Potassium channel modulators, compositions and uses

Abstract

The present invention discloses a compound having the structure represented by general formula I, its stereoisomer, its pharma- ceutically acceptable salt, or its solvate. Also disclosed are compositions, preparations, and uses comprising said compounds. The compounds of the present invention have significant activation effect on KCNQ2 / 3 potassium ions, and can be used in the treatment of diseases related to potassium channel ion flow, such as the use of medicines to treat central nervous system diseases. [Formula 1] JPEG2024519557000107.jpg47169

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention belongs to the technical field of pharmaceutical synthesis and design, and particularly relates to a compound for modulating potassium channels, or its stereoisomer, or its pharma- ceutical acceptable salt, pharmaceutical composition and its use. The compound has the function of modulating potassium channels, and can be used for the treatment of diseases or disorders that benefit from KCNQ channel openers. [Background technology] Treatment of central nervous system diseases has always been a difficult problem in the medical field. Traditional medicines are unable to prevent and treat acute and chronic central nervous system injuries, Alzheimer's disease, Parkinson's disease, epilepsy and other central nervous system diseases.

[0002] The chemical environment of cells is closely related to ion channels on the cell membrane, and ion channels are key to controlling neuronal excitability, making ion channels the most direct target for the treatment of central nervous system diseases. More than 10% of potassium channel subtypes are known to be related to human central nervous system diseases, and these are embodied in various ways, from direct control of neuronal excitability and homeostasis of the ion environment in the body to indirect effects via metabolism.

[0003] Currently, five types of KCNQ, KCNQ1 to KCNQ5, have been discovered. KCNQ potassium ion channels are an important branch of the potassium ion channel superfamily, and their gene mutations are associated with many genetic diseases. Among them, KCNQ1 (KvLQT) is mainly distributed in cardiac muscle, and 50% of hereditary LQT syndromes are associated with KCNQ1 mutations. KCNQ2 and KCNQ3 are the molecular basis of M-type potassium ion channels in nerve cells, and benign familial neonatal convulsions (BFNC) are associated with downregulation of M current caused by KCNQ2 and KCNQ3 gene mutations. KCNQ4 is mainly expressed in nerve conduction pathways, nerve nuclei, and inner ear hair cells related to hearing, and hereditary deafness (DFNA) is associated with mutations in the KCNQ4 gene. KCNQ5 is mainly expressed in muscle tissue.

[0004] KCNQ potassium channel openers have become a new direction in antiepileptic drug research. Retigabine was approved by the US FDA in June 2011 as a treatment for refractory partial seizures, and its excellent in vivo and in vitro performance and marketing success have demonstrated the importance of KCNQ potassium channels as drug targets. Furthermore, in vivo and in vitro studies have shown that retigabine also has potential therapeutic effects against anxiety, stroke, neurodegenerative diseases, and pain. At the same time, because KCNQ potassium channels have broad physiological functions, their openers also have a very wide range of potential uses in the treatment of many diseases. [Summary of the Invention] An object of the present invention is to provide a novel compound having potassium channel regulating function, or a pharma- ceutically acceptable salt or solvate thereof.

[0005] The present invention also provides a pharmaceutical composition comprising the above compound, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0006] The invention also provides the use of the above compound, stereoisomer, mixture of stereoisomers, or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for treating a disease, disorder, or condition that would benefit from a KCNQ channel opener.

[0007] The compounds of the present invention are effective in treating and preventing diseases and conditions affected by potassium ion channel activity, and can be used to treat a variety of diseases and disorders.

[0008] To achieve the above objects, the present invention provides a compound represented by Formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0009] [ka]

[0010] however: Ring A is a benzene ring or a 5-8 membered polycyclic ring containing 1-2 heteroatoms selected from N, O, or S; R 1 is hydrogen, halogen, C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkenyl, C 1 ~C 8 Alkenyloxy, spiroalkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkanoyl, C 1 ~C 8 Alkyl sulfonyl, amino sulfonyl, C 1 ~C 8Haloalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Haloalkenyloxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 and wherein the alkyl, alkoxy, alkenyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, alkylthio, alkanoyl, alkylsulfonyl, and aminosulfonyl are further selected from R 8 may be replaced by; R 2 are independently hydrogen, halogen, or C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 haloheterocycloalkoxy; Or, two R's 2 is connected to the same atom, and two R 2 may be the same or different, and together with the atom(s) linked thereto form a 3- to 6-membered ring or a 3- to 6-membered multiple ring; R 4 , R 5 , R 6 , R 7 , R 8 are independently hydrogen, halogen, or C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 haloheterocycloalkoxy, spiroalkyl; n is selected from 0, 1, and 2; m is selected from 0, 1, 2, 3, 4, 5; X 1 and X 2 are independently -CRaRb, -NRa, -O-, -C(O)-, -S-, -S(O)-, and -S(O). 2 - Selected from; Ra and Rb are each independently hydrogen, halogen, hydroxyl, amino, or C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 3 ~C 8 Cycloalkyl, C 1 ~C 8 Haloalkyl, C 1 ~C8 Haloalkoxy, C 3 ~C 8 halocycloalkyl;

[0011] [ka]

[0012] represents a chemical bond or is absent; Z is O or (CH 2 ) p where p is an integer from 1 to 6; R 3 is C 1 ~C 8 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkenyl, C 2 ~C 8 Alkenyl or C 2 ~C 8 alkynyl, wherein C 1 ~C 8 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkenyl, C 2 ~C 8 Alkenyl or C 2 ~C 8 The alkynyl may be substituted by one or more selected from halogen, nitro, cyano, amino or hydroxyl.

