formula B-5. Trialkylsilyl can be used to protect a hydroxyl group and can be removed by treating with aqueous acids such as acetic acid. If no protecting group is needed, B-3 can directly produce compound B-5.

[0732] Plan C

[0733]

[0734] As further illustrated in Scheme B, generally, the compounds of the present invention can be prepared by activating a suitably functionalized formic acid A-1 with (COCl) or SOCl in an organic solvent, followed by the addition of NH4OH to obtain C-1. Intermediate C-1 is then combined with various substituted Br compound C-2 materials using Xantphos-Pd-G2-mediated coupling conditions to deliver intermediate C-3. Compounds of formula C-3 can be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodine) benzene (PIDA) in methanol to provide compounds of formula B-3. In some cases, chiral HPLC conditions are used to separate B-3 into corresponding R and S isomers. Compounds of formula B-4 are obtained using standard amide coupling agents, such as, but not limited to, HATU, bases such as DIEA, and HO2C-R6-PG. When the protecting group PG is Boc, it is removed by treatment with TFA to obtain compounds of formula B-5. Trialkylsilyl groups can be used to protect hydroxyl groups and can be removed by treatment with aqueous acids such as acetic acid. If no protecting group is required, B-3 can directly produce compound B-5.

[0735] The above schemes are intended to illustrate and are not intended to be limiting in any way. Those skilled in the art can use these general schemes as a guide to prepare compounds of formula (I), but other methods can also be used to complete the synthesis of compounds of the present invention. Specific methods are provided for each example in the examples to further illustrate the synthesis of compounds of formula (I).

[0736] Intermediate 1

[0737] 2-Chloro-4-methyl-5-nitronicotinic acid methyl ester

[0738]

[0739] Reagents and conditions: a) phenyl dichlorophosphate, 160°C

[0740] 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 hours. The resulting solution was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide methyl 2-chloro-4-methyl-5-nitronicotinate (3 g, 69%) as a light yellow solid. LCMS (ESI): [M + H] + m / z calculated value 231.02, found value 230.85.

[0741] Intermediate 2

[0742] (S)-2-((tert-Butyldimethylsilyl)oxy)propanoic acid

[0743]

[0744] Reagents and conditions: TBSCl, imidazole, DCM

[0745] At 0 DEG C, to (S) -2- hydroxypropionic acid (1g, 11.11mmol) and imidazoles (2.27g, 33.32mmol) in DCM (15mL) solution, add TBSCl (2.00g, 13.33mmol).Then the mixture was heated at 25 DEG C for 16 hours.After the reaction was completed, the mixture was diluted with water and extracted with DCM (3x 30mL).The organic layer washed with salt water merged is used Na2SO4 is dried, and concentrated under vacuum to obtain crude (S) -2- ((tert-butyldimethylsilyl) oxygen base) propionic acid (1.4g), which is directly used in the next step without further purification.

[0746] Intermediate 3

[0747] (R)-2-((tert-Butyldimethylsilyl)oxy)propanoic acid

[0748]

[0749] Reagents and conditions: TBSCl, imidazole, DCM

[0750] At 0 DEG C, to (R) -2- hydroxypropionic acid (1g, 11.11mmol) and imidazoles (2.27g, 33.32mmol) in DCM (15mL) solution, add TBSCl (2.00g, 13.33mmol).Then, the mixture is warmed to room temperature and stirred for 16 hours.After the reaction is complete, the mixture is diluted with water and extracted with DCM (3x 30mL).The organic layer washed with salt water merged is used Na2SO4 dry, and concentrated under vacuum, to obtain crude (R) -2- ((tert-butyldimethylsilyl) oxygen base) propionic acid (1.6g), which is directly used in the next step without being further purified.

[0751] Intermediate 4

[0752]

[0753] 2-((tert-butyldimethylsilyl)oxy)acetic acid: At 0 ° C, to a solution of 2-hydroxyacetic acid (1g, 13.16mmol) and imidazoles (2.68g, 39.47mmol) in DCM (15mL), TBSCl (2.38g, 15.79mmol) was added. The mixture was then stirred at 25 ° C for 16 hours. Afterwards, the reaction was complete. The mixture was diluted with water and extracted with DCM (3x 30mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain crude 2-((tert-butyldimethylsilyl)oxy)acetic acid (1.6g), which was directly used in the next step without further purification.

[0754] Example 1B

[0755] 5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropionyl)-S-methylamino-1,1-disulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0756]

[0757] Reagents and conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH / THF / H2O

[0758] Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)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 layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to provide N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (140 mg, 63.8%) as a yellow solid. LCMS (ESI): C 30 H 35 [M+H] of ClF4N3O5SSi + m / z calculated value 688.17, found value 688.15.

[0759] Step 2: 5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoylidenesulfonyl)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 completion of the reaction, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 5-[4-[4-[4-(4-fluoro-2-methylpyridin-3-yl)oxy]-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (45.6 mg, 39.1%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.34(s,1H),8.12(s,1H),7.89(d,J=7.5Hz,1H),7.73-7.61(m,3H),7.36(s,1H),7.05 (dd,J=8.7,3.3Hz,1H),4.71(d,J=5.3Hz,1H),4.02(dd,J=6.8,5.4Hz,1H),3.46(s,3H),2.33(s,3H),1.26(d,J=6.8Hz,3H). LCMS(ESI):C 24 H 21 [M+H] of ClF4N3O5S + m / z calculated value 574.08, found value 574.00.

[0760] Example 2B

[0761] (R)-5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminoimidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0762]

[0763] Reagents and conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) AcOH / THF / H2O

[0764] Step 1: (R)-N-(3-(N-(2-((tert-Butyldimethylsilyl)oxy)acetyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.3 mmol), 2-((tert-butyldimethylsilyl)oxy)acetic acid (170.6 mg, 0.9 mmol) and HATU (170.5 mg, 0.45 mmol) in DMF (5 mL) was added DIEA (115.9 mg, 0.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction is complete, the resulting solution is diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer is washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue is purified by flash column chromatography on silica gel (PE / EtAOc=1 / 1) to provide (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (120 mg, 53.6%) as a yellow solid. LCMS (ESI): C 29 H 33 [M+H] of ClF4N3O5SSi + m / z calculated: 674.15, found: 674.05.

[0765] Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylamino-1-sulfonyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylamino-1-sulfonyl)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 completion of the reaction, 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a Celite® column, 150*21.2 mm, eluted with 50% to 90% MeCN / H2O containing 0.1% FA to afford (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (45.4 mg, 45.6%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.32(s,1H),8.13(s,1H),7.91(d,J=6.8Hz,1H),7.75-7.60(m,3H) ,7.36(s,1H),7.10-7.01(m,1H),4.79(d,J=5.5Hz,1H),3.95(d,J=4.9Hz,2H),3.45(s,3H),2.34(s,3H). LCMS(ESI):C 23 H 19 [M+H] of ClF4N3O5S + m / z calculated value 560.06, found value 560.10.

[0766] Example 3B

[0767] 5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropionyl)-S-methylamino-1,1-disulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0768]

[0769] Reagents and conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH / THF / H2O

[0770] Step 1: N-(3-((R)-N-((S)-2-((tert-Butyldimethylsilyl)oxy)propanoyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)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. The reaction was completed by LCMS. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=3 / 1) to provide N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (180 mg, 87.55%) as a colorless oil. LCMS (ESI): C 30 H 35 [M+H] of ClF4N3O5SSi + m / z calculated value 688.17, found value 688.15.

[0771] Step 2: 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylamino-1-sulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To a solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylamino-1-sulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (180 mg, 0.26 mmol) in THF (2.2 mL) and H2O (6.5 mL) was added AcOH (8.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 50% to 95% MeCN / H2O column (column, 150*21.2 mm, eluted with 0.05% NH3·H2O in 50% to 95% MeCN to afford 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (71.97 mg, 45.9%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.35(s,1H),8.12(s,1H),7.87(d,J=6.7Hz,1H),7.72-7.62(m,3H),7.36(s,1H), 7.05(dd,J=8.7,3.4Hz,1H),4.69(d,J=5.5Hz,1H),4.08-3.96(m,1H),3.44(s,3H),2.34(s,3H),1.24(d,J=6.8Hz,3H). LCMS(ESI):C 24 H 21 [M+H] of ClF4N3O5S + m / z calculated value 574.08, found value 573.95.

[0772] Example 4B

[0773] (R)-5-Chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0774]

[0775] Reagents and conditions: a) (tert-Butyloxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM

[0776] Step 1: (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-1-thio)phenyl)-4-(trifluoromethyl)benzamide (120 mg, 0.24 mmol), (tert-butyloxycarbonyl)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 completion of the reaction, 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 vacuum. The residue was purified by silica gel flash column chromatography (PE / EtAOc=1 / 1) to afford (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ-[4-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)-1-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-1-(trifluoromethyl)benzamido)phenyl)-1-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4 ... 6 -sulfanylidene)amino)-2-oxoethyl)carbamic acid tert-butyl ester (100 mg, 63.5%). LCMS (ESI): C 28 H 28 [M+H] of ClF4N4O6S + m / z calculated: 659.14, found: 659.10.

[0777] Step 2: (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To 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). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (50% to 95% MeCN / H2O containing 0.05% NH3) to afford (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (53.8 mg, 62.5%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.31(s,1H),8.13(s,1H),7.89(d,J=7.6Hz,1H),7.72-7.61(m ,3H),7.36(s,1H),7.05(dd,J=8.7,3.2Hz,1H),3.43(s,3H),3.23(s,2H),2.34(s,3H),1.69(bs,2H). LCMS(ESI):C 23 H 20 [M+H] of ClF4N4O4S + m / z calculated value 559.09, found value 559.05.

[0778] Example 5B

[0779] N-(3-((R)-N-(D-alanyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide

[0780]

[0781] Reagents and conditions: a) (tert-Butyloxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM

[0782] Step 1: ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a mixture of (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-1-thiopropan-2-yl)phenyl)-4-(trifluoromethyl)benzamide (120 mg, 0.24 mmol), (tert-butyloxycarbonyl)-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 completion of the reaction, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtAOc=1 / 1) to afford ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfanylidene)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (120 mg, 74.6%). LCMS (ESI): C 29 H 30 [M+H] of ClF4N4O6S + m / z calculated: 673.15, found: 673.10.

[0783] Step 2: N-(3-((R)-N-(D-alanyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: To ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl)-1-thioprop-2-yl)carbamate (120 mg, 0.18 mmol) in DCM (3 mL) was added TFA (0.5 mL). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (5-nitropropane-2-yl) column, 150*21.2 mm, eluted with 45% to 95% MeCN / H2O containing 0.05% NH3 to provide N-(3-((R)-N-(D-alanyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (73.9 mg, 72.4%) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ11.07(s,1H),8.33(s,1H),8.12(s,1H),7.88(d,J=7.7Hz,1H),7.73-7.61(m,3H),7.35(s,1H) ,7.05(dd,J=8.7,3.4Hz,1H),3.43(s,3H),3.28(d,J=6.9Hz,1H),2.34(s,3H),2.04-1.31(m,2H),1.16(d,J=7.5Hz,3H). LCMS(ESI):C 24 H 22 [M+H] of ClF4N4O4S + m / z calcd. 573.10, found 573.10.

