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] This application generally relates to sodium channel blocking compounds, their derivatives, and the use of such compounds as pharmacological agents. Background Technology

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

[0003] This invention provides a treatment for sodium channels with voltage gating. V 1.8 compounds with abnormal activity associated with symptoms such as pain, itching, and cough.

[0004] On the one hand, the present invention provides formula (I): (I), Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O) NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be completely or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-14 membered heteroaryl, any of which may have one or more of the substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-14 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B is selected from the group consisting of: monocyclic, bicyclic or spirocyclic cycloalkyl rings and monocyclic, bicyclic or spirocyclic heteroalkyl rings, wherein the heteroalkyl ring contains 1 to 4 heteroatoms independently selected from N, O and S, and wherein one or more carbons of the cycloalkyl ring or the heteroalkyl ring may optionally be substituted by one or more halogens or one or more haloalkyl groups. C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II):

[0005] in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; Rb Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0, 1, 2, 3, 4, 5, 6.

[0006] On the one hand, the present invention provides a compound of formula (I): (I), Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O)-NH-alkyl; NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be completely or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-7 membered heteroaryl, any of which may have one or more of the substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-6 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B can choose from the following groups: A monocyclic, bicyclic, or spirocyclic heteroalkyl ring, wherein the heteroalkyl ring contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of the heteroalkyl ring are optionally substituted with a haloalkyl group, wherein the haloalkyl chain may be completely or partially halogenated; and Monocyclic, bicyclic, or spirocyclic cycloalkyl rings; One or more carbons of the cycloalkyl or heteroalkyl ring are optionally substituted by one or more substituents independently selected from the group consisting of halogens, alkyl groups, cycloalkyl groups and haloalkyl groups, wherein the haloalkyl chain may be completely or partially halogenated. C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II):

[0007] in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R cIt is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0, 1, 2, 3, 4, 5, 6.

[0008] On the one hand, the present invention provides a compound of formula (I): (I), Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O)-NH-alkyl; NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be completely or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-7 membered heteroaryl, any of which may have one or more of the substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-6 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B can choose from the following groups: A monocyclic, bicyclic, or spirocyclic heteroalkyl ring, wherein the heteroalkyl ring contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of the heteroalkyl ring are optionally substituted with a haloalkyl group, wherein the haloalkyl chain may be completely or partially halogenated; and Monocyclic, bicyclic, or spirocyclic cycloalkyl rings; One or more carbons of the cycloalkyl or heteroalkyl ring are optionally substituted by one or more substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl and haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II):

[0009] in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; Rc It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0, 1, 2, 3, 4, 5, 6.

[0010] In some embodiments, in the compound of formula (I), R1 is selected from H and C1-C3 alkyl groups.

[0011] In some embodiments, R1 is H in the compound of formula (I).

[0012] In some embodiments, R2 is H in the compound of formula (I).

[0013] In some embodiments, R2 is not H.

[0014] In some embodiments, in the compound of formula (I), R2 is selected from H or formula (II): (II) in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3; and R3 and R4 are defined above.

[0015] In some embodiments, in the compound of formula (I), R2 is:

[0016] in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3; R3 and R4 are defined above.

[0017] In some embodiments, in the compound of formula (I), R2 is selected from H or formula (II): (II) in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3. R3 and R4 are defined above.

[0018] In some embodiments, in the compound of formula (I), R2 is

[0019] in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3. R3 and R4 are defined above.

[0020] In some embodiments, R2 is represented by equation (II) (described above), where X1 is not 0 and / or X2 is not 0.

[0021] In some embodiments, R2 is represented by formula (II) (described above), where X1 is not NH or NR' and X2 is not NH or NR'.

[0022] In some embodiments, X1 is O and X2 is NH in formula (II).

[0023] In some embodiments, X1 and X2 are 0 in equation (II).

[0024] In some embodiments, in formula (II), X1 is O and X2 is NH.

[0025] In various embodiments, in the compound of formula (I), R2 is selected from the group consisting of: H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino and -S(=O)R'.

[0026] In some embodiments, in the compound of formula (I), R2 is selected from the group consisting of: H, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0027] In some embodiments, in the compound of formula (I), R2 is selected from the group consisting of: H, , , , , , , , , , , , , , , , , , , , , , , , and .

[0028] In some embodiments, in the compound of formula (I), R2 is: .

[0029] In some embodiments, in the compound of formula (I), R2 is: Or its stereoisomers.

[0030] In some embodiments, in the compound of formula (I), A is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted 5- or 6-membered heteroaryl group having one or more heteroatoms; wherein the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom being in the form of an N-oxide, wherein A is optionally a pyridyl N-oxide, a pyrazinyl N-oxide, a pyrimidinyl N-oxide, or a pyridazinyl N-oxide.

[0031] In some embodiments, in the compound of formula (I), if ring A is a heteroaryl group, it contains one or more nitrogen atoms in the ring. In some embodiments, ring A contains one nitrogen atom. In some embodiments, such nitrogen atom 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, pyrimidinyl N-oxide, and pyridazinyl N-oxide. In some embodiments, ring A may include additional substituents.

[0032] In some embodiments, in the compound of formula (I), ring A is an optionally substituted aryl group.

[0033] In some embodiments, in the compound of formula (I), ring A is an optionally substituted heteroaryl group having a heteroatom.

[0034] In some embodiments, in the compound of formula (I), ring A is an optionally substituted heteroaryl group having two heteroatoms.

[0035] In some embodiments, in the compound of formula (I), ring A is at least substituted with trifluoromethyl.

[0036] In some embodiments, in the compound of formula (I), trifluoromethyl is the only substituent on ring A.

[0037] In some embodiments, in the compound of formula (I), ring A is at least substituted with cyclopropylmethyl.

[0038] In some embodiments, in the compound of formula (I), A is represented by the following formula:

[0039] Each of Q1, Q2, Q3, and Q4 is independently N, NO, or CR5; Wherein R5 is H; hydroxyl; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be completely or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be completely or partially halogenated; alkoxy; cycloalkoxy; haloalkoxy; nitro; cyano; -CH2-cycloalkyl; -CF2CH3; -CF2CF3; CH2CF2; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-heteroaryl; -CF2-heterocyclic; -CH(-CH3)-aryl; C( =O)-alkyl; -C(=O)cycloalkyl; -C(=O)-NH-alkyl; -C(=O)NH2; -C(=O)NHR'; -C(=O)NR'R''; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; NR'R''; -NHSO2R'; -NHC(=O)-alkyl; -NH(C=O)NR'R''; trifluoromethyl; cyclopropylmethyl; methylsulfonyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N.

[0040] In some embodiments, in the compound of formula (I), ring A is a pentagonal (5) or more saturated or partially unsaturated heterocycle having one or two independently substituted heteroatoms selected from N, O or S.

[0041] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0042] in: Q2 and Q4 are N and NO, respectively; Q2 is N or NO; Q4 is CR5; Q2 is CR5; Q4 is N or NO. R6 is H; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be completely or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be completely or partially halogenated; alkoxy; cycloalkyl; heterocyclic; NH2; NHR'; NR'R''; NHC(=O)R'; NHSO2R; -C(=O)R'; -C(=O)NHR'; -C(=O)NR'R''; -O-R'; -OC(=O)-R'; aryl; heteroaryl; -CF2CH3; -CF2CF3; R7 is H; hydroxyl; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be completely or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be completely or partially halogenated; alkoxy; cycloalkoxy; haloalkoxy; nitro; cyano; -CH2-cycloalkyl; -CF2CH3; -CF2CF3; CH2CF2; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-heteroaryl; -CF2-heterocyclic; -CH(-CH3)-aryl; C(= O)-alkyl; -C(=O)cycloalkyl; -C(=O)-NH-alkyl; -C(=O)NH2; -C(=O)NHR'; -C(=O)NR'R''; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; NR'R''; -NHSO2R'; -NHC(=O)-alkyl; -NH(C=O)NR'R''; trifluoromethyl; cyclopropylmethyl; methanesulfonyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N; Among them, no more than two of Q1, Q2, Q3 and Q4 are N or NO.

[0043] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0044] in: Q3 and Q4 are N; where Q3 is N or NO; Q4 is CR5; or where Q3 is CR5 and Q4 is N or NO; R5 is defined above; and R6 and R7 are defined above.

[0045] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0046] Where Q1 and Q4 are N and NO; Q1 is N and NO; Q4 is CR5; Q1 is CR5 and Q4 is N and NO; or Q1 and Q4 are CR5; and R6 and R7 are defined above.

[0047] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0048] in: Q1 and Q2 are N; and R6 and R7 are defined above.

[0049] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0050] in: Q1 is CR5, and Q2 is N; R6 and R7 are defined above.

[0051] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0052] Where Q1 is N; and Q2 is CR5; and R6 and R7 are defined above.

[0053] In some embodiments, in compounds of formula (I), the heteroaryl or aryl ring A is selected from the group consisting of:

[0054] In some embodiments, in compounds of formula (I), the heteroaryl or aryl ring A is selected from the group consisting of: .

[0055] In some embodiments, in the compound of formula (I), ring B is selected from the group consisting of: pyrrolidine, azacyclobutane, piperidine, piperazine, azacycloheptane, azacyclooctane, morpholine, thiomorpholine, oxazacycloheptane, isoindoline, dihydroisoquinoline, octahydroisoindoline, azabicyclo[2.2.1]heptane, azabicyclo[3.11]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.0]heptane, etc. The compounds are: cyclo[3.2.1]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxazaspiro[3.5]nonane, oxazaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine, hexahydrofuran[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.1.13,8]undecane.

[0056] In some embodiments, in the compound of formula (I), ring B is a spirocycloalkyl ring. In some embodiments, the spirocycloalkyl ring may be selected from spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, and spiro[6.3]decane, and may be attached at any position of the spirocycloalkyl ring in an open valence. In some embodiments, the spirocycloalkyl ring may be substituted with a halogen. In some preferred embodiments, the halogen substituted on the spirocycloalkyl ring is fluorine. In some embodiments, the spirocycloalkyl ring may be substituted with a haloalkyl ring. In some preferred embodiments, the haloalkyl ring substituted on the spirocycloalkyl ring is trifluoromethyl. In some embodiments, the spirocyclic heteroalkyl group is selected from the group consisting of: spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, and spiro[6.3]decane, and may be attached to the spiro group at any position in an open valence. In some embodiments, the spirocyclic heteroalkyl group contains at least one and at most four heteroatoms selected from N, O, or S. In some embodiments, the spirocyclic heteroalkyl group may be substituted with a halogen. In some preferred embodiments, the halogen substituted on the spirocyclic heteroalkyl group is fluorine. In some embodiments, the spirocyclic heteroalkyl group may be substituted with a haloalkyl group. In some preferred embodiments, the haloalkyl substituted on the spirocyclic heteroalkyl group is trifluoromethyl.

[0057] In some embodiments, the compound of formula (I) is further described as of formula (III): (III) Among them: B, C, R1 and R2 are defined above, and R6 and R7 are defined above.

[0058] In some embodiments, the compound of formula (I) is further described as of formula (IV): (IV) Wherein: B, C, R1 and R2 are defined above, and R5, R6 and R7 are defined above.

[0059] In some embodiments, the compound of formula (I) is further described as of formula (V): (V), Wherein: B, C, R1 and R2 are defined above, and R5, R6 and R7 are defined above.

[0060] In some embodiments, the compound of formula (I) is further described as of formula (VI): (VI) Among them: B, C, R1 and R2 are defined above, and R6 and R7 are defined above.

[0061] In some embodiments, the compound of formula (I) is further described as of formula (VII): (VII) Among them: B, C, R1 and R2 are defined above, and R6 and R7 are defined above.

[0062] In some embodiments, the compound of formula (I) is further described as formula (VIII): (VIII) Among them: B, C, R1 and R2 are defined above, and each R5 is defined independently above.

[0063] In some embodiments, the substituted or unsubstituted B is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0064] In some embodiments, in compounds of formula (I), the substituted or unsubstituted C is selected from the group consisting of: , , , , , , , , , , and .

[0065] In various embodiments, in the compound of formula (I), ring C is optionally fused with at least one ring selected from the group consisting of: optionally saturated carbocyclic groups containing 5-6 ring members or optionally saturated heterocyclic groups containing 5-6 ring members and 1-4 optionally charged heteroatoms.

[0066] In some embodiments, in the compound of formula (I), the ring C is a substituted or unsubstituted phenyl.

[0067] In some embodiments, in the compound of formula (I), the ring C is a substituted or unsubstituted pyridinyl group.

[0068] In some embodiments, in the compound of formula (I), the one or more substitutions on ring A are selected from the group consisting of: halogen, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6 alkyl, aryl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 heteroaryl and any combination thereof, wherein the heterocycloalkyl and the heteroaryl contain one or more heteroatoms selected from the group consisting of: N, O or S.

[0069] In some embodiments, in the compound of formula (I), the one or more substitutions on the A ring are selected from the group consisting of: methyl, trifluoromethyl, chlorine, fluorine, bromine, C1-C6 alkyl, phenyl, cycloalkyl, methylpyrazole, fused 1,4-dioxane and methylcyano.

[0070] In some embodiments, the one or more substitutions on ring A are selected from the group consisting of: -CH3, -CD3, -CF3, -Cl, -Br, -F, -CH2-CH2-CH=CH2, phenyl, -CH2-CN, -C(=O)-NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And any combination thereof.

[0071] In some embodiments, in compounds of formula (I), the substitutions on the A ring are selected from the group consisting of H, halogens, alkyl groups, and haloalkyl groups.

[0072] In some embodiments, in compounds of formula (I), these substitutions on the A ring are selected from the group consisting of methyl and -CF3.

[0073] In some embodiments, in compounds of formula (I), these substitutions on the A ring are selected from the group consisting of H and -CF3.

[0074] In some embodiments, in the compound of formula (I), A is a 6-membered aryl or heteroaryl ring.

[0075] In some embodiments, A is phenyl in the compound of formula (I).

[0076] In some embodiments, A in the compound of formula (I) is pyridine.

[0077] In some embodiments, in compounds of formula (I), the C ring is a 6-membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring.

[0078] In some embodiments, in the compound of formula (I), the C ring is phenyl.

[0079] In some embodiments, in the compound of formula (I), the C ring is pyridine.

[0080] In some embodiments, in the compound of formula (I), the C ring is piperidine.

[0081] In some embodiments, in the compound of formula (I), the C ring is pyrrolidine.

[0082] In some embodiments, in the compound of formula (I), R2 is:

[0083] in: X1 is O, and X2 is NR', and R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R' is H. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is C3-C4 cycloalkyl.

[0084] In some embodiments, in the compound of formula (I), R2 is:

[0085] in: X1 is O, and X2 is O, and R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R' is H. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is C3-C4 cycloalkyl.

[0086] In some embodiments, in compounds of formula (I), ring B is a 4-8 membered substituted or unsubstituted cycloalkyl or heteroalkyl group, wherein the heteroatom in the heteroalkyl group is selected from the group consisting of N or O. In some embodiments, the substitution on ring B is selected from the group consisting of one or more of the following: halogen; C1-C4 alkyl; oxyalkyl; alkoxyalkyl; substituted or unsubstituted C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl forms a spirocyclic ring with ring B; and partially or fully halogenated C1-C4 alkyl. In some embodiments, the halogen is fluorine. In some embodiments, the halogen is chlorine. In some embodiments, the C1-C4 alkyl group is methyl. In some embodiments, the C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, these substitutions are selected from the group consisting of -OCH3 and -CH2-O-CH3.

[0087] In some embodiments, ring C contains additional substitutions, wherein these substitutions are selected from the group consisting of H, halogens, and alkyl groups. In some embodiments, the halogen substitution in ring C is F.

[0088] In some embodiments, R1 is H.

[0089] In some embodiments, the compounds of the present invention do not include the compounds provided in WO 2023 / 150201, which is incorporated herein by reference in its entirety. In some embodiments, the compounds of the present invention do not include Examples 1-257.

[0090] Therefore, in some embodiments, the present invention provides compounds of formula (I), provided that the compounds of the present invention do not include Examples 1-257.

[0091] In some respects, the present invention provides compounds selected from the group consisting of:

[0092] In some respects, the present invention provides compounds selected from the group consisting of:

[0093] In some respects, the present invention provides compounds selected from the group consisting of:

[0094] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0095] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0096] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0097] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0098] In some embodiments, the compound of the present invention is selected from the group consisting of compounds listed in Tables 1A-1F: Table 1A.

[0099] Table 1B:

[0100] Table 1C:

[0101] Table 1D:

[0102] Table 1E:

[0103] Table 1F:

[0104] In some embodiments, the compound of the present invention is selected from the group consisting of compounds in Table 1G-1NN: Table 1G:

[0105] Table 1H:

[0106] Table 1J:

[0107] Table 1K:

[0108] Table 1L:

[0109] Table 1M:

[0110] Table 1N:

[0111] Table 1P:

[0112] Table 1Q:

[0113] Table 1R:

[0114] Table 1S:

[0115] Table 1T:

[0116] Table 1U:

[0117] Table 1V:

[0118] Table 1X:

[0119] Table 1Y:

[0120] Table 1Z:

[0121] Table 1AA:

[0122] Table 1BB:

[0123] Table 1CC:

[0124] Table 1DD:

[0125] Table 1EE:

[0126] Table 1FF:

[0127] Table 1GG:

[0128] Table 1HH:

[0129] Table 1JJ:

[0130] Table 1KK:

[0131] Table 1LL:

[0132] Table 1MM:

[0133] Table 1NN:

[0134] On the other hand, the present invention provides a voltage-gated sodium channel Na VInhibitors of 1.8. Inhibitors may have defined chemical structures, such as those of any of the compounds described above.

[0135] On the other hand, the present invention provides a method for treating the symptoms of a subject by providing the subject with the compounds of the present invention, such as any of the compounds described above.

[0136] This condition may be associated with abnormal activity of voltage-gated sodium channels.This condition may present with abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain from major trauma / injury, airway hyperresponsiveness, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopic dermatitis, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burns, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot's neurogenic osteoarthropathy, chemotherapy-induced stomatitis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic pruritus, chronic lower 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 other symptoms. External onset, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic osteophyte formation, intervertebral disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epilepsy, erythromelalgia, Fabry disease, facet joint syndrome, back surgery failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, pruritus, childhood Idiopathic arthritis, mastocytosis, myelodysplastic syndrome, migraine, multiple sclerosis, musculoskeletal injury, myofascial and orofacial pain, post-ischemic neurodegeneration, neurofibromatosis type II, neuropathic ophthalmopathy, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, congenital thyroid hypertrophy, 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, post-mastectomy 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 gangrenosa, peripheral neuropathy caused by radiotherapy, Raynaud's disease, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, vertebral displacement, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorder syndrome, tension headache, trigeminal neuralgia, vascular leg ulcers, vulvar pain or whiplash-related symptoms.On the other hand, the present invention provides a method for preparing a drug using any of the compounds of the present invention, such as those described above.

[0137] On the other hand, the present invention provides a product comprising the compounds of the present invention, such as any of the compounds described above, for treating a subject's condition, such as any of the conditions described above. Detailed Implementation

[0138] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. The definitions provided below are intended to supplement and illustrate, and not exclude, definitions that will be obvious to one of ordinary skill in the art upon reading this disclosure.

[0139] Unless otherwise stated, the portions described below are optionally substituted, meaning they may be substituted at one or more positions. As used herein, the terms substituted (whether preceded by the term "optionally") and substituent refer to the ability to replace one or more functional groups on a molecule with another one or more functional groups, provided that the valences of all atoms remain 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 may be the same or different at each position. Substituents may also be further substituted (e.g., an aryl substituent may have another substituent distant from it, such as another aryl group further substituted at one or more positions).

[0140] When the term "independently chosen" is used, the substituents referred to (e.g., R groups such as R1, R2, etc., or variables such as "m" and "n") can be the same or different. For example, both R1 and R2 can be substituted alkyl groups, or R1 can be hydrogen and R2 can be a substituted alkyl group, etc.

[0141] The terms "a / an" or "a(n)" as used herein with respect to a group of substituents mean at least one. For example, when a compound is substituted with "a" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Furthermore, in cases where the compound is partially substituted with R substituents, the group may be referred to as "R-substituted." In cases where the compound is partially R-substituted, the compound is partially substituted with at least one R substituent, and each R substituent is optionally different.

[0142] Unless otherwise stated herein, the named "R" or group will generally have a structure recognized in the art as corresponding to the group having that name. For illustrative purposes, some representative "R" groups described above are defined as follows.

[0143] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, where a group can be substituted by one or more of a plurality of substituents, such substitution is chosen to conform to the principles of chemical bonding and to obtain compounds that are not inherently unstable and / or, as known to those skilled in the art, may be unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions). For example, heterocyclic alkyl or heteroaryl groups are linked to the remainder of the molecule via cyclic heteroatoms according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0144] Unless otherwise explicitly defined, “substituent group” as used herein includes functional groups selected from one or more of the following portions as defined herein.

[0145] As used herein, the term hydrocarbon means any chemical group comprising hydrogen and carbon. Hydrocarbons can be substituted or unsubstituted. As those skilled in the art will know, all valences must be satisfied when any substitution occurs. Hydrocarbons can 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.

[0146] Unless otherwise stated, the term "alkyl" on its own or as part of another substituent means a straight-chain (i.e., unbranched) or branched, acyclic or cyclic saturated hydrocarbon group or a combination thereof, and may include divalent and polyvalent groups having a specified number of carbon atoms (e.g., C1-C1). 10 This refers to one to ten carbon atoms, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms. In specific embodiments, the term "alkyl" refers to C1-20 (including the terminal value), including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms, a straight-chain (i.e., "straight-chain"), branched, or cyclic saturated hydrocarbon group derived from a hydrocarbon moiety containing one to twenty carbon atoms by removing a single hydrogen atom.

[0147] 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 their homologs and isomers.

[0148] "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is linked to a linear alkyl chain. "Lower alkyl group" refers to an alkyl group having 1 to approximately 8 carbon atoms (i.e., C1-8 alkyl), such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. "Higher alkyl group" refers to an alkyl group having approximately 10 to approximately 20 carbon atoms, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.

[0149] Alkyl groups may optionally be substituted with one or more alkyl substituents, which may be the same as or different from those substituents (“substituted alkyl”). The term “alkyl substituent” includes, but is not limited to, alkyl, substituted alkyl, halogenated, arylamino, acyl, hydroxyl, aryloxy, alkoxy, alkylthio, arylthio, arylalkoxy, arylalkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. One or more oxygen atoms, sulfur atoms, or substituted or unsubstituted nitrogen atoms may optionally be inserted along the alkyl chain, wherein the nitrogen substituent is hydrogen, a lower alkyl group (also referred to herein as “alkylaminoalkyl”), or an aryl group.

[0150] Therefore, the term "substituted alkyl" includes alkyl groups in which one or more atoms or functional groups of an alkyl group are substituted by another atom or functional group, as defined herein, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate ester, cyano and mercapto substituted alkyl groups.

[0151] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term means a stable straight or branched chain having 1 to 20 carbon atoms or heteroatoms, or a cyclic hydrocarbon group having 3 to 15 carbon atoms or heteroatoms, wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroatoms O, N, P, and S, as well as Si, may be placed in any internal position of the heteroalkyl group or at the position where 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. At most two or three heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0152] As described above and as used herein, heteroalkyl groups include those groups that are attached to the rest of the molecule by a heteroatom, such as -C(O)NR', ​​-NR'R'', -OR', -SR, -S(O)R and / or -S(O2)R'.

[0153] “Cycloalkyl” refers to a saturated monocyclic or polycyclic system with about 3 to about 15 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Cycloalkyl groups may also optionally be substituted with alkyl substituents, oxo groups, and / or alkylene groups as defined herein. One or more oxygen atoms, sulfur atoms, or substituted or unsubstituted nitrogen atoms may optionally be inserted along the cyclic alkyl chain, wherein the nitrogen substituent is hydrogen, an unsubstituted alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc.

[0154] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group as defined above, which is connected to the parent molecule via an alkylene moiety, such as a C1-20 alkylene moiety, as also defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0155] The term "carbocyclic group" refers to a monocyclic or polycyclic system with about 3 to about 15 ring members, all of which are carbon atoms. Unless otherwise stated, a carbocyclic group can be saturated, partially saturated (i.e., having one or more double or triple bonds), or aromatic.

[0156] The term "heterocyclic group" refers to a monocyclic or polycyclic system of about 3 to about 15 ring members, wherein at least one ring member is a heteroatom, such as N, O, or S. Unless otherwise stated, heterocyclic groups 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-oxetanebutyl, 2-oxetanepentenyl, aziranebutyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyrinyl, thio-tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, 1,3-oxazinyl, 1,3-thiazinyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolyl, pyrazolyl, tetrazolyl, imidazolyl, isothiazolyl, triazolyl, azirbicyclo-octyl, diazirbicyclo-octyl, and all alkyl, alkoxy, haloalkyl, and haloalkoxy substituted derivatives of any of the above groups.

[0157] The terms "cyclohexaalkyl" and "heterocyclic alkyl" refer to saturated ring systems comprising one or more heteroatoms, such as 3- to 10-membered cycloalkyl ring systems. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S). Examples of heterocyclic alkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 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, etc.

[0158] Cycloalkyl rings may optionally be fused or otherwise connected to other cycloalkyl rings and / or non-aromatic hydrocarbon rings. Heterocycles include heterocycles having one to three heteroatoms such as oxygen, sulfur, and nitrogen, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatomium may optionally be quaternized. Examples include, but are not limited to, bicyclic or tricyclic groups comprising fused six-membered rings having one to three heteroatoms independently selected from oxygen, sulfur, 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) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatomium may optionally be quaternized, and (iv) any of the above heterocycles may be fused to aryl or heteroaryl rings. Representative cyclic heteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolidinyl, imidazolinyl, imidazolinyl, pyrazolyl, piperidinyl, piperazinyl, indololinyl, quininecycloyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrofuranyl, etc.

[0159] Unsaturated hydrocarbons, carbocyclic or heterocyclic groups have one or more double or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers.

[0160] As used herein, the term "alkenyl" refers to a C2-C group derived from a carbon-carbon double bond by removing a single hydrogen molecule. 20 (Including terminal values), monovalent groups of straight-chain or branched hydrocarbon moieties. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0161] 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, cyclohepttrienyl, and cyclooctenyl.