[0013] Furthermore, preferred compounds of the present invention, stereoisomers thereof, or pharma- ceutically acceptable salts thereof, specifically have the structure represented by Formula I:

[0014] however: Ring A is a benzene ring or a 5-8 membered polycyclic ring containing 1-2 heteroatoms selected from N, O, or S; R 1 are independently hydrogen, halogen, or C 1 ~C8 Alkyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkanoyl, C 1 ~C 8 Alkyl sulfonyl, amino sulfonyl, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 haloheterocycloalkoxy; R 2 are independently hydrogen, halogen, or C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Ahlol Kil, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 haloheterocycloalkoxy; R 4 , R 5 , R 6 , R 7 are independently hydrogen, halogen, or C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 haloheterocycloalkoxy; n is selected from 0, 1, and 2; m is selected from 0, 1, 2, 3, 4, 5; X 1 and X 2 are independently -CRaRb, -NRa, -O-, -C(O)-, -S-, -S(O)-, and -S(O). 2 - Selected from; Ra and Rb are each independently hydrogen, halogen, hydroxyl, amino, or C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 3 ~C 8Cycloalkyl, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 halocycloalkyl;

[0015] [ka]

[0016] represents a chemical bond or is absent; Z is O or (CH 2 ) p where p is an integer from 1 to 6; R 3 is C 1 ~C 8 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkenyl, C 2 ~C 8 Alkenyl or C 2 ~C 8 alkynyl, wherein 1 ~C 8 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkenyl, C 2 ~C 8 Alkenyl or C 2 ~C 8 Alkynyl is substituted by one or more halogen, nitro, cyano, amino or hydroxyl;

[0017] [ka]

[0018] If it is expressed as X 1 , X 2 are each independently selected from -CRa-, -N-;

[0019] [ka]

[0020] It is expressed as R 4 , R 5 , R 6 , R 7 None of X is selected from chlorine, 1 is CH or O, and R 2 is H and ring A is a benzene ring, R 1 is C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkanoyl, C 1 ~C 8 Alkyl sulfonyl, amino sulfonyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 haloheterocycloalkoxy;

[0021] [ka]

[0022] It is expressed as R 4 , R 5 , R 6 , R 7 is not selected from chlorine, and ring A is a thiophene ring, m is selected from 2, 3, 4, and 5; R 2 is not selected from hydrogen.

[0023] In the present invention, when n and m are greater than 1, it is a multiple substitution, and in this case, the multiple substitutions may be substituted on one carbon atom or on multiple atoms of the corresponding ring structure; and in the case of multiple substitution, the multiple substituents may be the same or different. When two substituents are bonded to the same carbon atom, the two substituents and the carbon atoms bonded to them together form C 3 ~C 6 It may also form a cycloalkyl.

[0024] Preferably, ring A is a benzene ring or a 5-membered polycyclic ring containing 1 to 2 heteroatoms selected from N, O, or S.

[0025] Preferably, R 1 is H, C 1 ~C 5 Alkoxy, C 1 ~C 5 Alkenyloxy, C 1 ~C 5 Haloalkoxy, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkoxy, C 3 ~C 4 Heterocycloalkyl, C 3 ~C 4 Heterocycloalkoxy, C 1 ~C 4 Alkylthio, halogen, C 1 ~C 4 alkylsulfonyl; R 1 is further halogen, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 It may be substituted by one or more of haloalkoxy, spiroalkyl. Preferably, R 1 is H, C 1 ~C 4 Alkoxy, C 1 ~C 4Haloalkoxy, C 3 ~C 6 Cycloalkyl, C 3 ~C 4 Heterocycloalkyl, C 1 ~C 4 Alkylthio, halogen, C 1 ~C 4 R is selected from alkylsulfonyl. 1 is more preferably H, F, Cl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, hexafluoroisopropoxy, trifluorobutoxy, cyclopropanoxy, cyclobutanoxy, cyclopentanoxy, cyclohexanoxy, oxetanoxy, methylthio, methylsulfonyl,

[0026] [ka]

[0027] is selected from.

[0028] Preferably, R 2 are independently hydrogen, halogen, or C 1- C 3 More preferably, R 2 is H, methyl. More preferably, R 2 is H or X 1 More preferably, R 2 H, X 1 or the two methyls are X 1 and forms a cycloalkyl.

[0029] Preferably, R 3 is C 1 ~C 5 More preferably, R 3 is tert-butyl.

[0030] Preferably, the R 4 , R 5 , R 6 , R 7 are each independently H, methyl, or halogen (more preferably Cl). More preferably, 4 , R 6 is H or Cl; 5 , R 7 is methyl.

[0031] Preferably, Z is (CH 2 ) p and more preferably -CH 2 -It is.

[0032] Further, among the compounds of the present invention, stereoisomers thereof, or pharma- ceutically acceptable salts thereof, preferred compounds have a structure represented by general formula IIa, IIb, or IIc.