[0784] Example 6B

[0785] (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylaminoimidenesulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide

[0786]

[0787] Reagents and conditions: a) 1-((tert-Butoxycarbonyl)amino)cyclobutane-1-carboxylic acid, HATU, DIEA, DMF; b) TFA, DCM

[0788] Step 1: (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6(R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-1-thio)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) were added DIEA (92.7 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred at 50 ° C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtAOc=1 / 1) to afford (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ- 4 ... 6 -sulfylidene)carbamoyl)cyclobutyl)carbamic acid tert-butyl ester (120 mg, 71.8%). LCMS (ESI): C 31 H 32 [M+H] of ClF4N4O6S + m / z calculated value 699.17, found value 699.15.

[0789] Step 2: (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: To (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl)-thiodiphenyl)carbamoyl)cyclobutyl)carbamate (120 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.5 mL). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 50% to 95% MeCN / H2O column (column, 150*21.2 mm, eluted with 0.05% NH3 in 50% to 95% MeCN / H2O containing 0.05% NH3) to provide (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylaminoylidenesulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (15.70 mg, 15.4%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.38(s,1H),8.12(s,1H),7.88(d,J=7.7Hz,1H),7.75-7.63(m,3H),7.37(s,1 H),7.05(dd,J=8.7,3.3Hz,1H),3.46(s,3H),2.46-2.37(m,2H),2.34(s,3H),2.14-1.91(m,2H),1.88-1.65(m,4H). LCMS(ESI):C 26 H 24 [M+H] of ClF4N4O4S + m / z calculated value 599.12, found value 599.05.

[0790] Example 7B

[0791] (R)-N-(3-(N-(2-amino-2-methylpropionyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide

[0792]

[0793] Reagents and conditions: a) 2-((tert-Butoxycarbonyl)amino)-2-methylpropanoic acid, HATU, DIEA, DMF; b) TFA, DCM

[0794] Step 1: (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6(R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-1-ylsulfonyl)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) were added DIEA (154.5 mg, 1.2 mmol) at room temperature. The reaction mixture was heated at 50 ° C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtAOc=1 / 1) to afford (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ- 4 ... 6 -sulfanylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (100 mg, 60.9%). LCMS (ESI): C 30 H 32 [M+H] of ClF4N4O6S + m / z calculated value 687.17, found value 687.10.

[0795] Step 2: (R)-N-(3-(N-(2-amino-2-methylpropionyl)-S-methylaminosulfonyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide: To (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl)-2-methyl-1-oxopropyl-2-yl)carbamate (100 mg, 0.15 mmol) in DCM (3 mL) was added TFA (0.5 mL). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a Celite 500 nm column, 150*21.2 mm, eluted with 50% to 95% MeCN / H2O containing 0.05% NH3 to provide (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylaminosulfonyl)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 (400MHz, DMSO-d6) δ11.05(s,1H),8.34(s,1H),8.11(s,1H),7.86(d,J=7.4Hz,1H),7.71-7.62(m,3H),7 .37(s,1H),7.04(dd,J=8.7,3.4Hz,1H),3.42(s,3H),2.34(s,3H),1.96-1.50(m,2H),1.19(d,J=3.3Hz,6H). LCMS(ESI):C 25 H 24 [M+H] of ClF4N4O4S + m / z calculated value 587.12, found value 587.10.

[0796] Example 8B

[0797] (S)-N-((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene)pyrrolidine-2-carboxamide formate

[0798]

[0799] Reagents and conditions: a) (tert-Butyloxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM

[0800] Step 1: To a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (tert-butyloxycarbonyl)-L-proline (139 mg, 0.64 mmol) in DMF (5 mL) was added HATU (183 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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 as a yellow solid 6 -sulfylidene)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 50.6%). LCMS (ESI): C 31 H 33 [M+H] of F4N4O6S + m / z calculated 665.21, found 665.10.

[0801] Step 2: To (S)-2-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a solution of tert-butyl pyrrolidine-1-carboxylate (120 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL). 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 phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by column chromatography (HPLC, 150*21.2 mm, eluted with 40% to 95% MeCN / H2O containing 0.05% NH3) to obtain (S)-N-((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ as a white solid. 6 -sulfylidene)pyrrolidine-2-carboxamide formate (75.6 mg, 72.8%). 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.43(d,J=1.8Hz,1H),8.23(s,1H),7.93-7.82(m,2H),7.72-7.64(m,4H),7.24(s,1H),7.07(dd,J=8.7, 3.3Hz,1H),3.86(dd,J=8.5,6.5Hz,1H),3.49(s,3H),3.03-2.79(m,2H) ,2.33(s,3H),2.18-2.05(m,1H),1.95-1.82(m,1H),1.77-1.56(m,2H). LCMS(ESI):C 26 H 25 [M+H] of F4N4O4S + m / z calculated value 565.16, found value 565.05.

[0802] Example 9B

[0803] N-(3-((R)-N-(D-Alanyl)-S-methylaminosulfonyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide

[0804]

[0805] Reagents and conditions: a) (tert-Butyloxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM

[0806] Step 1: To a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (tert-butyloxycarbonyl)-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) at room temperature. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 29 H 31 [M+H] of F4N4O6S + m / z calculated value 639.19, found value 639.10.

[0807] Step 2: To ((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)amino)-1-oxopropyl-2-yl)carbamate (90 mg, 0.15 mmol) in DCM (10 mL) was added TFA (1 mL). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (500ng / ml) using a 40% to 90% MeCN / H2O column (150*21.2 mm, eluted with 0.1% formic acid in 40% to 90% MeCN to afford N-(3-((R)-N-(D-alanyl)-S-methylaminosulfonyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (40 mg, 53.3%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.37(s,1H),7.91-7.89(d,J=7.6Hz,2H),7.69-7.6 2(m,4H),7.24(s,1H),7.08-7.05(m,1H),3.43(s,3H),2.33(s,3H),1.17(d,J=7.2Hz,3H). LCMS(ESI):C 24 H 23 [M+H] of F4N4O4S + m / z calculated value 539.14, found value 539.05.

[0808] Example 10B

[0809] (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)aminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0810]

[0811] Reagents and conditions: a) N-(tert-butyloxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM

[0812] Step 1: To a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and N-(tert-butyloxycarbonyl)-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) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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 as a white oil. 6 -sulfanylidene)amino)-2-oxoethyl)(methyl)carbamic acid tert-butyl ester (110 mg, 53.65%). LCMS (ESI): C 29 H 31 [M+H] of F4N4O6S+ m / z calculated value 639.19, found value 639.05.

[0813] Step 2: To (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 (-thio)amino)-2-oxoethyl) (methyl)carbamate (110 mg, 0.17 mmol) in DCM (10 mL) was added TFA (1 mL). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by using a 4% to 90% MeCN / H2O column (HPLC-MS / MS: 500 nm, eluted with 0.1% formic acid in 40% to 90% MeCN) to obtain (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)aminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide (68.9 mg, 67.2%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.38(s,1H),7.92-7.89(m,2H),7.69-7.65(m,4H ),7.24(s,1H),7.08-7.05(m,1H),3.44(s,3H),3.20(s,2H),2.33(s,3H),2.23(s,3H). LCMS(ESI):C 24 H 23 [M+H] of F4N4O4S + m / z calculated value 539.14, found value 539.05.

[0814] Example 11B

[0815] (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0816]

[0817] Reagents and conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) TFA, DCM

[0818] Step 1: To a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)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) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=2 / 1 to 1 / 1) to give (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylaminoimidesulfonyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (100 mg, 49.02%) as a white oil. LCMS (ESI): C 29 H 34 [M+H] of F4N3O5SSi + m / z calculated value 640.19, found value 640.05.

[0819] Step 2: To a solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylaminosulfonyl)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 completion of the reaction, the solution was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a Celite® 5-[4-nitro-2-methylpyridin-3-yl) column, 150*21.2 mm, eluted with 40% to 90% MeCN / H2O containing 0.1% formic acid to give (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (72.3 mg, 87%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.36(s,1H),7.93-7.90(m,2H),7.69-7.63(m,4H),7.23 (s,1H),7.08-7.05(m,1H),4.80-4.78(m,1H),3.94(d,J=5.6Hz,2H),3.44(s,3H),2.33(s,3H). LCMS(ESI):C 23 H 20 [M+H] of F4N3O5S + m / z calculated 526.11, found 526.00.

[0820] Example 12B

[0821] 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropionyl)-S-methylaminoimidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0822]

[0823] Reagents and conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF, H2O

[0824] Step 1: To a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (112 mg, 0.55 mmol) in DMF (5 mL) was added HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.02 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=2 / 1 to 1 / 1) to give N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoimidenesulfonyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (100 mg, 47.8%) as a white oil. LCMS (ESI): C 30 H36 [M+H] of F4N3O5SSi + m / z calculated 654.21, found 654.10.

[0825] Step 2: To a solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propionyl)-S-methylaminosulfonyl)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 completion of the reaction, the solution was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5um C 18 The residue was purified by using a 4% to 90% MeCN / H2O column (HPLC-MS / MS:

[0247] , 150*21.2 mm, eluted with 0.1% formic acid in 40% to 90% MeCN / H2O) to obtain 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (62.3 mg, 78%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.39(s,1H),7.91-7.87(m,2H),7.69-7.65(m,4H),7.23(s,1H),7.0 8-7.05(m,1H),4.68(d,J=5.6Hz,1H),4.04-4.01(m,1H),3.43(s,3H),2.33(s,3H),1.24(d,J=6.8Hz,3H). LCMS(ESI):C 24 H 22 [M+H] of F4N3O5S + m / z calculated value 540.12, found value 540.05.

[0826] Example 13B

[0827] 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropionyl)-S-methylaminoimidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0828]

[0829] Reagents and conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propionic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O

[0830] Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)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) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction is complete, the resulting solution is diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase is washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue is purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to obtain N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminosulfonyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (200 mg, 47.7%) as a yellow oil. LCMS (ESI): C 30 H 36 [M+H] of F4N3O5SSi + m / z calculated 654.20, found 654.10.

[0831] Step 2: 2-((6-Fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylaminoimidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To a solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoimidenesulfonyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (200 mg, 0.31 mmol) in THF (3 mL) was added CH3CO2H (3 mL) and HO (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by using a 4% to 90% MeCN / H2O column (HPLC-MS / MS: ... 1 H NMR (400MHz, CD3OD) δ8.41(dd,J=4.0,2.1Hz,1H),7.91-7.86(m,2H),7.78-7.75(m,1H),7.67-7.60(m,2H),7.53(dd,J=8.7 ,6.5Hz,1H),7.18(s,1H),6.92(dd,J=8.6,3.1Hz,1H),4.21(m,1H),3.43(s,3H),2.39(s,3H),1.40(dd,J=6.9,1.9Hz,3H). LCMS(ESI):C 24 H 22 [M+H] of F4N3O5S + m / z calculated value 540.11, found value 540.10.