[0162] As used in this article, "alkynyl" refers to a straight-chain or branched C2-C group containing at least one carbon-carbon triple bond. 20 The monovalent group of a hydrocarbon. Examples of "alkynyl" include ethynyl, 2-propynyl (propynyl), l-propynyl, pentyynyl, hexynyl, and heptynyl.

[0163] The term "alkylene" itself, or part of another substituent, refers to a straight-chain or branched divalent aliphatic hydrocarbon group derived from an alkyl group having 1 to about 20 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Alkylenes can be straight-chain, branched, or cyclic. Alkylenes can also be optionally unsaturated and / or substituted with one or more "alkyl 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 alkylenes include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (CH2)3; cyclohexylene (-C6H) 10 -), -CH=CH-CH=CH-, -CH=CH-CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)qN(R)-(CH2)r-, where each of q and r is independently an integer from 0 to about 20, for example 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 a lower alkyl group; methylenedioxy (-O-CH2-O-); and ethylenedioxy (-O-(CH2)2-O-).

[0164] The term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, those exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy any or both of the chain ends (e.g., alkylene oxo, alkylene dioxo, alkylene amino, alkylene diamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0165] The term "spirocyclic" refers to a polycyclic compound in which two rings share a single atom (e.g., carbon) as the only common member of the two rings. Therefore, "spirocyclic alkyl" refers to a cycloalkyl compound having two rings sharing a single carbon atom, and "spiroheterocyclic alkyl" or "spiroheterocyclic alkyl" refers to a cycloheteroalkyl compound having two rings sharing a single carbon atom or other atom (e.g., nitrogen).

[0166] Unless otherwise stated, the term "aryl" means an aromatic hydrocarbon substituent that can be a single ring or multiple rings fused together or covalently linked (such as one to three rings).

[0167] The term "heteroaryl" refers to and contains one to four heteroatoms selected from N, O, and S (in the case of multiple rings, in each individual ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group can be linked to the rest of the molecule via a carbon atom or a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrole, 2-pyrrole, 3-pyrrole, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-... -Thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and 6-quinolinyl. The substituents in each of the aryl and heteroaryl ring systems indicated above are selected from the group of acceptable substituents described below. The terms "aryl" and "heteroaryl" refer to the divalent forms of aryl and heteroaryl rings, respectively.

[0168] When a heteroalkyl, heterocycloalkyl, or heteroaryl group includes a specific number of members (e.g., "3 to 7 members"), the term "member" refers to a carbon atom or a heteroatom.

[0169] Each term in the foregoing is intended to include both substituted and unsubstituted forms of the indicated group. In some cases, these groups are explicitly defined as substituted, such as "substituted aryl". Optional substituents are provided below.

[0170] The substituents may be one or more groups selected from, but not limited to, the following groups: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R'', -OC(O)R, -C(O)R, -CO2R, -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R, -NR''C(O)OR', -NR-C(NR'R'')=NR''', -S(O)R, -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, CF3, fluorinated C1-C4 alkyl groups, and -NO2, in the range of zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R'', R''', and R'''' can each independently refer to hydrogen, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (e.g., an aryl substituted with 1-3 halogens), a substituted or unsubstituted alkyl, an alkoxy or thioalkoxy, or an aralkyl. 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-C 10 aryl, heterocyclic, heteroaryl, amino, cyano, nitro, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl(C6-C 10Aryl, -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, the "alkoxy" group is an alkyl group that is connected to the rest of the molecule by a divalent oxygen.

[0171] When the compounds of this disclosure include more than one R group, each R group is selected independently, for example, as if each R', R'', R''', and R'''' group were selected independently when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, 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, those skilled in the art will understand that the term "alkyl" is intended to include groups comprising a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0172] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula -TC(O)-(CRR'). q The ring is -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A-(CH2)rB-, where 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.

[0173] One of the individual bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -(CRR')s-X'-(C''R''')d-, where s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R'' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0174] As used herein, the term "acyl" refers to an organic acid group in which the -OH group of the carboxyl group is replaced by another substituent and has the general formula RC(=O)-, where R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined herein. Therefore, the term "acyl" specifically includes aryl acyl groups, such as 2-(furan-2-yl)acetyl)- and 2-phenylacetyl. 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.

[0175] The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group partially attached to the parent molecule via an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and may include C1-C 20 (Including end values), straight-chain, branched or cyclic saturated or unsaturated oxy-hydrocarbon chains, including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy, etc.

[0176] As used herein, the term "alkoxyalkyl" refers to alkyl-O-alkyl ethers, such as methoxyethyl or ethoxymethyl.

[0177] "Aryloxy group" refers to an aryl-O- group, wherein the aryl group, as previously described, includes substituted aryl groups. As used herein, the term "aryloxy group" may refer to phenoxy or hexoxy groups, as well as alkyl groups, substituted alkyl groups, halogenated or alkoxy-substituted phenoxy or hexoxy groups.

[0178] "Arylalkyl" means aryl-alkyl, wherein the aryl and alkyl groups are as previously described and include substituted aryl and substituted alkyl groups. Exemplary arylalkyl groups include benzyl, phenethyl, and naphthylmethyl.

[0179] "Arylalkoxy" refers to an aralkyl-O- group, wherein the aralkyl group is as previously described. An exemplary arylalkoxy is a benzyloxy, i.e., C6H5CH2-O-. Arylalkoxy may be optionally substituted.

[0180] "Alkoxycarbonyl" refers to an alkyl-OC (=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl.

[0181] "Aryloxycarbonyl" refers to an aryl-OC (=O)- group. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphthoxy-carbonyl.

[0182] "Arylalkoxycarbonyl" refers to an aralkyl-OC(=O)- group. An exemplary arylalkoxycarbonyl is a benzyloxycarbonyl.

[0183] "Carbamoyl" refers to the amide group of the formula -C(=O)NH2.

[0184] "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 an alkyl and / or substituted alkyl group as previously described. "Dialkylcarbamoyl" refers to an R'RN-C(=O)- group, wherein each of R and R' is independently an alkyl and / or substituted alkyl group as previously described.

[0185] As used herein, the term "carbonyldioxy" refers to the carbonate group of the formula -OC(=O)-OR.

[0186] "Acyloxy group" refers to an acyl-O- group, wherein the acyl group is as previously described.

[0187] The term "amino" refers to the -NH2 group and to a nitrogen-containing group known in the art that is derived from ammonia by the substitution 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.

[0188] As used herein, “aminoalkyl” refers to an amino group covalently bonded to an alkylene linking group. More specifically, as used herein, the terms alkylamino, dialkylamino, and trialkylamino refer to one, two, or three alkyl groups, respectively, that are partially bonded to the parent molecule via a nitrogen atom, as previously defined. The term alkylamino refers to a group having the structure -NHR', where R' is an alkyl group as previously defined; while the term dialkylamino refers to a group having the structure -NR'R'', where R' and R'' are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R''R''', where R', R'', and R''' are each independently selected from the group consisting of alkyl groups. Additionally, R', R'', and / or R''' together may optionally be -(CH2). k , where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidinyl, trimethylamino, and propylamine.

[0189] The 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.

[0190] The terms alkyl thioether and thioalkoxy refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups that are partially attached to the parent molecule via a sulfur atom. Examples of thioalkoxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, etc.

[0191] "Acylamino" refers to an acyl-NH- group, wherein the acyl group is as previously described. "Aromatic acylamino" refers to an aromatic acyl-NH- group, wherein the aromatic acyl group is as previously described.

[0192] The term "carbonyl" refers to a -C(=O)- group and may include aldehyde groups represented by the general formula RC(=O)H.

[0193] The term "carboxyl group" refers to the COOH group. This type of group is also referred to as the "carboxylic acid" part in this document.

[0194] The term "cyano" refers to the -CN group.

[0195] The terms “halogenated,” “halogenated,” and “halogen” refer to fluorine, chlorine, bromine, and iodine groups.

[0196] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Additionally, the term "haloalkyl" includes both 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.

[0197] The terms “halocycloalkyl” and “cyclohaloalkyl” refer to cycloalkyl groups having one or more halogens.

[0198] The term "hydroxyl group" refers to the -OH group.

[0199] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a -OH group.

[0200] The term "thiol" refers to the -SH group.

[0201] The term "oxo" refers to an oxygen atom that is double-bonded to a carbon atom or another element.

[0202] The term "nitro" refers to the -NO2 group.

[0203] The term "thiolated" refers to compounds previously described herein in which carbon or oxygen atoms are replaced by sulfur atoms.

[0204] The term "sulfate" refers to the -SO4 group.

[0205] As used herein, the terms thiohydroxyl or thiol refer to groups of the formula -SH.

[0206] More specifically, the term "sulfide" refers to a compound having a group of the formula -SR.

[0207] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R'.

[0208] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R.

[0209] The term urea group refers to the urea group of the formula -NH-CO-NH2.

[0210] Throughout the specification and claims, the given chemical formula or name shall cover all tautomers, homologues, optical and stereoisomers, as well as racemic mixtures in which such isomers and mixtures exist.

[0211] Some compounds disclosed herein may have asymmetric carbon atoms (optical or chiral centers) or double bonds; in absolute stereochemistry, they can be defined as enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomers in the form of amino acids and individual isomers (R)- or (S)- or D- or L-. The compounds disclosed herein do not include compounds known in the art that are too unstable to be synthesized and / or isolated. This 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 geometrically asymmetric centers, and unless otherwise specified, the compounds are expected to include both E and Z geometric isomers.

[0212] Unless otherwise stated, the structures described herein are intended to include all stereochemical forms of the structures; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are all within the scope of this disclosure.

[0213] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, and all such tautomeric forms of these compounds are within the scope of this 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 isomer to another.

[0214] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds having the inventive structure comprising hydrogen replaced by deuterium or tritium, or carbon replaced by carbon enriched by 13C or 14C, are within the scope of this disclosure.

[0215] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may use tritium (3H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling with radioactive isotopes. All isotopic variations of the compounds disclosed herein, whether radioactive or non-radioactive, are covered within the scope of this disclosure.

[0216] The compounds disclosed herein can exist in the form of salts, and specifically in pharmaceutically acceptable salt forms. This 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 containing amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Base addition salts, such as sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts, are also included. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid (pure or in a suitable inert solvent) or by ion exchange. Acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid; and those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids such as arginine salts and salts of organic acids such as glucuronic acid or galacturonic acid are also included. Certain specific compounds of this disclosure contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt.

[0217] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner.

[0218] The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0219] Some compounds of this disclosure may exist in both unsolvable and solvable forms, including hydrated forms. Generally, solvable forms are equivalent to unsolvable forms and are covered within the scope of this disclosure. Some compounds of this disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.

[0220] In addition to salt forms, this disclosure also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. Furthermore, prodrugs can be converted into the compounds of this disclosure in an in vitro environment by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of this disclosure.

[0221] The term "protecting group" refers to a chemical part of a compound that blocks some or all of its reactive parts and prevents such parts from participating in a chemical reaction until the protecting group is removed, such as those listed and described in TW Greene, PGM Wuts, *Protective Groups in Organic Synthesis*, 3rd ed., John Wiley & Sons (1999). When using different protecting groups, it may be advantageous for each (different) protecting group to be removed by different methods. Cleavage of protecting groups under entirely different reaction conditions allows for different removals of such protecting groups.

[0222] For example, protecting groups can be removed by acid, base, and hydrogenolysis. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect the carboxyl and hydroxyl reactive moieties in the presence of amino groups protected by Cbz groups that can be removed by hydrogenolysis and base-labile Fmoc groups. In the presence of amines terminated with acid-labile groups such as tert-butyl carbamate or with carbamates that are stable in both acids and bases but can be removed by hydrolysis, the carboxylic acid and hydroxyl reactive moieties can be terminated with base-labile groups (such as, but not limited to, methyl, ethyl, and acetyl).

[0223] The reactive moiety of carboxylic acids and hydroxyl groups can be capped with hydrolyzable protecting groups such as benzyl, while the amine group capable of forming hydrogen bonds with acids can be capped with base-unstable groups such as Fmoc. The reactive moiety of carboxylic acids can be capped with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while the coexisting amine group can be capped with fluorine-unstable silyl carbamate.

[0224] Allyl-terminated groups are useful in the presence of both acid- and base-protecting groups, as the former is stable and can subsequently be removed by metal or π-acid catalysts. For example, in the presence of acid-instantaneous tert-butyl carbamate or base-instantaneous amine acetate protecting groups, allyl-terminated carboxylic acids can be deprotected using a palladium(O)-catalyzed reaction. Another form of protecting group is a resin that can be linked to a compound or intermediate. As long as the residue is linked to the resin, the functional group is capped and does not react. Once released from the resin, the functional group becomes reactive.

[0225] Compounds: The present invention provides compounds for regulating (e.g., inhibiting) the activity of voltage-gated sodium channels.

[0226] On the one hand, the present invention provides formula (I): (I), Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O) NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be completely or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-14 membered heteroaryl, any of which may have one or more of the substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-14 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B is selected from the group consisting of: monocyclic, bicyclic or spirocyclic cycloalkyl rings and monocyclic, bicyclic or spirocyclic heteroalkyl rings, wherein the heteroalkyl ring contains 1 to 4 heteroatoms independently selected from N, O and S, and wherein one or more carbons of the cycloalkyl ring or the heteroalkyl ring may optionally be substituted by one or more halogens or one or more haloalkyl groups. C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II):

[0227] in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a-(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0, 1, 2, 3, 4, 5, 6.

[0228] On the one hand, the present invention provides a compound of formula (I): (I), Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O)-NH-alkyl; NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be completely or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-7 membered heteroaryl, any of which may have one or more of the substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-6 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B can choose from the following groups: A monocyclic, bicyclic, or spirocyclic heteroalkyl ring, wherein the heteroalkyl ring contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of the heteroalkyl ring are optionally substituted with a haloalkyl group, wherein the haloalkyl chain may be completely or partially halogenated; and Monocyclic, bicyclic, or spirocyclic cycloalkyl rings; One or more carbons of the cycloalkyl or heteroalkyl ring are optionally substituted by one or more substituents independently selected from the group consisting of halogens, alkyl groups, cycloalkyl groups and haloalkyl groups, wherein the haloalkyl chain may be completely or partially halogenated. C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II):

[0229] in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0, 1, 2, 3, 4, 5, 6.

[0230] On the one hand, the present invention provides a compound of formula (I): (I), Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O)-NH-alkyl; NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be completely or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-7 membered heteroaryl, any of which may have one or more of the substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-6 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B can choose from the following groups: A monocyclic, bicyclic, or spirocyclic heteroalkyl ring, wherein the heteroalkyl ring contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of the heteroalkyl ring are optionally substituted with a haloalkyl group, wherein the haloalkyl chain may be completely or partially halogenated; and Monocyclic, bicyclic, or spirocyclic cycloalkyl rings; One or more carbons of the cycloalkyl or heteroalkyl ring are optionally substituted by one or more substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl and haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II):

[0231] in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R aIt is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0, 1, 2, 3, 4, 5, 6.

[0232] In some embodiments, in the compound of formula (I), R1 is selected from H and C1-C3 alkyl groups.

[0233] In some embodiments, R1 is H in the compound of formula (I).

[0234] In some embodiments, R2 is H in the compound of formula (I).

[0235] In some embodiments, R2 is not H.

[0236] In some embodiments, in the compound of formula (I), R2 is selected from H or formula (II): (II) in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3; and R3 and R4 are defined above.

[0237] In some embodiments, in the compound of formula (I), R2 is:

[0238] in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3; R3 and R4 are defined above.

[0239] In some embodiments, in the compound of formula (I), R2 is selected from H or formula (II): (II) in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3. R3 and R4 are defined above.

[0240] In some embodiments, in the compound of formula (I), R2 is

[0241] in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3. R3 and R4 are defined above.

[0242] In some embodiments, R2 is represented by equation (II) (described above), where X1 is not 0 and / or X2 is not 0.

[0243] In some embodiments, R2 is represented by formula (II) (described above), where X1 is not NH or NR' and X2 is not NH or NR'.

[0244] In some embodiments, X1 is O and X2 is NH in formula (II).

[0245] In some embodiments, X1 and X2 are 0 in equation (II).

[0246] In some embodiments, in formula (II), X1 is O and X2 is NH.

[0247] In various embodiments, R2 is selected from the group consisting of: H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino and -S(=O)R'.

[0248] In some embodiments, in the compound of formula (I), R2 is selected from the group consisting of: H, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0249] In some embodiments, in the compound of formula (I), R2 is selected from the group consisting of: H, , , , , , , , , , , , , , , , , , , , , , , , and .

[0250] In some embodiments, in the compound of formula (I), R2 is: .

[0251] In some embodiments, in the compound of formula (I), R2 is: Or its stereoisomers.

[0252] In some embodiments, in the compound of formula (I), A is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted 5- or 6-membered heteroaryl group having one or more heteroatoms; wherein the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom being in the form of an N-oxide, wherein A is optionally a pyridyl N-oxide, a pyrazinyl N-oxide, a pyrimidinyl N-oxide, or a pyridazinyl N-oxide.

[0253] In some embodiments, in the compound of formula (I), if ring A is a heteroaryl group, it contains one or more nitrogen atoms in the ring. In some embodiments, ring A contains one nitrogen atom. In some embodiments, such nitrogen atom 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, pyrimidinyl N-oxide, and pyridazinyl N-oxide. In some embodiments, ring A may include additional substituents.

[0254] In some embodiments, in the compound of formula (I), ring A is an optionally substituted aryl group.

[0255] In some embodiments, in the compound of formula (I), ring A is an optionally substituted heteroaryl group having a heteroatom.

[0256] In some embodiments, in the compound of formula (I), ring A is an optionally substituted heteroaryl group having two heteroatoms.

[0257] In some embodiments, in the compound of formula (I), ring A is at least substituted with trifluoromethyl.

[0258] In some embodiments, in the compound of formula (I), trifluoromethyl is the only substituent on ring A.

[0259] In some embodiments, in the compound of formula (I), ring A is at least substituted with cyclopropylmethyl.

[0260] In some embodiments, in the compound of formula (I), A is represented by the following formula:

[0261] Each of Q1, Q2, Q3, and Q4 is independently N, NO, or CR5; Wherein R5 is H; hydroxyl; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be completely or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be completely or partially halogenated; alkoxy; cycloalkoxy; haloalkoxy; nitro; cyano; -CH2-cycloalkyl; -CF2CH3; -CF2CF3; CH2CF2; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-heteroaryl; -CF2-heterocyclic; -CH(-CH3)-aryl; C( =O)-alkyl; -C(=O)cycloalkyl; -C(=O)-NH-alkyl; -C(=O)NH2; -C(=O)NHR'; -C(=O)NR'R''; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; NR'R''; -NHSO2R'; -NHC(=O)-alkyl; -NH(C=O)NR'R''; trifluoromethyl; cyclopropylmethyl; methylsulfonyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N.

[0262] In some embodiments, in the compound of formula (I), ring A is a pentagonal (5) or more saturated or partially unsaturated heterocycle having one or two independently substituted heteroatoms selected from N, O or S.

[0263] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0264] in: Q2 and Q4 are N and NO, respectively; Q2 is N or NO; Q4 is CR5; Q2 is CR5; Q4 is N or NO. R6 is H; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be completely or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be completely or partially halogenated; alkoxy; cycloalkyl; heterocyclic; NH2; NHR'; NR'R''; NHC(=O)R'; NHSO2R; -C(=O)R'; -C(=O)NHR'; -C(=O)NR'R''; -O-R'; -OC(=O)-R'; aryl; heteroaryl; -CF2CH3; -CF2CF3; R7 is H; hydroxyl; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be completely or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be completely or partially halogenated; alkoxy; cycloalkoxy; haloalkoxy; nitro; cyano; -CH2-cycloalkyl; -CF2CH3; -CF2CF3; CH2CF2; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-heteroaryl; -CF2-heterocyclic; -CH(-CH3)-aryl; C(= O)-alkyl; -C(=O)cycloalkyl; -C(=O)-NH-alkyl; -C(=O)NH2; -C(=O)NHR'; -C(=O)NR'R''; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; NR'R''; -NHSO2R'; -NHC(=O)-alkyl; -NH(C=O)NR'R''; trifluoromethyl; cyclopropylmethyl; methanesulfonyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N; Among them, no more than two of Q1, Q2, Q3 and Q4 are N or NO.

[0265] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0266] in: Q3 and Q4 are N; where Q3 is N or NO; Q4 is CR5; or where Q3 is CR5 and Q4 is N or NO; R5 is defined above; and R6 and R7 are defined above.

[0267] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0268] Where Q1 and Q4 are N and NO; Q1 is N and NO; Q4 is CR5; Q1 is CR5 and Q4 is N and NO; or Q1 and Q4 are CR5; and R6 and R7 are defined above.

[0269] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0270] in: Q1 and Q2 are N; and R6 and R7 are defined above.

[0271] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0272] in: Q1 is CR5, and Q2 is N; R6 and R7 are defined above.

[0273] In some embodiments, in the compound of formula (I), ring A is represented by the following formula:

[0274] Where Q1 is N; and Q2 is CR5; and R6 and R7 are defined above.

[0275] In some embodiments, in compounds of formula (I), the heteroaryl or aryl ring A is selected from the group consisting of:

[0276] In some embodiments, in compounds of formula (I), the heteroaryl or aryl ring A is selected from the group consisting of: .

[0277] In some embodiments, in the compound of formula (I), ring B is selected from the group consisting of: pyrrolidine, azacyclobutane, piperidine, piperazine, azacycloheptane, azacyclooctane, morpholine, thiomorpholine, oxazacycloheptane, isoindoline, dihydroisoquinoline, octahydroisoindoline, azabicyclo[2.2.1]heptane, azabicyclo[3.11]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.0]heptane, etc. The compounds are: cyclo[3.2.1]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxazaspiro[3.5]nonane, oxazaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine, hexahydrofuran[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.1.13,8]undecane.

[0278] In some embodiments, in the compound of formula (I), ring B is a spirocycloalkyl ring. In some embodiments, the spirocycloalkyl ring may be selected from spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, and spiro[6.3]decane, and may be attached at any position of the spirocycloalkyl ring in an open valence. In some embodiments, the spirocycloalkyl ring may be substituted with a halogen. In some preferred embodiments, the halogen substituted on the spirocycloalkyl ring is fluorine. In some embodiments, the spirocycloalkyl ring may be substituted with a haloalkyl ring. In some preferred embodiments, the haloalkyl ring substituted on the spirocycloalkyl ring is trifluoromethyl. In some embodiments, the spirocyclic heteroalkyl group is selected from the group consisting of: spiro[4.2]heptane, spiro[4.3]octane, spiro[4.4]nonane, spiro[5.2]octane, spiro[5.3]nonane, spiro[5.4]decane, spiro[6.2]nonane, and spiro[6.3]decane, and may be attached to the spiro group at any position in an open valence. In some embodiments, the spirocyclic heteroalkyl group contains at least one and at most four heteroatoms selected from N, O, or S. In some embodiments, the spirocyclic heteroalkyl group may be substituted with a halogen. In some preferred embodiments, the halogen substituted on the spirocyclic heteroalkyl group is fluorine. In some embodiments, the spirocyclic heteroalkyl group may be substituted with a haloalkyl group. In some preferred embodiments, the haloalkyl substituted on the spirocyclic heteroalkyl group is trifluoromethyl.

[0279] In some embodiments, the compound of formula (I) is further described as of formula (III): (III) Among them: B, C, R1 and R2 are defined above, and R6 and R7 are defined above.

[0280] In some embodiments, the compound of formula (I) is further described as of formula (IV): (IV) Wherein: B, C, R1 and R2 are defined above, and R5, R6 and R7 are defined above.

[0281] In some embodiments, the compound of formula (I) is further described as of formula (V): (V), Wherein: B, C, R1 and R2 are defined above, and R5, R6 and R7 are defined above.

[0282] In some embodiments, the compound of formula (I) is further described as of formula (VI): (VI) Among them: B, C, R1 and R2 are defined above, and R6 and R7 are defined above.

[0283] In some embodiments, the compound of formula (I) is further described as of formula (VII): (VII) Among them: B, C, R1 and R2 are defined above, and R6 and R7 are defined above.

[0284] In some embodiments, the compound of formula (I) is further described as formula (VIII): (VIII) Among them: B, C, R1 and R2 are defined above, and each R5 is defined independently above.

[0285] In some embodiments, the substituted or unsubstituted B is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0286] In some embodiments, in compounds of formula (I), the substituted or unsubstituted C is selected from the group consisting of: , , , , , , , , , , and .

[0287] In various embodiments, in the compound of formula (I), ring C is optionally fused with at least one ring selected from the group consisting of: optionally saturated carbocyclic groups containing 5-6 ring members or optionally saturated heterocyclic groups containing 5-6 ring members and 1-4 optionally charged heteroatoms.

[0288] In some embodiments, in the compound of formula (I), the ring C is a substituted or unsubstituted phenyl.

[0289] In some embodiments, in the compound of formula (I), the ring C is a substituted or unsubstituted pyridinyl group.

[0290] In some embodiments, in the compound of formula (I), the one or more substitutions on ring A are selected from the group consisting of: halogen, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6 alkyl, aryl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 heteroaryl and any combination thereof, wherein the heterocycloalkyl and the heteroaryl contain one or more heteroatoms selected from the group consisting of: N, O or S.

[0291] In some embodiments, in the compound of formula (I), the one or more substitutions on the A ring are selected from the group consisting of: methyl, trifluoromethyl, chlorine, fluorine, bromine, C1-C6 alkyl, phenyl, cycloalkyl, methylpyrazole, fused 1,4-dioxane and methylcyano.

[0292] In some embodiments, the one or more substitutions on ring A are selected from the group consisting of: -CH3, -CD3, -CF3, -Cl, -Br, -F, -CH2-CH2-CH=CH2, phenyl, -CH2-CN, -C(=O)-NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And any combination thereof.

[0293] In some embodiments, in compounds of formula (I), the substitutions on the A ring are selected from the group consisting of H, halogens, alkyl groups, and haloalkyl groups.

[0294] In some embodiments, in compounds of formula (I), these substitutions on the A ring are selected from the group consisting of methyl and -CF3.