[0033] [ka]

[0034] In the above general formula, X 1 , X 2 Between is a double bond or a single bond.

[0035] Preferably, X 3 are N, O, and S.

[0036] Further, among the compounds of the present invention, stereoisomers thereof, or pharma- ceutically acceptable salts thereof, preferred compounds have a structure represented by general formula III.

[0037] [ka]

[0038] R 1 is C 1-8 Alkoxy, C 3-8 Cycloalkoxy, C 2 ~C8 Heterocycloalkoxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkylsulfonyl, C 1-8 Haloalkoxy, C 3-8 halocycloalkoxy; n is selected from 1.

[0039] Further, the present invention relates to a compound, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, which has the general formula IV:

[0040] [ka]

[0041] R 1 is C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2 ~C 6 Heterocycloalkoxy, C 1 ~C 3 Alkylthio, C 1 ~C 3 Alkylsulfonyl, C 1-6 Haloalkoxy, C 3-6 halocycloalkoxy.

[0042] Further, the present invention relates to a compound, a stereoisomer, or a pharma- ceutically acceptable salt thereof, which is represented by the general formula IIc-2:

[0043] [ka]

[0044] X 1 , X 2 is a double bond or a single bond; n is selected from 2; R 1 is halogen, C 1 ~C 8 Alkyl, C 1 ~C8 Alkoxy, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkyl, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkanoyl, C 1 ~C 8 Alkyl sulfonyl, amino sulfonyl, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Halocycloalkyl, C 3 ~C 8 Halocycloalkoxy, C 2 ~C 8 Haloheterocycloalkyl, C 2 ~C 8 haloheterocycloalkoxy.

[0045] Further, the present invention relates to a compound, a stereoisomer, or a pharma- ceutically acceptable salt thereof, which has the general formula III:

[0046] [ka]

[0047] R 1 is halogen, C 1-8 Alkoxy, C 3-8 Cycloalkoxy, C 2 ~C 8 Heterocycloalkoxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkylsulfonyl, C 1-8 Haloalkoxy, C 3-8 halocycloalkoxy; n is selected from 2.

[0048] Further, the compound of the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, preferably said compound has a structure represented by general formula V:

[0049] [ka]

[0050] R 1 is halogen, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 2 ~C 6 Heterocycloalkoxy, C 1 ~C 3 Alkylthio, C 1 ~C 3 Alkylsulfonyl, C 1-6 Haloalkoxy, C 3-6 halocycloalkoxy.

[0051] Further, preferred compounds of the present invention are those represented by the general formula IIa to IIc or IIc-2: X 1 , X 2 CH 2 and there is a single bond between them; R 4 and R 6 is H;R 5 and R 7 is methyl; m is selected from 2, 3, 4, and 5; R 2 is not selected from hydrogen.

[0052] A preferred compound of the present invention is represented by the general formula IIa to IIc or IIc-2: R 6 is Cl; R 4 , R 5 , R 7 At least two of are not selected from hydrogen.

[0053] Preferably, the compound has a structure represented by general formula Va:

[0054] [ka]

[0055] R 1 ' is H, F; R 1 teeth

[0056] [ka]

[0057] It is.

[0058] Preferably, it is a compound selected from the following compounds, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof:

[0059] [Table 1] JPEG0007681132000017.jpg221169JPEG0007681132000018.jpg156169

[0060] Preferably, the compound is the following compound:

[0061] N-(4-(7-Methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (001) N-(4-(7-ethoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (002) N-(4-(7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (003) N-(4-(7-(sec-butoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (004) N-(4-(7-(difluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (005) N-(2,6-dimethyl-4-(7-(trifluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (006) N-(2,6-dimethyl-4-(7-(2,2,2-trifluoroethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (007) N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (008) N-(4-(7-cyclopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (009) N-(4-(7-cyclobutoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (010) N-(4-(7-(cyclopentoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (011) N-(4-(7-(cyclohexyloxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (012) N-(2,6-dimethyl-4-(7-(oxetan-3-yl-oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (013) N-(2,6-dimethyl-4-(7-(methylthio)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (014) N-(2,6-dimethyl-4-(7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (015) N-(4-(7-fluoro-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (016) N-(4-(5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (017) N-(4-(2-chloro-8,8-dimethyl-4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepin-5-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (018) N-(4-(8,8-dimethyl-4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepin-5-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (019) N-(4-(2-chloro-4,4-dimethyl-4,5,6,8-tetrahydro-7H-thieno[2,3-c]azepin-7-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (020) N-(4-(4,4-dimethyl-4,5,6,8-tetrahydro-7H-thieno[2,3-c]azepin-7-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (021) N-(4-(7-fluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (022) N-(4-(8-fluoro-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (023) N-(4-(8-fluoro-1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (024) N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (025) N-(4-(8-fluoro-1,1-dioxo-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (026) N-(4-(7-fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (027) N-(4-(7-fluoro-5-methyl-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (028) N-(3-fluoro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2-methylphenyl)-3,3-dimethylbutyramide (029) N-(4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,3,6-trimethylphenyl)-3,3-dimethylbutyramide (030) N-(3-chloro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (031) (R)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (032) (S)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (033) (R)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (032) (S)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (033) N-(4-(8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (034) N-(4-(8-fluoro-7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (035) (S)-N-(4-(8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (036) (R)-N-(4-(8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (037) N-(4-(8-fluoro-7-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (038) N-(4-(7-(sec-butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (039) (S)-N-(4-(7-(sec-butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (040) (R)-N-(4-(7-(sec-butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (041) N-(4-(7-cyclopropoxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (042) N-(4-(7-cyclobutoxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (043) N-(4-(7-(cyclopentoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (044) N-(4-(7-(cyclohexyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (045) N-(4-(7,8-difluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (046) N-(4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (047) N-(3-chloro-4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (048) N-(4-(7,8-difluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (049) (E)-N-(2,6-dimethyl-4-(7-((4,4,4-trifluorobut-2-en-1-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (050) N-(4-(7-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (051) N-(2,6-dimethyl-4-(7-(2,2,2-trifluoro-1-methoxyethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl))phenyl)-3,3-dimethylbutyramide (052) N-(2,6-dimethyl-4-(7-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (053) N-(2,6-dimethyl-4-(7-((1-(trifluoromethyl)cyclopropyl)methoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (054) N-(4-(7-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (055) N-(2,6-dimethyl-4-(7-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (056) N-(2,6-dimethyl-4-(7-(2,2,3,3-tetrafluoropropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (057) N-(2,6-dimethyl-4-(7-(3,3,3-trifluoropropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (058) N-(2,6-dimethyl-4-(7-((4-(trifluoromethyl)cyclohexyl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (059) N-(2,6-dimethyl-4-(7-(4,4,4-trifluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (060) N-(2,6-dimethyl-4-(7-((4,4,5,5,5-pentafluoropentyl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (061) N-(2,6-dimethyl-4-(7-(2,2,4,4,4-pentafluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (062) N-(4-(7-(4-fluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (063) [Terminology] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Unless otherwise stated, all patent documents, publications, etc. referred to in this invention are incorporated by reference in their entirety. In the event that there are multiple definitions of the same term in this invention, the definition in this specification shall prevail.