[0832] Example 14B

[0833] (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylaminoylidenesulfonyl)phenyl)-4-(trifluoromethyl)benzamide

[0834]

[0835] Reagents and conditions: a) (tert-Butyloxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM

[0836] Step 1: (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-substituted sulfonyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (tert-butyloxycarbonyl)glycine (96 mg, 0.55 mmol) in DMF (2 mL) was added HATU (159 mg, 0.42 mmol) and DIEA (133 mg, 1.03 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x3). The combined organic phases were washed with brine, dried over NaSO, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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 as a yellow oil. 6 -sulfanylidene)amino)-2-oxoethyl)carbamic acid tert-butyl ester (150 mg, 74.9%). LCMS (ESI): C 28 H 29 [M+H] of F4N4O6S + m / z calculated: 625.17, found: 625.05.

[0837] Step 2: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-5-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide: To a solution of tert-butyl (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ-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 completion of the reaction, the solution was diluted with NaHCO 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by using a 4% to 95% MeCN / H2O column (HPLC-MS / MS: 500 nm, eluted with 0.05% NH3) to obtain (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylaminosulfonyl)phenyl)-4-(trifluoromethyl)benzamide (50 mg, 39.7%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.36(s,1H),7.91(d,J=7.7Hz,2H),7.69-7.62(m,4H),7 .24(s,1H),7.07(dd,J=8.7,3.4Hz,1H),3.44(s,3H),3.24(s,2H),2.33(s,3H),1.99(bs,2H). LCMS(ESI):C 23 H 21 [M+H] of F4N4O4S + m / z calculated 525.12, found 525.00.

[0838] Example 15B

[0839] N-(3-((R)-N-(D-Alanyl)-S-methylaminosulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide

[0840]

[0841] Reagents and conditions: a) (tert-Butyloxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM

[0842] Step 1: ((R)-1-(((R)-(3-(2-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-substitutedsulfonyl)phenyl)-3-(trifluoromethyl)benzamide (100 mg, 0.21 mmol) and (tert-butyloxycarbonyl)-D-alanine (78 mg, 0.41 mmol) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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 as a yellow solid 6 -sulfanylidene)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (80 mg, 59.1%). LCMS (ESI): C 29 H 30 [M+H] of F5N4O6S + m / z calculated 657.18, found 657.00.

[0843] Step 2: N-(3-((R)-N-(D-alanyl)-S-methylaminosulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide: To ((R)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL). 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 layer was washed with salt water, dried over sodium sulfate, and concentrated under vacuum. The HPLC was performed by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 5-[4-nitro-4-oxo-5-nitro-2-pyridin-3-yl)-4-nitro-3-oxo-4-nitropropane-2-yl)-dextrin (5-[4-nitro-4-oxo-5-nitro-2-pyridin-3-yl)-4-nitro-3-oxo-4-nitropropane-2-yl)-dextrin (5-[4-nitro-4-oxo-5-nitro-2-pyridin-3-yl)-dextrin) as a white solid ...nitro-4-oxo-5-nitro-2-pyridin-3-yl)-dextrin) as a white solid (5-nitro-4-oxo-5-nitro-2-pyridin-3-yl)-dextrin) as a white 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.39(s,1H),7.95-7.80(m,3H),7.74-7.64(m,2H),7.15(dd,J=8.6,3.2H z,1H),6.79(d,J=8.9Hz,1H),3.46(s,3H),3.32-3.27(m,1H),2.30(s,3H),1.71(s,2H),1.17(d,J=6.9Hz,3H). LCMS(ESI):C 24 H 22 [M+H] of F5N4O4S + m / z calculated 557.13, found 557.00.

[0844] Example 16B

[0845] (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0846]

[0847] Reagents and conditions: a) (tert-Butyloxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM

[0848] Step 1: (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo ) -λ 6To a mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-substitutedsulfonyl)phenyl)-3-(trifluoromethyl)benzamide (100 mg, 0.21 mmol) and (tert-butyloxycarbonyl)glycine (72 mg, 0.41 mmol) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, 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 NaSO, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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 as a yellow solid 6 -sulfanylidene)amino)-2-oxoethyl)carbamic acid tert-butyl ester (80 mg, 60.4%). LCMS (ESI): C 28 H 28 [M+H] of F5N4O6S + m / z calculated 643.16, found 643.00.

[0849] Step 2: (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S-methylamino-1-sulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To (R)-(2-(((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)amino)-2-oxoethyl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL). 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 layer was washed with salt water, dried over sodium sulfate, and concentrated under vacuum. The HPLC was performed by preparative HPLC (Gemini 5 μm C 18The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 5-[4-[4-biphenyl]-1-oxo-2-nitro-4-oxo-5-nitro-2-nitro-3-ol (5-[4-biphenyl]-1-oxo-2-nitro-3-ol)-4-nitro ... 1 H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.37(s,1H),7.98-7.80(m,3H),7.73-7.63(m,2H),7.15(d d,J=8.7,3.3Hz,1H),6.79(d,J=8.9Hz,1H),3.46(s,3H),3.24(s,2H),2.30(s,3H),2.01(s,2H). LCMS(ESI):C 23 H 20 [M+H] of F5N4O4S + m / z calculated value 543.11, found value 543.05.

[0850] Example 17B

[0851] (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)aminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0852]

[0853] Reagents and conditions: a) N-(tert-butyloxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM

[0854] Step 1: (R)-(2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylamino-substitutedsulfonyl)phenyl)-3-(trifluoromethyl)benzamide (100 mg, 0.21 mmol) and N-(tert-butyloxycarbonyl)-N-methylglycine (78 mg, 0.41 mmol) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over NaSO, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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 as a yellow solid 6 -sulfanylidene)amino)-2-oxoethyl)(methyl)carbamic acid tert-butyl ester (80 mg, 59.0%). LCMS (ESI): C 29 H 30 [M+H] of F5N4O6S + m / z calculated 657.18, found 657.00.

[0855] Step 2: (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)aminoimidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To (R)-(2-(((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 (-sulfylidene)amino)-2-oxoethyl) (methyl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL). 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 layer was washed with salt water, dried over sodium sulfate, and concentrated under vacuum. The HPLC was performed by preparative HPLC (Gemini 5 μm C 18The residue was purified by using a 4% to 95% MeCN / H2O column (HPLC-MS / MS:

[0247] , 150*21.2 mm, eluted with 0.05% NH3 in 40% to 95% MeCN / H2O) to obtain (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N-(methylglycyl)aminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide (41.3 mg, 60.1%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.39(s,1H),7.96-7.80(m,3H),7.74-7.65(m,2H),7.15(d d,J=8.7,3.4Hz,1H),6.79(d,J=8.8Hz,1H),3.46(s,3H),3.19(s,2H),2.30(s,3H),2.21(s,3H). LCMS(ESI):C 24 H 22 [M+H] of F5N4O4S + m / z calculated value 557.13, found value 557.05.

[0856] Example 18B

[0857] 2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropionyl)-S-methylamino-1,1-disulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0858]

[0859] Reagents and conditions: a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O

[0860] Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.31 mmol) and (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (126 mg, 0.62 mmol) in DMF (5 mL) was added HATU (176 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol) at room temperature. 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 (50 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to obtain N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propionyl)-S-methylaminosulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 57.8%) as a yellow solid. LCMS (ESI): C 30 H 35 [M+H] of F5N3O5SSi + m / z calculated 672.20, found 672.05.

[0861] Step 2: 2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylamino-1-sulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To a solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylamino-1-sulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF (3 mL) and H2O (1 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was diluted with water (30 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C18 The residue was purified by using a 4% to 95% MeCN / H2O column (HPLC-MS / MS: ... 1 H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.40(s,1H),7.97-7.78(m,3H),7.74-7.65(m,2H),7.15(dd,J=8.7,3.4Hz,1H ),6.79(d,J=8.9Hz,1H),4.70(d,J=5.6Hz,1H),4.10-3.97(m,1H),3.45(s,3H),2.30(s,3H),1.24(d,J=6.8Hz,3H).

[0862] LCMS (ESI): C 24 H 21 [M+H] of F5N3O5S + m / z calculated 558.11, found 558.00.

[0863] Example 19B

[0864] 2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropionyl)-S-methylamino-1,1-disulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0865]

[0866] Reagents and conditions: a) (R)-2-((tert-butyldimethylsilyl)oxy)propionic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O

[0867] Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.31 mmol) and (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (126 mg, 0.62 mmol) in DMF (5 mL) was added HATU (176 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol) at room temperature. 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 (50 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to obtain N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propionyl)-S-methylaminosulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 57.8%) as a yellow solid. LCMS (ESI): C 30 H 35 [M+H] of F5N3O5SSi + m / z calculated 672.20, found 672.05.

[0868] Step 2: 2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylamino-1-sulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To a mixture of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylamino-1-sulfonyl)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 completion of the reaction, the solution was diluted with water (30 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 5-[4-[4-[4-(4-fluoro-2-methylpyridin-3-yl)oxy]-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide (40.5 mg, 40.6%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.39(s,1H),7.97-7.78(m,3H),7.76-7.64(m,2H),7.15(dd,J=8.6,3.4Hz,1H ), 6.79 (d, J = 8.8Hz, 1H), 4.73 (d, J = 5.3Hz, 1H), 4.10-3.95 (m, 1H), 3.48 (s, 3H), 2.30 (s, 3H), 1.27 (d, J = 6.8Hz, 3H). LCMS(ESI):C 24 H 21 [M+H] of F5N3O5S + m / z calculated 558.11, found 558.00.

[0869] Example 20B

[0870] (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide

[0871]

[0872] Reagents and conditions: a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) AcOH, THF / H2O

[0873] Step 1: (R)-N-(3-(N-(2-((tert-Butyldimethylsilyl)oxy)acetyl)-S-methylaminoylidenesulfonyl)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-methylaminoylidenesulfonyl)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) were added HATU (176.24 mg, 0.464 mmol) and DIEA (119.81 mg, 0.927 mmol) at room temperature. 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 (50mL) and extracted with DCM (30mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=2 / 1 to 1 / 1) to obtain (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylaminosulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120mg, 53.14%) as a yellow solid. LCMS (ESI): C 29 H 33 [M+H] of F5N3O5SSi + m / z calculated: 658.19, found: 658.10.

[0874] Step 2: (R)-2-Fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminoylidenesulfonyl)phenyl)-3-(trifluoromethyl)benzamide: To a solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylaminoylidenesulfonyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.1824 mmol) in THF (1 mL) and H2O (3 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. The aqueous solution was then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by HPLC-MS / MS (HPLC-MS / MS) using a 5-[4-[4-[4-(4-[4-(4-(2-hydroxyacetyl)-S-methylamino]-1,4-dextrin and 1,4-dextrin as a column, 150*21.2 mm, eluted with 40% to 50% to 95% MeCN / H2O containing 0.1% FA) to give (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide (27.2 mg, 26.32%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),8.36(s,1H),7.98-7.80(m,3H),7.74-7.65(m,2H),7.15(dd,J=8.7, 3.3Hz, 1H), 6.79 (d, J = 8.9Hz, 1H), 4.79 (t, J = 6.2Hz, 1H), 3.94 (d, J = 5.9Hz, 2H), 3.47 (s, 3H), 2.30 (s, 3H). LCMS(ESI):C 23 H 19 [M+H] of F5N3O5S + m / z calculated value 544.10, found value 543.80.