[0295] In some embodiments, in compounds of formula (I), these substitutions on the A ring are selected from the group consisting of H and -CF3.

[0296] In some embodiments, in the compound of formula (I), A is a 6-membered aryl or heteroaryl ring.

[0297] In some embodiments, A is phenyl in the compound of formula (I).

[0298] In some embodiments, A in the compound of formula (I) is pyridine.

[0299] In some embodiments, in compounds of formula (I), the C ring is a 6-membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring.

[0300] In some embodiments, in the compound of formula (I), the C ring is phenyl.

[0301] In some embodiments, in the compound of formula (I), the C ring is pyridine.

[0302] In some embodiments, in the compound of formula (I), the C ring is piperidine.

[0303] In some embodiments, in the compound of formula (I), the C ring is pyrrolidine.

[0304] In some embodiments, in the compound of formula (I), R2 is:

[0305] in: X1 is O, and X2 is NR', and R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R' is H. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is C3-C4 cycloalkyl.

[0306] In some embodiments, in the compound of formula (I), R2 is:

[0307] in: X1 is O, and X2 is O, and R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic. In some embodiments, R' is H. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is C3-C4 cycloalkyl.

[0308] In some embodiments, in compounds of formula (I), ring B is a 4-8 membered substituted or unsubstituted cycloalkyl or heteroalkyl group, wherein the heteroatom in the heteroalkyl group is selected from the group consisting of N or O. In some embodiments, the substitution on ring B is selected from the group consisting of one or more of the following: halogen; C1-C4 alkyl; oxyalkyl; alkoxyalkyl; substituted or unsubstituted C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl forms a spirocyclic ring with ring B; and partially or fully halogenated C1-C4 alkyl. In some embodiments, the halogen is fluorine. In some embodiments, the halogen is chlorine. In some embodiments, the C1-C4 alkyl group is methyl. In some embodiments, the C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, these substitutions are selected from the group consisting of -OCH3 and -CH2-O-CH3.

[0309] In some embodiments, ring C contains additional substitutions, wherein these substitutions are selected from the group consisting of H, halogens, and alkyl groups. In some embodiments, the halogen substitution in ring C is F.

[0310] In some embodiments, R1 is H.

[0311] In some embodiments, the compounds of the present invention do not include the compounds provided in WO 2023 / 150201, which is incorporated herein by reference in its entirety. In some embodiments, the compounds of the present invention do not include Examples 1-257.

[0312] Therefore, in some embodiments, the present invention provides compounds of formula (I), provided that the compounds of the present invention do not include Examples 1-257.

[0313] In some respects, the present invention provides compounds selected from the group consisting of:

[0314] In some respects, the present invention provides compounds selected from the group consisting of:

[0315] In some respects, the present invention provides compounds selected from the group consisting of:

[0316] In some embodiments, the compound of formula (I) is selected from the group consisting of:

[0317] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0318] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0319] In some embodiments, the compound of the present invention is selected from the group consisting of:

[0320] In some embodiments, the compound of the present invention is selected from the group consisting of compounds listed in Tables 1A-1F.

[0321] In some embodiments, the compound of the present invention is selected from the group consisting of compounds listed in Tables 1G-1NN.

[0322] Composition This invention provides pharmaceutical compositions containing the compounds of this invention, as described above. The pharmaceutical compositions may be in forms suitable for oral use, such as tablets, lozenges, tablets, instant solvents, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically palatable formulation. Tablets contain compounds mixed with non-toxic, pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binding agents such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated using known techniques to delay disintegration in the stomach and reduce absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated using techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for controlled release. The preparation and administration of the compounds are discussed in U.S. Patent No. 6,214,841 and U.S. Publication No. 2003 / 0232877, the contents of which are incorporated herein by reference.

[0323] Formulations for oral use may also be presented in the form of hard gelatin capsules, wherein the compound is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules, wherein the compound is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0324] Alternative oral formulations for controlling the gastrointestinal hydrolysis of compounds can be achieved using controlled-release formulations, wherein the compounds of the present invention are encapsulated in an enteric coating.

[0325] Aqueous suspensions may contain compounds mixed with excipients suitable for preparing aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of olefin oxides and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecetylacetyl cetyl alcohol), or condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate with esters derived from fatty acids and hexitols). Aqueous suspensions may also contain one or more preservatives (e.g., ethylparaben or n-propylparaben), one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0326] Oily suspensions can be formulated by suspending compounds in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (e.g., liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (as described above) and flavorings may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants such as ascorbic acid.

[0327] Dispersible powders or granules suitable for preparing aqueous suspensions by adding water provide compounds that can be mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents include, for example, sweeteners, flavoring agents, and coloring agents.

[0328] These pharmaceutical compositions of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid paraffin) or a mixture of these oils. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phospholipids, such as soybean, lecithin, and esters or metaesters derived from fatty acids, and hexitan anhydrides, such as sorbitan monooleate, and condensation products of said metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0329] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, and / or coloring agents. Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. Sterile injectable formulations can also be in the form of sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can be used in the preparation of injectable formulations.

[0330] In some embodiments, the formulation is a continuously released formulation. In some embodiments, the formulation is not a continuously released formulation. In some embodiments, the formulation is non-injectable. In some embodiments, the formulation does not contain D. 50 Particles with a (volume-weighted median diameter) of less than 10 micrometers. In some embodiments, the formulation does not contain polymer surface stabilizers. In some embodiments, the formulation is not an aqueous suspension.

[0331] The composition can be formulated for administration via a specific mechanism. The composition can be formulated for oral, intravenous, enteral, parenteral, skin, oral, topical, nasal, or pulmonary administration. The composition can be formulated for administration by injection or via an implantable medical device (e.g., a stent, or a drug-eluting stent or balloon equivalent).

[0332] The composition can be formulated into a single daily dose. The composition can also be formulated into multiple daily doses, such as two, three, four, five, six or more daily doses.

[0333] Methods of treating symptoms This invention provides a method for treating a subject's condition using the compounds of this invention. This method can be used to treat conditions related to voltage-gated sodium channels (Na+). V 1.8 Any symptoms associated with abnormalities (e.g., increased activity). Symptoms associated with increased activity of voltage-gated sodium channels and the use of inhibitors to treat such symptoms are known in the art and described in, for example, International Patent Publications Nos. WO 2020 / 014243, WO 2020 / 014246, and WO 2020 / 092187, the contents of each of which are incorporated herein by reference.

[0334] For example, and not limited to, symptoms may include abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain from major trauma / injury, airway hyperresponsiveness, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopic dermatitis, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burns, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot's neurogenic osteoarthropathy, chemotherapy-induced stomatitis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic pruritus, chronic lower back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, etc. Continued unilateral facial pain with additional episodes, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic osteophyte formation, 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, back surgery failure syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythromelalgia, irritable bowel syndrome, pruritus, juvenile idiopathic Arthritis, mastocytosis, myelodysplastic syndrome, migraine, multiple sclerosis, musculoskeletal injury, myofascial and orofacial pain, post-ischemic neurodegeneration, neurofibromatosis type II, neuropathic ophthalmopathy, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, congenital thyroid hypertrophy, 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, post-mastectomy 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 gangrenosa, peripheral neuropathy caused by radiotherapy, Raynaud's disease, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, vertebral displacement, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorder syndrome, tension headache, trigeminal neuralgia, vascular leg ulcers, vulvar pain or whiplash-related symptoms.

[0335] Methods of treating a subject's condition may include providing the subject with the composition of the present invention. The composition may be provided to the subject by any suitable route or manner of administration. For example, and not limited to, the composition may be administered via buccal, skin, enteral, intra-arterial, intramuscular, intraocular, intravenous, nasal, oral, parenteral, pulmonary, rectal, subcutaneous, topical, percutaneous, by injection, or through or on an implantable medical device.

[0336] The composition may be provided according to a dosing regimen. The dosing regimen may include one or more of the following: dosage, frequency of administration, and duration of administration.

[0337] Dosage can be delivered at any suitable interval. For example, and not limited to, it can be delivered once a day, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once a week, twice a week, three times a week, four times a week, or five times a week.

[0338] Dosage can be provided in a single dose, i.e., the dose can be provided as a single tablet, capsule, pill, etc. Alternatively, dosage can be provided in separate doses, i.e., the dose can be provided as multiple tablets, capsules, pills, etc.

[0339] Dosage can be administered for a specified period of time. For example, and not limited to, doses can be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, or longer.

[0340] Example Methods for preparing the compounds of the present invention, as well as intermediates used in their synthesis, are provided in the general synthetic scheme and specific synthetic procedures below. Unless otherwise stated, chemicals are purchased from standard commercial suppliers and used upon receipt. Otherwise, their preparation is readily available and known to those skilled in the art, or is referenced or described herein. Abbreviations are consistent with those in the ACS style guide. “Dried” glassware means oven / dryer dried. Unless otherwise stated, solvents are ACS grade.

[0341] Unless otherwise specified, all reactions were carried out under positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware with magnetic stirring. Unless otherwise specified, chemicals were purchased from standard commercial suppliers and used upon receipt. Yields were not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or ChemAxon.

[0342] The reaction was monitored by thin-layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE™. Purification was performed using Biotage Isolera One rapid chromatography or one of the preparative HPLC methods mentioned below.

[0343] Preparation method 1 Equipment: Shimadzu LCMS 2020 quality-oriented preparative HPLC system; Column: Gemini 5 µm 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 nm and 254 nm; Preparation method 2 Equipment: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5 μm 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 nm and 254 nm.

[0344] Preparation method 3 Equipment: Shimadzu LC-20AP preparative HPLC system; Column: Gemini 5 μm 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 nm and 254 nm.

[0345] Collect analytical LCMCs using one of the following methods: Method 1 Equipment: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 µm, 3.0 mm × 30 mm; Mobile phase: MeCN (0.05% HCOOH) - water (0.05% HCOOH); Gradient: MeCN from 5% to 95% in 1.4 min, held for 0.6 min, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 nm and 254 nm PDA.

[0346] Method 2 Equipment: Shimadzu LCMS 2020 mass spectrometer; XBridge BEH C 18 2.5 µm, 3.0 mm × 30 mm; Mobile phase: MeCN-water (0.1% NH4OH); Gradient: MeCN from 5% to 95% in 1.8 min, held for 0.7 min, total run time is 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 °C; Wavelength: 214 nm and 254 nm PDA.

[0347] Method 3 Equipment: Shimadzu LCMS 2020 mass spectrometer; Column: HALO C 18 2.7 µm, 3.0 mm × 30 mm; Mobile phase: MeCN (0.05% TFA) - water (0.05% TFA); Gradient: MeCN from 5% to 95% in 1.4 min, held for 0.6 min, total run time 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50 °C; Wavelength: 214 nm and 254 nm PDA.

[0348] The following methods were used to prepare the Shimadzu Nexera UC preparative SFC system (SFE-30A, LC-30AD). SF SFC chiral splitting is performed on SFC-30A. Method 1 Column: Daicel chiralpak-AS-H 5 μm 250 x 20 mm; Mobile phase: CO2 / MeOH [0.1% NH3 (7 M in MeOH)], the CO2 / MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[0349] Method 2 Column: Dassault Chiralpak-OJ-H 5 μm 250 * 20 mm; Mobile phase: CO2 / MeOH (0.1% HCOOH), the CO2 / MeOH ratio varies for different compounds; Oven temperature: 40℃; Flow rate: 38 mL / min.

[0350] Method 3 Column: Dassault Chiralpak-OD-H 5 μm 250 x 20 mm; Mobile phase: CO2 / MeOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[0351] Method 4 Column: Dassault Chiralpak-AD-H 5 μm 250 x 20 mm; Mobile phase: CO2 / i-PrOH, the ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[0352] Method 5 Column: Dassault Chiralpak-IC 5 μm 250 x 20 mm; Mobile phase: CO2 / EtOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[0353] Unless otherwise stated, 1 H NMR spectra were recorded on a Bruker AVANCE NEO 400 MHz digital NMR spectrometer. Chemical shifts δ are referenced to parts per million (ppm) relative to TMS and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet), dq (doublet of quadruplet), hep (septet), m (multiplicity), pent (quintet), td (doublet of triplet), qd (doublet of quadruplet), app. (apparent), and br. (broad). The coupling constant J is referenced to the nearest 0.1 Hz.

[0354] Abbreviations and acronyms When the following abbreviations are used in this article, they have the following meanings:

[0355] General synthesis scheme The following schemes and examples illustrate several methods for preparing the compounds of the present invention. The present invention further provides methods for preparing compounds of structural formula I as defined above. In some cases, the order of the preceding reaction schemes may be varied to promote the reaction or avoid unwanted reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

[0356] Option A

[0357] As shown in Scheme B, generally, the compounds of the present invention can be prepared by reacting a substituted cyclic amine (B) with a base such as DIEA or an inorganic base such as K2CO3 or Cs2CO3 to obtain intermediate A-2. Intermediate A-2 can be converted to the corresponding acid A-3 by treating A-2 with a base (such as aqueous EtOH or MeOH containing KOH). Intermediates A-4, A-5, and A-7 can be formed by treating A-3 and amine C under amide coupling conditions, or by activating appropriately functionalized formic acid A-3 in DCM with (COCl)2 or POCl3 and an amine C base such as DIEA or pyridine. Intermediate A-4 can be prepared directly by treating A-2 and amine C in the presence of Me3Al and toluene as solvents. Compounds of formula A-4 and A-5 are independently treated with ammonium carbonate and PIDA in methanol to deliver compounds of formula A-6. Compound A-6 can also be formed from intermediate A-7 by removing protecting groups such as Boc under acidic conditions.

[0358] Option B

[0359] As further explained in Scheme B, generally, the compounds of the present invention can be prepared by activating appropriately functionalized formic acid A-3 in dioxane with (COCl)2 or SOCl2, followed by the addition of NH4OH to obtain B-1. Then, using Xantphos-Pd-G2 mediated coupling conditions, intermediate B-1 can be combined with materials of various substituted Br compounds to deliver intermediates A-4 and A-7. Compound A-4 is treated with ammonium carbonate and PIDA in methanol to deliver compound A-6. Compound A-6 can also be formed from intermediate A-7 by removing protecting groups such as Boc under acidic conditions.

[0360] Option C

[0361] As further explained in Scheme C, generally, the compounds of the present invention can be prepared by derivatizing compounds of formula A-6 using R3 or R' substituents. Acylation of A-6 with an activated acid such as an acyl chloride and TEA, followed by removal of any protecting group, yields compounds of formula A-8 or A-9. When A-8 or A-9 is an N-acylated sulfonamide, the carbonyl group can be reduced to a methylene group (CH2) with borane to provide the corresponding N-alkyl derivative. Alternatively, the N-alkyl derivative can be obtained by alkylation with an alkyl halide (such as, but not limited to, iodomethane) and a base (such as diisopropylethylamine) or by Pd-mediated coupling of A-6 with an alkylboronic acid.

[0362] Specific synthesis Example 1 3-(azacyclohepta-1-yl)-N-(3-(S-methylaminopyromylatesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0363] Reagents and conditions: a) DIEA, aziridine, dioxane, 60℃; b) HI (57%), 40℃, 5 hours; c) CuI, TBAI, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, HMPA, 90℃; d) LiOH.H2O, MeOH:THF:H2O (1:2:1, v / v), room temperature; e) 3-(methylthioalkyl)aniline, HATU, DIEA, DMF, room temperature; f) (NH4)2CO3, (diacetoxyiodine)benzene, MeOH, room temperature.

[0364] Step 1.3 methyl 3-(azacyclohepta-1-yl)-6-chloropyridazine-4-carboxylate: At room temperature, azacycloheptadecane (1.26 g, 12.7 mmol) was added to a solution of methyl 3,6-dichloropyridazine-4-carboxylate (2.50 g, 12.1 mmol) in dioxane (20 mL), followed by the addition of DIEA (4.21 mL, 24.2 mmol). The mixture was stirred at room temperature for another 3 hours. At the end of this period, the solvent was evaporated and the crude product was subjected to chromatographic analysis of SiO2 using a gradient of 0–25% EtOAc / DCM to provide methyl 3-(azacyclohepta-1-yl)-6-chloropyridazine-4-carboxylate (2.86 g, 87.8%). 1H NMR (300 MHz, CDCl3)δ 7.40 (s, 1H), 4.03 (s, 1H), 3.92 (s, 3H), 3.58 – 3.48 (m, 5H), 1.86 (qd, J= 6.2, 5.4, 2.4 Hz, 5H), 1.60 – 1.47 (m, 5H) Step 2.3 3-(azacyclohepta-1-yl)-6-iodadiazine-4-carboxylate: A mixture of 3-(azacyclohepta-1-yl)-6-iodadiazine-4-carboxylate (3.26 g, 12.1 mmol) and HI (25 mL, 57% v / v) was stirred overnight at 50-55 °C. After cooling to room temperature, the separated solids were filtered and washed with water (2 x 20 mL). The filter cake was dissolved in EtOAc, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give 3-(azacyclohepta-1-yl)-6-iodadiazine-4-carboxylate (2.16 g, 49.52%). LCMS: m / z 362.1 [M+H] + Step 3.3 Methyl 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: Under nitrogen atmosphere, tetrabutylammonium iodide (1.10 g, 2.99 mmol) was added to a mixture of methyl 3-(azacyclohepta-1-yl)-6-iodopyridazine-4-carboxylate (2.16 g, 5.98 mmol) in HMPA (25 mL) and CuI (1.62 g, 8.49 mmol). The reaction mixture was degassed for 5 minutes. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (7.61 mL, 59.8 mmol) was slowly added to the mixture, and the mixture was stirred at 90 °C for 1.5 hours. The mixture was filtered and washed with EtOAc (3 x 100 mL). Water (50 mL) was added to the filtrate, and the filtrate was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and filtered. The filtrate was evaporated, and the residue was subjected to chromatographic analysis using SiO₂ eluted with a gradient of 0–20% EtOAc / hexane to give methyl 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (0.667 g, 37%). LCMS: m / z 304.1 [M+H] + Step 4: 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: LiOH·H2O was added to a solution of methyl 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid in 20 mL of a mixture of MeOH:THF:H2O (1:2:1, v / v). The mixture was then stirred at 50 °C for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature and the solvent was evaporated. The solid material was suspended in water (10 mL) and the pH was adjusted to 3 with 1 N HCl solution. The mixture was extracted with EtOAc (3 x 50 mL), the combined EtOAc was washed with brine (30 mL) and dried over Na2SO4, filtered, and the solvent was evaporated to give 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.489 g, 77%). 1 HNMR (300 MHz, DMSO- d 6) δ 7.86 (s, 1H), 3.63 (t, J = 5.6 Hz, 4H), 1.90 –1.71 (m, 4H), 1.60 – 1.36 (m, 4H) Step 5.3 -(azacyclohepta-1-yl)-N-[3-(methylthioalkyl)phenyl]-6-(trifluoromethyl)pyridazin-4-carboxamide: At room temperature, DIEA (0.151 mL, 0.864 mmol) was added to a mixture of 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-4-carboxylic acid (0.100 g, 0.346 mmol), 3-(methylthioalkyl)aniline (0.0529 g, 0.380 mmol), and HATU (0.263 g, 0.691 mmol) in DMF (3 mL), and stirring was continued for 6 hours. At the end of this time period, water (5 mL) was added and extracted with EtOAc (2 x 25 mL). The combined EtOAc layers were washed with 1 M LiCl (20 mL), followed by washing with brine (20 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was subjected to gradient chromatography with EtOAc / DCM over SiO2 to provide 3-(azacyclohepta-1-yl)-N-[3-(methylthioalkyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.128 g, 90%). LCMS: m / z 411.4 [M+H] + Step 6.3 -(azacyclohepten-1-yl)-N-{3-[imino(methyl)oxo-λ 6[3-Thioalkyl]phenyl}-6-(trifluoromethyl)pyridazin-4-carboxamide: At room temperature, (NH4)2CO3 (0.0386 g, 0.402 mmol) and PIDA (0.199 g, 0.616 mmol) were added to a solution of 3-(azacyclohepta-1-yl)-N-[3-(methylthioalkyl)phenyl]-6-(trifluoromethyl)pyridazin-4-carboxamide (0.110 g, 0.268 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness, and the crude product was subjected to chromatographic analysis of SiO2 with a gradient of 0-15 MeOH / DCM to provide 3-(azacyclohepta-1-yl)-N-{3-[imino(methyl)oxo-λ} 6 [Thioalkyl]phenyl}-6-(trifluoromethyl)pyridazine-4-carboxamide (15.4 g, 13%). 1 H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 8.22 – 8.02 (m, 2H), 7.81 (dt, J = 8.0, 1.2 Hz, 1H), 7.70 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 3.68 (t, J =5.7 Hz,4H), 3.12 (s, 3H), 1.85 (s, 4H), 1.54(bs, 4H). LC-MS: m / z 442.5[M+H] + Example 2 3-(azacyclohepta-1-yl)-5-methyl-N-(2-(S-methylaminopyridylsulfonyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0365] Reagents and conditions: a) 2-(methylthio)pyridine-4-amine, HATU, DIEA, DMF, room temperature; b) (NH4)2CO3, (diacetoxyiodine)benzene, MeOH, room temperature.

[0366] Step 1: 3-(azacyclohepta-1-yl)-N-[2-(methylthioalkyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazin-4-carboxamide: At room temperature, DIEA (0.151 ml, 0.864 mmol) was added to a mixture of 3-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-4-carboxylic acid (0.100 g, 0.346 mmol), HATU (0.263 g, 0.691 mmol), and 2-(methylthioalkyl)pyridin-4-amine (0.0485 g, 0.346 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 16 hours. At the end of this time period, water (5 mL) was added and extracted with EtOAc (2 x 25 mL). The EtOAc layers were combined and washed with 1 M LiCl (10 mL), followed by washing with brine, drying (Na2SO4), filtering, and evaporating the solvent to obtain the crude product. The crude product was subjected to chromatographic analysis with a gradient of 0-20% EtOAc / DCM using SiO2 to provide 3-(azacyclohepten-1-yl)-N-[2-(methylthioalkyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.030 g, 21%). LC-MS: m / z 412.2 [M+H] + Step 2: 3-(azacyclohepta-1-yl)-N-{2-[imino(methyl)oxo-λ 6 [2-(methylthioalkyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazin-4-carboxamide: At room temperature, (NH4)2CO3 (0.0911 g, 0.0948 mmol) and PIDA (0.0468 g, 0.145 mmol) were added to a solution of 3-(azacyclohepta-1-yl)-N-[2-(methylthioalkyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazin-4-carboxamide (0.026 g, 0.0632 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness, and the crude product was subjected to chromatographic analysis of SiO2 with a gradient of 0-15 MeOH / DCM to provide 3-(azacyclohepta-1-yl)-N-{2-[imino(methyl)oxo-λ 6 [Thioalkyl]pyridin-4-yl}-6-(trifluoromethyl)pyridazine-4-carboxamide (0.121 g, 43.3%). 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 8.65 (d, J = 5.5 Hz, 1H), 8.20 (dd, J = 5.5, 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 3.63 (q, J =4.8, 4.3 Hz, 4H), 3.26 (s, 3H), 1.85 (bs, 4H), 1.54 (bs, 4H). LC-MS: m / z 443.5[M+H] + Example 3 2-(4,4-Difluoroazacyclohepta-1-yl)-6-methyl-N-(2-aminosulfonylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

[0367] Reagents and conditions: a) 4,4-difluoroazacycloheptane hydrochloride, DIEA, dioxane, 80℃; b) trimethylboroxane, Pd(dppf)Cl2, K2CO3, dioxane / H2O, 100℃; c) NBS, DCM; d) Pd(dppf)Cl2, Et3N, EtOH, CO, 110℃; e) KOH, MeOH / H2O, 70℃; f) ((3-aminophenyl)(methyl)(oxo)-λ 6 -Thiodimethyl) tert-butyl carbamate, POCl3, pyridine; f) TFA, DCM Step 1: 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane: A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.6 mmol), 4,4-difluoroazacycloheptane hydrochloride (0.95 g, 5.5 mmol), and DIEA (1.19 g, 9.2 mmol) in dioxane (20 mL) was heated at 80 °C for 5 hours. The mixture was then concentrated, and the residue was purified by silica gel rapid column chromatography (PE / EtOAc = 5 / 1) to give 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane (900 mg, 62.5%). LCMS (ESI): C 12 H 13 ClF5N2[M + H] + The calculated value of m / z is 315.07, and the experimental value is 315.05.

[0368] Step 2: 4,4-Difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azacycloheptane: Under a nitrogen atmosphere, a mixture of 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane (850 mg, 2.7 mmol), trimethylboroxane (3.39 g, 27 mmol), Pd(dppf)Cl2 (98.73 mg, 0.135 mmol), and K2CO3 (1.12 g, 8.1 mmol) in dioxane / H2O (4 / 1, 25 mL) was heated at 100 °C for 16 hours. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 5 / 1) to give 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azacycloheptane (800 mg, 91%). LCMS (ESI): C 13 H 16 F5N2[M + H] + The calculated value of m / z is 295.13, and the experimental value is 295.00.

[0369] Step 3: 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane: NBS (508 mg, 2.85 mmol) was added to a solution of 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azacycloheptane (700 mg, 2.38 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and purified directly by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane (650 mg, 65.9%). LCMS (ESI): C 13 H 15 BrF5N2[M +H] + The calculated value of m / z is 373.04, and the experimental value is 372.95.

[0370] Step 4: Ethyl 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate: In a high-pressure reactor under a CO (30 atm) atmosphere, a mixture of 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptaane (600 mg, 1.6 mmol), Pd(dppf)Cl2 (58.5 mg, 0.08 mmol), and triethylamine (485 mg, 4.8 mmol) in EtOH (10 mL) was heated at 110 °C for 16 hours. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give ethyl 2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (550 mg, 94%). LCMS (ESI): C 16 H 20 F5N2O2[M + H] + The calculated value of m / z is 367.15, and the experimental value is 367.00.

[0371] Step 5: 2-(4,4-Difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid: At room temperature, KOH (0.84 g, 15 mmol) was added to a solution of ethyl 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (550 mg, 1.5 mmol) in MeOH / H₂O (1 / 1, 20 mL). The mixture was heated at 70 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (420 mg, 83%). LCMS (ESI): C 14 H 16 F5N2O2[M + H] + The calculated value of m / z is 339.12, and the experimental value is 338.95.