[0062] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any claims. In this specification and the appended claims, it is to be noted that singular referents such as "a," "an," and "the" include plural referents unless the text indicates otherwise. It is also to be noted that "or" means "and / or" unless otherwise indicated. Furthermore, terms such as "comprises," "contains," and the like are non-limiting.

[0063] "Substituted" means that a hydrogen atom is replaced by a substituent. Note that the substituents on a particular atom are limited by its valency. i ~C j ", "C i-j " includes a start and end range, where i and j are both integers representing the number of carbon atoms. For example, C 1 ~C 4 , C 1 ~C 8 , C 3 ~C 8 , C 1-6 , C 3-6 etc.

[0064] C, H, O, S, N, F, Cl, Br, I, etc., relating to the groups and compounds described in the present invention include their isotopes. At the same time, C, H, O, S, N, F, Cl, Br, I contained in the groups and compounds of the present invention can be replaced by one or more corresponding isotopes, if necessary, and the isotopes of carbon 12 C. 13 C. 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), oxygen isotopes 16 O. 17 O. 18 O, isotopes of sulfur 32 S, 33 S, 34 S, 36 S, an isotope of nitrogen 14 N, 15 N, an isotope of fluorine 17 F, 19 F, an isotope of chlorine 35 Cl, 37 Cl, isotopes of bromine 79 Br, 81 Br, etc., but are not limited to these.

[0065] The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group containing 1 to 8 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, p-pentyl, n-hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, etc. Alkyl may be substituted with one or more substituents, and in the case of multiple substitutions, the substituents may be the same or different; said substituents are independently selected from D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfonyl, alkylamido, C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Hydroxyalkyl, C1 ~C 8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Halocycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamino, spiroalkyl, C 6 ~C 12 Aryl, C 5 ~C 14 Heteroaryl, C 3 ~C 12 It is a heterocyclyl.

[0066] The terms "alkenyl" and "alkylene" as used herein refer to a straight or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C=C double bond, and include, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-pentenyl, 5-pentenyl, 6-pentenyl, 7-pentenyl, 8-pentenyl, 9-pentenyl, 10-pentenyl, 11-pentenyl, 12-pentenyl, 13-pentenyl, 14-pentenyl, 15-pentenyl, 16-pentenyl, 17-pentenyl, 18-pentenyl, 19-pentenyl, 20-pentenyl, 21-pentenyl, 22-pentenyl, 23-pentenyl, 24-pentenyl, 25-pentenyl, 26-pentenyl, 27-pentenyl, 28-pentenyl, 29-pentenyl, 30-pentenyl, 31-pentenyl, 32-pentenyl, 33-pentenyl, 34-pentenyl, 35-pentenyl, 36-pentenyl, 37-pentenyl, 38-pentenyl, 39-pentenyl, 40-pentenyl, 41-pentenyl, 42-pentenyl, 43-pentenyl, 44-pentenyl, 45-pentenyl, 46-pentenyl, 47-pentenyl, 48-pentenyl, Examples of hexenyl include, but are not limited to, 1-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-methyl-2-hexenyl, 2-methyl-2-hexenyl, 2-methyl-3-hexenyl, 3,5-dimethyl-2-hexenyl, 3,3-dimethyl-1-pentenyl, 3-methyl-2-ethyl-1-butenyl, 1-octenyl, 2-octenyl, and the like. Alkenyl can be substituted with one or more substituents, in which case the substituents can be the same or different; said substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, amido, sulfonamido, spiroalkyl.