[0875] Example 21B

[0876] (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene)pyrrolidine-2-carboxamide

[0877]

[0878] Reagents and conditions: a) (tert-Butyloxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM

[0879] Step 1: (S)-2-(((R)-(3-(2-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 To a mixture of (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylaminosulfonyl)phenyl)-3-(trifluoromethyl)benzamide (150 mg, 0.31 mmol) and (tert-butyloxycarbonyl)-L-proline (133.39 mg, 0.62 mmol) in DMF (5 mL) was added HATU (175.89 mg, 0.46 mmol) and DIEA (119.57 mg, 0.93 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After completion of the reaction, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=2 / 1 to 1 / 1) to give (S)-2-(((R)-(3-(2-chloro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ as a yellow solid 6 -sulfylidene)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 51.23%). LCMS (ESI): C 31 H 32 [M+H] of F5N4O6S + m / z calculated: 683.2, found: 681.05.

[0880] Step 2: (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6 -sulfylidene)pyrrolidine-2-carboxamide: at room temperature, to (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ 6To a solution of tert-butyl pyrrolidine-1-carboxylate (120 mg, 0.17 mmol) in DCM (10 mL) was added TFA (1 mL). 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 NaHCO3 aqueous solution. 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 vacuum. The product was purified by preparative HPLC (Gemini 5 μm C 18 The residue was purified by column chromatography (HPLC, 150*21.2 mm, eluted with 50% to 60% to 95% MeCN / H2O containing 0.05% NH3) to obtain (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ as a white solid. 6 -sulfylidene)pyrrolidine-2-carboxamide (41.3 mg, 38.8%). 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.42(s,1H),7.89-7.67(m,5H),7.15(dd,J=8.7,3.4Hz,1H),6.79(d,J=8.8Hz,1H),3.51(dd,J=8.5,5. 8Hz,1H),3.45(s,3H),2.90-2.83(m,1H),2.61(dt,J=10.0,6.8Hz,1H) ,2.30(s,3H),2.02-1.93(m,1H),1.79-1.71(m,1H),1.61-1.43(m,2H). LCMS(ESI):C 26 H 24 [M+H] of F5N4O4S + m / z calculated value 583.15, found value 582.90.

[0881] The following compounds were prepared using the techniques of the intermediates and examples described above.

[0882]

[0883]

[0884]

[0885] Example 30B

[0886] Compound Profiling Human NaV1.8 / β3 Cell Line - SyncroPatch384PE Assay

[0887] Compounds were tested on recombinant human Nav1.8 / b3 stably transfected CHO cells using the SyncroPatch384PE system (Nylon Technologies, Inc.), an automated patch clamp device. Cells were cultured at 37°C / 5% CO2 in Ham's F-12 supplemented with 10% fetal bovine serum, 100U / mL penicillin G sodium, 100mg / mL streptomycin sulfate, and selective antibiotics (0.01mg / ml blasticidin, 0.4mg / ml Zeocin, and 0.25mg / 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. Cells were washed in HBSS to remove Accutase and resuspended in extracellular solution and then immediately used in SynchroPatch384PE using an 8-well NPC-384 chip. All experiments were performed at ambient temperature. The intracellular solution contained (mM): CsCl 50; CsF 90; MgCl 5; EGTA 1; HEPES 10; and the pH was adjusted to 7.2 with CsOH. The extracellular solution contained (mM): NaCl 137; KCl 4.0; CaCl 3.8; MgCl 1; HEPES 10; and glucose 10; and the pH was adjusted to 7.4 with NaOH. 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.

[0888] Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3.33 in extracellular solution to generate an 8-point concentration-response curve. Each plate contained a historical positive control and up to ten compounds. 300 μM tetracaine and 0.3% DMSO + 0.03% pluronic acid were used as high and low controls, respectively.

[0889] According to Nyon Standard procedure carries out whole-cell patch clamp recording.Cell is maintained at the holding potential of-120mV.The depolarization step of applying 10mV continues 30 milliseconds (P1 measurement), is followed by the hyperpolarization step of-100mV and continues 100 milliseconds.The inactivation step of being applied in-35mV continues 10 seconds, then steps into-100mV and continues 20 milliseconds, then steps into 10mV and continues 30 milliseconds (P2 measurement), and then returns to-100mV and continues 30 milliseconds.The sweep interval is 15 seconds.After setting up the whole-cell configuration in extracellular solution, cell is washed with stable baseline current in the extracellular solution containing 0.3%DMSO and 0.03% pluronic acid.Then by SynchroPatch384 PE system, compound is applied in each hole, and electric current is recorded five minutes in extracellular solution, applies tetracaine subsequently to realize complete blocking at the end of experiment. The potency of compounds was assessed on two readouts, resting state blockade (P1 measurement) or inactivated state blockade (P2 measurement) to obtain IC50 values. Values ​​were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.

[0890] The following table shows the effects of the compounds on human Na V The potency is 1.8, where "A" indicates an IC50 of less than or equal to 5 nM, "B" indicates an IC50 of greater than 5 nM to less than or equal to 50 nM, "C" indicates an IC50 of greater than 50 nM to less than or equal to 100 nM, "D" indicates an IC50 of greater than 100 nM to less than or equal to 200 nM, and "E" indicates an IC50 of greater than 200 nM.

[0891] Examples P1 P2 1B A A 2B A A 3B A A 4B A A 5B A A 6B A A 7B A A 8B A A 9B A A 10B B B 11B B B 12B B B 13B B B 14B B B 15B A A 16B A A 17B A A 18B A A 19B A A 21B B B 22B A A 23B A A 24B A A 25B A A 26B A A 27B A A 28B A A 29B A A

[0892] (C) The third group of compounds

[0893] In one aspect, the present invention provides a compound of formula (I):

[0894]

[0895] and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

[0896] A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from the group consisting of O, S or N;

[0897] wherein the one or more substitutions 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, cycloalkyloxy, haloalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N;

[0898] B is a substituted or unsubstituted aryl or heteroaryl group, wherein the substitutions are selected from the group consisting of: a substituted or unsubstituted C1-C8 alkyl group, a deuterated C1-C4 alkyl group in which the alkyl chain may be fully or partially deuterated, a halo-C1-C4 alkyl group in which the alkyl chain is fully or partially halogenated, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8 alkoxy, wherein the haloalkoxy chain may be a fully or partially halogenated haloalkoxy, or arylalkoxy;

[0899] C is a substituted or unsubstituted aryl or heteroaryl, wherein one or more substitutions are independently selected from the group consisting of halo, C1-C8 alkyl, haloalkyl, alkoxy;

[0900] R1 is selected from the group consisting of: H and C1-C4 alkyl;

[0901] R2 is selected from the group consisting of: Formula (II):

[0902] -C(=O)NH2 and -C(=O)NR'R";

[0903] in,

[0904] m and n are independently 0 or 1; and

[0905] X1 is O, and X2 is NH or NR'; or

[0906] X1 and X2 are both O, NH or NR'; or

[0907] X1 is O, and X2 is NR3; wherein 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;

[0908] R4 is selected from the group consisting of -NH2, -NR'R", C1-C4 alkyl, C3-C8-cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl and heterocyclyl.

[0909] 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 can be in the form of an N-oxide. In certain embodiments, the N-oxide containing ring B is selected from pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0910] In another embodiment, the compound is a compound of formula (III):

[0911]

[0912] wherein Q, T and W are independently N or CR6;

[0913] R6 is H, halogen, -CD3, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, or substituted or unsubstituted cycloalkoxy;

[0914] R5 is H, -OH, halo, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6 membered cycloalkyl, any of which may have one or more substituents;

[0915] X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, -OCF3.

[0916] In another embodiment, the compound is of formula (IV):

[0917]

[0918] in:

[0919] Z is CR 10 , N or N + O - ; where R 10 It is H, halo, -CD3, C1-C8 alkyl, haloalkyl or alkoxy.

[0920] In certain embodiments, Ring A is a substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S.

[0921] In certain embodiments, Ring A is a substituted or unsubstituted pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0922] In certain embodiments, Ring A is a substituted or unsubstituted 6-membered heteroaryl group having at least one heteroatom, wherein the heteroatom is N. In certain embodiments, Ring A is a substituted or unsubstituted 6-membered heteroaryl group having at least 2 N atoms.

[0923] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0924]

[0925] wherein Q1, Q2, Q3 and Q4 are independently selected from the group consisting of: N, N + O - or CR7; wherein at least two of Q1, Q2, Q3 and Q4 are CR7;

[0926] R7 is H, -OH, halo, -CD3, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF3, -OCF3, substituted or unsubstituted 5- or 6-membered ring heterocyclyl or heteroaryl, saturated heterocyclyl or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl or O-cycloheteroalkyl.

[0927] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0928]

[0929] in,

[0930] Q2 and Q4 are independently N or N + O - ;

[0931] Q2 is N or N + O - ; Q4 is CR7; or

[0932] Q2 is CR7, Q4 is N or N + O - ;

[0933] R8 and R9 are independently selected from the group consisting of H, -OH, halo, -CD3, substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR', NR'R", aryl, heteroaryl, -CF2CH3 and -CF2CF3;

[0934] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0935]

[0936] in,

[0937] Q3 and Q4 are independently N or N + O - ;

[0938] Q3 is N or N + O - , and Q4 is CR7; or

[0939] Q3 is CR7, Q4 is N or N + O - ; wherein R7, R8 and R9 are defined above.

[0940] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0941]

[0942] in,

[0943] Q1 and Q4 are independently N or N + O - ;

[0944] Q1 is N or N + O - , and Q4 is CR7;

[0945] Q1 is CR7, and Q4 is N or N + O - ;or

[0946] Q1 or Q4 is CR7; wherein R7, R8 and R9 are defined above.

[0947] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0948]

[0949] wherein Q1 and Q2 are N; and wherein R8 and R9 are as defined above.

[0950] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0951] wherein Q1 is CR7, Q2 is N; and R7, R8 and R9 are as defined above.

[0952] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), A is:

[0953]

[0954] wherein Q1 is N; Q2 is CR7; and R7, R8, and R9 are as defined above.

[0955] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), R2 is:

[0956] wherein m and n are independently 0 or 1;

[0957] X1 is O, and X2 is NH, and R4 is an alkyl group, such as methyl.

[0958] In other embodiments, in the compounds of Formula (I), Formula (III) and / or Formula (IV), R2 is:

[0959] wherein m and n are independently 0 or 1;

[0960] X1 is O, and X2 is O, and R4 is NH2 or an alkyl group, such as methyl.

[0961] In other embodiments, R2 is -S(=O)CH3. In another embodiment, in these compounds of formula (III) and / or formula (IV), Q is N or CH; R5 is methyl or -OMe, and X is F or CN. In other embodiments, in these compounds of formula (III) and / or formula (IV), Q is CF. In other embodiments, R7, R8 and R9 are independently selected from the group consisting of H, methyl, fluorine, chlorine, bromine, CF3, cyclopropyl, difluorophenyl and dimethylpyrazole. In other embodiments, in these compounds 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.