[0372] Step 6: ((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 62-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.35 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ)carbamate: At 0 °C, tert-butyl carbamate was reacted with 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.35 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ)carbamate. 6 3-(thionyl)carbamate tert-butyl ester Int-3 (115 mg, 0.43 mmol) was added dropwise to a solution of pyridine (6 mL) with POCl3 (0.3 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 2) to provide a yellow oil of ((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (57 mg, 24.4%). LCMS (ESI): C 26 H 32 F5N4O4S [M + H] + The calculated value of m / z is 591.21, and the experimental value is 591.10.

[0373] Step 7: 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide: At room temperature, to ((3-(2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl thiocarbamate (57 mg, 0.10 mmol) was added to a solution of DCM (3 mL) with 1 mL of TFA. The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The final mixture was concentrated under vacuum and analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was used for purification (eluting with 50% to 80% MeCN / H2O containing 0.1% formic acid) to give 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide (11.3 mg, 23.2%) as a white solid. LCMS (ESI): C 21 H 24 F5N4O2S [M + H] + The calculated value of m / z is 491.15, and the experimental value is 491.05.1 H NMR (400MHz, DMSO- d 6) δ 10.81 (s, 1 H), 8.31 (s, 1 H), 8.04-7.85 (m, 2 H), 7.67 (d, J =7.8 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 1 H), 3.71 (s, 2 H), 3.59-3.33 (m, 5 H), 3.13 (s, 3 H), 2.40-2.67 (m, 2 H), 2.03-1.83 (m, 4 H).

[0374] Example 4 ( R )-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide

[0375] Reagents and conditions: POCl3, pyridine, ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: ( R )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (250 mg, 0.740 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)λ 6 220 mg (0.814 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (4 mL) with POCl3 (375 µL). The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give a yellow oil. R)-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (120 mg, 27.5%). LCMS (ESI): C 26 H 32 F5N4O4S [M + H] + The calculated value of m / z is 591.21, and the experimental value is 591.15.

[0376] Step 2: ( R )-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide: at room temperature, to ( R )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (120 mg, 0.200 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the filtrate was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 * 21.2 mm) was used for purification with 30% to 90% ACN-H2O containing 0.1% formic acid to obtain a white solid. R )-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide (55 mg, 56.12%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.78 (s, 1 H), 8.29 (s, 1 H), 7.94-7.82 (m, 2 H), 7.65 (d, J = 8 Hz, 1 H), 7.59-7.55 (m, 1 H), 4.20 (s, 1 H), 3.49-3.47 (m, 2 H), 3.33-3.31 (m, 2H), 3.05 (s, 3 H), 2.33 (s, 3 H), 1.96-1.92 (m, 2 H), 1.89-1.86 (m, 4 H). LCMS(ESI):C21 H 24 F5N4O2S [M + H] + The calculated value of m / z is 491.16, and the experimental value is 490.95.

[0377] Example 5 ( S )-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide

[0378] Reagents and conditions: a) POCl3, pyridine, ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: ( S )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (250 mg, 0.644 mmol) and (S)-((3-aminophenyl)(methyl)(oxo)λ 6 208.76 mg (0.773 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (4 mL) with POCl3 (500 µL). The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give a white oily substance. S )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (130 mg, 34.21%). LCMS (ESI): C 26 H 32 F5N4O4S [M +H] + The calculated value of m / z is 591.21, and the experimental value is 591.40.

[0379] Step 2: ( S)-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide: at room temperature, to ( S )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (130 mg, 0.22 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 * 21.2 mm) was further purified by elution with 30% to 90% ACN-H2O containing 0.1% formic acid to obtain (S)-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide (62 mg, 57.51%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ10.79 (s, 1 H), 8.29 (s, 1 H), 7.95 (d, J = 10.5 Hz, 2 H), 7.70-7.52 (m, 2 H), 4.27 (bs, 1 H), 3.71 (s, 2 H), 3.47 (t, J = 5.5 Hz, 2 H), 3.07 (s, 3 H), 2.52 (s, 3 H), 2.33 (s, 2 H), 2.04-1.81 (m, 4 H). LCMS(ESI):C 21 H 24 F5N4O2S [M + H] + The calculated value of m / z is 491.16, and the experimental value is 491.20.

[0380] Example 6 3-(4,4-Difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyromylatesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0381] Reagents and conditions: a) DIEA, 4,4-difluorozazepine heptane hydrochloride, dioxane, 60℃; c) HI (57%), 40℃, 5 hours; d) Cu, [Ph₂SCF₃] + [OTf] - 60℃; e) KOH, MeOH, H2O 70℃; e)(i) ((3-aminophenyl)(methyl)(oxo)-λ 6 (ii) tert-butyl carbamate (-thionyl) pyridine, POCl3, 60°C; Step 1: Methyl 6-chloro-3-(4,4-difluoroazacyclohepta-1-yl)pyridazin-4-carboxylate: DIEA (3.75 g, 29.1 mmol) was added to a solution of methyl 3,6-dichloropyridazin-4-carboxylate (2 g, 9.7 mmol) and 4,4-difluoroazacyclohepta-methyl hydrochloride (2.0 g, 11.6 mmol) in 1,4-dioxane (30 mL). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was complete. The mixture was concentrated and purified by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give methyl 6-chloro-3-(4,4-difluoroazacyclohepta-1-yl)pyridazin-4-carboxylate (1.6 g, 54.1%) as a yellow solid. LCMS (ESI): C 12 H 15 ClF2N3O2[M + H] + The calculated m / z value is 306.08, and the experimental value is 305.90.

[0382] Step 2: Methyl 3-(4,4-difluoroazacyclohepta-1-yl)-6-iodadiazine-4-carboxylate: A solution of methyl 6-chloro-3-(4,4-difluoroazacyclohepta-1-yl)pyridazine-4-carboxylate (1.6 g, 5.2 mmol) in HI (15 mL, 57% aqueous solution) was heated overnight at 40 °C. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give methyl 3-(4,4-difluoroazacyclohepta-1-yl)-6-iodadiazine-4-carboxylate (1.8 g, 87.4%) as a yellow solid. LCMS (ESI): C 12 H 15 IF₂N₃O₂[M + H] + The calculated value of m / z is 398.02, and the experimental value is 397.85.

[0383] Step 3: Methyl 3-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: methyl 3-(4,4-difluoroazacyclohepta-1-yl)-6-iodopyridazine-4-carboxylate (1.8 g, 4.5 mmol), Cu (0.87 g, 13.6 mmol), and [Ph2SCF3] were added. + [OTf] - A solution of 3.6 g (9.0 mmol) in DMF (20 mL) was heated at 60 °C for 5 hours. LCMS showed the reaction was complete. The mixture was then filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 4) to give methyl 3-(4,4-difluoroazacycloheptan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (1.2 g, 78.9%) as a yellow solid. LCMS (ESI): C 12 H 14 F3F2N3O2[M + H] + The calculated value of m / z is 340.11, and the experimental value is 339.95.

[0384] Step 4: 3-(4,4-Difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-4-carboxylic acid: At room temperature, KOH (1.05 g, 18.8 mmol) was added to a solution of methyl 3-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-4-carboxylic acid (800 mg, 2.35 mmol) in MeOH / H₂O (1 / 1, 20 mL). The mixture was heated at 70 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH 3-4 with 1N HCl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 3-(4,4-difluoroazacycloheptan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (620 mg, 81.2%) as a yellow solid. LCMS (ESI): C 12 H 13 F5N3O2[M + H] + The calculated value of m / z is 326.09, and the experimental value is 325.95.

[0385] Step 5: At 0°C, react 3-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (80 mg, 0.246 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 620 μL of POCl3 was added to a solution of tert-butyl 3-thionyl)carbamate (66.5 mg, 0.246 mmol) in pyridine (2.5 mL). The mixture was stirred at 0 °C for 1 h. LCMS showed that the reaction was complete. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated to give a crude intermediate. The crude intermediate was dissolved in DCM (3 mL) and TFA (1 mL) was added. The solution was stirred at room temperature for 1 h, then concentrated and passed by preparative HPLC (column: Gemini-C). 18 Purification was performed using a 150 x 21.2 mm, 5 μm mobile phase (ACN-H2O (0.1% FA), gradient: 20%-38%-60%) to obtain the title compound as a white solid (18.1 mg, 15.4% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 11.07 (s, 1 H), 8.26 (s, 1 H), 8.08 (s, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.62(t, J = 7.9 Hz, 1 H), 4.25 (s, 1 H), 3.87 (m, 2 H), 3.58 (m, 2 H), 3.06 (s, 3H), 2.36 (m, 2 H), 2.12-1.86 (m, 4 H). LCMS(ESI):C 19 H 21 F5N5O2S [M + H] + The calculated value of m / z is 478.13, and the experimental value is 478.05.

[0386] Example 7 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0387] Reagents and conditions: a) Nitromethane, Et3N, DMSO; b) DIEA, aziridine, dioxane, 60℃; c) HI (57%), 40℃, 5 hours; d) Cu, [Ph2SCF3] + [OTf] - 60 ℃; e) KOH, MeOH, H2O 70℃; f) ((3-aminophenyl)(methyl)(oxo)-λ 6 (ii) tert-butyl carbamate (-thionyl) pyridine, POCl3, 60°C; Step 1: Methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate: MeNO2 (1.48 g, 24.3 mmol) was added to a solution of methyl 3,6-dichloropyridazine-4-carboxylate (1 g, 4.86 mmol) in DMSO (10 mL). The mixture was stirred at room temperature for 30 min. Then, TEA (0.74 g, 7.29 mmol) was added dropwise to the reaction at 0 °C. The reaction was stirred at room temperature for 3 h. After the reaction was complete, the mixture 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 rapid column chromatography (PE / EtOAc = 10 / 1) to give methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (0.9 g, 84.3%) as a white solid. LCMS (ESI): C7H7Cl2N2O2[M+H] + The calculated value of m / z is 220.99, and the experimental value is 220.85.

[0388] Step 2: Methyl 3-(azacyclohepta-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate: DIEA (1583 mg, 12.27 mmol) was added to a solution of methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (900 mg, 4.09 mmol) and azacycloheptadecane (484 mg, 4.89 mmol) in 1,4-dioxane (10 mL). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was complete. The mixture was concentrated and purified by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give methyl 3-(azacyclohepta-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate (680 mg, 58.8%) as a yellow solid. LCMS (ESI): C 13 H 19 ClN3O2[M + H] + The calculated value of m / z is 284.11, and the experimental value is 284.10.

[0389] Step 3: Methyl 3-(azacyclohepta-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate: A solution of methyl 3-(azacyclohepta-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate (680 mg, 2.4 mmol) in HI (10 mL, 57% aqueous solution) was heated overnight at 40 °C. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give methyl 3-(azacyclohepta-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (500 mg, 55.5%) as a yellow solid. LCMS (ESI): C 13 H 19 IN3O2[M + H] + The calculated value of m / z is 376.05, and the experimental value is 376.10.

[0390] Step 4: Methyl 3-(azacyclohept-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: 3-(azacyclohept-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (500 mg, 1.33 mmol), Cu (257 mg, 4.02 mmol), and [Ph2SCF3] were added. + [OTf] - A solution of (1064 mg, 2.66 mmol) in DMF (10 mL) was heated at 60 °C for 5 hours. LCMS showed the reaction was complete. The mixture was then filtered through diatomaceous earth. The filtrate was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 4 / 1) to give methyl 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (350 mg, 82.7%) as a yellow solid. LCMS (ESI): C 14 H 19 F3N3O2[M + H] + The calculated value of m / z is 318.14, and the experimental value is 318.05.

[0391] Step 5: 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: At room temperature, KOH (580 mg, 8.8 mmol) was added to a solution of methyl 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (350 mg, 1.1 mmol) in MeOH / H₂O (1 / 1, 8 mL). The mixture was heated at 70 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH 3-4 with 1N HCl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (250 mg, 74.8%) as a yellow solid. LCMS (ESI): C 13 H 17 F3N3O2[M + H] + The calculated value of m / z is 304.12, and the experimental value is 304.05.

[0392] Step 6: ((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbamate)phenyl)(methyl)(oxo)-λ 6 3-(thionyl)carbamate tert-butyl ester: At room temperature, tert-butyl ester is reacted with 3-(azacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.33 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 6 3-(thionyl)-tert-butyl carbamate (89 mg, 0.33 mmol) was added to a solution of pyridine (4 mL) with POCl3 (30 μL). The mixture was heated at 60 °C for 1 hour. LCMS showed the reaction was complete. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 2) to give a yellow oil of ((3-(3-(azacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (20 mg, 10.9%). LCMS (ESI): C 25 H 32 F3N5O4S [M + H] + Calculated m / z value: 556.22; Experimental value: [M + H] + 556.15.

[0393] Step 7: 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazin-4-carboxamide: At 0°C, to ((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazin-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 tert-butyl 3-(thionyl)carbamate (20 mg, 0.04 mmol) was added to a solution of TFA (0.4 mL) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (column: Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA), gradient: 30%-40%-70%) to give 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminoylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (5 mg, 30.5%) as a white solid. 1 H NMR (400MHz, DMSO- d 6) δ 11.16 (s, 1 H), 8.28 (s, 1 H), 7.88 (d, J = 7.9 Hz, 1 H), 7.72(d, J = 8.1 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.34 (s, 1 H), 3.73 (t, J = 5.9Hz, 4H), 3.08 (s, 3H), 2.30 (s, 3H), 1.76 (s, 4H), 1.49 (s, 4H). LCMS(ESI):C 20 H 25 F3N5O2S [M + H] + The calculated value of m / z is 456.17, and the experimental value is 456.05.

[0394] Example 8 N-((3-aminophenyl)(methyl)(oxo)-λ 6 -thionyl)-3-(azacycloheptyl-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0395] Oxaloyl chloride (30 µL) was added to a solution of 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.33 mmol) in DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL) and added dropwise to (3-aminophenyl)(imino)(methyl)-λ 6 - Thionyl ketone (73 mg, 0.43 mmol) and DIEA (64 mg, 0.49 mmol) were added to a mixture of THF (1 mL). The mixture was stirred at 40 °C for 2 hours. LCMS showed that the reaction was complete. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated. The residue was subjected to preparative HPLC (column: Gemini-C). 18 150 x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA), gradient: 20%-38%-60%). Purification was performed to obtain N-((3-aminophenyl)(methyl)(oxo)-λ as a white solid. 6 (-thionyl)-3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (10 mg, 6.7%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.31 (t, J = 7.9 Hz, 1 H), 7.17 (s, 1 H), 7.10 (d, J = 7.7 Hz, 1 H), 6.88(dd, J = 8.1, 1.9 Hz, 1 H), 5.79 (s, 2 H), 3.75-3.62 (m, 4 H), 3.60 (s, 3 H), 2.27 (s, 3 H), 1.74 (s, 4 H), 1.56-1.37 (m, 4 H). LCMS(ESI):C 20 H 25 F3N5O2S [M +H] + The calculated value of m / z is 456.17, and the experimental value is 456.00.

[0396] Example 9 4-(azacyclohepta-1-yl)-N-(3-(S-methylaminopyromylatesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0397] Reagents and conditions: a) DIEA, aziridine, dioxane, 60℃; b) HI (57%), 40℃, 5 hours; c) Cu, [Ph₂SCF₃] + [OTf] - 60℃; d) ((3-aminophenyl)(methyl)(oxo)-λ 6 tert-butyl 3-thionyl)carbamate, Me3Al, toluene, 90℃ Step 1: Methyl 4-(azacyclohepta-1-yl)-6-chloropyridazine-3-carboxylate: DIEA (9.4 g, 72.9 mmol) was added to a solution of methyl 4,6-dichloropyridazine-3-carboxylate (5 g, 24.3 mmol) and azacycloheptadecane (2.89 g, 29.2 mmol) in 1,4-dioxane (60 mL). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was complete. The mixture was concentrated and purified by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give methyl 4-(azacyclohepta-1-yl)-6-chloropyridazine-3-carboxylate (3.5 g, 53.8%) as a yellow solid. LCMS (ESI): C 12 H 17 ClN3O2[M + H] + The calculated value of m / z is 270.10, and the experimental value is 270.05.

[0398] Step 2: Methyl 4-(azacyclohepta-1-yl)-6-iodadiazine-3-carboxylate: A solution of methyl 4-(azacyclohepta-1-yl)-6-iodadiazine-3-carboxylate (3.5 g, 11.8 mmol) in HI (30 mL, 57% aqueous solution) was stirred overnight at 40 °C. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give methyl 4-(azacyclohepta-1-yl)-6-iodadiazine-3-carboxylate (3.5 g, 82.2%) as a yellow solid. LCMS (ESI): C 12 H 17 IN3O2[M + H] + The calculated value of m / z is 362.03, and the experimental value is 362.00.

[0399] Step 3: Methyl 4-(azacyclohept-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate: 4-(azacyclohept-1-yl)-6-iodopyridazine-3-carboxylate (2.5 g, 6.9 mmol), Cu (1.35 g, 20.7 mmol), and [Ph2SCF3] were added. + [OTf] -A solution of 5.5 g (13.8 mmol) in DMF (30 mL) was heated at 60 °C for 5 hours. LCMS showed the reaction was complete. The mixture was then filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 3) to give methyl 4-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (1 g, 47.7%) as a yellow solid. LCMS (ESI): C 13 H 17 F3N3O2[M + H] + The calculated value of m / z is 304.12, and the experimental value is 303.95.

[0400] Step 4: 4-(azacyclohepta-1-yl)-N-(3-(S-methylaminopyromylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide: At 0°C, to ((3-aminophenyl)(methyl)(oxo)-λ 6 Me3Al (1 M in hexane, 2.18 mL, 2.18 mmol) was added dropwise to a solution of tert-butyl 4-(thionyl)carbamate (534 mg, 1.98 mmol) in toluene (5 mL). The mixture was stirred at 0 °C for 0.5 h. Then, methyl 4-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.66 mmol) in toluene (3 mL) was added at the same temperature. The resulting mixture was heated at 90 °C for 2 h. LCMS showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated, and analyzed by preparative HPLC (column: Gemini-C). 18 Purification was performed using a mobile phase of 150 x 21.2 mm and a flow rate of 5 μm (ACN-H2O (0.1% FA), gradient: 20%-38%-60%) to obtain 4-(azacyclohepta-1-yl)-N-(3-(S-methylaminoylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (60 mg, 20.6%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.30 (s, 1 H), 8.37 (s, 1 H), 7.96 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.62 (t,J = 7.9 Hz, 1H), 7.34 (s, 1 H), 4.22 (s, 1 H), 3.64-3.48 (m, 4 H), 3.07 (s, 3 H), 1.74 (s, 4 H), 1.48 (s, 4 H). LCMS(ESI):C 19 H 23 F3N5O2S [M + H] + The calculated value of m / z is 442.14, and the experimental value is 442.00.

[0401] Example 10 ( R 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0402] Reagents and conditions: POCl3, pyridine, ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: ( R )-((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-(thionyl)carbamate tert-butyl ester: At 50 °C, 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.330 mmol) and ( R 133.70 mg (0.495 mmol) of tert-butyl carbamate (3-aminophenyl)(methyl)(oxo)-16-thionyl)carbamate (2 mL) was added dropwise to a mixture of pyridine (2 mL) with added POCl3 (150 µL). The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give a yellow oil. R )-((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (60 mg, 32.72%). LCMS (ESI): C25 H 33 F3N5O4S [M +H] + The calculated value of m / z is 556.22, and the experimental value is 556.40.

[0403] Step 2: ( R )-3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to ( R TFA (0.5 mL) was added to a solution of tert-butyl carbamate (60 mg, 0.108 mmol) in DCM (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, 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 first purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) and then further purified by preparative HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% formic acid) to obtain a white solid. R 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (15 mg, 30%, 96.05% purity, 99% ee). 1 H NMR (400 MHz, DMSO- d 6) δ 11.16 (s, 1 H), 8.27 (s, 1 H), 7.92-7.85 (m, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.62 (t, J = 7.9Hz, 1H), 4.26 (s, 1H), 3.73 (t, J = 5.8 Hz, 4 H), 3.07 (s, 3 H), 2.30 (s, 3H), 1.76 (s, 4 H), 1.49 (s, 4 H). LCMS(ESI):C 20 H 23 F3N5O2S [M - H] -The calculated value of m / z is 454.15, and the experimental value is 454.10.

[0404] Example 11 ( S 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0405] Reagents and conditions: POCl3, pyridine, ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: (S)-((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazin-4-carboxamido)phenyl)(methyl)(oxo)-16-thionyl)carbamate tert-butyl carbamate: At 50 °C, 3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazin-4-carboxylic acid (100 mg, 0.330 mmol) and ( S 133.70 mg (0.495 mmol) of tert-butyl carbamate (3-aminophenyl)(methyl)(oxo)-16-thionyl)carbamate (2 mL) was added to a mixture of POCl3 (150 µL). The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 1 / 1) to give a yellow oily substance. S )-((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (47 mg, 25.7%). LCMS (ESI): C 25 H 33 F3N5O4S [M + H] + The calculated value of m / z is 556.22, and the experimental value is 556.15.

[0406] Step 2: ( S )-3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to ( S)-((3-(3-(azacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 TFA (0.5 mL) was added to a solution of tert-butyl 3-thionyl)carbamate (47 mg, 0.08 mmol) in DCM (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the filtrate was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified first by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) and then by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was further purified by elution with 30% to 90% MeCN / H2O containing 0.1% formic acid to obtain a white solid. S 3-(azacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (18 mg, 49.45%, 98% purity, 100% ee). 1 H NMR (400 MHz, DMSO- d 6) δ 11.16 (s, 1 H), 8.27 (s, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.64-7.60 (m, 1H), 4.26 (s, 1 H), 3.74-3.71 (m, 4 H), 3.07 (s, 3 H), 2.29 (s, 3 H), 1.76 (s, 4 H), 1.49 (s, 4 H). LCMS(ESI):C 20 H 25 F3N5O2S [M + H] + The calculated value of m / z is 456.17, and the experimental value is 456.10.

[0407] Example 12 5-Chloro-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide

[0408] Reagents and conditions: a) DIEA, 6-azaspiro[2.5]octane hydrochloride, dioxane, 100℃; b) NCS, DMF; c) KOH, MeOH, H2O, 60℃; d) POCl3, pyridine, ((3-bromophenyl)(methyl)(oxo)-λ 6 -Thiolide tert-butyl ester; TFA, DCM, room temperature Step 1: Methyl 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid: DIEA (1.82 g, 14 mmol) was added to a mixture of methyl 2-chloro-6-methylnicotinic acid (1.3 g, 7 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.03 g, 7 mmol) in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (40 mL), and extracted with DCM (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to provide methyl 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (1 g, 55.6%) as a white solid. LCMS (ESI): C 15 H 21 N₂O₂[M + H] + The calculated value of m / z is 261.16, and the experimental value is 260.95.

[0409] Step 2: Methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid: NCS (0.534 g, 4 mmol) was added to a mixture of methyl 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (0.950 g, 3.64 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to give methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (0.750 g, 70.0%) as a white oil. LCMS (ESI): C 15 H 20 ClN2O2[M + H] + The calculated value of m / z is 295.12, and the experimental value is 294.95.

[0410] Step 3: 5-Chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid: At room temperature, KOH (0.561 g, 25 mmol) was added to a solution of methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (0.700 g, 2.5 mmol) in MeOH / H2O (1 / 1, 15 mL). The mixture was heated at 60 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with DCM (20 mL). The aqueous phase was then adjusted to pH = 3 with 1 N HCl and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (560 mg, 79.6%) as a white solid. LCMS (ESI): C 14 H 18 ClN2O2[M + H] + The calculated value of m / z is 281.10, and the experimental value is 280.95.

[0411] Step 4: ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodiyl) tert-butyl carbamate: At room temperature, 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (500 mg, 1.78 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 6 3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octyl-6-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (120 mg, 12.64%). LCMS (ESI): C 26 H 34 ClN4O4S [M + H] + The calculated value of m / z is 533.20, and the experimental value is 533.05.

[0412] Step 5: 5-Chloro-6-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide: to ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl 3-thionyl)carbamate (120 mg, 0.23 mmol) in DCM (3 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 residue was purified first by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) and then by preparative HPLC (Gemini 5 μmC). 18 The column (150 x 21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% formic acid) was further purified to give the title compound (41 mg, 41.44%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.81 (s, 1 H), 8.39 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.80 (s, 1 H), 7.65 (d, J = 8 Hz, 1 H), 7.60-7.56 (m, 1 H), 4.21 (s, 1 H), 3.36-3.32 (m, 4 H), 3.05 (s, 3 H), 2.46 (s, 3 H), 1.38-1.35 (s, 4 H), 0.28 (s, 4 H). LCMS(ESI):C 21 H 26 ClN4O2S [M + H] + The calculated value of m / z is 433.14, and the experimental value is 433.05.

[0413] Example 13 6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0414] Reagents and conditions: a) DIEA, 4,4-difluoroazacycloheptane hydrochloride, acetonitrile, room temperature; b) (cyclopropylmethyl)zinc(II) bromide, CuI, PdCl2(PPh3)2, DMF; c) KOH, MeOH, H2O; d) (COCl)2, DMF, DCM, NH4OH; e) Cs2CO3, ((3-bromophenyl)(methyl)(oxo)-λ 6 f) tert-butyl carbamate (-thionyl) carbamate, Xantphos-Pd-G2, dioxane, 100°C; f) TFA, DCM, room temperature. Step 1: Methyl 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid: A mixture of methyl 2,6-dichloronicotinic acid 1 (2.0 g, 9.7 mmol), 4,4-difluoroazacyclohepta-methyl hydrochloride (1.67 g, 9.7 mmol), and DIEA (3.75 g, 29.1 mmol) in dioxane (25 mL) was heated at 80 °C for 5 hours. The mixture was then concentrated and purified directly by silica gel rapid column chromatography (PE / EtOAc = 6 / 1) to give methyl 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (2.22 g, 67%). LCMS (ESI): C 13 H 16 ClF2N2O2[M + H] + The calculated value of m / z is 305.09, and the experimental value is 305.90.