[0067] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain radical containing 1 to 8 carbon atoms and containing at least one C≡C triple bond, and includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 4-methyl-1-butynyl, 2-methyl-3-butynyl, 1-methyl-4-butynyl, 1-hexynyl, 2 ... Examples of hexynyl include, but are not limited to, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2,2-dimethyl-4-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-methyl-3-hexynyl, 3-methyl-1-hexynyl, 3,3-dimethyl-1-hexynyl, 4-methyl-1-hexynyl, and the like. Alkynyl can be substituted with one or more substituents, in which case the substituents can be the same or different; said substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, amido, sulfonamido, spiroalkyl.

[0068] As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

[0069] The term "cycloalkyl" as used herein refers to a non-aromatic monovalent hydrocarbon radical, monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond, a bridged ring, a spirocyclic ring, or a fused ring), containing 3 to 12 carbon atoms, in which one or more of the chemical bonds may be double or triple bonds. "Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydroindenyl, decahydronaphthalenyl, bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexenyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1 ... Examples include, but are not limited to, cyclo[3.2.1]octanyl, bicyclo[3.2.1]octanyl, bicyclo[5.1.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]nonyl, bicyclo[3.2.2]nonyl, bicyclo[5.2.1]decyl, bicyclo[4.2.2]decyl, spiro[2.2]pentanyl, spiro[2.3]hexyl, spiro[2.4]heptanyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.5]nonyl, spiro[3.4]octyl, spiro[3.3]heptanyl, spiro[4.5]decyl, spiro[4.4]nonyl, and the like. Cycloalkyl may be substituted with one or more substituents, in which case the substituents may be the same or different; said substituents are independently selected from the group consisting of D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfonyl, alkylamido, C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkylamino, C 1 ~C 8Haloalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Halocycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 ~C 12 Aryl, C 5 ~C 14 Heteroaryl, C 3 ~C 12 It is a heterocyclyl.

[0070] The term "cycloalkenyl" as used herein refers to a non-aromatic monovalent hydrocarbon radical, monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond, a bridged ring, a spiro ring, or a fused ring) containing 3 to 12 carbon atoms and at least one C=C double bond, and includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloalkenyl, spiro[2.2]pent-1-alkenyl, spiro[2.2]pent-1,4-dialkenyl, spiro[2.3]hex-1-alkenyl, spiro[2.3]hex-1,4-dialkenyl, spiro[3.3]hept-1-al ... Examples include, but are not limited to, pyro[3.3]hept-1,5-dialkenyl, spiro[3.4]oct-1-alkenyl, spiro[3.4]oct-1,6-dialkenyl, spiro[3.4]oct-5-alkenyl, spiro[3.4]oct-6-alkenyl, spiro[3.4]oct-1-alkenyl, bicyclo[2.1.1]hex-1-alkenyl, bicyclo[2.1.1]hex-2-alkenyl, bicyclo[3.1.1]hept-1-alkenyl, bicyclo[3.1.1]hept-2-alkenyl, bicyclo[2.2.1]hept-1-alkenyl, bicyclo[2.2.1]hept-2-alkenyl, and the like. Cycloalkenyl may be substituted with one or more substituents, in which case the substituents may be the same or different; said substituents are independently selected from D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfonyl, alkylamido, C 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Halocycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 ~C 12 Aryl, C 5 ~C 12 Heteroaryl, C 3 ~C 12 It is a heterocyclyl.

[0071] The terms "heterocyclyl" and "heterocycloalkyl" as used herein refer to a monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond, a bridged ring, a spirocyclic ring, or a fused ring), saturated or unsaturated (containing one or more conjugated or incompletely conjugated double bonds) divalent cyclic hydrocarbon radical having 3 to 15 ring atoms and having one or more heteroatoms selected from N, O, and S. Heterocyclyl includes pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, thienyl, furyl, triazolyl, oxazolyl, imidazolyl, indazolyl, indolizinyl, indolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroiso ... isoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, pteridinyl, purinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, oxiranyl, oxetanyl, oxanyl, oxepanyl, oxocanyl, aziridinyl, azetidinyl, azacyclopentenyl, azepanyl, azacyclooctyl, thiacyclobutanyl, thiazepine, dihydrofuryl, dihydrothienyl, dihydropyranyl, tetrahydrofuryl, tetrahydro Thiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl, tetrahydroimidazolyl, hexahydropyridazinyl, hexahydropyrimidinyl, thienoazepine, benzazepine, benzimidazolyl, benzofuryl, benzothienyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, benzoxadiazolyl, benzoxazolyl, benzisoxazolyl, imidazopyridyl, imidazothiazolyl , pyrrolopyridyl, thienopyrrolyl, thienothienyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrrolyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, 1-azaspiro[2.2]pentyl, 1-azaspiro[2.3]hexyl, 4-azaspiro[2.3]hexyl, 5-azaspiro[2.3]3]hexyl, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 1-azaspiro[2.5]octyl, 2-azaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2-azaspiro[3.5]nonyl, 6-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-azaspiro[4.4 ]nonyl, 2-azaspiro[4.4]nonyl, 8-azaspiro[4.5]decyl, 2,8-diazaspiro[4.5]decyl, 1-oxaspiro[2.2]pentyl, 1-oxaspiro[2.3]hexyl, 4-oxaspiro[2.3]hexyl, 5-oxaspiro[2.3]hexyl, 2-oxaspiro[3.3]heptyl, 1-oxaspiro[2.5]octyl, 2-oxaspiro[3.4]o octyl, 6-oxaspiro[3.4]octyl, 2-oxaspiro[3.5]nonyl, 6-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 1-oxaspiro[4.4]nonyl, 2-oxaspiro[4.4]nonyl, 8-oxaspiro[4.5]decane, decahydroquinolinyl, decahydroisoquinolinyl, 2-azabicyclo[1.1.1]pentanyl, 2-oxabicyclo [1.1.1]pentanyl, azabicyclo[2.1.1]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[3.1.1]heptanyl, oxabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1]heptyl, azabicyclo[4.1.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, etc. Heterocyclyl may be substituted with one or more substituents, and in the case of multiple substitutions, the substituents may be the same or different; said substituents are independently selected from D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfonyl, alkylamido, C. 1 ~C 8 Alkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Hydroxyalkyl, C 1 ~C8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Halocycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 6 ~C 12 Aryl, C 5 ~C 14 Heteroaryl, C 3 ~C 12 Heterocyclyl. As defined herein, the term "heterocyclyl" may include aromatic heterocyclic groups, non-aromatic heterocyclic groups, or aliphatic heterocyclic groups having at least one heteroatom.