[0962] In certain embodiments of the present invention, R2 does not comprise -C(=O)NH2 or -C(=O)NR'R".

[0963] In certain embodiments, R2 is of formula (II):

[0964]

[0965] in,

[0966] m and n are independently 0 or 1; and

[0967] X1 and X2 are not both O, NH or NR'.

[0968] In other embodiments, the compound of the present invention is selected from the group consisting of:

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984] The third group of compounds provided herein are prepared by the methods and procedures described below.The intermediates described in this section can be used to prepare the third group of compounds.

[0985] Methods for preparing the compounds of the present invention and the intermediates used in their synthesis are provided in the general synthetic schemes and specific synthetic steps below. Unless otherwise stated, chemicals were purchased from standard commercial suppliers and used as received. Otherwise, their preparation is easy and known to those of ordinary skill in the art, or referenced or described herein. Abbreviations are consistent with those in the ACS style guide. "Dry" glassware means oven / dessicator dried. Unless otherwise stated, solvents are ACS grade.

[0986] Unless otherwise noted, all reactions were performed under a positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware with magnetic stirring. 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.

[0987] Use purchased from EMD MILLIPORE TM The reaction was monitored by thin layer chromatography (TLC) on 0.25 mm silica gel 60 F254 plates. Purification was performed using Biotage Isolera One flash chromatography or using one of the preparative HPLC methods mentioned below.

[0988] Preparation method 1

[0989] Equipment: Shimadzu LCMS2020 mass-directed preparative HPLC system; column: Gemini 5um C 18 Column, 150*21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.1% HCOOH, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0990] Preparation method 2

[0991] Equipment: Shimadzu LC-20AP preparative HPLC system; column: Gemini 5um C 18 Column, 150*21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.1% TFA, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0992] Preparation method 3

[0993] Equipment: Shimadzu LC-20AP preparative HPLC system; column: Gemini 5um C18 Column, 150 x 21.2 mm; general gradient: 30% to 90% MeCN / H2O containing 0.05% ammonia, the gradient can be slightly adjusted for specific compounds; flow rate: 20 ml / min; column temperature: ambient temperature; UV wavelength: 214 and 254 nm.

[0994] Collect and analyze LCMC using one of the following methods.

[0995] Analytical Method 1

[0996] Equipment: Shimadzu LCMS2020 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 in 1.4 minutes, held for 0.6 minutes, with a total run time of 2.5 minutes; flow rate: 1.8 ml / min; column temperature: 50°C; wavelengths: 214 and 254 nm PDA.

[0997] Analysis Method 2

[0998] Equipment: Shimadzu LCMS2020 spectrometer; XBridge BEH C 18 2.5 μm, 3.0 mm × 30 mm mobile phase: MeCN-water (0.1% NH4OH); gradient: 5% to 95% MeCN in 1.8 minutes, hold for 0.7 minutes, total run time of 3.0 minutes; flow rate: 1.0 ml / min; column temperature: 50°C; wavelength: 214 and 254 nm PDA.

[0999] Analysis Method 3

[1000] Equipment: Shimadzu LCMS2020 spectrometer; column: HALO C 18 2.7 μm, 3.0 mm × 30 mm mobile phase: MeCN (0.05% TFA)-water (0.05% TFA); gradient: 5% to 95% MeCN in 1.4 minutes, hold for 0.6 minutes, total run time of 2.5 minutes; flow rate: 1.8 ml / min; column temperature: 50°C; wavelength: 214 and 254 nm PDA.

[1001] The following method was used to analyze the Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD SF , SFC-30A) for SFC chiral separation:

[1002] Analytical Method 4

[1003] Column: Chiralpak-AS-H (5 μm, 250 x 20 mm) from Daicel; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M in MeOH)], with different CO 2 / MeOH ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[1004] Analytical Method 5

[1005] Column: Chiralpak-OJ-H, 5 μm, 250×20 mm; mobile phase: CO 2 / MeOH (0.1% HCOOH), with different CO 2 / MeOH ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[1006] Analytical Method 6

[1007] Column: Chiralpak-OD-H 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / MeOH, with different ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[1008] Analytical Method 7

[1009] Column: Chiralpak-AD-H 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / i-PrOH, with different ratios for different compounds; oven temperature: 40°C; flow rate: 38 ml / min.

[1010] Analytical Method 8

[1011] Column: Chiralpak-IC 5 μm 250 x 20 mm from Daicel; mobile phase: CO 2 / EtOH, with different ratios for different compounds; oven temperature: 40° C.; flow rate: 38 ml / min.

[1012] Unless otherwise stated, 1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz digital NMR spectrometer. Chemical shifts δ are quoted in parts per million (ppm) relative to TMS and are calibrated using residual undeuterated solvent as an internal reference. The following abbreviations are used to indicate multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet), dq (doublet of quadruplet), hep (septet), m (multiplet), pent (quintet), td (triplet of doublet), qd (quadruple of doublet), app. (apparent), and br. (broad). Coupling constants J are quoted to the nearest 0.1 Hz.

[1013] General synthetic scheme

[1014] Several methods for preparing the compounds of the present invention are described in the following schemes and examples. The present invention further provides methods for preparing compounds of formula I as defined above. In some cases, the order in which the preceding reaction schemes are performed may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

[1015] Compounds of formula (I) can be prepared from A-1 starting materials or intermediates, but are 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-dichlorobenzene-6-methylpyrimidine-5-carboxylate, ethyl 5-bromo-2-chloro-4-methylnicotinate, ethyl 5-bromo-3-fluoro-2-iodoisonicotinate, ethyl 2,6-chloro-4-methylbutyrate, ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate, methyl 2-fluoro-5-nitronicotinate, 2-chloro-4,6-dimethylnicotinic acid, which are commercially available, synthesized using published procedures, or synthesized by methods known to those skilled in the art. The starting materials and intermediates can be modified to prepare still other intermediates having alternative or additional groups, such as alkyl, fluoroalkyl, trifluoromethyl, cyano, halogen, chloro, bromo, iodo, amino, nitro, aryl, heteroaryl, alkoxycarbonyl, alkoxy, aryloxy, heteroaryloxy, etc. For each of the examples, methods are shown for converting the above starting materials to compounds of formula (I).

[1016] Plan A

[1017]

[1018] As shown in scheme A, generally, formula (I) compound can be synthesized from A-1 starting material or intermediate. Ring A and X of A-1 can first be modified to obtain intermediate A-1 suitable for subsequent modification. Modification can include but is not limited to exchanging halogen with trifluoromethyl, metal-catalyzed coupling to introduce alkyl, aromatic or heteroaromatic groups, treating with nitric acid to introduce nitro groups, reducing nitro groups to amino groups or other conversions known to those skilled in the art. In the presence of alkalis such as K2CO3, Cs2CO3, NaH, KH or other organic bases, the X group of A-1 can be replaced by various substituted phenols or heteroaromatic alcohols to provide A-2 type intermediates. A-2 type intermediates may or may not be further modified on ring A, and formate is subsequently hydrolyzed with KOH or LiOH in an aqueous solvent to obtain formic acid intermediate A-3. Intermediate A-3 can be reacted with HATU, TBTU, EDC or T3P in an organic solvent and a base such as DIEA using a standard amide coupling reagent, and substituted aniline or heteroaryl aniline to obtain a compound of formula (I). If desired, the compound of formula (I) can be further modified to provide another compound of formula (I). Alternatively, intermediate A-2 can be treated with ammonia, a primary amine (R1NH2) or a dialkylaluminum amide to obtain formamide A-4, which can be metal-catalyzed coupled with a halo-substituted aniline or heteroaryl aniline to obtain a compound of formula (I).

[1019] Plan B

[1020]

[1021] As shown in scheme B, usually, compound of the present invention can be prepared by using alkalis such as DIEA or such as K CO Or Cs CO Deng inorganic bases make substituted compound A-1 and aryl or heteroaryl alcohol B reaction, to obtain intermediate A-2.By in aqueous EtOH or MeOH or MeOH / THF / H In the mixture of O, use alkali treatment A-2 such as KOH or LiOH or NaOH, intermediate A-2 can be converted into corresponding acid A-3.Intermediate A-5 can be by utilizing amide coupling condition treatment A-3 and amine C, or by using (COCl) Or POCl And activate suitable functionalized formic acid A-4 in DCM, DMF or THF such as amine C alkalis such as DIEA or pyridine.Formula A-6 compound can be formed by removing protecting groups such as Boc under acidic conditions.In some cases, chiral HPLC can be used that A-6 is separated into corresponding R and S isomers. The R- and S-isomers can also be prepared by coupling the acid with enantiomerically pure amine C followed by deprotection.

[1022] Plan C

[1023]

[1024] As further illustrated in Scheme B, generally, the compounds of the present invention can be prepared by activating an appropriately functionalized formic acid A-3 with (COCl) or SOCl in an organic solvent, followed by the addition of NH4OH to yield B-1. Intermediate B-1 can then be combined with various substituted Br compounds using Xantphos-Pd-G2-mediated coupling conditions to deliver intermediate B-2. Compounds of formula B-2 are treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to deliver compounds of formula B-3. In some cases, B-3 is separated into the corresponding R and S isomers using chiral HPLC conditions.

[1025] Intermediate 1

[1026] 2-((6-Fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid

[1027]

[1028] Reagents and conditions: a) Fuming HNO3, H2SO4, 0℃ to 50℃; b) PhOPOCl2, 160℃; c) Cs2CO3, MeCN, 50℃; d) Fe, NH4Cl, MeOH / H2O, 50℃; e) p-TsOH·H2O, NaNO2, KI, MeCN / H2O, room temperature; f) CuI, DMF, N2, 120℃; g) LiOH, THF / MeOH / H2O, room temperature

[1029] Step 1.2-hydroxy-4-methyl-5-nitronicotinate: To a solution of methyl 2-hydroxy-4-methylnicotinate (40 g, 0.24 mol) in H2SO4 (200 mL) was added fuming HNO3 (13 mL) dropwise at 0 ° C. The mixture was heated to 50 ° C for 5 hours. The resulting mixture was poured into ice water (3 L). The precipitate was collected by filtration, washed with water and dried under vacuum to give crude methyl 2-hydroxy-4-methyl-5-nitronicotinate (26 g, 51% yield) as a yellow solid. LCMS (ESI): [M+H] + m / z calculated value 213.05, found value 212.90.

[1030] Step 2.2-chloro-4-methyl-5-nitronicotinic acid methyl ester: A solution of 2-hydroxy-4-methyl-5-nitronicotinic acid methyl ester 5 (8.0 g, 37.8 mmol) in phenyl dichlorophosphate (40 mL) was heated to 160 ° C for 2 hours. The resulting solution was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1) to provide 2-chloro-4-methyl-5-nitronicotinic acid methyl ester (6 g, 69% yield) as a light yellow solid. LCMS (ESI): [M+H] + m / z calcd. 231.02, found 231.00.