[0415] Step 2: Methyl 6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinate: Evacuate the mixture of Zn powder (2.2 g, 33.6 mmol) and I2 (850 mg, 3.36 mmol) in a 250 mL three-necked flask and backfill with N2 three times, then add N2. Carefully heat the flask with a hot air blower until the I2 sublimates. Then immediately add (bromomethyl)cyclopropane (2.27 g, 16.8 mmol) to a solution of DMF (8 mL) via a syringe. Stir the mixture for 10 minutes while maintaining the temperature at approximately 80 °C. Then remove the heater and stirrer. Under a nitrogen atmosphere, the clear supernatant was added dropwise to a stirred solution of methyl 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (1.7 g, 5.6 mmol), CuI (320 mg, 1.68 mmol), and Pd(pph3)2Cl2 (390 mg, 0.56 mmol) in DMF (4 mL). The mixture was heated at 110 °C for 5 hours. The mixture was then quenched with water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a crude product. The residue was purified by silica gel column chromatography (PE / EA, 4 / 1) to give methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (1.3 g, 64%) as a white solid. LCMS (ESI): C 17 H 23 F2N2O2[M + H] + The calculated value of m / z is 325.17, and the experimental value is 325.25.

[0416] Step 3: 6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid: At room temperature, KOH (0.69 g, 12.3 mmol) was added to a solution of methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (400 mg, 1.23 mmol) in MeOH / H₂O (1 / 1, 8 mL). The mixture was heated at 70 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH 3-4 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (360 mg, 84.7%). LCMS (ESI): C 16 H 21F2N2O2[M + H] + The calculated value of m / z is 311.16, and the experimental value is 311.00.

[0417] Step 4: 6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide: Oxaloyl chloride (81.84 mg, 0.64 mmol) was added to a solution of 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (100 mg, 0.32 mmol) in DCM (5 mL) and DMF (10 µL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was concentrated to remove the solvent. The residue was then dissolved in THF (5 mL) and added to NH3-H2O (2 mL) under vigorous stirring. The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum to give crude 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide (96 mg, 86.7%), which could be used in the next step without further purification. LCMS (ESI): C 16 H 22 F2N3O [M + H] + The calculated value of m / z is 310.17, and the experimental value is 309.95.

[0418] Step 5: ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazacycloheptane-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodiyl) tert-butyl carbamate: Under a N2 atmosphere, 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide 5 (90 mg, 0.29 mmol), ((3-bromophenyl)(methyl)(oxo)-λ 6 A solution of tert-butyl 3-thionyl)carbamate (195 mg, 0.58 mmol), Cs₂CO₃ (285 mg, 0.87 mmol), and Xantphos-Pd-G₂ (26 mg, 0.029 mmol) in 1,4-dioxane (5 mL) was heated overnight at 110 °C. LCMS showed the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to give a yellow oily substance ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 62-Thiodimethyl)carbamate tert-butyl ester (50 mg, 27%). LCMS (ESI): C 28 H 37 F2N4O4S [M + H] + The calculated value of m / z is 563.25, and the experimental value is 563.20.

[0419] Step 6: 6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminomethylenesulfonyl)phenyl)nicotinamide: At room temperature, to ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl 3-thionyl)carbamate (50 mg, 0.089 mmol) was added to a solution of TFA (1 mL) in DCM (3 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated, and the residue was subjected to preparative HPLC (column: Gemini-C10). 18 Purification was performed using a mobile phase of ACN-H2O (0.1% FA) and a gradient of 50%-80% to obtain 6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide (15 mg, 35%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ10.65 (s, 1 H), 8.34 (s, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.63 (m, 2 H), 7.56-7.61 (t, J = 7.9 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.93-5.81 (m, 1 H), 5.08-4.94 (m, 2 H), 4.19 (s, 1 H), 3.63 (s, 2 H), 3.42 (t, J = 5.7 Hz, 2 H), 3.05(s, 3 H), 2.73 (t, J = 7.5 Hz, 2 H), 2.48-2.42 (m, 2 H), 2.39-2.26 (m, 2 H), 2.01-1.80 (m, 4 H). LCMS(ESI):C 23 H 29F2N4O2S [M + H] + The calculated value of m / z is 463.20, and the experimental value is 463.10.

[0420] Example 14 N-(3-(S-methylaminopyromylsulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0421] Reagents and conditions: a) DIEA, 6-azaspiro[2.5]octane hydrochloride, dioxane, 80℃; b) HI, 40℃; c) Cu, [Ph₂SCF₃] + [OTf] - d) DMF, 60℃; e) KOH, MeOH, H2O, 70℃; f) POCl3, pyridine, ((3-bromophenyl)(methyl)(oxo)-λ 6 - Thionyl tert-butyl ester; e) TFA, DCM, room temperature Step 1: Methyl 6-chloro-3-(6-azaspiro[2.5]oct-6-yl)pyridazine-4-carboxylate (3): DIEA (1.87 g, 14.4 mmol) was added to a mixture of methyl 3,6-dichloropyridazine-4-carboxylate (1.5 g, 7.2 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.06 g, 7.2 mmol) in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to give methyl 6-chloro-3-(6-azaspiro[2.5]oct-6-yl)pyridazine-4-carboxylate (1.1 g, 54.37%) as a yellow oil. LCMS (ESI): C 13 H 17 ClN3O2[M + H] + The calculated value of m / z is 282.10, and the experimental value is 281.95.

[0422] Step 2: Methyl 6-iodo-3-(6-azaspiro[2.5]oct-6-yl)pyridazine-4-carboxylate: HI (55%, 10 mL) was added to a solution of methyl 6-chloro-3-(6-azaspiro[2.5]oct-6-yl)pyridazine-4-carboxylate (1.1 g, 3.91 mmol) at room temperature. The mixture was heated at 40 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give crude methyl 6-iodo-3-(6-azaspiro[2.5]oct-6-yl)pyridazine-4-carboxylate (800 mg, 54.9%) as a yellow solid, which could be used directly in the next step without further purification. LCMS (ESI): C 13 H 17 IN3O2[M + H] + The calculated value of m / z is 374.04, and the experimental value is 373.90.

[0423] Step 3: Methyl 3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: 600 mg (1.6 mmol) of methyl 6-iodo-3-(6-azaspiro[2.5]oct-6-yl)pyridazine-4-carboxylate and Cu (30.7 mg, 4.8 mmol) and [Ph2SCF3] were added. + [OTf] - The mixture (123 mg, 3.2 mmol) in DMF (10 mL) was heated at 60 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (40 mL), and extracted with DCM (40 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give methyl 3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (330 mg, 65.6%) as a yellow solid. LCMS (ESI): C 14 H 17 F3N3O2[M + H] + The calculated value of m / z is 316.13, and the experimental value is 316.00.

[0424] Step 4: 3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: At room temperature, KOH (560 mg, 10 mmol) was added to a solution of methyl 3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (330 mg, 1.05 mmol) in MeOH / H2O (10 mL). The mixture was heated at 70 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with DCM (20 mL). The aqueous phase was adjusted to pH 3 with 1 N HCl and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give 3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (240 mg, 75.9%) as a white solid. LCMS (ESI): C 13 H 15 F3N3O2[M + H] + The calculated value of m / z is 302.11, and the experimental value is 301.90.

[0425] Step 5: ((3-(3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carbamate)phenyl)(methyl)(oxo)-16-thionyl)carbamate: At room temperature, tert-butyl 3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (240 mg, 0.8 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 6 325 mg, 1.2 mmol) of tert-butyl carbamate (-thionyl)carbamate was added to a mixture of pyridine (4 mL) and POCl3 (350 µL). The mixture was stirred under room temperature for 2 hours. The mixture was then diluted with water (4 mL) and extracted with DCM (4 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 rapid column chromatography (PE / EtOAc = 1 / 1) to give a yellow oily substance ((3-(3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl) tert-butyl carbamate (85 mg, 19.1%). LCMS (ESI): C 25 H 31 F3N5O4S [M + H] + The calculated value of m / z is 554.21, and the experimental value is 554.10.

[0426] Step 6: N-(3-(S-methylaminoylidenesulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: At room temperature, TFA (1 mL) was added to a solution of ((3-(3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-16-thionyl)carbamate tert-butyl ester (85 mg, 0.153 mmol) in DCM (3 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 residue was purified first by silica gel rapid chromatography (PE / EtOAc = 1 / 1) and then by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% formic acid) was further purified to obtain N-(3-(S-methylaminoylsulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (44 mg, 98.3% purity) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.08 (s, 1 H), 8.29 (s, 1 H), 8.02 (s, 1 H), 7.91 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1 H), 4.25 (s, 1 H), 3.71-3.67 (m, 4 H), 3.06 (s, 3 H), 1.46-1.42 (m, 4 H), 0.35 (s, 4 H). LCMS(ESI):C 20 H 23 F3N5O2S [M + H] + The calculated value of m / z is 454.15, and the experimental value is 454.10.

[0427] Example 15 5-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0428] Reagents and conditions: a) DIEA, 4,4-difluoroazacycloheptane hydrochloride, dioxane; b) NCS, DMF; c) MeOH / H2O, KOH, 70℃; d) ((3-aminophenyl)(methyl)(oxo)-λ 6 -Thiodimethyl) tert-butyl carbamate, pyridine, POCl3; e) DCM, TFA Step 1: Methyl 2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinate: A mixture of methyl 2-chloro-6-methylnicotinate (1.0 g, 5.4 mmol), 4,4-difluoroazacyclohepta-methyl hydrochloride (1.11 g, 6.4 mmol), and DIEA (1.39 g, 10.8 mmol) in dioxane (20 mL) was heated at 80 °C for 5 hours. The mixture was then concentrated, and the residue was purified by silica gel rapid column chromatography (PE / EtOAc = 5 / 1) to give methyl 2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinate (720 mg, 42.6%). LCMS (ESI): C 14 H 18 F2N2O2[M + H] + The calculated value of m / z is 285.14, and the experimental value is 285.15.

[0429] Step 2: 5-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinate: NCS (394 mg, 2.95 mmol) was added to a solution of 2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinate (700 mg, 2.46 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then diluted with water (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc, 4 / 1) to give 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinate (680 mg, 78%) as a yellow solid. LCMS (ESI): C 14 H 18 ClF2N2O2[M + H] + The calculated value of m / z is 319.10, and the experimental value is 319.00.

[0430] Step 3: 5-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinic acid: At room temperature, KOH (1.14 g, 20.4 mmol) was added to a solution of methyl 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinic acid (650 mg, 2.03 mmol) in MeOH / H₂O (1 / 1, 10 mL). The mixture was heated at 70 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH 3-4 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinic acid (600 mg, 86.9%). LCMS (ESI): C 13 H 16 ClF2N2O2[M + H] + The calculated value of m / z is 305.09, and the experimental value is 304.90.

[0431] Step 4: ((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl carbamate (-thionyl)carbamate: At 0 °C, tert-butyl carbamate was reacted with 5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinic acid (120 mg, 0.39 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 6 3-(thionyl)-tert-butyl carbamate (160 mg, 0.59 mmol) was added dropwise to a solution of pyridine (6 mL) with POCl3 (0.3 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 2) to provide a yellow oil of ((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (65 mg, 27%). LCMS (ESI): C 25 H 32 ClF2N4O4S [M +H] + The calculated value of m / z is 557.18, and the experimental value is 557.15.

[0432] Step 5: 5-Chloro-2-(4,4-difluoroazacyclohep-1-yl)-6-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)nicotinamide: At room temperature, to ((3-(5-chloro-2-(4,4-difluoroazacyclohep-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl thiocarbamate (65 mg, 0.12 mmol) was added to a solution of DCM (3 mL) with TFA (1 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The final mixture was concentrated under vacuum and analyzed by preparative HPLC (Gemini 5 μm C). 18 The solution was purified by column chromatography (150 x 21.2 mm) with 50% to 80% MeCN / H2O containing 0.1% formic acid to give 5-chloro-2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide (10.1 mg, 18.8%) as a white solid. LCMS (ESI): C 20 H 24 ClF2N4O2S [M + H] + The calculated value of m / z is 457.13, and the experimental value is 457.00. 1 H NMR (400 MHz, DMSO- d 6) δ0.74 (s, 1 H), 8.32 (s, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.77 (s, 1 H), 7.66(d, J = 8.0 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 3.64-3.57 (m, 2 H), 3.42-3.38(m, 2 H), 3.09 (s, 3 H), 2.45 (s, 3 H), 2.35-2.25 (m, 2 H), 2.02-1.89 (m, 2H), 1.87-1.80 (m, 2H).

[0433] Example 16 ( R 5-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0434] Reagents and conditions: POCl3, pyridine, ( R)-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: ( R )-((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl carbamate (-thionyl)carbamate: at 50 °C, tert-butyl carbamate was reacted with 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinic acid (250 mg, 0.820 mmol) and ( R 3-((3-aminophenyl)(methyl)(oxo)-16-thionyl)carbamate tert-butyl ester (244 mg, 0.902 mmol) was added to a mixture of pyridine (4 mL) and POCl3 (373 µL). The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 1 / 1) to give a yellow oil. R )-((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (120 mg, 26.3%). LCMS (ESI): C 25 H 32 ClF2N4O4S [M + H] + The calculated value of m / z is 557.18, and the experimental value is 557.10.

[0435] Step 2: ( R )-5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide: at room temperature, to ( R )-((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (120 mg, 0.210 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the filtrate was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was used for purification with 30% to 90% ACN-H2O containing 0.1% formic acid to obtain a white solid. R 5-Chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide (67 mg, 69.8%, 100% ee). 1 HNMR (400 MHz, DMSO- d 6, ppm) δ 10.72 (s, 1 H), 8.30 (s, 1 H), 7.93 (d, J = 8 Hz, 1 H), 7.77 (s, 1 H), 7.65 (d, J = 8 Hz, 1 H), 7.59-7.55 (m, 1 H), 4.21 (s, 1H), 3.62-3.60 (m, 2 H), 3.42-3.39 (m, 2 H), 3.05 (s, 3 H), 2.28 (s, 3 H),2.29-2.26 (m, 2 H), 1.95-1.91 (m, 2 H), 1.85-1.73 (m, 2 H). LCMS(ESI):C 20 H 24 ClF2N4O2[M + H] + The calculated value of m / z is 457.13, and the experimental value is 456.90.

[0436] Example 17 ( S 5-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0437] Reagents and conditions: a) POCl3, pyridine, ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: ( S )-((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-6-methylnicotinic acid (250 mg, 0.8224 mmol) and ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 266.447 mg (0.9868 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (5 mL) and POCl3 (500 µL) was added dropwise. The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL 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 rapid column chromatography (PE / EtOAc = 2 / 1) to give a white solid ( S )-((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (150 mg, 32.80%). LCMS (ESI): C 25 H 32 ClF2N4O4S [M + H] + The calculated value of m / z is 557.17, and the experimental value is 557.05.

[0438] Step 2: ( S )-5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide: at room temperature, to ( S )-((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (150 mg, 0.27 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18The solution was purified by elution with 30% to 90% ACN-H2O containing 0.1% formic acid on a column of 150 x 21.2 mm to give (S)-5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-6-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)nicotinamide (54.5 mg, 44.3%) as a white solid. 1 HNMR (400 MHz, DMSO- d 6) δ 10.74 (s, 1 H), 8.31 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 3.61(dd, J = 6.4, 3.6 Hz, 2 H), 3.40 (s, 2 H), 3.09 (s, 3 H), 2.45 (s, 3 H), 2.30(d, J = 14.7 Hz, 2 H), 1.95 (t, J = 12.2 Hz, 2 H), 1.88-1.78 (m, 2 H). LCMS(ESI):C 20 H 24 ClF2N4O2S [M + H] + The calculated value of m / z is 457.12, and the experimental value is 457.20.

[0439] Example 18 ( R )-3-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0440] Reagents and conditions: a) R )-((3-aminophenyl)(methyl)(oxo)-λ 6 (b) Thionyl) tert-butyl carbamate, POCl3, pyridine; Step 1: ( R )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 63-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 91 mg (0.34 mmol) of tert-butyl 3-thionyl carbamate was added dropwise to a solution of pyridine (5 mL) with POCl3 (50 µL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. 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 rapid column chromatography (PE / EtOAc = 3 / 1) to provide a yellow solid ( R )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl) tert-butyl carbamate (82 mg, 45.8%). LCMS (ESI): C 24 H 29 F5N5O4S [M + H] + The calculated value of m / z is 578.19, and the experimental value is 578.05.

[0441] Step 2: ( R )-3-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to ( R )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 90 mg (0.16 mmol) of tert-butyl 3-thionyl)carbamate was added to a solution of TFA (0.5 mL) in DCM (1.5 mL). The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The final mixture was concentrated under vacuum and analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was purified by elution with 30% to 90% MeCN / H2O containing 0.1% formic acid to give a white solid. R 3-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminoethylenetetrasulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (38 mg, 50%, 99% ee). LCMS (ESI): C19 H 21 F5N5O2S [M + H] + The calculated value of m / z is 478.14, and the experimental value is 478.25. 1 H NMR (400 MHz, DMSO- d 6) δ 11.07 (s, 1 H), 8.26 (s, 1 H), 8.08 (s, 1H), 7.94 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.9 Hz, 1H), 4.25 (s, 1 H), 3.87 (s, 2 H), 3.58 (t, J = 5.7 Hz, 2 H), 3.06 (s, 3 H), 2.39 (s, 2 H), 2.19-1.98 (m, 2 H), 1.96-1.85 (d, J = 5.1 Hz, 2 H).

[0442] Example 19 ( S )-3-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0443] Reagents and conditions: a) S )-((3-aminophenyl)(methyl)(oxo)-λ 6 (b) Thionyl) tert-butyl carbamate, POCl3, pyridine; Step 1: ( S )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 tert-butyl carbamate (-thionyl)carbamate was reacted with 3-(4,4-difluoroazacyclohep-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) at 0 °C with ( S )-((3-aminophenyl)(methyl)(oxo)-λ 691 mg (0.34 mmol) of tert-butyl 3-thionyl carbamate was added dropwise to a solution of pyridine (5 mL) with POCl3 (50 µL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (20 mL) 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 rapid column chromatography (PE / EtOAc = 1 / 2) to provide a yellow solid ( S )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl) tert-butyl carbamate (90 mg, 50.8%). LCMS (ESI): C 19 H 21 F5N5O2S [M - Boc + H] + The calculated value of m / z is 478.14, and the experimental value is 478.05.

[0444] Step 2: ( S )-3-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to ( S )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 90 mg (0.16 mmol) of tert-butyl 3-thionyl)carbamate was added to a solution of TFA (0.5 mL) in DCM (1.5 mL). The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The final mixture was concentrated under vacuum and analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was purified by elution with 30% to 90% MeCN / H2O containing 0.1% formic acid to give a white solid. S )-3-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (53 mg, 71.6%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.08 (s, 1 H), 8.28 (s, 1 H), 8.08 (s, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.72 (d,J = 7.8 Hz, 1 H), 7.63 (t, J =7.9 Hz, 1 H), 3.87 (s, 2 H), 3.58 (t, J = 5.4 Hz, 2 H), 3.10 (s, 3 H), 2.45-2.31 (m, 2 H), 2.12-2.00 (m, 2 H), 1.98-1.88 (m, 2 H). LCMS(ESI):C 19 H 21 F5N5O2S[M + H] + The calculated value of m / z is 478.14, and the experimental value is 478.50.

[0445] Example 20 3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyromylatesulfonyl)phenyl)-6-phenylpyridazine-4-carboxamide

[0446] Reagents and conditions: a) K2CO3, Pd(dppf)Cl2, phenylboronic acid, dioxane / water, 100℃; b) MeOH / H2O, KOH, 70℃; c) SOCl2, 1 hour, room temperature, NH4OH; d) 1-bromo-3-(methylsulfinyl)benzene, Cs2CO3, Xantphos-Pd-G2, dioxane, 100℃; e) PhI(OAc)2, NH2CO2NH4, MeOH, 70℃.

[0447] Step 1: Methyl 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate: Methyl 6-chloro-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazine-4-carboxylate (600 mg, 1.88 mmol) and phenylboronic acid (1.146 g, 9.401 mmol) in 1,4-dioxane / H2O (4 / 1, 10 mL), potassium carbonate (779 mg, 5.641 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (137 mg, 0.188 mmol) were heated at 100 °C for 6 hours under a N2 atmosphere. The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 3 / 1) to give methyl 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate (600 mg, 88.2%) as a white oil. LCMS (ESI): C 19 H 22 F2N3O2[M + H] + The calculated value of m / z is 362.17, and the experimental value is 362.00.

[0448] Step 2: 3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazin-4-carboxylic acid: At room temperature, KOH (0.852 g, 15.19 mmol) was added to a solution of methyl 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazin-4-carboxylic acid (0.550 g, 1.519 mmol) in MeOH / H2O (1 / 1, 10 mL). The mixture was heated at 70 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with DCM (10 mL). The aqueous phase was then adjusted to pH = 3 with 1 N HCl and extracted with DCM (10 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid (500 mg, 65.8%) as a white solid. LCMS (ESI): C 18 H 20 F2N3O2[M + H] + The calculated value of m / z is 348.15, and the experimental value is 348.00.

[0449] Step 3: 3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazin-4-carboxamide: A solution of 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazin-4-carboxylic acid (450 mg, 1.293 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated. The residue was diluted with THF and added dropwise to a stirred solution of ammonium hydroxide (5 mL). The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazine-4-carboxamide (420 mg, 93.8%) as a white solid. LCMS (ESI): C 18 H 21 F2N4O [M + H] + The calculated value of m / z is 347.17, and the experimental value is 347.05.

[0450] Step 4.3 -(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6-phenylpyridazin-4-carboxamide: At room temperature, 1-bromo-3-(methylsulfinyl)benzene (946 mg, 3.456 mmol), cesium carbonate (975 mg, 2.995 mmol), and Xantphos-Pd-G2 (204 mg, 0.230 mmol) were added to a solution of 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-phenylpyridazin-4-carboxamide (400 mg, 1.152 mmol) in dioxane (8 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was complete, 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 silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6-phenylpyridazine-4-carboxamide (120 mg, 21.5%) as a white solid. LCMS (ESI): C 25 H 27 F2N4O2S [M + H] + The calculated value of m / z is 485.18, and the experimental value is 485.10.

[0451] Step 5: 3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminoylsulfonyl)phenyl)-6-phenylpyridazin-4-carboxamide: At room temperature, PhI(OAc)2 (199 mg, 0.618 mmol) and ammonium carbamate (58 mg, 0.741 mmol) were added to a solution of 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6-phenylpyridazin-4-carboxamide (120 mg, 0.247 mmol) in MeOH (5 mL). 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 (5 mL), and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was first purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1), and then by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was further purified by elution with 30% to 90% ACN-H2O containing 0.1% formic acid to give 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminoylsulfonyl)phenyl)-6-phenylpyridazine-4-carboxamide (28 mg, 20%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6, ppm) δ 11.08 (s, 1 H), 8.32 (s, 1H), 7.89 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8 Hz, 1 H), 7.62 (d, J = 8 Hz, 1 H),7.59-7.57 (m, 2 H), 7.55-7.51 (m, 2H), 7.49-7.46 (m, 1 H), 4.24 (s, 1 H),3.78-3.76 (m, 2 H), 3.67-3.64 (m, 2 H), 3.06 (s, 3 H), 2.35-2.32 (m, 2 H), 2.19 (s, 3 H), 2.06-2.04 (m, 2 H), 1.89-1.87 (m, 2 H). LCMS(ESI):C 25 H 28 F2N5O2S[M + H] + The calculated value of m / z is 500.20, and the experimental value is 499.95.

[0452] Example 21 4-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyromylatesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0453] Reagents and conditions: a) DIEA, 4,4-difluoroazacycloheptanylhydrogen chloride, dioxane, 80℃; b) NH3-MeOH, 65℃; c) HI, 40℃; d) Cu, [Ph2SCF3] + [OTf] - e) Cs2CO3, 1-bromo-3-(methylsulfinyl)benzene, Xantphos-Pd-G2, dioxane, 100℃; f) PhI(OAc)2, NH2CO2NH4, MeOH.

[0454] Step 1: Methyl 6-chloro-4-(4,4-difluoroazacyclohepta-1-yl)pyridazin-3-carboxylate: DIEA (6.27 g, 48.6 mmol) was added to a solution of methyl 4,6-dichloropyridazin-3-carboxylate (5.0 g, 24.3 mmol) and 4,4-difluoroazacyclohepta-hydrochloride (4.98 g, 29.2 mmol) in 1,4-dioxane (50 mL). The mixture was heated at 80 °C for 4 hours. LCMS showed the reaction was complete. The mixture was concentrated and purified by silica gel rapid column chromatography (PE / EtOAc = 15 / 1) to give methyl 6-chloro-4-(4,4-difluoroazacyclohepta-1-yl)pyridazin-3-carboxylate (4.8 g, 64.9%) as a white solid. LCMS (ESI): C 12 H 15 ClF2N3O2[M + H] + The calculated m / z value is 306.08, and the experimental value is 305.90.

[0455] Step 2: 6-Chloro-4-(4,4-difluoroazacyclohepta-1-yl)pyridazin-3-carboxamide: A solution of methyl 6-chloro-4-(4,4-difluoroazacyclohepta-1-yl)pyridazin-3-carboxylate (4.8 g, 15.7 mmol) in NH3-MeOH (7 M, 15 mL) was heated at 60 °C for 16 hours in a high-pressure reactor. The reaction mixture was concentrated to give crude 6-chloro-4-(4,4-difluoroazacyclohepta-1-yl)pyridazin-3-carboxamide (4.8 g), which could be used in the next step without purification. LCMS (ESI): C 11 H 14 ClF2N4O [M + H]+ The calculated value of m / z is 291.08, and the experimental value is 290.95.

[0456] Step 3: 4-(4,4-Difluoroazacyclohepta-1-yl)-6-iodadiazine-3-carboxamide: A solution of 6-chloro-4-(4,4-difluoroazacyclohepta-1-yl)pyridazine-3-carboxamide (2.5 g, 8.62 mmol) in HI (10 mL, 57% aqueous solution) was heated at 40 °C for 5 hours. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(4,4-difluoroazacyclohepta-1-yl)-6-iodadiazine-3-carboxamide (2.2 g, 66.8%) as a white solid. LCMS (ESI): C 11 H 14 F2IN4O [M + H] + The calculated value of m / z is 383.02, and the experimental value is 382.85.