[0072] The term "spiroalkyl" as used herein refers to a 3- to 12-membered carbon ring formed when two carbon atoms in an alkyl are bonded to the same carbon atom in the parent molecular group.

[0073] The term "alkoxy" as used herein refers to alkyl-O-, where alkyl is as defined above. Illustrative examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentoxy, and the like. "Alkoxy" further includes substituted alkoxy, where the substitution is D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamido, spiroalkyl, C. 1 ~C 8 Alkyl, C 1 ~C8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Cyclohexyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be heteroaryl.

[0074] The term "alkenyloxy" as used herein refers to alkenyl-O-, where alkenyl is as defined above. "Alkenyloxy" further includes substituted alkenyloxy, where the substituents are D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 6 ~C 12 Aryl, C5 ~C 14 It may be heteroaryl.

[0075] The term "cycloalkoxy" as used herein refers to cycloalkyl-O-, where cycloalkyl is as defined above. Illustrative examples of "cycloalkoxy" as used herein include, but are not limited to, cyclopropanyloxy, cyclobutanyloxy, cyclopentanyloxy, cyclohexanyloxy, cycloheptanyloxy, cyclooctanyloxy, bicyclo[1.1.0]butanyloxy, bicyclo[2.1.0]pentanyloxy, bicyclo[2.2.0]hexanyloxy, bicyclo[1.1.1]pentanyloxy, bicyclo[2.1.1]hexanyloxy, and the like. "Cycloalkoxy" further includes substituted cycloalkoxy, where the substituents are D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamido, spiroalkyl, C. 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be heteroaryl.

[0076] The term "heterocycloalkoxy" as used herein refers to heterocycloalkyl-O-, where heterocycloalkyl is as defined above. Illustrative examples of "heterocycloalkoxy" as used herein include, but are not limited to, oxiranyloxy, oxetanyloxy, oxolyloxy, oxanyloxy, aziridinyloxy, azetidinyloxy, azacyclopentyloxy, azacyclohexyloxy, and the like. "Heterocycloalkoxy" further includes substituted heterocycloalkoxy, where the substituents are D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C. 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 1 ~C 8 Haloalkyl, C 1 ~C 8 Halohydroxyalkyl, C 1 ~C 8 Haloalkoxy, C 1 ~C 8 Haloalkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 3 ~C 12 Cyclohexyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be a heteroaryl.

[0077] The term "haloalkyl" as used herein refers to straight or branched alkyl substituted with halogen (preferably fluorine, chlorine, bromine, iodine), where "alkyl" is as defined above. Illustrative examples of "haloalkyl" as used herein include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, tetrafluoroethyl, pentafluoroethyl, 1,1,1-trifluoropropan-2-yl, and the like. "Haloalkyl" further includes substituted haloalkyl, the substituents of which are D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C. 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be heteroaryl. The halogen substituents in "haloalkyl" may be one or more and may be substituted on one atom or on different atoms.

[0078] The term "haloalkoxy" as used in the present invention refers to haloalkyl-O-, where haloalkyl is as defined above. Examples of "haloalkoxy" as used in the present invention include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, trifluoroisopropoxy, tetrafluoroisopropoxy, hexafluoroisopropoxy, monofluorobutoxy, difluorobutoxy, trifluorobutoxy, trifluoro-sec-butoxy, trifluoro-tert-butoxy, trifluoroisobutoxy, hexafluoroisobutoxy, trifluoropentyloxy, tetrafluoropentyloxy, pentafluoropentyloxy, trifluoroisoamyloxy, monochloromethoxy, dichloromethoxy, monochloroethoxy, dichloroethyl, chloropropyl, etc. "Haloalkoxy" further includes substituted haloalkoxy, where the substituents are D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be a heteroaryl.