[1031] Step 3. 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate: To a solution of 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 hour. After completion of the reaction, the mixture was concentrated under vacuum and the residue was directly purified by flash column chromatography on silica gel (PE / EtOAc=4 / 1 to 3 / 1) to afford 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate (4.2 g, 77% yield) as a light yellow solid. LCMS (ESI): C 14 H 13 [M+H] of FN3O5 + m / z calcd. 322.09, found 322.00.

[1032] Step 4.5-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 NHCl (4.91 g, 91.7 mmol), Fe (3.66 g, 65.5 mmol). The mixture was heated at 60 °C for 2 hours. After that, 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 vacuum to provide methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (3.7 g, 97% yield) as a yellow solid. LCMS (ESI): C 14 H 15 [M+H] of FN3O3 + m / z calculated value 292.11, found value 291.95.

[1033] Step 5. 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate: To a solution of TsOH·H2O (3.94 g, 20.7 mmol) and 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (2 g, 6.9 mmol) in MeCN (60 mL) was added a solution of NaNO2 (950 mg, 13.8 mmol) and KI (2.86 g, 17.3 mmol) in H2O (10 mL) at 0°C. The mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the mixture was quenched with water (100 mL) and adjusted to pH = 8-9 with saturated aqueous NaHCO3. The solution was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1 to 1 / 1) to afford methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate (2.2 g, 78% yield) as a yellow solid. LCMS (ESI): C 14 H 13 [M+H] of FIN2O3 + m / z calcd. 403.00, found 402.90.

[1034] Step 6. 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinate: To a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate (1.2 g, 3 mmol) and CuI (1.14 g, 6 mmol) in DMF (30 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.88 g, 15 mmol) dropwise under an atmosphere of N at room temperature. The mixture was heated at 120 °C for 6 hours. After completion of the reaction, the resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 15 H 13 [M+H] of F4N2O3 + m / z calculated value 345.09, found value 344.95.

[1035] 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 completion of the reaction, 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (900 mg, 94% yield) as a white solid. LCMS (ESI): C 14 H 11 [M+H] of F4N2O3 + m / z calculated value 331.07, found value 330.90.

[1036] Intermediate 2

[1037] 5-Bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid

[1038]

[1039] 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, room temperature

[1040] Step 1: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinic acid methyl ester: To a solution of 2-chloro-4-methyl-5-nitronicotinic acid methyl ester (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 completed, the mixture was concentrated under vacuum and directly purified by silica gel flash column chromatography (PE / EtOAc=3 / 1) to provide 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinic acid methyl ester (2.7 g, 53.6%) as a light yellow solid. LCMS (ESI): C 14 H 13 [M+H] of FN3O5 + m / z calculated value 322.09, found value 321.95.

[1041] Step 2: 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To a solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate (2.5 g, 7.8 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 ° C for 1 hour. After the reaction was 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 vacuum to provide methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (1.4 g, 61.9%) as a yellow solid. LCMS (ESI): C 14 H 15 [M+H] of FN3O3 + m / z calculated 292.11, found 292.00.

[1042] Step 3: 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To a solution of 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 complete, the resulting solution was diluted with water (80 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 14 H 13 [M+H] of BrFN2O3 + m / z calculated value 357.01, found value 356.85.

[1043] 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 x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinic acid (490 mg, 82%) as a brown solid. LCMS (ESI): C 13 H 11 [M+H] of BrFN2O3 + m / z calculated value 341.00, found value 340.85.

[1044] Intermediate 3

[1045] 3-((6-Fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid

[1046]

[1047] Reagents and conditions: a) 6-fluoro-2-methylpyridin-3-ol, DIEA, DMF, 100°C; b) LiOH, THF, H2O, room temperature

[1048] Step 1: 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-methyl carboxylate: A mixture of 3-chloro-5-methyl-6-(trifluoromethyl)pyridazine-4-methyl carboxylate (500mg, 1.97mmol), 6-fluoro-2-methylpyridin-3-ol (375mg, 2.95mmol), DIEA (381mg, 2.95mmol) in DMF (10mL) was heated at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The resulting solution was diluted with water (80mL) and extracted with EtOAc (50mLx 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 14 H 12 [M+H] of F4N3O3 + m / z calculated value 346.08, found value 345.90.

[1049] 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 1N 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 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): C 13 H 10 [M+H] of F4N3O3 + m / z calculated value 332.07, found value 331.90.

[1050] Intermediate 4

[1051] 5-Bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid

[1052]

[1053] 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, room temperature

[1054] Step 1: 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinic acid methyl ester: To a solution of 2-chloro-4-methyl-5-nitronicotinic acid methyl ester (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 hour. After the reaction was completed, the mixture was concentrated under vacuum and directly purified by silica gel flash column chromatography (PE / EtOAc=4 / 1 to 3 / 1) to provide 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinic acid methyl ester (2.5 g, 56%) as a light yellow solid. LCMS (ESI): C 16 H 14 [M+H] of N3O6 + m / z calculated value 344.09, found value 343.95.

[1055] Step 2: 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: To a solution of 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinic acid methyl ester (2.5 g, 7.3 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 ° C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (2 g, 87.7%) as a yellow solid. LCMS (ESI): C 16 H 16 [M+H] of N3O4+ m / z calculated value 314.11, found value 313.90.

[1056] Step 3: 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: To a solution of 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 x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1) to give 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (500 mg, 41%) as a yellow solid. LCMS (ESI): C 16 H 14 [M+H] of BrN2O4 + m / z calculated value 377.01, found value 377.05.

[1057] Step 4: 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid: To a solution of 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid methyl ester (500 mg, 1.33 mmol) in THF (3 mL), MeOH (3 mL) and H2O (3 mL) was added LiOH.H2O (336 mg, 8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was 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 x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid (420 mg, 61%) as a brown solid. LCMS (ESI): C 15 H 12 [M+H] of BrN2O4 + m / z calculated value 363.00, found value 362.85.

[1058] Intermediate 5

[1059] 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid

[1060]

[1061] Reagents and conditions: a) TsOH·H2O, acetonitrile, 0°C, NaNO2, KI, 0°C; b) methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 100°C; c) LiOH·H2O, THF / MeOH / H2O, room temperature

[1062] Step 1: Methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate: To a solution of TsOH·H2O (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 NaNO2 (167 mg, 2.43 mmol) and potassium iodide (503 mg, 3.03 mmol) in H2O (1.8 mL) with stirring in air at 0°C. The reaction mixture was stirred at room temperature for 2.5 hours. After that, 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1 to 1 / 1) to provide methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate (400 mg, 74.01%) as a colorless oil. LCMS (ESI): C 16 H 14 [M+H] of IN2O4 + m / z calcd. 425.00, found 424.95.

[1063] Step 2: 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate: Under an atmosphere of N2, to a stirred solution of 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate (380 mg, 0.89 mmol) and copper (I) iodide (341 mg, 1.79 mmol) in DMF (40 mL) was added dropwise 2,2-difluoro-2-(fluorosulfonyl)acetate (860 mg, 4.48 mmol) at room temperature. 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 x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (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): C 17 H 14 [M+H] of F3N2O4 + m / z calculated value 367.09, found value 367.05.

[1064] 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 x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to provide 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (140 mg, 48.53%) as a white solid. LCMS (ESI): C 16 H 12 [M+H] of F3N2O4 + m / z calculated value 353.08, found value 353.05.

[1065] Intermediate 6

[1066] 4-(4-Cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid

[1067]

[1068] Reagents and conditions: a) 4-hydroxy-3-methylbenzonitrile, NaH, DMF; b) NaI, ACN, AcCl; c) [Ph2SCF3][OTf] - , Cu, DMF, 60°C; d) LiOH, THF, H2O, room temperature

[1069] Step 1: NaH (348 mg, 14.49 mmol, 60%) is added to a solution of 4-hydroxy-3-methylbenzonitrile (1.28 g, 9.66 mmol) in DMF (10 mL). The mixture is 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 is stirred at room temperature for 1 hour. The mixture is quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue is purified by silica gel flash column chromatography (PE / EtOAc=2 / 1) to provide methyl 6-chloro-4-(4-cyano-2-methylphenoxy)pyridazine-3-carboxylate (1850 mg, 63.05%) as a yellow solid. LCMS (ESI): C 14 H 11 [M+H] of ClN3O3 + m / z calcd. 304.05, found 304.10.

[1070] Step 2: At 0 ° C, to a solution of 6-chloro-4-(4-cyano-2-methylphenoxy)pyridazine-3-carboxylic acid methyl ester (1000 mg, 3.29 mmol) in MeCN (10 mL) was added NaI (4939 mg, 32.92 mmol). Then, at 0 ° C, a solution of AcCl (568 mg, 7.24 mmol) in MeCN (5 mL) was added dropwise to the mixture. The mixture was stirred at room temperature for 6 hours. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=2 / 1) to obtain 4-(4-cyano-2-methylphenoxy)-6-iodopyridazine-3-carboxylic acid methyl ester (800 mg, 61.48%) as a yellow solid. LCMS (ESI): C 14 H 11 [M+H] of IN3O3 + m / z calculated value 395.98, found value 396.15.

[1071] Step 3: To a solution of methyl 4-(4-cyano-2-methylphenoxy)-6-iodopyridazine-3-carboxylate (800 mg, 2.02 mmol) and Cu (386 mg, 6.07 mmol) in DMF (10 mL) was added [Ph2SCF3][OTf] - To the 4- (4-cyano-2-methylphenoxy) -6- (trifluoromethyl) pyridazine -3- carboxylic acid methyl ester (420 mg, 55.36%) of 4- (4-cyano-2-methylphenoxy) -6- (trifluoromethyl) pyridazine -3- carboxylic acid methyl ester (1473 mg, 3.64 mmol). The mixture was heated at 60 ° C for 16 hours. The mixture was then filtered through celite. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 5 / 1) to provide 4- (4-cyano-2-methylphenoxy) -6- (trifluoromethyl) pyridazine -3- carboxylic acid methyl ester (420 mg, 55.36%) as a yellow solid. LCMS (ESI): C 15 H 11 [M+H] of F3N3O3 + m / z calculated value 338.07, found value 338.15.

[1072] Step 4: at room temperature, to a solution of methyl 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylate (420 mg, 1.25 mmol) in THF / H2O (1 / 1, 10 mL) was added LiOH (522 mg, 12.5 mmol). 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 x3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid (380 mg, 94.40% yield) as a yellow solid. LCMS (ESI): C 14 [M+H] of H9F3N3O3 + m / z calculated value 324.06, found value 324.10.

[1073] Intermediate 7

[1074] 4-(3,4-Difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid

[1075]

[1076] Reagents and conditions: a) NaOH, H2O2, H2O, 0°C; b) 4,6-dichloropyridazine-3-carboxylic acid methyl ester, NaH, DMF; c) NaI, ACN, AcCl; d) 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, DMF, 120°C; e) LiOH, THF, H2O, room temperature

[1077] Step 1: At 0 ° C, to a solution of (3,4-difluoro-2-methoxyphenyl)boronic acid (2 g, 10.64 mmol) in THF (20 mL) was added NaOH (850 mg, 21.28 mmol), H2O (5 mL) and H2O2 (1 mL, 30%). The mixture was stirred at room temperature for 1 hour. The mixture 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 sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 3 / 1) to provide 3,4-difluoro-2-methoxyphenol (1.2 g, 70.59%) as a yellow solid. 1 H NMR (400MHz, CDCl3-d6, ppm) δ6.74-6.61 (m, 2H), 4.81 (s, 1H), 3.85 (s, 3H).