[0457] Step 4: 4-(4,4-Difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide: 4-(4,4-difluoroazacyclohepta-1-yl)-6-iodopyridazin-3-carboxamide (2.2 g, 5.76 mmol), Cu (1.1 g, 17.28 mmol), and [Ph2SCF3] were added. + [OTf] - The mixture (4.6 g, 11.52 mmol) in DMF (15 mL) was heated at 60 °C for 5 hours. LCMS showed the reaction was complete. The mixture was then filtered through diatomaceous earth. The filtrate was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 5 / 1) to give 4-(4,4-difluoroazacycloheptan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (1.3 g, 69.5%) as a yellow oil. LCMS (ESI): C 12 H 14 F5N4O [M + H] + The calculated value of m / z is 325.11, and the experimental value is 324.95.

[0458] Step 5: 4-(4,4-Difluoroazacyclohepta-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazin-3-carboxamide: A solution of 4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide (200 mg, 0.60 mmol), 1-bromo-3-(methylsulfinyl)benzene (262 mg, 1.2 mmol), Cs₂CO₃ (587 mg, 1.8 mmol), and Xantphos-Pd-G₂ (55 mg, 0.06 mmol) in 1,4-dioxane (6 mL) was heated overnight at 100 °C under a nitrogen atmosphere. LCMS showed the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 4 / 1) to give 4-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (120 mg, 43%) as a white oil. LCMS (ESI): C 19 H 20 F5N4O2S[M + H] + The calculated value of m / z is 463.12, and the experimental value is 463.00.

[0459] Step 6: 4-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide: At room temperature, PhI(OAc)2 (347.49 mg, 1.08 mmol) and ammonium carbamate (100.98 mg, 1.29 mmol) were added to a solution of 4-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (120 mg, 0.25 mmol) in MeOH (5 mL). The reaction mixture was heated at 70 °C for 3 hours. The mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was subjected to preparative HPLC (Gemini 5 μm C). 18 The column, 150 x 21.2 mm, was eluted with 50% to 55% ACN-H2O containing 0.1% FA to give 4-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminoylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (15 mg, 12.1%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 11.34 (s, 1H), 8.38 (s, 1H), 7.99 (d, J = 8.1 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 7.43 (s, 1 H), 4.25 (s, 1 H), 3.67 (s, 2 H), 3.56 (t, J = 5.7Hz, 2H), 3.07 (s, 3H), 2.37-2.23 (m, 2H), 2.12-1.00 (m, 2H), 1.94-1.84(s, 2H). LCMS(ESI):C 19 H 21 F5N5O2S[M + H] + The calculated value of m / z is 478.14, and the experimental value is 478.05.

[0460] Example 22 6-Cyclopropyl-3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)pyridazine-4-carboxamide

[0461] Reagents and conditions: a) K3PO4, Pd(dppf)Cl2, cyclopropylboronic acid, THF / water, 90℃, MW; b) MeOH / H2O, KOH, 70℃; c) SOCl2, 1 hour, room temperature, NH4OH; d) 1-bromo-3-(methylsulfinyl)benzene, Cs2CO3, Xantphos-Pd-G2, dioxane, 100℃; e) PhI(OAc)2, NH2CO2NH4, MeOH, 70℃ Step 1. Methyl 6-chloro-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazine-4-carboxylate: At room temperature under nitrogen, a mixture of methyl 6-chloro-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazine-4-carboxylate (600 mg, 1.880 mmol) and cyclopropylboronic acid (323 mg, 3.760 mmol) in THF (10 mL) was supplemented with potassium phosphate (797 mg, 3.760 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (137 mg, 0.188 mmol). After the addition, the reaction mixture was heated in a microwave reactor at 90 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 3 / 1) to give methyl 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazine-4-carboxylate (550 mg, 90.0%) as a white oil. LCMS (ESI): C 16 H 22 F2N3O2[M + H] + The calculated value of m / z is 326.17, and the experimental value is 326.00.

[0462] Step 2: 6-Cyclopropyl-3-(4,4-Difluoroazacyclohepta-1-yl)-5-methylpyridazin-4-carboxylic acid: At room temperature, KOH (861 mg, 15.38 mmol) was added to a solution of methyl 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazin-4-carboxylic acid (500 mg, 1.538 mmol) in MeOH / H2O (1 / 1, 10 mL). The mixture was heated at 70 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with DCM (10 mL). The aqueous phase was then adjusted to pH = 3 with 1 N HCl and extracted with DCM (10 mL x 3). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazine-4-carboxylic acid (380 mg, 79.5%) as a white solid. LCMS (ESI): C 15 H 20 F2N3O2[M + H] + The calculated value of m / z is 312.15, and the experimental value is 312.00.

[0463] Step 3: 6-Cyclopropyl-3-(4,4-Difluoroazacycloheptan-1-yl)-5-methylpyridazine-4-carboxamide: A solution of 6-cyclopropyl-3-(4,4-difluoroazacycloheptan-1-yl)-5-methylpyridazine-4-carboxylic acid (350 mg, 1.125 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was dissolved in THF (3 mL) and added dropwise to a stirred solution of ammonium hydroxide (5 mL). The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the filtrate was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazine-4-carboxamide (280 mg, 80.4%) as a white solid. LCMS (ESI): C 15 H 21 F2N4O [M + H] + The calculated value of m / z is 311.17, and the experimental value is 311.05.

[0464] Step 4: 6-Cyclopropyl-3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazin-4-carboxamide: At room temperature, 1-bromo-3-(methylsulfinyl)benzene (526 mg, 2.411 mmol), cesium carbonate (678 mg, 2.087 mmol), and Xantphos-Pd-G2 (143 mg, 0.161 mmol) were added to a solution of the obtained 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methylpyridazin-4-carboxamide (250 mg, 0.803 mmol) in dioxane (8 mL). The reaction mixture was heated at 100 °C for 16 hours under nitrogen. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide (90 mg, 25.1%) as a white solid. LCMS (ESI): C 22 H 27 F2N4O2S [M + H] + The calculated value of m / z is 449.18, and the experimental value is 450.10.

[0465] Step 5: 6-Cyclopropyl-3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminoylsulfonyl)phenyl)pyridazin-4-carboxamide: At room temperature, PhI(OAc)2 (161 mg, 0.501 mmol) and ammonium carbamate (46 mg, 0.600 mmol) were added to a solution of 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazin-4-carboxamide (90 mg, 0.200 mmol) in MeOH (5 mL). 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 (15 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 first purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1), and then by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm, eluted with 30% to 90% ACN-H2O containing 0.1% formic acid) was further purified to give 6-cyclopropyl-3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)pyridazine-4-carboxamide (52 mg, 56%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.11 (s, 1 H), 8.39 (s, 1 H), 7.92 (d, J = 8 Hz, 1 H), 7.77 (d, J = 7.2 Hz, 1 H), 7.70-7.66 (m, 1 H), 3.67-3.63 (m, 2 H), 3.58-3.55 (m, 2 H), 2.50 (s, 3 H), 2.33 (s, 3 H), 2.29-2.15 (m, 3 H), 2.01-2.00 (m, 2 H), 1.83-1.81 (m, 2 H), 1.01-0.98 (m, 4 H). LCMS(ESI):C 22 H 28 F2N5O2S [M + H] + The calculated value of m / z is 464.20, and the experimental value is 464.00.

[0466] Example 23 ( S6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0467] Reagents and conditions: a) KOH, THF, H2O, 80℃; b) ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 c) tert-butyl carbamate (-thionyl)carbamate, POCl3, pyridine; c) potassium trifluoroborate (cyclopropylmethyl)trifluoroborate, Cs2CO3, Pd(OAc)2, Ru-Phos, toluene / H2O, 100℃; d) TFA, DCM Step 1: 6-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid: At room temperature, KOH (368 mg, 6.6 mmol) was added to a solution of methyl 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (200 mg, 0.66 mmol) in THF / H₂O (1 / 1, 10 mL). The mixture was heated at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and then 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 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (180 mg, 94.7% yield) as a white solid. LCMS (ESI): C 12 H 14 ClF2N2O2[M + H] + The calculated value of m / z is 291.07, and the experimental value is 290.95.

[0468] Step 2: ( S )-((3-(6-chloro-2-(4,4-difluoroazacyclohepten-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl carbamate (-thionyl)carbamate: at 0 °C, 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (120 mg, 0.41 mmol) and ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6224 mg (0.83 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (5 mL) and POCl3 (100 µL). The reaction solution was stirred at 0 °C for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 2 / 1) to give a yellow oil. S )-((3-(6-chloro-2-(4,4-difluoroazacyclohepten-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl) tert-butyl carbamate (110 mg, 49.5%). LCMS (ESI): C 24 H 29 ClF2N4O4SNa [M + H] + The calculated value of m / z is 565.16, and the experimental value is 565.10.

[0469] Step 3: ( S )-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl 3-thionyl)carbamate: Under a N2 atmosphere, ( S )-((3-(6-chloro-2-(4,4-difluoroazacyclohepten-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 A mixture of tert-butyl 3-thionyl)carbamate (90 mg, 0.167 mmol), potassium (cyclopropylmethyl)trifluoroborate (83 mg, 0.52 mmol), cesium carbonate (163 mg, 0.5 mmol), Pd(OAc)₂ (15 mg, 0.07 mmol), and Ru-phos (24 mg, 0.052 mmol) in toluene / H₂O (10 / 1, 11 mL) was heated at 100 °C for 16 hours. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to give a yellow oily substance. S )-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (50 mg, 53.8%). LCMS (ESI): C 28 H37 F2N4O4S [M + H] + The calculated value of m / z is 563.25, and the experimental value is 563.20.

[0470] Step 4: ( S )-6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide: at room temperature, to ( S )-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 50 mg (0.09 mmol) of tert-butyl thiocarbamate (THB) was added to a solution of DCM (3 mL) with TFA (0.3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated and the residue was adjusted to pH 8-9 with saturated NaHCO3 aqueous solution. The aqueous solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 * 21.2 mm) was used for purification with 35% to 85% MeCN / H2O containing 0.1% trifluoroacetic acid to provide a white solid ( S 6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminoylsulfonyl)phenyl)nicotinamide (13.3 mg, 32.4%). 1 H NMR (400 MHz, DMSO-d6) δ10.64 (s, 1 H), 8.34 (s, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.73-7.47 (m, 3 H), 6.70 (d, J = 7.6 Hz, 1 H), 4.18 (s, 1 H), 3.63 (s, 2 H), 3.42 (t, J = 5.8 Hz, 2H), 3.04 (s, 3 H), 2.53 (d, J = 7.0 Hz, 2 H), 2.32 (t, J= 10.9 Hz, 2 H), 2.03-1.90 (m, 2 H), 1.89-1.76 (m, 2 H), 1.12-1.02 (m, 1 H), 0.58-0.39 (m, 2 H), 0.26-0.17 (m, 2 H). LCMS(ESI):C 23 H 29 F2N4O2S [M + H] + The calculated value of m / z is 463.20, and the experimental value is 463.10.

[0471] Example 24 ( R 6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0472] Reagents and conditions: a) R )-((3-aminophenyl)(methyl)(oxo)-λ 6 a) tert-butyl carbamate (-thionyl)carbamate, POCl3, pyridine; b) potassium trifluoroborate ((cyclopropylmethyl)trifluoroborate), Cs2CO3, Pd(OAc)2, Ru-Phos, toluene / H2O, 100℃; c) TFA, DCM Step 1: ( R )-((3-(6-chloro-2-(4,4-difluoroazacyclohepten-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 -Thiodiyl) tert-butyl carbamate: at 0 °C, to 6-chloro-2-(4,4-difluoroazacyclohepta-1-yl)nicotinic acid (150 mg, 0.52 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 279 mg, 1.03 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (5 mL) and POCl3 (100 µL). The reaction solution was stirred at 0 °C for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 2 / 1) to give a yellow oil. R )-((3-(6-chloro-2-(4,4-difluoroazacyclohepten-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 63-Thiodimethyl)carbamate tert-butyl ester (140 mg, 49.8%). LCMS (ESI): C 24 H 29 ClF2N4O4SNa [M + Na] + The calculated value of m / z is 565.16, and the experimental value is 565.10.

[0473] Step 2: ( R )-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl 3-thionyl)carbamate: Under a N2 atmosphere, ( R )-((3-(6-chloro-2-(4,4-difluoroazacyclohepten-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 A mixture of tert-butyl 3-thionyl)carbamate (140 mg, 0.26 mmol), potassium (cyclopropylmethyl)trifluoroborate (83 mg, 0.52 mmol), cesium carbonate (250 mg, 0.78 mmol), Pd(OAc)₂ (15 mg, 0.07 mmol), and Ru-phos (24 mg, 0.052 mmol) in toluene / H₂O (10 / 1, 11 mL) was heated at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to give ( R )-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl) tert-butyl carbamate (75 mg, 51.3%). LCMS (ESI): C 28 H 37 F2N4O4S [M + H] + The calculated value of m / z is 563.25, and the experimental value is also 563.25.

[0474] Step 3: ( R )-6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide: at room temperature, to ( R )-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6tert-butyl 3-thionyl)carbamate (75 mg, 0.13 mmol) was added to a solution of DCM (3 mL) with TFA (0.3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated and the residue was adjusted to pH 8-9 with saturated NaHCO3 solution. The aqueous solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 * 21.2 mm) was used for purification with 35% to 85% MeCN / H2O containing 0.1% trifluoroacetic acid to provide a white solid ( R 6-(cyclopropylmethyl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminoylsulfonyl)phenyl)nicotinamide (26.2 mg, 39%). 1 H NMR (400 MHz, DMSO- d 6) δ10.64 (s, 1 H), 8.34 (s, 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.73-7.47 (m, 3 H), 6.70 (d, J = 7.6 Hz, 1 H), 4.18 (s, 1 H), 3.63 (s, 2 H), 3.42 (t, J = 5.8 Hz, 2H), 3.04 (s, 3 H), 2.53 (d, J = 7.0 Hz, 2 H), 2.32 (t, J = 10.9 Hz, 2 H), 2.03-1.90 (m, 2 H), 1.89-1.76 (m, 2 H), 1.12-1.02 (m, 1 H), 0.58-0.39 (m, 2 H), 0.26-0.17 (m, 2 H). LCMS(ESI):C 23 H 29 F2N4O2S [M + H] + The calculated value of m / z is 463.20, and the experimental value is 463.15.

[0475] Example 25 6-Methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinamide

[0476] Reagents and conditions: a) 6-azaspiro[2.5]octane hydrochloride, DIEA, dioxane; b) trimethylboroxane, Pd(dppf)Cl2, K2CO3, dioxane / H2O, 100℃; c) NBS, DCM; d) Pd(dppf)Cl2, Et3N, EtOH, CO, 110℃; e) KOH, MeOH / H2O, 70℃; f) ((3-aminophenyl)(methyl)(oxo)-λ 6 -Thiodimethyl) tert-butyl carbamate, POCl3, pyridine; g) TFA, DCM Step 1: 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: DIEA (3.60 g, 27.90 mmol) was added to a mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (3 g, 13.95 mmol) and 6-azaspiro[2.5]octane hydrochloride (2.06 g, 13.95 mmol) in 1,4-dioxane (50 mL) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 20 / 1) to provide 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (2.5 g, 61.6%) as a yellow oil. LCMS (ESI): C 13 H 15 ClF3N2[M + H] + The calculated value of m / z is 291.09, and the experimental value is 291.00.

[0477] Step 2: 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: A mixture of 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (2.5 g, 8.59 mmol), trimethylboroxane (10.78 g, 85.9 mmol), Pd(dppf)Cl2 (628 mg, 0.86 mmol), and K2CO3 (3.55 g, 25.77 mmol) in dioxane / H2O (4 / 1, 25 mL) was heated at 100 °C for 16 hours under a N2 atmosphere. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 20 / 1) to give 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.9 g, 81.6%) as a yellow oil. LCMS (ESI): C 14 H 18 F3N2[M + H] + The calculated value of m / z is 271.14, and the experimental value is 271.10.

[0478] Step 3: 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: NBS (1.37 g, 7.71 mmol) was added to a solution of 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.9 g, 7.01 mmol) in DCM (30 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and purified directly by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.5 g, 65.9%) as a yellow oil. LCMS (ESI): C 14 H 17 BrF3N2[M + H] + The calculated value of m / z is 351.05, and the experimental value is 351.00.

[0479] Step 4: Ethyl 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinate: In a high-pressure reactor under a CO (30 atm) atmosphere, a mixture of 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.5 g, 4.30 mmol), Pd(dppf)Cl2 (157.16 mg, 0.21 mmol), and triethylamine (1.30 g, 12.9 mmol) in EtOH (10 mL) was heated at 110 °C for 16 hours. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 10 / 1) to give ethyl 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinic acid (1.3 g, 94%) as a yellow solid. LCMS (ESI): C 17 H 22 F3N2O2[M + H] + The calculated value of m / z is 343.17, and the experimental value is 343.15.

[0480] Step 5: 6-Methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinic acid: At room temperature, KOH (2.12 g, 37.9 mmol) was added to a solution of ethyl 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinic acid (1.3 g, 3.79 mmol) in MeOH / H2O (1 / 1, 40 mL). The mixture was heated at 70 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH 3-4 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinic acid (900 mg, 75.4%) as a yellow solid. LCMS (ESI): C 15 H 18 F3N2O2[M + H] + The calculated value of m / z is 315.13, and the experimental value is 315.15.

[0481] Step 6: (methyl(3-(6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 63-Thiodiyl) tert-butyl carbamate: At room temperature, 6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinic acid (250 mg, 0.7936 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 6 322.62 mg, 1.1904 mmol) tert-butyl carbamate was added to a mixture of pyridine (8 mL) and POCl3 (750 µL).

[0482] The reaction mixture was stirred at room temperature for 2 hours. The mixture was then 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 rapid column chromatography (PE / EtOAc = 1 / 1) to give (methyl(3-(6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ as a yellow solid. 6 3-Thiodimethyl)carbamate tert-butyl ester (190 mg, 42.2%). LCMS (ESI): C 27 H 34 F3N4O4S [M + H] + The calculated value of m / z is 567.23, and the experimental value is 567.15.

[0483] Step 7: 6-Methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinamide: to (methyl(3-(6-methyl-2-(6-azaspiro[2.5]oct-6-yl)-5-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2 mL of TFA was added to a solution of tert-butyl thiocarbamate (190 mg, 0.3351 mmol) in DCM (6 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 residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The sample was purified by elution with 40% to 85% ACN-H2O containing 0.1% formic acid on a column of 150 x 21.2 mm to give a white solid (50 mg, 32%). 1 H NMR (400 MHz, DMSO-) d6) δ 10.77 (s, 1 H), 8.34 (s, 1 H), 7.97-7.86 (m, 2 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 3.64-3.52 (m, 4 H), 3.07 (s, 3H), 2.50 (s, 3 H), 1.41-1.32 (m, 4 H), 0.31 (s, 4 H). LCMS(ESI):C 22 H 26 F3N4O2S [M+ H] + The calculated value of m / z is 467.18, and the experimental value is 467.10.

[0484] Example 26 ( R )-5-chloro-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide

[0485] Reagents and conditions: a) R )-((3-aminophenyl)(methyl)(oxo)-λ 6 (b) Thionyl) tert-butyl carbamate, POCl3, pyridine; Step 1: ( R )-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo)-16-thionyl)carbamate: At 50 °C, 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (250 mg, 0.892 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 375 µL of POCl3 was added to a mixture of 265 mg (0.982 mmol) of thiodimethyl (thiodimethyl)carbamate (4 mL) and pyridine (4 mL). The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 1 / 1) to give a yellow oily substance. R)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (120 mg, 25.3%). LCMS (ESI): C 26 H 34 ClN4O4S [M + H] + The calculated value of m / z is 533.20, and the experimental value is 533.15.

[0486] Step 2: ( R )-5-chloro-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide: at room temperature, to ( R )-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (120 mg, 0.225 mmol) in DCM (3 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 residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was used for purification with 30% to 90% ACN-H2O containing 0.1% formic acid to obtain a white solid. R 5-Chloro-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (70 mg, 71.4%). 1 H NMR (400 MHz, DMSO-) d 6, ppm) δ 10.82 (s, 1 H), 8.41 (s, 1 H), 7.89 (d, J = 7.6 Hz, 1H), 7.80 (s, 1 H), 7.67 (d, J = 8 Hz, 1 H), 7.62-7.58 (m, 1 H), 3.36-3.33 (m, 4H), 3.11 (s, 3 H), 2.46 (s, 3 H), 1.38-1.36 (m, 4 H), 0.29 (s, 4 H). LCMS(ESI):C 21 H 26ClN4O2S [M + H] + The calculated value of m / z is 433.15, and the experimental value is 433.05.

[0487] Example 27 ( S )-5-chloro-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide

[0488] Reagents and conditions: a) S )-((3-aminophenyl)(methyl)(oxo)-λ 6 (b) Thionyl) tert-butyl carbamate, POCl3, pyridine; Step 1: ( S )-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo) - λ 6 2-Thiodimethyl)carbamate tert-butyl ester: At room temperature, 5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (200 mg, 0.7143 mmol) and ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 232.29 mg (0.8571 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (5 mL) and POCl3 (500 µL). The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL 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 rapid column chromatography (PE / EtOAc = 2 / 1) to give a white solid ( S )-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo) - λ 6 3-Thiodimethyl)carbamate tert-butyl ester (120 mg, 31.5%). LCMS (ESI): C 26 H 34 ClN4O4S [M + H] + The calculated value of m / z is 533.20, and the experimental value is 533.15.

[0489] Step 2: ( S)-5-chloro-6-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide: at room temperature, to ( S )-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)phenyl)(methyl)(oxo) - λ 6 1 mL of TFA was added to a solution of tert-butyl thiocarbamate (120 mg, 0.2169 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was used for purification with 45% to 95% ACN-H2O containing 0.1% formic acid to provide a white solid ( S 5-Chloro-6-methyl-N-(3-(S-methylaminoylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (42 mg, 44.72%). 1 H NMR (400 MHz, DMSO-d6, ppm) δ 10.81 (s, 1 H), 8.39 (s, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.80 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.59 (t, J =7.9 Hz, 1 H), 3.36 (d, J = 5.2 Hz, 4 H), 3.06 (s, 3 H), 2.47 (s, 3 H), 1.43-1.31 (m, 4 H), 0.29 (s, 4 H). LCMS(ESI):C 21 H 26 ClN4O2S [M + H] + The calculated value of m / z is 433.15, and the experimental value is 433.10.

[0490] Example 28 ( R 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0491] Reagents and conditions: a) DIEA, 4,4-difluoroazacycloheptane hydrochloride, dioxane, 80℃; b) KOH, MeOH, H2O, 70℃; c) POCl3, pyridine, ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 d) Thionyl) tert-butyl carbamate; d) TFA, DCM, room temperature Step 1: Ethyl 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: A solution of ethyl 3-chloro-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 2.99 mmol), 4,4-difluoroazacyclohepta-hydrochloride (613 mg, 3.58 mmol), and DIEA (1155 mg, 8.96 mmol) in dioxane (10 mL) was heated at 80 °C for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under vacuum and purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to provide ethyl 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 73.1%) as a yellow solid.

[0492] LCMS (ESI): C 15 H 19 F5N3O2[M + H] + The calculated value of m / z is 368.14, and the experimental value is 367.95.

[0493] Step 2: 3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: At room temperature, KOH (872 mg, 21.80 mmol) was added to a solution of ethyl 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (800 mg, 2.48 mmol) in MeOH / H₂O (1 / 1, 10 mL). The mixture was heated at 70 °C for 5 hours. After the reaction was complete, the mixture was concentrated to remove most of the MeOH. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and then 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 3-(4,4-difluoroazacycloheptan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (600 mg, 81.2%) as a yellow solid. LCMS (ESI): C 13 H 15F5N3O2[M + H] + The calculated value of m / z is 340.11, and the experimental value is 340.00.

[0494] Step 3: ( R )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 -Thiodiol)carbamic acid Uncle Butyl ester (175 mg, 0.65 mmol) was added dropwise to a solution of pyridine (10 mL) with POCl3 (100 µL). The mixture was heated at 50 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 3) to provide a yellow solid ( R )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (90 mg, 25.9%). LCMS (ESI): C 20 H 23 F5N5O2S[M - Boc + H] + The calculated value of m / z is 492.15, and the experimental value is also 492.15.

[0495] Step 4: ( R )-3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to ( R )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 690 mg (0.15 mmol) of tert-butyl thiocarbamate (THB) was added to a solution of DCM (1.5 mL) with 0.5 mL of TFA. The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The final mixture was concentrated under vacuum and analyzed by preparative HPLC (Gemini 5µm C). 18 The column (150 x 21.2 mm) was purified by elution with 30% to 90% ACN-H2O containing 0.1% ammonium hydroxide to give a yellow solid. R 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (15 mg, 20.3%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.11(s, 1 H), 8.27 (s, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 4.28 (s, 1 H), 3.85 (s, 2 H), 3.69 (t, J = 5.9 Hz, 2H), 3.08 (s, 3 H), 2.33 (s, 3 H), 2.11-1.99 (m, 2 H), 1.93-1.81 (m, 2 H), 1.23 (s, 2 H). LCMS(ESI):C 20 H 23 F5N5O2S [M + H] + The calculated value of m / z is 492.15, and the experimental value is 492.10.

[0496] Example 29 ( S 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0497] Reagents and conditions: a) POCl3, pyridine, ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 - (b) Thioyl) tert-butyl carbamate; TFA, DCM, room temperature Step 1: ( S )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-(3-thionyl)-16-thionyl)carbamate tert-butyl ester: POCl3 (400 µL) was added dropwise to a mixture of 3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol) and (S)-((3-aminophenyl)(methyl)(oxo)-16-thionyl)carbamate tert-butyl ester (191.16 mg, 0.708 mmol) in pyridine (3.2 mL) at 50 °C. The reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1) to give a yellow solid ( S )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl) tert-butyl carbamate (120 mg, 34.2%). LCMS (ESI): C 25 H 31 F5N5O4S [M + H] + The calculated value of m / z is 592.19, and the experimental value is 592.15.