[0079] The term "halocycloalkyl" as used herein refers to cycloalkyl substituted with halogen (preferably fluorine, chlorine, bromine, iodine), where cycloalkyl is as defined above. The halogen substituents in "halocycloalkyl" may be one or more, and may be substituted on one atom or on different atoms.

[0080] The term "halocycloalkoxy" as used herein refers to halocycloalkyl-O-, where "halocycloalkoxy" further includes substituted halocycloalkoxy, where the substituents are D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be a heteroaryl.

[0081] The term "haloheterocycloalkyl" as used herein refers to heterocycloalkyl substituted with halogen (preferably fluorine, chlorine, bromine, iodine), where heterocycloalkyl is as defined above. The halogen substitution in "haloheterocycloalkyl" may be single or multiple, and may be substituted on one atom or on different atoms.

[0082] The term "haloheterocycloalkoxy" as used herein refers to haloheterocycloalkyl-O-, where haloheterocycloalkyl is as defined above. "Haloheterocycloalkoxy" includes further substituted "haloheterocycloalkoxy", the substituents of which are D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C, C-alkyl ... 1 ~C 8 Alkyl, C 1 ~C 8 Hydroxyalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Alkylamino, C 3 ~C 12 Cycloalkyl, C 3 ~C 12 Heterocyclyl, C 6 ~C 12 Aryl, C 5 ~C 14 It may be heteroaryl.

[0083] The term "alkylthio" as used herein refers to alkyl-S-, where alkyl is as defined above. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

[0084] The term "alkanoyl" as used herein refers to alkyl-C(O)-, where alkyl is defined above.

[0085] As used herein, the term "alkylsulfonyl" refers to alkyl-S(O) 2 -, where alkyl is as defined above.

[0086] As used herein, the term "aminosulfonyl" refers to amino-S(O) 2 - refers to.

[0087] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that can be prepared by a method well known to those skilled in the art. The salt may be a salt formed with an acid or a base, etc. A preferred type of salt is a salt of a compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, lysinic acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, isethionic acid, pamoic acid, tannic acid, etc.; and acidic amino acids such as aspartic acid, glutamic acid, etc. A preferred type of salt is the salt formed by the compound of the present invention and a base. Suitable bases for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and the like; organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, and the like.

[0088] The second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical solutions. The pharmaceutical composition according to the present invention can be composed of one or more of the compounds described in any one of the above technical solutions and other compounds, or can be composed of one or more of the compounds described in any one of the above technical solutions.

[0089] Another object of the present invention is to provide a pharmaceutical formulation comprising one or more of the compounds described above.Preferably, the pharmaceutical formulation comprises a tablet, a powder, a capsule, an injection, a granule, a spray.In another aspect, the present invention provides the use of the compounds represented by general formulas I-V as described herein, their stereoisomers, mixtures of stereoisomers, or pharma-ceutically acceptable salts in the treatment of diseases, disorders, or conditions that benefit from agonistic KCNQ.

[0090] In another aspect, the present invention provides the use of a compound of formula I-V as described herein in the preparation of a medicament for treating a disease sensitive to an increase in potassium channel ion flux, in particular in the preparation of a medicament for treating a central nervous system disease.

[0091] In some embodiments, the condition in a subject in need thereof comprises epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, stroke, complications of cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome, or tinnitus.

[0092] The present inventors have confirmed through experiments that the compounds of the present invention have a significant activating effect on KCNQ2 / 3 potassium ions.

[0093] The inventors have confirmed through experiments that the present invention has a significant effect of inducing a left shift of the half open circuit voltage.

[0094] The inventors of the present invention have confirmed through experiments that the present invention can significantly inhibit the occurrence of hind limb stiffness in mice with epilepsy induced by MES.

[0095] The present inventors have confirmed through experiments that the compound of the present invention has superior brain exposure. [Mode for carrying out the invention] The enablement of the present invention is illustrated by the following examples, but those skilled in the art should understand that modifying or replacing the corresponding technical features according to the teachings of the prior art also falls within the protection scope of the present invention.

[0096] Example 1: N-(4-(7-Methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (001)

[0097] [ka]

[0098] Step 1, 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (1g, 6.17mmol) was dissolved in 10mL of DMF, cesium carbonate (4.02g, 12.33mmol) was added, iodomethane (1.31g, 9.25mmol) was added at 0℃, and the mixture was reacted at 80℃ for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, 30mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, and concentrated under reduced pressure. A large amount of white solid was precipitated, filtered by suction, and the cake was dried to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate 001-1: 6-methoxy-3,4-dihydronaphthalene-1(2H)-one (1.06g), with a yield of 96%. LC-MS (ESI-MS): 177[M+H] + Used directly in next step.

[0099] Step 2: Dissolve intermediate 001-1 (1g, 5.67mmol) in 10mL concentrated hydrochloric acid, slowly add sodium azide (737.86mg, 11.35mmol) at 0℃, slowly return to room temperature, and react for 6 hours. After the reaction is completed, slowly add saturated potassium carbonate aqueous solution to make the reaction system pH about 8, extract with ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and obtain intermediate 001-2: 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (0.52mg) by silica gel column chromatography, the yield was 48%. LC-MS (ESI-MS): 192[M+H] + .