[1078] Step 2: NaH (0.36 g, 8.99 mmol, 60%) is added to a solution of 3,4-difluoro-2-methoxyphenol (1.2 g, 7.49 mmol) in DMF (10 mL). The mixture is stirred at room temperature for 30 minutes. The mixture is then added dropwise to a solution of 4,6-dichloropyridazine-3-carboxylic acid methyl ester (1.54 g, 7.49 mmol) in DMF (5 mL). The mixture is stirred at room temperature for 1 hour. LCMS shows that the reaction is complete. The mixture is quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue is purified by flash column chromatography on silica gel (eluting with PE / EtOAc=2 / 1) to provide 6-chloro-4-(3,4-difluoro-2-methoxyphenoxy)pyridazine-3-carboxylic acid methyl ester (0.8 g, 32.3%) as a yellow solid. LCMS (ESI): C 13 H 10 [M+H] of ClF2N2O4 + m / z calculated value 331.03, found value 330.90.

[1079] Step 3: At 0 ° C, to a solution of 6-chloro-4-(3,4-difluoro-2-methoxyphenoxy)pyridazine-3-formic acid methyl ester (800 mg, 2.42 mmol) in MeCN (10 mL) was added NaI (3640 mg, 24.24 mmol). Then at 0 ° C, a solution of AcCl (415 mg, 5.32 mmol) in MeCN (5 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. LCMS shows that the reaction is complete. The mixture is quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (elution PE / EtOAc=2 / 1) to provide methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-iodopyridazine-3-carboxylate (800 mg, 78.43%) as a yellow solid. LCMS (ESI): C 13 H 10 [M+H] of F2IN2O4 + m / z calculated value 422.97, found value 422.85.

[1080] Step 4: To a solution of 4-(3,4-difluoro-2-methoxyphenoxy)-6-iodopyridazine-3-methyl carboxylate (800 mg, 1.89 mmol) and CuI (720 mg, 3.79 mmol) in DMF (10 mL) is added 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (2912 mg, 15.17 mmol). The mixture is heated at 120 ° C for 2 hours. LCMS shows that the reaction is complete. The mixture is then filtered through celite. The filtrate is diluted with water (30 mL) and extracted with EtOAc (30 mL x3). The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=5 / 1) to provide methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylate (360 mg, 52.17%) as a yellow solid. LCMS (ESI): C 14 H 10 [M+H] of F5N2O4 + m / z calculated value 365.06, found value 365.15.

[1081] Step 5: At 0 ° C, to a solution of methyl 4- (3,4-difluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-3-carboxylate (310 mg, 0.85 mmol) in THF / H2O (1 / 1, 8 mL) was added LiOH (204 mg, 8.52 mmol). The mixture was stirred at 0 ° C for 1 hour. After the reaction was complete, the mixture was concentrated to remove THF. The aqueous phase was adjusted to pH = 3-4 with 1N HCl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 4- (3,4-difluoro-2-methoxyphenoxy) -6- (trifluoromethyl) pyridazine-3-carboxylic acid (220 mg, 73.83%) as a yellow solid. LCMS (ESI): C 13 [M+H] of H8F5N2O4 + m / z calculated value 351.04, found value 350.90.

[1082] Intermediate 8

[1083] 3-Bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide

[1084]

[1085] Reagents and conditions: a) Et3N, DCM, room temperature

[1086] 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 that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1 to 5 / 1) to provide 3-bromo-N, N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (1.4 g, 83.33%) as a colorless oil. LCMS (ESI): C 24 H 26 The calculated value of [M+Na] m / z of BrNO6SNa is 560.06, and the experimental value is 560.05.

[1087] Intermediate 9

[1088] tert-Butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfanylidene)carbamate

[1089]

[1090] Reagents and conditions: a) Add acrylonitrile, TEA2, DCM; b) EtMgBr, Ti(Oi-Pr)4, Et2O, room temperature; c) TEA, Boc2O, DCM, 0°C to room temperature; d) PhI(OAc)2, AcONH4, EtOH, room temperature; e) DMAP, Boc2O, TEA, DCM, room temperature

[1091] Step 1: 3-((3-bromophenyl)thio)propionitrile: A mixture of 3-bromobenzenethiol (4 g, 0.021 mol), acrylonitrile (1.24 g, 0.023 mol) and TEA (6.44 g, 0.063 mol) in DCM (40 mL) was stirred at room temperature for 3 hours. After the reaction was complete, the resulting solution was diluted with water (25 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=20 / 1) to provide 3-((3-bromophenyl)thio)propionitrile (4.6 g, 84.91% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3, ppm) δ7.55 (t, J=1.8Hz, 1H), 7.42 (dd, J=7.9, 0.8Hz, 1H), 7.36 -7.31(m,1H),7.21(t,J=7.9Hz,1H),3.15(t,J=7.2Hz,2H),2.62(t,J=7.3Hz,2H).

[1092] Step 2: 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine: To a mixture of 3-((3-bromophenyl)thio)propionitrile (3 g, 0.012 mol) in Et2O (100 mL) was added titanium tetraisopropoxide (3.88 g, 0.014 mol) and ethylmagnesium bromide (5 mL, 1 mol / L in THF) at room temperature under N2. 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 phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to provide 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine (1.9 g, 50.81% yield) as a colorless oil. LCMS (ESI): C 13 H 21 [M+H] of BrNS +m / z calcd. 302.06, found 302.0.

[1093] 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 Boc O (4.12 g, 0.019 mol) in DCM (50 mL) was added TEA (1.91 g, 0.019 mol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with DCM (25 mL x 3). The combined organic phases were washed with brine, dried over Na SO and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=10 / 1) to afford tert-butyl (1-((3-bromophenyl)thio)-3-ethylpentan-3-yl)carbamate (1.5 g, 58.73% yield) as a colorless oil. LCMS (ESI): C 18 H 29 [M+H] of BrNO2 + m / z calcd. 402.11, found 402.1.

[1094] Step 4: tert-butyl (1-(3-bromophenylaminosulfonyl)-3-ethyl amyl-3-yl) carbamate: by tert-butyl (1-((3-bromophenyl) thio)-3-ethyl amyl-3-yl) carbamate (1.5g, 3.7mmol), PhI(OAc) (3.58g, 0.011mol) and NH4OAc (0.57g, 0.0074mol) in EtOH (30mL) mixture at room temperature stirred 6 hours.After completion of the reaction, gained solution is diluted with water (50mL) and extracted with EtOAc (25mL x 3).By the organic phase washed with salt water, through Na2SO4 drying, concentrate under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=1 / 1) to afford tert-butyl (1-(3-bromophenylaminosulfonyl)-3-ethylpentan-3-yl)carbamate (0.95 g, 59.46% yield) as a white solid. LCMS (ESI): C 18 H 30 [M+H] of BrN2O3S + m / z calcd. 435.12, found 435.0.

[1095] Step 5: tert-Butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfanylidene)carbamate: A mixture of tert-butyl (1-(3-bromophenylaminosulfonyl)-3-ethylpentan-3-yl)carbamate (0.95 g, 2.19 mmol), Boc O (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 completion of the reaction, the resulting solution was diluted with water (100 mL) and extracted with DCM (25 mL x 3). The combined organic phases were washed with brine, dried over Na SO and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (100% DCM) to provide 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): C 23 H 38 [M+H] of BrN2O5S + m / z calculated value 533.17, found value 533.1.

[1096] Intermediate 10

[1097] tert-Butyl ((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16-sulfanylidene)carbamate

[1098]

[1099] Reagents and conditions: a) t-BuOK, DMF, room temperature; b) PhI(OAc)2, NH4OAc, 50°C; c) DMAP, Boc2O, THF, 50°C; d) Fe, NH4Cl, EtOH / H2O, 70°C

[1100] Step 1.2-methyl-4-((3-nitrophenyl)thio)butan-2-ol: A mixture of 3-nitrobenzenethiol (600.00 mg, 3.87 mmol), 4-bromo-2-methylbutan-2-ol (775.07 mg, 4.64 mmol), t-BuOK (650.81 mg, 5.80 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to provide 2-methyl-4-((3-nitrophenyl)thio)butan-2-ol (800 mg, 77.17% yield) as a yellow oil. 1 HNMR(400MHz,DMSO-d6,ppm)δ8.08-7.94(m,2H),7.77-7.71(m,1H),7.60(t,J =8.0Hz,1H),4.42(s,1H),3.17-3.05(m,2H),1.75-1.62(m,2H),1.15(s,6H).

[1101] Step 2. (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16-thione: 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), NH4OAc (766.63 mg, 9.95 mol) in EtOH (20 mL) was stirred at 50° C. for 3 hours. After the reaction was complete, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (60 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EtOAc=2 / 1) to provide (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16-thione (640 mg, 63.80% yield) as a yellow oil. LCMS (ESI): C 11 H 17 [M+H] of N2O4S + m / z calcd. 273.09, found 273.0.

[1102] Step 3. tert-Butyl ((3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(3-nitrophenyl)(oxo)-16-thioylidene)carbamate: To a mixture of (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16-thione (500 mg, 1.84 mmol), (Boc)O (1.60 g, 0.0073 mol) in THF (10 mL) at 25° C. was added DMAP (560.79 mg, 4.59 mmol). The reaction mixture was stirred at 50° C. for 16 hours. After completion of the reaction, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined org...

Claims

1. A compound of formula (I): And pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from the group consisting of O, S or N; wherein one or more substitutions 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, cycloalkyloxy, haloalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N; B is a substituted or unsubstituted aryl or heteroaryl, wherein the substitution is selected from the group consisting of: a substituted or unsubstituted C1-C8 alkyl, a deuterated C1-C4 alkyl in which the alkyl chain may be fully or partially deuterated, a halo-C1-C4 alkyl in which the alkyl chain is fully or partially halogenated, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8alkoxy, haloalkoxy wherein the haloalkoxy chain may be fully or partially halogenated, or arylalkoxy; C is a substituted or unsubstituted aryl or heteroaryl, wherein 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 selected from the group consisting of: Formula (II): -C(=O)NH2 and -C(=O)NR'R"; in, m and n are independently 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 and X2 are both O, NH or NR'; or X1 is O, and X2 is NR3; wherein 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.

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

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

4. The compound according to claim 2, wherein the B ring comprising the N-oxide is selected from the group consisting of pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

5. The compound according to claim 1, wherein the compound is a compound of formula (III): in: 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, -C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6 membered cycloalkyl, any of which may have one or more substituents; X is H, halo, -CD3, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF3, -OCF3.

6. The compound according to claim 1, wherein the compound is a compound of formula (IV): in: Z is CR 10 , N or N + O - ;in R 10 It is H, halo, -CD3, C1-C8 alkyl, haloalkyl or alkoxy.