[0498] Step 2: ( S )-3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to the obtained ( S )-((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (120 mg, 0.203 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18The column (150 x 21.2 mm) was used for purification with 30% to 90% ACN-H2O containing 0.1% formic acid to obtain a white solid. S )-3-(4,4-difluoroazacyclohep-1-yl)-5-methyl-N-(3-(S-methylaminoylidenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (20 mg, 20%). 1 H NMR (400 MHz, DMSO- d 6) δ11.12 (s, 1 H), 8.27 (s, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.73 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1 H), 3.85 (s, 2 H), 3.69 (t, J = 5.8 Hz, 2 H), 3.08 (s, 3 H), 2.37 (d, J = 16.1 Hz, 2 H), 2.33 (s, 3 H), 2.12-2.02 (m, 2 H), 1.92-1.85 (m, 2 H). LCMS(ESI):C 20 H 23 F5N5O2S [M + H] + The calculated value of m / z is 492.15, and the experimental value is 492.00.

[0499] Example 30 ( S )-6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0500] Reagents and conditions: a) POCl3, pyridine, ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 b) tert-butyl carbamate (-thionyl) carbamate; TFA, DCM, room temperature Step 1: ( S )-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazacycloheptane-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6tert-butyl carbamate (-thionyl)carbamate: at 50 °C, 6-(3-buten-1-yl)-2-(4,4-difluoroazacycloheptyl-1-yl)nicotinic acid (175 mg, 0.564 mmol) and ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6 250 µL of POCl3 was added to a mixture of tert-butyl 3-thionyl)carbamate (168 mg, 0.620 mmol) and pyridine (4 mL). After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 1 / 1) to give a yellow oily substance. S )-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazacycloheptane-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (80 mg, 25.15%). LCMS (ESI): C 28 H 37 F2N4O4S [M + H] + The calculated value of m / z is 563.25, and the experimental value is 563.20.

[0501] Step 2: ( S )-6-(3-Buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide: at room temperature, to ( S )-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazacycloheptane-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (80 mg, 0.143 mmol) in DCM (3 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 residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 * 21.2 mm) was purified by elution with 30% to 90% ACN-H2O containing 0.1% formic acid to obtain a white solid. S)-6-(3-buten-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminoylidenesulfonyl)phenyl)nicotinamide (23 mg, 35%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.68 (s, 1 H), 8.37 (s, 1 H), 7.91 (d, J = 7.6Hz, 1 H), 7.66-7.56 (m, 2 H), 6.65 (d, J =8 Hz, 1 H), 5.92-5.82 (m, 1 H), 5.07-4.95 (m, 2 H), 3.64-3.62 (m, 2 H), 3.43-3.40 (m, 2 H), 3.14 (s, 3 H), 2.74-2.67 (m, 2 H), 2.45-2.43 (m, 2 H), 2.34-2.32 (s, 2 H), 1.93-1.84 (m, 4 H). LCMS(ESI):C 23 H 29 F2N4O2S [M + H] + The calculated value of m / z is 463.20, and the experimental value is 463.10.

[0502] Example 31 3-(4,4-Difluoroazacyclohepta-1-yl)-5-methyl-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazin-4-carboxamide

[0503] Reagents and conditions: a) POCl3, pyridazine-4-amine, pyridine At room temperature, POCl3 (150 µL) was added dropwise to a mixture of 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (150 mg, 0.44 mmol) and pyridazine-4-amine (84 mg, 0.88 mmol) in pyridine (6 mL). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the resulting solution was diluted with water (40 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified first by silica gel rapid column chromatography (DCM / MeOH = 20 / 1) and then by preparative HPLC (Gemini 5 μm C). 18The column (150 x 21.2 mm) was further purified with 35% to 75% ACN-H2O containing 0.1% TFA to give 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazin-4-carboxamide (25.2 mg, 13%) as a white solid. LCMS (ESI): C 17 H 18 F5N6O [M + H] + The calculated value of m / z is 417.15, and the experimental value is 417.00. 1 H NMR (400 MHz, DMSO- d 6) δ 11.51 (s, 1 H), 9.31 (d, J = 2.3 Hz, 1H), 9.18 (d, J = 5.9 Hz, 1 H), 8.07 (dd, J = 5.8, 2.7 Hz, 1 H), 3.83 (s, 2 H), 3.61 (t, J = 5.9 Hz, 2 H), 2.37 (d, J = 15.7 Hz, 2 H), 2.32 (s, 3 H), 2.16-1.94 (m, 2 H), 1.94-1.79 (m, 2 H).

[0504] Example 32 4-(4,4-Difluoroazacyclohepta-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide

[0505] Reagents and conditions: a) Tf2O, Et3N, DCM, 0℃; b) 4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide, Cs2CO3, Xantphos-Pd-G2, pyridazin-4-yl ester of trifluoromethanesulfinic acid, dioxane, 100℃.

[0506] Step 1: Pyridazin-4-yltrifluoromethanesulfonate: At 0 °C, Tf₂O (1056 mg, 3.74 mmol) was added to a solution of pyridazin-4-ol (300 mg, 3.12 mmol) and Et₃N (630 mg, 6.24 mmol) in DCM (20 mL). The mixture was stirred at the same temperature for 30 min. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to provide pyridazin-4-yltrifluoromethanesulfinate as a yellow oil (100 mg, 14% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.81 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 2.7 Hz, 1H), 6.63 (dd, J = 8.6, 2.8 Hz, 1 H).

[0507] Step 2: 4-(4,4-Difluoroazacyclohepta-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide: Xantphos-Pd-G2 (53 mg, 0.06 mmol) was added to a solution of 4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide (100 mg, 0.31 mmol), pyridazin-4-yl trifluoromethanesulfinate (100 mg, 0.46 mmol), and Cs₂CO₃ (202 mg, 0.62 mmol) in 1,4-dioxane (5 mL). The mixture was then heated at 100 °C for 16 hours under a N₂ atmosphere. The resulting mixture was filtered through diatomaceous earth. The filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was first purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 1), and then by preparative HPLC (Gemini 5µm C). 18 The column (150 x 21.2 mm, eluted with 30% to 90% ACN-H2O containing 0.1% formic acid) was further purified to give 4-(4,4-difluoroazacyclohepta-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide (7 mg, 6%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 11.68 (s, 1 H), 9.51 (d, J = 2.2 Hz, 1 H), 9.13 (d, J = 5.9 Hz, 1 H), 8.10 (dd, J = 5.8, 2.5 Hz, 1 H), 7.49 (s, 1 H), 3.71-3.60 (m, 2 H), 3.49 (t, J = 5.6 Hz, 2 H), 2.32 (s, 2 H), 2.04 (t, J = 12.4 Hz, 2H), 1.90 (d, J = 4.9 Hz, 2 H). LCMS(ESI):C 16 H 16 F5N6O [M + H] + The calculated value of m / z is 403.12, and the experimental value is 402.95.

[0508] Example 33 ( R )-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide

[0509] Reagents and conditions: a) 4,4-4,4-difluoroazacycloheptane hydrochloride, DIEA, dioxane, 100℃; b) KOH, THF:H2O (1:1, v / v), 70℃; c) ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 d) tert-butyl carbamate (-thionyl) POCl3, pyridine, room temperature; d) TFA, DCM, room temperature Step 1: Ethyl 2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate: A solution of ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate (prepared by known method WO2019166822) (800 mg, 2.9962 mmol), 4,4-difluoroazacyclohepta-methyl hydrochloride (1.03 g, 5.99 mmol), and DIEA (1.16 g, 8.99 mmol) in dioxane (12 mL) was heated at 100 °C for 4 hours. LCMS showed the reaction was complete. The mixture was concentrated under vacuum and purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to provide ethyl 2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (710 mg, 64.74%) as a yellow solid. LCMS (ESI): C 16 H 20 F5N2O2[M + H] + The calculated value of m / z is 367.15, and the experimental value is 367.10.

[0510] Step 2: 2-(4,4-Difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: At room temperature, KOH (1.09 g, 19.40 mol) was added to a solution of ethyl 2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (710 mg, 1.94 mmol) in THF / H₂O (1 / 1, 10 mL). The mixture was heated at 70 °C for 5 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (540 mg, 82.4%) as a yellow solid. LCMS (ESI): C 14 H 16 F5N2O2[M + H] + The calculated value of m / z is 339.12, and the experimental value is 339.05.

[0511] Step 3: ( R )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 62-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (100 mg, 0.2958 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (96.21 mg, 0.3550 mmol) was added dropwise to a mixture of pyridine (3 mL) and POCl3 (100 µL). The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 2 / 1) to give a yellow solid ( R )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 2-Thiodimethyl)carbamate tert-butyl ester (50 mg, 29%). LCMS (ESI): C 26 H 32 F5N4O4S [M + H] + The calculated value of m / z is 591.22, and the experimental value is 591.15.

[0512] Step 4: ( R )-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide: at room temperature, to ( R )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl thiocarbamate (50 mg, 0.0846 mmol) was added to a solution of DCM (3 mL) with TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18 Purified using a column (150 x 21.2 mm) eluted with 50% to 55% ACN-H2O containing 0.1% formic acid to provide a white solid. (R)-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide (14.4 mg, 34.7%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.90(s, 1 H), 8.33 (s, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.16 (s, 1 H), 3.68-3.63 (m, 2 H), 3.58 (t, J = 6.0Hz, 2H), 3.10 (s, 3H), 2.36-2.21 (m, 5H), 2.06-1.95 (m, 2H), 1.88-1.75(m, 2H). LCMS(ESI):C 21 H 24 F5N4O2S [M + H] + The calculated value of m / z is 491.16, and the experimental value is 491.00.

[0513] Example 34 ( S )-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide

[0514] Reagents and conditions: a) R )-((3-aminophenyl)(methyl)(oxo)-λ 6 (b) tert-butyl carbamate (thionyl) POCl3, pyridine, room temperature; Step 1: ( S )-((3-(2-(4,4-difluoroazacyclohep-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-16-thionyl)carbamate: at room temperature, to 2-(4,4-difluoroazacyclohep-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (150 mg, 0.4438 mmol) and ( S )-((3-aminophenyl)(methyl)(oxo)-λ 6144.32 mg (0.5325 mmol) tert-butyl carbamate was added dropwise to a mixture of pyridine (3 mL) with POCl3 (100 µL). The reaction was monitored by LCMS. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL 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 rapid column chromatography (PE / EtOAc = 2 / 1) to give a yellow solid ( S )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (50 mg, 19.06%). LCMS (ESI): C 26 H 32 F5N4O4S [M + H] + The calculated value of m / z is 591.22, and the experimental value is 591.15.

[0515] Step 2: ( S )-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide: at room temperature, to ( S )-((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl thiocarbamate (50 mg, 0.0846 mmol) was added to a solution of DCM (3 mL) with TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was purified by elution with 50% to 55% ACN-H2O containing 0.1% formic acid to provide a white solid ( S )-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide (20.6 mg, 49.3%). 1 H NMR (400 MHz, DMSO- d6) δ 10.90(s, 1 H), 8.33 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.72-7.57 (m, 2 H), 7.16(s, 1 H), 3.65 (d, J = 7.9 Hz, 2 H), 3.58 (t, J = 6.0 Hz, 2 H), 3.09 (s, 3 H), 2.36-2.20 (m, 5 H), 2.08-1.94 (m, 2 H), 1.87-1.77 (m, 2 H). LCMS(ESI):C 21 H 24 F5N4O2S [M + H] + The calculated value of m / z is 491.16, and the experimental value is 491.00.

[0516] Example 35 ( R 6-(but-3-en-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide

[0517] Reagents and conditions: a) R )-((3-aminophenyl)(methyl)(oxo)-λ 6 (b) tert-butyl carbamate (thionyl) POCl3, pyridine, room temperature; Step 1: ( R )-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazacyclohept-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl carbamate (-thionyl)carbamate: at 50 °C, 6-(but-3-en-1-yl)-2-(4,4-difluoroazacycloheptyl-1-yl)nicotinic acid (250 mg, 0.806 mmol) and ( R )-((3-aminophenyl)(methyl)(oxo)-λ 63-Thiodimethyl)carbamate tert-butyl ester (239 mg, 0.887 mmol) was added to a mixture of pyridine (4 mL) and POCl3 (350 µL). The mixture was stirred at room temperature for 1 hour, then cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 1 / 1) to give a yellow oily substance. R )-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazacyclohept-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiolide) tert-butyl carbamate (60 mg, 13%). LCMS (ESI): C 28 H 37 F2N4O4S [M + H] + The calculated value of m / z is 563.25, and the experimental value is 563.15.

[0518] Step 2: ( R )-6-(but-3-en-1-yl)-2-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(S-methylaminopyridylsulfonyl)phenyl)nicotinamide: at room temperature, to ( R )-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazacyclohept-1-yl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (80 mg, 0.143 mmol) in DCM (3 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 residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 x 21.2 mm) was purified by elution with 50% to 80% ACN-H2O containing 0.1% formic acid to obtain a white solid. R )-6-(but-3-en-1-yl)-2-(4,4-difluoroazacyclohep-1-yl)-N-(3-(S-methylaminoylidenesulfonyl)phenyl)nicotinamide (23 mg, 35%). 1 H NMR (400 MHz, DMSO- d6) δ 10.73 (s, 1 H), 8.43 (s, 1 H), 7.68-7.63 (m, 1 H), 7.62-7.61 (m, 3 H), 6.66 (d, J =7.6 Hz, 1 H), 5.89-5.82 (m, 1 H), 5.02-4.95 (m, 2 H), 3.64-3.62 (m, 2 H), 3.43-3.40 (m, 2 H), 3.31 (s, 3 H), 2.75-2.71 (m, 2 H), 2.45-2.43 (m, 2H), 2.42-2.32 (m, 2H), 1.93-1.84 (m, 4H). LCMS(ESI):C 23 H 29 F2N4O2S [M + H] + The calculated value of m / z is 463.20, and the experimental value is 463.05.

[0519] Example 36 4-(azacyclohepta-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0520] Reagents and conditions: a) 2-methoxypyridine-4-amine, Me3Al (1 M in hexane), toluene, 0℃; b) TMSI, CH3CN, 0-50℃ Step 1: 4-(azacyclohepta-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: Me3Al (1 M in hexane, 3.26 mL, 3.26 mmol) was added dropwise to a solution of 2-methoxypyridin-4-amine (368 mg, 2.97 mmol) in toluene (4 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, methyl 4-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (300 mg, 0.99 mmol) in toluene (2 mL) was added at the same temperature. The mixture was heated at 90 °C for 2 h. LCMS showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE = 1 / 1) to give 4-(azacyclohepta-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (300 mg, 76.9%) as a yellow solid. LCMS (ESI): C 18 H 21 F3N5O2[M + H] + The calculated value of m / z is 396.16, and the experimental value is 396.00.

[0521] Step 2: 4-(azacyclohepta-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: At room temperature, TMSI (141 mg, 1.01 mmol) was added to a solution of 4-(azacyclohepta-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide 7 (200 mg, 0.51 mmol) in ACN (3 mL). The mixture was heated at 50 °C for 5 hours. LCMS showed the reaction was complete. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated, and analyzed by preparative HPLC (column: Gemini-C). 18 Purification was performed using a mobile phase of ACN-H2O (0.1% FA) and a gradient of 20%-38%-60% to obtain 4-(azacyclohepta-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (15 mg, 7.8%) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 11.31 (s, 1 H), 11.05 (s, 1 H), 7.35 (t, J = 3.5 Hz, 2 H), 6.84 (d, J = 1.9 Hz, 1 H), 6.44 (dd, J = 7.2, 1.8Hz, 1H), 3.57-3.50 (m, 4H), 1.74 (s, 4H), 1.48 (s, 4H). LCMS(ESI):C 17 H 19 F3N5O2[M + H] + The calculated value of m / z is 382.15, and the experimental value is 382.00.

[0522] Example 37 4-(azacyclohepta-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0523] Reagents and conditions: a) 3-(methylsulfonyl)aniline, Me3Al, toluene, 90℃ Me3Al (1 M in hexane, 2.18 mL, 2.18 mmol) was added dropwise to a solution of 3-(methylsulfonyl)aniline (338 mg, 1.98 mmol) in toluene (5 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, methyl 4-(azacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.66 mmol) in toluene (3 mL) was added at the same temperature. The resulting mixture was heated at 90 °C for 2 h. LCMS showed that the reaction was complete. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated, and analyzed by preparative HPLC (column: Gemini-C). 18 Purification was performed using a mobile phase of 150 x 21.2 mm and a mobile phase of 5 μm (ACN-H2O (0.1% FA), gradient 20%-38%-60%) to obtain 4-(azacyclohepta-1-yl)-N-(3-(methanesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (80 mg, 28%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 11.41 (s, 1 H), 8.39 (s, 1 H), 8.01 (d, J= 7.5 Hz, 1 H), 7.76-7.62 (m, 2 H), 7.36 (s, 1 H), 3.63-3.52 (m, 4 H), 3.24 (s, 3 H), 1.74 (s, 4 H), 1.47 (s, 4H). LCMS(ESI):C 19 H 22 F3N4O3S [M + H] + The calculated value of m / z is 443.13, and the experimental value is 443.10.

[0524] Example 38 N-(3-Carbamoylphenyl)-4-(4,4-Difluoroazacyclohep-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0525] Reagents and conditions: a) 3-bromobenzonitrile, Cs2CO3, Xantphos-Pd-G2, 1,4-dioxane, 100℃; b) K2CO3, H2O2 (30%, v / v), DMSO, room temperature.

[0526] Step 1: Under a nitrogen atmosphere, a mixture of 4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (250 mg, 0.62 mmol), 3-bromobenzonitrile (335 mg, 1.86 mmol), Cs₂CO₃ (606 mg, 1.86 mmol), and Xantphos-Pd-G₂ (52 mg, 0.06 mmol) in 1,4-dioxane (5 mL) was heated overnight at 100 °C. LCMS showed the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 4 / 1) to give N-(3-cyanophenyl)-4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 75.7%) as a white solid. LCMS (ESI): C 19 H 17 F5N5O [M+ H] + The calculated value of m / z is 426.14, and the experimental value is 426.00.

[0527] Step 2: N-(3-carbamoylphenyl)-4-(4,4-difluoroazacyclohep-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: K₂CO₃ (100 mg, 0.72 mmol) and H₂O₂ (30% solution, 0.5 mL) were added to a solution of N-(3-cyanophenyl)-4-(4,4-difluoroazacyclohep-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (100 mg, 0.24 mmol) in DMSO (5 mL). The solution was stirred at room temperature for 4 hours. LCMS showed the reaction was complete. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was subjected to preparative HPLC (column: Gemini-C). 18 The sample was purified to give N-(3-carbamoylphenyl)-4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (40 mg, 38%) as a white solid. The mobile phase was ACN-H2O (0.05% NH3), gradient: 20%-80%. LCMS (ESI): C 19 H 20 F5N5O2[M + H] + The calculated value of m / z is 444.15, and the experimental value is 444.30. 1 H NMR (400 MHz, DMSO- d 6) δ 11.11 (s, 1 H), 8.22 (s, 1H), 7.99 (s, 1 H), 7.86 (d, J = 8.2 Hz, 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.41 (s, 2 H), 3.72-3.63 (m, 2 H), 3.58 (t, J = 5.7 Hz, 2 H), 2.37-2.24 (m, 2 H), 2.13-2.19 (m, 2 H), 1.93-1.84 (m, 2 H).

[0528] Example 39 4-(4,4-Difluoroazacyclohepta-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0529] Reagents and conditions: a) 1-Bromo-3-(methylsulfonyl)benzene, Cs₂CO₃, Xantphos-Pd-G₂, 1,4-dioxane, 100℃ Under a nitrogen atmosphere, a solution of 4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (100 mg, 0.30 mmol), 1-bromo-3-(methylsulfonyl)benzene (143 mg, 0.61 mmol), Cs₂CO₃ (293 mg, 0.9 mmol), and Xantphos-Pd-G₂ (27 mg, 0.03 mmol) in 1,4-dioxane (3 mL) was heated overnight at 100 °C. LC-MS showed the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was subjected to preparative HPLC (column: Gemini-C). 18 Purification was performed using a mobile phase of 150 x 21.2 mm and a flow rate of 5 μm (ACN-H2O (0.05% FA), gradient: 35%-85%) to obtain 4-(4,4-difluoroazacyclohepta-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (36 mg, 25%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.41 (s,1 H), 8.40 (s, 1 H), 8.05 (d, J = 7.5 Hz, 1 H), 7.88 - 7.61 (m, 2 H), 7.44 (s, 1 H), 3.70-3.63 (m, 2 H), 3.55 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.37 - 2.24 (s, 2 H), 2.16 - 1.96 (m, 2 H), 1.94 -1.83 (m, 2 H). LCMS(ESI):C 19 H 20 F5N4O3S[M +H] + The calculated value of m / z is 479.12, and the experimental value is 479.05.

[0530] Example 40 4-(4,4-difluoroazacyclohepta-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide

[0531] Reagents and conditions: a) 4-bromo-2-methoxypyridine, Cs₂CO₃, Xantphos-Pd-G₂, 1,4-dioxane, 100℃; b) TMSI, CH₃CN, 0-50℃ Step 1: 4-(4,4-Difluoroazacyclohepta-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide: A mixture of 4-(4,4-difluoroazacyclohepta-1-yl)-6-(trifluoromethyl)pyridazin-3-carboxamide (250 mg, 0.77 mmol), 4-bromo-2-methoxypyridine (215 mg, 1.16 mmol), Cs₂CO₃ (625 mg, 1.93 mmol), and Xantphos-Pd-G₂ (18 mg, 0.02 mmol) in dioxane (5 mL) was heated at 100 °C for 16 hours. LCMS showed the reaction was complete. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 3) to provide 4-(4,4-difluoroazacyclohepta-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 61.9%) as a yellow solid. LCMS (ESI): C 18 H 19 F5N5O2[M + H] + The calculated value of m / z is 432.15, and the experimental value is 432.10.

[0532] Step 2: 4-(4,4-difluoroazacyclohepta-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: At room temperature, TMSI (97 mg, 0.70 mmol) was added to a solution of 4-(4,4-difluoroazacyclohepta-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (150 mg, 0.35 mmol) in MeCN (2 mL). The mixture was heated at 50 °C for 5 hours. LCMS showed the reaction was complete. The final mixture was concentrated under vacuum. The residue was purified first by silica gel rapid column chromatography (DCM / MeOH = 10 / 1) and then by preparative HPLC (Gemini 5 μm C). 18The column (150 x 21.2 mm) was further purified by elution with 30% to 90% ACN-H2O containing 0.1% formic acid to give 4-(4,4-difluoroazacycloheptan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (62 mg, 43%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 11.34 (s,1 H), 11.08 (s, 1 H), 7.44 (s, 1 H), 7.36 (d, J = 7.0 Hz, 1 H), 6.86 (d, J = 1.8Hz, 1 H), 6.47 (d, J = 7.1 Hz, 1 H), 3.70-3.58 (m, 2 H), 3.51 (t, J = 5.6 Hz, 2H), 2.36-2.24 (m, 2 H), 2.11-2.01 (m, 2 H), 1.92-1.85 (m, 2 H). LCMS(ESI):C 17 H 17 F5N5O2[M + H] + The calculated value of m / z is 418.13, and the experimental value is 418.05.

[0533] Example 41 5-Chloro-2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide

[0534] Reagents and conditions: a) NCS, MeCN, 60°C; b) KOH, EtOH, THF, 80°C; R )-((3-aminophenyl)(methyl)(oxo)-λ 6 d) tert-butyl carbamate (-thionyl) POCl3, pyridine, 80℃; d) TFA, DCM, room temperature Step 1: Methyl 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: NCS (228 mg, 1.70 mmol) was added to a solution of methyl 2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (500 mg, 1.42 mmol) in MeCN (10 mL) at 25 °C. The mixture was heated at 60 °C for 6 hours. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 3 / 1) to provide methyl 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (450 mg, 79.0%) as a yellow solid. LCMS (ESI): C 16 H 19 ClF5N2O2[M + H] + The calculated value of m / z is 401.11, and the experimental value is 400.95.

[0535] Step 2: 5-Chloro-2-(4,4-difluoroazacycloheptan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: At room temperature, KOH (1.25 g, 22.44 mmol) was added to a solution of ethyl 5-chloro-2-(4,4-difluoroazacycloheptan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (450 mg, 1.12 mmol) in THF / EtOH / H2O (1 / 1, 10 mL). The mixture was heated at 80 °C for 5 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF and EtOH. The aqueous phase was adjusted to pH 3-4 with 1 NHCl and then 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 5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (350 mg, 83.7%) as a yellow solid. LCMS (ESI): C 14 H 15 ClF5N2O2[M + H] + The calculated value of m / z is 373.08, and the experimental value is 373.05.

[0536] Step 3: 3-(5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-16-thionyl)carbamate tert-butyl: At room temperature, POCl3 (150 µL) was added dropwise to a mixture of 5-chloro-2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (200 mg, 0.73 mmol) and ((3-aminophenyl)(methyl)(oxo)-16-thionyl)carbamate tert-butyl (174 mg, 0.87 mmol) in pyridine (5 mL). The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 2 / 1) to give tert-butyl ((3-(5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-16-thionyl)carbamate (50 mg, 28.6%) as a yellow solid. LCMS (ESI): C 26 H 30 ClF5N4O4SNa [M + H] + The calculated value of m / z is 647.15, and the experimental value is 647.10.

[0537] Step 4: 5-Chloro-2-(4,4-difluoroazacyclohep-1-yl)-4-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide: At room temperature, to ((3-(5-chloro-2-(4,4-difluoroazacyclohep-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide)phenyl)(methyl)(oxo)-λ 6 TFA (1 mL) was added to a solution of tert-butyl thiocarbamate (50 mg, 0.08 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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 analyzed by preparative HPLC (Gemini 5 μm C). 18The column (150 * 21.2 mm) was purified by elution with 30% to 85% MeCN / H2O containing 0.1% formic acid to provide 5-chloro-2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-6-(trifluoromethyl)nicotinamide (14.1 mg, 33.5%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1 H), 8.29 (s, 1H), 7.89 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1H), 4.24 (s, 1 H), 3.62 (dt, J = 12.0, 5.3 Hz, 4 H), 3.07 (s, 3 H), 2.41-2.21 (m, 5 H), 2.08-1.96 (m, 2 H), 1.86-1.78 (m, 2 H). LCMS(ESI):C 21 H 23 ClF5N4O2S [M +H] + The calculated value of m / z is 525.12, and the experimental value is 525.10.

[0538] Example 42 2-(4,4-Difluoroazacyclohepta-1-yl)-4-methyl-N-(3-(S-methylaminopyridylsulfonyl)phenyl)-5-phenylnicotinamide

[0539] Reagents and conditions: a) 4,4-dimethoxybut-2-one, AcOH, NCCH2CN, piperidine, toluene; b) H2SO4, H2O, 50℃; c) H2SO4, H2O, 120℃; d) SOCl2, MeOH, 70℃; e) NBS, DCM, 0℃; f) PhOPOCl2, 170℃; g) KOH, THF, H2O, 80℃; h) 4,4-difluoroazacycloheptanane, HCl, K2CO3, DIEA, NMP, 140℃; i) ((3-aminophenyl)(methyl)(oxo)-λ 6 -Thiodimethyl) tert-butyl carbamate, POCl3, pyridine, 50℃; j) phenylboronic acid, K2CO3, Pd(dppf)Cl2, dioxane, H2O, 100℃; k) TFA, DCM Step 1: 2-(4,4-Dimethoxybut-2-yl)malononitrile: Piperidine (6.44 g, 0.076 mol) was added in portions over 20 minutes to a stirred solution of 4,4-dimethoxybut-2-one (100 g, 0.76 mol), acetic acid (4.54 g, 0.076 mol), and malononitrile (45 g, 0.68 mol) in toluene (250 mL). The reaction mixture was stirred overnight at room temperature. The mixture was washed with H2O (200 mL), dried over Na2SO4, and concentrated under vacuum to give crude 2-(4,4-dimethoxybut-2-yl)malononitrile (50 g), which was used directly in the next step.

[0540] Step 2: 4-Methyl-2-oxo-1,2-dihydropyridine-3-carboxynitrile: The crude product 2-(4,4-dimethoxybut-2-yl)malononitrile (50 g, about 278 mmol) was added dropwise to a stirred solution of concentrated H₂SO₄ (30 mL) at a reaction temperature not exceeding 30 °C. The reaction mixture was then heated at 50 °C for 2 hours. The resulting reaction mixture was cooled to room temperature and slowly added to ice-cold H₂O (200 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxynitrile (25 g, 67%) as a white solid. LCMS (ESI): C₇H₇N₂O[M + H] + The calculated value of m / z is 135.06, and the experimental value is 134.95.

[0541] Step 3: 4-Methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid: A solution of 25 g (187 mmol) of 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxynitrile in 40 mL of 50% H₂SO₄ aqueous solution was heated at 120 °C for 8 hours. The reaction mixture was then cooled to room temperature and slowly poured into ice water. The precipitate was collected by filtration, washed with water, and dried under vacuum to give crude 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 g, 52.1% yield), which could be used in the next step without further purification. LCMS (ESI): C₇H₈NO₃[M + H] + The calculated value of m / z is 154.05, and the experimental value is 154.0.

[0542] Step 4: Methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: SOCl2 (15 mL) was added dropwise to a solution of 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 65.3 mmol) in MeOH (120 mL). The mixture was then heated at 65 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated to give a crude product. The crude product was diluted with ice water and extracted with DCM (3 × 80 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10 g, 91.7%), which could be used in the next step without further purification. LCMS (ESI): C8H 10 NO3[M + H] + The calculated value of m / z is 168.07, and the experimental value is 168.0.

[0543] Step 5: Methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: NBS (10.64 g, 59.8 mmol) was added to a solution of methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10.0 g, 59.8 mmol) in DCM (100 mL) at 0 °C. The solution was stirred at the same temperature for 30 minutes. The mixture was then washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give crude methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (16.5 g, 80% purity, 89.6%). LCMS (ESI): C8H9BrNO3[M + H] + The calculated m / z value is 245.98, and the experimental value is 246.

[0544] Step 6: Methyl 5-bromo-2-chloro-4-methylnicotinate: A solution of methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (4.0 g, 16.3 mmol) in phenyl dichlorophosphate (30 mL) was heated at 170 °C for 4 hours. The solution was cooled to room temperature, diluted with water, and extracted with DCM (2 x 70 mL). The combined organic matter was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel rapid column chromatography (PE / EtOAc = 12 / 1) to obtain methyl 5-bromo-2-chloro-4-methylnicotinate (2.7 g, 63.2%). LCMS (ESI): C8H8BrClNO2[M+ H] + The calculated value of m / z is 263.94, and the experimental value is 263.75.

[0545] Step 7: 5-Bromo-2-chloro-4-methylnicotinic acid: At room temperature, KOH (3.19 g, 57 mmol) was added to a solution of methyl 5-bromo-2-chloro-4-methylnicotinic acid (1.5 g, 5.7 mmol) in THF / H₂O (1 / 1, 30 mL). The mixture was heated at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH 3-4 with 1 N HCl and then extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 5-bromo-2-chloro-4-methylnicotinic acid (1.30 g, 90.9% yield) as a white solid. LCMS (ESI): C₇H₆BrClNO₂[M + H] + The calculated value of m / z is 249.93, and the experimental value is 251.85.

[0546] Step 8: 5-Bromo-2-(4,4-Difluoroazacycloheptan-1-yl)-4-methylnicotinic acid: A solution of 5-bromo-2-chloro-4-methylnicotinic acid (400 mg, 1.59 mmol), 4,4-difluoroazacycloheptanane hydrochloride (543 mg, 3.18 mmol), K₂CO₃ (1.43 g, 10.34 mmol), and DIEA (821 mg, 6.36 mmol) in NMP (10 mL) was heated at 140 °C for 6 hours. LCMS showed the reaction was complete. The mixture was concentrated under vacuum and purified directly by silica gel rapid column chromatography (PE / EtOAc = 2 / 1 to 1 / 1) to provide 5-bromo-2-(4,4-difluoroazacycloheptan-1-yl)-4-methylnicotinic acid (320 mg, 60% purity, 34.7% yield) as a yellow solid. LCMS (ESI): C 13 H 16 BrF₂N₂O₂[M + H] + The calculated value of m / z is 351.04, and the experimental value is 350.9.

[0547] Step 9: ((3-(5-bromo-2-(4,4-difluoroazacyclohepten-1-yl)-4-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 tert-butyl carbamate (-thionyl)carbamate: At 50 °C, tert-butyl carbamate was reacted with 5-bromo-2-(4,4-difluoroazacyclohepten-1-yl)-4-methylnicotinic acid (150 mg, 0.43 mmol) and ((3-aminophenyl)(methyl)(oxo)-λ 6232 mg (0.86 mmol) tert-butyl carbamate (3-thionyl)carbamate was added dropwise to a mixture of pyridine (3 mL) and POCl3 (100 µL). The reaction solution was stirred at 50 °C for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 2 / 1) to give ((3-(5-bromo-2-(4,4-difluoroazacyclohepten-1-yl)-4-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiolide) tert-butyl carbamate (80 mg, 31%). LCMS (ESI): C 25 H 32 BrF₂N₄O₄S [M + H] + The calculated value of m / z is 603.13, and the experimental value is 603.05.

[0548] Step 10: ((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-5-phenylnicotinamide)phenyl)(methyl)(oxo)-λ 6 3-(5-bromo-2-(4,4-difluoroazacyclohepta-1-yl)-4-methylnicotinamide)phenyl)(methyl)(oxo)-λ 6 A mixture of tert-butyl thiocarbamate (50 mg, 0.083 mmol), phenylboronic acid (31 mg, 0.25 mmol), potassium carbonate (34.5 mg, 0.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (6 mg, 0.008 mmol) in 1,4-dioxane / H₂O (4 / 1, 2 mL) was heated at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtAOc = 3 / 1) to obtain a white oily substance ((3-(2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-5-phenylnicotinamide)phenyl)(methyl)(oxo)-λ 6 3-Thiodimethyl)carbamate tert-butyl ester (40 mg, 80%). LCMS (ESI): C 31 H 37 F2N4O4S [M + H] +The calculated value of m / z is 599.25, and the experimental value is 599.20.

[0549] Step 11: 2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-5-phenylnicotinamide: At room temperature, to ((3-(2-(4,4-difluoroazacyclohepta-1-yl)-4-methyl-5-phenylnicotinamide)phenyl)(methyl)(oxo)-λ 6 40 mg (0.067 mmol) of tert-butyl thiocarbamate (THB) was added to a solution of DCM (3 mL) with 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 a saturated aqueous solution of NaHCO3. The aqueous solution was then 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 analyzed by preparative HPLC (Gemini 5 μm C). 18 The column (150 * 21.2 mm) was purified by elution with 30% to 85% ACN-H2O containing 0.1% FA to provide 2-(4,4-difluoroazacyclohepten-1-yl)-4-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-5-phenylnicotinamide (14.5 mg, 42.6%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.88 (s, 1 H), 8.38 (s, 1 H), 8.08 (s, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 7.37 (dd, J = 19.8, 7.2Hz, 3 H), 4.22 (s, 1 H), 3.58 (s, 4 H), 3.06 (s, 3 H), 2.31 (d, J = 13.4 Hz, 2H), 2.15 (s, 3 H), 2.01 (s, 2 H), 1.82 (d, J = 5.8 Hz, 2 H). LCMS(ESI):C 26 H 29 F2N4O2S [M + H]+ The calculated value of m / z is 499.20, and the experimental value is 499.10.

[0550] Example 43 ( R )-3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)aminoiminosulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0551] Reagents and conditions: a) HATU, DIEA, N-(tert-butoxycarbonyl)-N-methylglycine, DMF, room temperature; b) TFA, DCM, room temperature. Step 1: ( R )-(2-(((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 -Thiodiyl)amino)-2-oxoethyl)(methyl)carbamate tert-butyl ester: towards ( R A mixture of 3-(4,4-difluoroazacyclohepta-1-yl)-5-methyl-N-(3-(S-methylaminomethylenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (150 mg, 0.31 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (87 mg, 0.46 mmol) in DMF (10 mL) was supplemented with HATU (175 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 2 / 1 to 1 / 1) to give a white oily substance. R )-(2-(((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 2-Thio(dimethyl)amino)-2-oxoethyl(methyl)carbamate tert-butyl ester (110 mg, 53.6%). LCMS (ESI): C 28 H 36 F5N6O5S [M + H] + The calculated value of m / z is 663.24, and the experimental value is 663.20.

[0552] Step 2: (R )-3-(4,4-difluoroazacyclohep-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)aminoylidenesulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: at room temperature, to ( R )-(2-(((3-(3-(4,4-difluoroazacyclohepten-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ 6 110 mg (0.16 mmol) of tert-butyl 2-thionylamino)-2-oxoethyl(methyl)carbamate (TFA) (0.5 mL) was added to a solution of DCM (5 mL). The reaction mixture was stirred at room temperature for ...

Claims

1. A compound of formula (I): （I）， Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O)N H2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be fully or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-14 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-14 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B is selected from the group consisting of: monocyclic, bicyclic or spirocyclic cycloalkyl rings and monocyclic, bicyclic or spirocyclic heteroalkyl rings, wherein the heteroalkyl ring contains 1 to 4 heteroatoms independently selected from N, O and S, and wherein one or more carbons of the cycloalkyl ring or the heteroalkyl ring may optionally be substituted by one or more halogens or one or more haloalkyl groups. C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II): in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0、1、2、3、4、5、6。 2. A compound of formula (I): （I）， Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O) NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be fully or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-6 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B can choose from the following groups: A monocyclic, bicyclic, or spirocyclic heteroalkyl ring, wherein the heteroalkyl ring contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of the heteroalkyl ring are optionally substituted with a haloalkyl group, wherein the haloalkyl chain may be completely or partially halogenated; and Monocyclic, bicyclic, or spirocyclic cycloalkyl rings; One or more carbons of the cycloalkyl or heteroalkyl ring are optionally substituted by one or more substituents independently selected from the group consisting of halogens, alkyl groups, cycloalkyl groups, and haloalkyl groups, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II): in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0、1、2、3、4、5、6。 3. A compound of formula (I): （I）， Or its pharmaceutically acceptable salts, stereoisomers, or solvates. in: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S, and N, wherein A is unsubstituted or substituted by one or more substituents selected from the group consisting of: H; halogenated; substituted or unsubstituted C1-C6 alkyl; C1-C6 branched alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C1-C6 alkoxy; C1-C6 cycloalkoxy; C3-C6 haloalkoxy; nitro; cyano; -CH2-(C3-C8)-cycloalkyl; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-aryl; -CH(-CH3)-aryl; C(=O)-(C1-C6)-alkyl; -C(=O)-cycloalkyl; -C(=O)-NH-alkyl; -C(=O) NH2; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; -NR'R''; -NHSO2R1; -NHC(=O)-alkyl; -NH(C=O)NR'R''; C1-C6 fluoroalkyl, wherein the fluoroalkyl chain may be fully or partially fluorinated; bromine; chlorine; fluorine; iodine; cyclopropylmethyl; sulfonylmethyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl; 6-14 membered aryl or 5-7 membered heteroaryl, any of which may have one or more substituents listed herein, wherein the 3-8 membered heterocycloalkyl or the 5-6 membered heteroaryl contains at least one heteroatom independently selected from O, S and N; B can choose from the following groups: A monocyclic, bicyclic, or spirocyclic heteroalkyl ring, wherein the heteroalkyl ring contains 1-4 heteroatoms independently selected from N, O, and S, wherein one or more N atoms of the heteroalkyl ring are optionally substituted with a haloalkyl group, wherein the haloalkyl chain may be completely or partially halogenated; and Monocyclic, bicyclic, or spirocyclic cycloalkyl rings; One or more carbons of the cycloalkyl or heteroalkyl ring are optionally substituted by one or more substituents independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl and haloalkyl, wherein the haloalkyl chain may be completely or partially halogenated; C is selected from the group consisting of: aryl, heteroaryl, heterocyclic, cycloalkyl and bridged cycloalkyl, wherein the aryl, heteroaryl, heterocyclic and bridged cycloalkyl contain one or more substitutions selected from the group consisting of (other than R2 group): H, halogen, alkyl, cyano, haloalkyl and nitro; R1 is selected from H and C1-C3 alkyl groups; R2 is H, -C(=O)NH2, -C(=O)NHR', -C(=O)NR'R'', -C(=O)OH, alkylamino, and -S(=O)R' or formula (II): in: X1 is O, and X2 is NH or NR'; X1 is 0, and X2 is NR3; or X1 and X2 are independently selected from NH and NR'; in, R3 is independently selected from -(C=O)-(CH2) n R a -(C=O)-(CH2) n -(OCH2CH2) n R a -(C=O)-(CH2) n -(OCH2CH2O) n R a -(C=O)-(CH2) n -(NHCH2CH2) n R a -(C=O)-(CH2) n - (NHCH2CH2O) n R a -(CH2) n R a -(CH2)n(CR b R c )R a -(C=O)-(NHCH2CH2NH) n R a -(C=O)-(CHR) b )R a -(CH2) n (CR b R c (CH2)nR a or -(C=O)-(CR) b R c )R a ; R a It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R b Selected from F, C1-C6-alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbon cycloyl, and 4-7 membered heterocyclic groups having one or more heteroatoms; R c It is a C1-C6-alkyl or F; R c R b Together with the carbon atoms to which it is attached, it forms a 3-6 membered carbon ring or a 4-6 membered heterocycle with one or more heteroatoms; R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclic groups, wherein R4 is optionally surrounded by one or more R d replace; Where R d It is H, C1-C6-alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CF2-aryl, -NH2, -NR'R'', aminocycloalkyl, 4 to 7-membered heterocyclic, -OH, -COONH2, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide or amino; and n = 0、1、2、3、4、5、6。 4. The compound according to any one of claims 1 to 3, wherein R2 is selected from H or formula (II): (II), in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3. R3 is defined in claim 1.

5. The compound according to any one of claims 1 to 3, wherein R2 is: in: m and p are 0 or 1; and X1 is O, and X2 is NH or NR'; or X1 is 0, and X2 is NR3. R3 is defined in claim 1.

6. The compound according to any one of claims 1 to 3, wherein A is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted 5- or 6-membered heteroaryl group having one or more heteroatoms; wherein the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom being capable of being in the form of an N-oxide, wherein A is optionally a pyridyl N-oxide, a pyrazinyl N-oxide, a pyrimidinyl N-oxide, or a pyridazinyl N-oxide.

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

8. The compound according to any one of claims 1 to 3, wherein A is an optionally substituted aryl group.

9. The compound according to any one of claims 1 to 3, wherein A is an optionally substituted heteroaryl group having a heteroatom.

10. The compound according to any one of claims 1 to 3, wherein A is an optionally substituted heteroaryl group having two heteroatoms.

11. The compound according to any one of claims 1 to 3, wherein the heteroaryl A is at least substituted with a trifluoromethyl group.

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

13. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: Each of Q1, Q2, Q3, and Q4 is independently N, NO, or CR5; Wherein R5 is H; hydroxyl; halogen; -CD3; substituted or unsubstituted C1-C6 alkyl; deuterated C1-C6 alkyl, wherein the alkyl chain may be fully or partially deuterated; branched alkyl; allyl; alkenyl; alkynyl; halo-C1-C4 alkyl, wherein the haloalkyl chain may be fully or partially halogenated; alkoxy; cycloalkoxy; haloalkoxy; nitro; cyano; -CH2-cycloalkyl; -CF2CH3; -CF2CF3; CH2CF2; -CF2-cycloalkyl; -CH(CH3)-cycloalkyl; -CH2-aryl; -CF2-heteroaryl; -CF2-heterocyclic; -CH(-CH3)-aryl; C (=O)-alkyl; -C(=O)cycloalkyl; -C(=O)-NH-alkyl; -C(=O)NH2; -C(=O)NHR'; -C(=O)NR'R''; hydroxyl; -COOH (and its esters); alkylsulfonyl; arylsulfonyl; sulfonamide; amino; NR'R''; -NHSO2R'; -NHC(=O)-alkyl; -NH(C=O)NR'R''; trifluoromethyl; cyclopropylmethyl; methylsulfonyl; 3-8 membered cycloalkyl; 3-8 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-8 membered heterocycloalkyl contains at least one heteroatom independently selected from O, S and N.

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

15. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: in: Q2 and Q4 are N and NO, respectively; Q2 is N or NO; Q4 is CR5; Q2 is CR5; Q4 is N or NO. R6 is H, halogen, -CD3, C1-C6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, NH2, NHR', NR'R'', NHC(=O)R', NHSO2R, -C(=O)R', -C(=O)NHR', -C(=O)NR'R'', aryl, heteroaryl, -CF2CH3, -CF2CF3; R7 represents H, hydroxyl, halogen, -CD3, C1-C6 alkyl, branched alkyl, allyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, nitro, cyano, -CH2-cycloalkyl, -CF2CH3, -CF2CF3, CH2CF2, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-heteroaryl, -CF2-heterocyclic, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C( =O)NH2, -C(=O)NHR', -C(=O)NR'R'', hydroxyl, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR'R'', -NHSO2R', -NHC(=O)-alkyl, -NH(C=O)NR'R'', trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-6 membered cycloalkyl, 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; Among them, no more than two of Q1, Q2, Q3 and Q4, or N or NO.

16. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: in: Q3 and Q4 are N; where Q3 is N or NO; Q4 is CR5; or where Q3 is CR5 and Q4 is N or NO; R5 is defined in claim 9; and R6 and R7 are defined in claim 15 above.

17. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: Wherein Q1 and Q4 are N and NO; Q1 is N and NO; Q4 is CR5; Q1 is CR5 and Q4 is N and NO; or Q1 and Q4 are CR5; and wherein R6 and R7 are defined in claim 15 above.

18. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: in: Q1 and Q2 are N; and R6 and R7 are defined in claim 15 above.

19. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: in: Q1 is CR5, and Q2 is N; R6 and R7 are defined in claim 15 above.

20. The compound according to any one of claims 1 to 3, wherein A is represented by the following formula: Wherein Q1 is N; and Q2 is CR5; and R6 and R7 are defined in claim 15 above.

21. The compound according to any one of claims 1 to 3, wherein the heteroaryl or aryl ring A is selected from the group consisting of: 。 22. The compound according to any one of claims 1 to 3, wherein B is selected from the group consisting of: pyrrolidine, aziridine, piperidine, piperazine, aziridine-heptane, aziridine-octane, morpholine, thiomorpholine, oxaziridine-heptane, isoindoline, dihydroisoquinoline, octahydroisoindole, aziridine-[2.2.1]heptane, aziridine-[3.11]heptane, aziridine-[4.1.0]heptane, aziridine-[3.2.1]octane, diaziridine-[3.2.1]octane, aziridine-[3.2.0]heptane, oxaziridine-[3.2.0]heptane, oxaziridine-[3.2.1]octane, oxaziridine-[3.2.0]heptane, oxaziridine-[3.2.1]octane, oxaziridine-[3.2.0]heptane, oxaziridine-[3.2.1]octane, oxaziridine-[3.2.0]heptane, oxaziridine-[3.2.1]octane, oxaziridine-[3.2.1]octane, oxaziridine-[3.2.0]octane, oxaziridine-[3.2.1 ... The following compounds are listed: aza-azabicyclo[3.2.l]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxaza-azaspiro[3.5]nonane, oxaza-azaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine, hexahydrofuran[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.l.l3,8]undecane.

23. The compound according to any one of claims 1 to 3, wherein C is phenyl.

24. The compound according to any one of claims 1 to 3, wherein C is pyridyl.

25. The compound according to any one of claims 1 to 3, wherein in formula (II), X1 is O and X2 is NH.

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

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

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

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

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

31. The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (VIII): (VIII), in: B, C, R1, R2, and R5 are defined above.

32. The compound according to any one of claims 1 to 3, wherein substituted or unsubstituted B is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

33. The compound according to any one of claims 1 to 3, wherein C is selected from the group consisting of: , , , , , , , , , , and .

34. The compound according to any one of claims 1 to 3, wherein R1 is H.

35. The compound according to any one of claims 1 to 3, wherein R2 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , and .

36. The compound according to any one of claims 1 to 3, wherein R2 is: 。 37. The compound according to any one of claims 1 to 3, wherein C comprises an additional substitution, wherein the substitution is selected from the group consisting of H, halogens and alkyl groups.

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

39. The compound according to any one of claims 1 to 3, wherein the one or more substitutions on the A ring are selected from the group consisting of: halogen, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6 alkyl, aryl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 heteroaryl and any combination thereof, wherein the heterocycloalkyl and the heteroaryl contain one or more heteroatoms selected from N, O or S.

40. The compound according to any one of claims 1 to 3, wherein the one or more substitutions on the A ring are selected from the group consisting of: methyl, trifluoromethyl, chlorine, fluorine, bromine, C1-C6 alkyl, phenyl, cycloalkyl, methylpyrazole, fused 1,4-dioxane and methylcyano.

41. The compound according to any one of claims 1 to 3, wherein the one or more substitutions on the A ring are selected from the group consisting of: -CH3, -CD3, -CF3, -Cl, -Br, -F, -CH2-CH2-CH=CH2, phenyl, -CH2-CN, -C(=O)-NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And any combination thereof.

42. The compound according to any one of claims 1 to 3, wherein the substitution on the A ring is selected from the group consisting of H, halogens, alkyl groups and haloalkyl groups.

43. The compound according to any one of claims 1 to 3, wherein the substitution on the A ring is selected from the group consisting of methyl and -CF3.

44. The compound according to any one of claims 1 to 3, wherein the substitution on the A ring is selected from the group consisting of H and -CF3.

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

46. ​​The compound according to claim 45, wherein A is a phenyl group.

47. The compound according to claim 45, wherein A is pyridine.

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

49. The compound according to any one of claims 1 to 3, wherein the C ring is phenyl.

50. The compound according to any one of claims 1 to 3, wherein the C ring is pyridine.

51. The compound according to any one of claims 1 to 3, wherein the C ring is piperidine.

52. The compound according to any one of claims 1 to 3, wherein the C ring is pyrrolidine.

53. The compound according to any one of claims 1 to 3, wherein R2 is: in: X1 is O, and X2 is NR', and R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclic.

54. The compound according to any one of claims 1 to 3, wherein R2 is: in: X1 is O, and X2 is O, and R4 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl or heterocyclic.

55. The compound according to claim 53 or claim 54, wherein R' is H.

56. The compound according to claim 53 or claim 54, wherein R4 is a C1-C3 alkyl group.

57. The compound according to claim 53 or claim 54, wherein R4 is methyl.

58. The compound according to claim 53 or claim 54, wherein R4 is an ethyl group.

59. The compound according to claim 53 or claim 54, wherein R4 is a C3-C4 cycloalkyl group.

60. The compound according to any one of claims 1 to 3, wherein the B ring is a 4-8 member substituted or unsubstituted cycloalkyl or heteroalkyl group, wherein the heteroatom in the heteroalkyl group is selected from the group consisting of N or O.

61. The compound of claim 59, wherein the substitution on ring B is selected from one or more of the following: halogen; C1-C4 alkyl; oxyalkyl; alkoxyalkyl; substituted or unsubstituted C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl forms a spirocycle with ring B; and partially or fully halogenated C1-C4 alkyl.

62. The compound according to claim 61, wherein the halogen is fluorine.

63. The compound according to claim 61, wherein the halogen is chlorine.

64. The compound according to claim 61, wherein the C1-C4 alkyl group is methyl.

65. The compound according to claim 61, wherein the C3-C6 cycloalkyl group is cyclopropyl.

66. The compound of claim 61, wherein the substitution is selected from the group consisting of -OCH3 and -CH2-O-CH3.

67. A compound selected from the group consisting of:

68. A compound selected from the group consisting of:

69. A compound selected from the group consisting of:

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

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

72. A method of treating a subject's condition, the method comprising providing the subject with the compound according to any one of claims 1 to 71.

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

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