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

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

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

10. The compound according to claim 1, wherein A is Wherein Q1, Q2, Q3 and Q4 are independently selected from the group consisting of: 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 ring heterocyclyl or heteroaryl, saturated heterocyclyl or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl or O-cycloheteroalkyl.

11. The compound according to claim 1, wherein A is in, Q2 and Q4 are independently N or N + O - ; Q2 is N or N + O - ; Q4 is CR7; or Q2 is CR7, Q4 is N or N + O - ; R8 and R9 are independently selected from the group consisting of: H, -OH, halo, -CD3, substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR', NR'R", aryl, heteroaryl, -CF2CH3 and -CF2CF3; R7 is described in claim 10.

12. The compound according to claim 1, wherein A is in, Q3 and Q4 are independently N or N + O - ; Q3 is N or N + O - , and Q4 is CR7; or Q3 is CR7, Q4 is N or N + O - ; wherein R7, R8 and R9 are defined above.

13. The compound according to claim 1, wherein A is in, Q1 and Q4 are independently N or N + O - ; 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; wherein R7, R8 and R9 are defined above.

14. The compound according to claim 1, wherein A is wherein Q1 and Q2 are N; and wherein R8 and R9 are as defined above.

15. The compound according to claim 1, wherein A is wherein Q1 is CR7, Q2 is N; and R7, R8 and R9 are as defined above.

16. The compound according to claim 1, wherein A is in, Q1 is N; Q2 is CR7; R7, R8 and R9 are defined above.

17. The compound of claim 1, wherein R1 is H.

18. The compound according to claim 1, wherein R2 is: wherein m and n are independently 0 or 1; X1 is O, and X2 is NH, and R4 is alkyl.

19. The compound according to claim 1, wherein R2 is: wherein m and n are independently 0 or 1; X1 is O, and X2 is O, and R4 is NH2 or an alkyl group, such as methyl.

20. The compound of claim 1, wherein R2 is -S(=O)CH3.

21. The compound according to claim 5, wherein Q is N or CH; R5 is methyl or -OMe, and X is F or CN.

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

23. The compound according to claim 6, wherein R 10 It is H or F.

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

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

26. A compound according to any one of claims 11 to 16, wherein R7, R8 and R9 are independently selected from the group consisting of: H, methyl, fluorine, chlorine, bromine, CF3, cyclopropyl, difluorophenyl and dimethylpyrazole.

27. The compound of claim 1, wherein R2 does not comprise -C(=O)NH2 or -C(=O)NR'R".

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

29. The compound according to claim 1, wherein R2 is formula (II): in, m and n are independently 0 or 1; and X1 and X2 are not both O, NH or NR'.

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

31. A compound of formula (I): and pharmaceutically acceptable salts, hydrates and solvates thereof, in, A is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one or more groups selected from the group consisting of: halo-C1-C4 alkyl, wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, wherein the alkyl chain may be fully or partially deuterated, C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8alkoxy, haloalkoxy wherein the haloalkoxy chain may be fully or partially halogenated, or arylalkoxy; B is aryl or heteroaryl, wherein the aryl may have 1 to 4 substituents and the heteroaryl may have 1 to 3 substituents independently selected from halogen, C1-C8 alkyl, haloalkyl or alkoxy; R1, R2, R3 and R4 are independently selected from H, halogen, -OH, C1-C6-alkyl, C1-C6 fluoroalkyl wherein the fluoroalkyl chain may be fully or partially fluorinated, C3-C8 branched alkyl, C3-C8 branched fluoroalkyl wherein the branched fluoroalkyl chain may be fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N; R5 is H or C1-C3 alkyl; and R6-C(=O)NH2, -C(=O)NHR', -C(=O)NR'R", or formula (II): in: X1 and X2 are both O, NH or NR'; or X1 is O, and X2 is NH or NR'; R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

32. The compound according to claim 31, wherein the compound is a compound of formula (III): in, R1, R2, R3, R4, R5, R6 and B are described in claim 1; 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, hydroxy, halogen, -CD3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl or substituted or unsubstituted 3-6 membered cycloalkyl.

33. The compound according to claim 31, wherein B is: wherein R6 is as described above; Z is CR 10 , N or N + O - ; where R 10 It is H, halo, -CD3, C1-C8 alkyl, haloalkyl or alkoxy.

34. The compound according to claim 33, wherein R6 is in: X1 and X2 are both O, NH or NR'; or X1 is O, and X2 is NH or NR'; R7 is NH2, NHR', NR'R", C1-C3 alkyl, C3-C8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

35. The compound according to claim 33, wherein R6 is in: X1 is O, X2 is NH, and R7 is C1-C3 alkyl.

36. The compound of claim 31, wherein R6 does not include -C(=O)NH2, -C(=O)NHR' or -C(=O)NR'R".

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

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

39. The compound of claim 31, wherein R1 is H, -CH3 or F.

40. The compound of claim 31, wherein R2 is chloro, -CF3, H, 2-pyrazoline or 1-methyl-1H-pyrazol-4-yl.

41. The compound of claim 31, wherein R3 is H, -CF3 or F.

42. The compound of claim 31, wherein R4 is H.

43. The compound of claim 32, wherein R8 is H, -CH3 or -O-CH3.

44. The compound of claim 32, wherein R7 is -CH3.

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

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

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

48. The compound according to claim 33, wherein Z is CR 10 , and R 10 It is H or F.

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

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

51. A compound of formula (I): And pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one or more groups selected from the group consisting of: halo-C1-C4 alkyl, wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C1-C8 alkyl, deuterated C1-C4 alkyl, wherein the alkyl chain may be fully or partially deuterated, C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8alkoxy, haloalkoxy wherein the haloalkoxy chain may be fully or partially halogenated, and arylalkoxy; R1, R2, R3 and R4 are independently selected from hydrogen, -OH, halogen, C1-C6-alkyl, C1-C6-fluoroalkyl in which the fluoroalkyl chain may be fully or partially fluorinated, C3-C8 branched alkyl, C3-C8 branched fluoroalkyl in which the branched fluoroalkyl chain may be fully or partially fluorinated, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, NR'R", 3-8-membered cycloalkyl, 3-8-membered cycloalkenyl, 3-6-membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N, a saturated or unsaturated 5-membered or more ring or an aryl ring optionally containing 1 or more heteroatoms independently selected from O, S and N, wherein each 5-membered or more ring is unsubstituted or substituted with one to five substituents selected from the following: 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 5-6 ring members, wherein the heterocyclyl includes 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 或 -(CR b R c ) n -(NHCH2CH2NH) n R a ; Where R a is H, C1-C6-alkyl, C2-C8 branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4-7 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 independently selected from H, F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is H, C1-C6 alkyl or F; R c and R b Optionally forming a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R7 is NH2, -NHR', C1-C3 alkyl, substituted or unsubstituted C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclyl.

52. The compound according to claim 51, wherein the compound is a compound of formula (II): wherein Ring B and the groups R1, R2, R3, R4, R5, R6 and R7 are as described in claim 1; R8 is H, hydroxy, halogen, -C-D, C-C-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH-cycloalkyl, -CH(CH)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl 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.

53. The compound according to claim 51, wherein the compound is a compound of formula (III): in, R1, R2, R3, R4, R5, R6 and R7 are described in claim 1; R8, W, T, Q and X are described in claim 52; Z is CH, N, CF or N + -O - .

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

55. The compound of claim 52, wherein R8 is -CH3.

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

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

58. The compound of claim 51, wherein R1 is H or F.

59. The compound of claim 51, wherein R2 is H, chloro or CF3.

60. The compound of claim 51, wherein R3 is H or CF3.

61. The compound of claim 51, wherein R4 is H.

62. The compound of claim 51, wherein R5 is H.

63. The compound of claim 51, wherein R7 is methyl.

64. A compound according to claim 51, wherein 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.

65. The compound of claim 52, wherein R9 is H.

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

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

68. A compound of formula (I): And pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from the group consisting of O, S or N; wherein one or more substitutions 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, cycloalkyloxy, haloalkoxy, nitro, cyano, -C(R')(R")-cycloalkyl, C(R')(R")-aryl, -NR'R", substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N; B is a substituted or unsubstituted aryl or heteroaryl, wherein the substitution is selected from the group consisting of: a substituted or unsubstituted C1-C8 alkyl, a deuterated C1-C4 alkyl in which the alkyl chain may be fully or partially deuterated, a halo-C1-C4 alkyl in which the alkyl chain is fully or partially halogenated, a C3-C 10 Cycloalkyl, halogen, cyano, nitro, C1-C8alkoxy, haloalkoxy wherein the haloalkoxy chain may be fully or partially halogenated, and arylalkoxy; C is a substituted or unsubstituted aryl or heteroaryl, wherein 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 selected from the group consisting of: -(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 ; Where R a is H, C1-C8-alkyl or branched alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 4-7 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, 3-7 membered carbocyclic group or heterocyclic group having one or more heteroatoms; Rc is H, C1-C6 alkyl or F; R c and R b together optionally form a 3-6 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.

69. The compound according to claim 68, wherein the compound is a compound of formula (II): in: A, C, R1, R2 and R3 are 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, -C3, C1-C6-alkyl, branched alkyl, haloalkyl wherein the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkyloxy, haloalkoxy, cyano, -CH2-cycloalkyl, -CH(CH3)-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl 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; A, C, R1, R2 and R3 are as described in claim 68.

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

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

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

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

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

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

76. The compound according to claim 68, wherein A is Wherein Q1, Q2, Q3 and Q4 are independently selected from the group consisting of: N, N + O - or CR6; wherein at least two of Q1, Q2, Q3 and Q4 are CR6; 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.

77. The compound according to claim 68, wherein A is in, Q2 and Q4 are independently N or N + O - ; Q2 is N or N + O - , and Q4 is CR6; or Q2 is CR6, and Q4 is N or N + O - ; R7 and R8 are independently selected from the group consisting of: H, -OH, halo, -CD3, substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH2, NHR', NR'R", aryl, heteroaryl, -CF2CH3 and -CF2CF3; R6 is described in claim 76.

78. The compound according to claim 69, wherein A is in, Q3 and Q4 are N; Q3 is N, N + O - ; Q4 is CR6; or Q3 is CR6, Q4 is N or N + O - ; wherein R7 and R8 are defined in claim 77.

79. The compound according to claim 67, wherein A is in Q1 and Q4 are independently N or N + O - ; Q1 is N or N + O - , and Q4 is CR6; or Q1 is CR6, and Q4 is N or N + O - ; wherein R6, R7 and R8 are defined in claim 77.

80. The compound of claim 68, wherein A is: wherein Q1 and Q2 are N; wherein R7 and R8 are as defined in claim 77.

81. The compound according to claim 68, wherein A is wherein Q1 is CR6, and Q2 is N; R6 is as defined in claim 76, and R7 and R8 are as defined in claim 77 above.

82. The compound according to claim 68, wherein A is in, Q1 is N; Q2 is CR6; R6 is as defined in claim 9, and R7 and R8 are as defined in claim 77 above.

83. The compound of claim 68, wherein R1 is H.

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

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

86. The compound of claim 69, wherein R4 is methyl.

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

88. The compound of claim 68, wherein R3 is methyl.

89. A compound according to claim 68, wherein 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.

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

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

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

Images