[0100] Step 3: Dissolve intermediate 001-2 (250 mg, 1.31 mmol) in 1 mL of tetrahydrofuran, slowly add lithium aluminum hydride (2.6 mL, 5.23 mmol, 2 M in THF) at 0°C, warm to reflux, and react for 4 hours. After the reaction is completed, slowly add water until bubbles no longer appear from the reaction system, concentrate under reduced pressure, dissolve the residue in ethyl acetate, and concentrate under reduced pressure to obtain intermediate 001-3: 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (200 mg), yield 86%. LC-MS (ESI-MS): 178[M+H] + .

[0101] Step 4: Intermediate 001-3 (100 mg, 0.56 mmol) was dissolved in 2 mL of 1,4-dioxane and successively treated with N-(2,6-dimethyl-4-bromophenyl)-3,3-dimethylbutyramide (252.38 mg, 0.84 mmol), Pd 2 (dba) 3(25.83 mg, 0.02 mmol), XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) (26.90 mg, 0.05 mmol), sodium tert-butoxide (162.66 mg, 1.69 mmol) were added, and the mixture was replaced with nitrogen gas, and then reacted at 80°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, suction filtered, and the solid residue was washed with ethyl acetate, and then washed three times with saturated ammonium chloride solution. The organic phase was concentrated, and the target compound 001 (90 mg) was obtained by silica gel column chromatography, with a yield of 40%. LC-MS (ESI-MS): 395 [M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 8.1, 2.6 Hz, 1H), 6.48 (s, 2H), 6.40 (brs, 1H), 4.49 (s, 2H), 3.75 (s, 3H), 3.73 - 3.70 (m, 2H), 2.95 - 2.88 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.88 - 1.82 (m, 2H), 1.12 (s, 9H). Example 2: N-(4-(7-ethoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (002)

[0102] [ka]

[0103] The target compound 002 (35 mg) was prepared by referring to the synthesis route and synthesis method of Example 1 and replacing methyl iodide with ethyl bromide. LC-MS (ESI-MS): 409 [M+H] + , 1 H NMR (400 MHz, CDCl 3) δ 7.16 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.61 (dd, J = 8.2, 2.6 Hz, 1H), 6.49 (d, J = 6.1 Hz, 2H), 6.39 (brs, 1H), 4.48 (s, 2H), 3.97 (q, J = 7.0 Hz, 2H), 3.73 - 3.68 (m, 2H), 2.93 - 2.87 (m, 2H), 2.23 (s, 2H), 2.14 (s, 6H), 1.88 - 1.82 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H), 1.12 (s, 9H). Example 3: N-(4-(7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (003)

[0104] [ka]

[0105] The target compound 003 (46 mg) was prepared by replacing methyl iodide with 2-bromopropane according to the synthesis route and method of Example 1. LC-MS (ESI-MS): 423 [M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 7.15 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 8.2, 2.5 Hz, 1H), 6.48 (s, 2H), 6.42 (brs, 1H), 4.51 - 4.44 (m, 3H), 3.71 (d, J = 4.6 Hz, 2H), 2.92 - 2.85 (m, 2H), 2.23 (s, 2H), 2.14 (s, 6H), 1.85 (d, J = 4.3 Hz, 2H), 1.30 (d, J = 6.1 Hz, 6H), 1.12 (s, 9H). Example 4: N-(4-(7-(sec-butoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (004)

[0106] [ka]

[0107] The target compound 004 (60 mg) was prepared by referring to the synthesis route and synthesis method of Example 1 and replacing methyl iodide with 2-bromobutane. LC-MS (ESI-MS): 437 [M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 7.15 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 8.2, 2.5 Hz, 1H), 6.49 (d, J = 7.5 Hz, 2H), 6.42 (brs, 1H), 4.49 (s, 2H), 4.22 (dd, J = 12.1, 6.1 Hz, 1H), 3.75 - 3.68 (m, 2H), 2.93 - 2.86 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.88 - 1.80 (m, 2H), 1.75 - 1.68 (m, 2H), 1.25 (s, 3H), 1.12 (s, 9H), 0.95-0.92 (m, 3H). Example 5: N-(4-(7-(difluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (005)

[0108] [ka]

[0109] Step 1: 6-hydroxy-3,4-dihydro-2H-1-naphthone (2 g, 12.33 mmol) was dissolved in 10 mL of DMF, and potassium iodide (2.07 g, 12.45 mmol), tetrabutylammonium iodide (4.78 g, 12.45 mmol), sodium difluorobromoacetate (2.45 g, 12.45 mmol), and cesium carbonate (8.04 g, 24.66 mmol) were added in sequence, and the mixture was reacted at 100 ° C. overnight. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and filtered by suction. The organic phase was washed twice with saturated sodium bicarbonate, twice with saturated ammonium chloride, concentrated under reduced pressure, and the product 6-(difluoromethoxy)-3,4-dihydronaphthalene-1(2H)-one (1.4 g) was obtained by silica gel column chromatography, with a yield of 53%. LC-MS (ESI-MS): 213[M+H] + .

[0110] The subsequent steps were performed according to the synthesis route and method of Example 1, and the target compound 005 (28 mg) was prepared by replacing 6-methoxy-3,4-dihydronaphthalen-1(2H)-one with 6-(difluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one (1.4 g). LC-MS (ESI-MS): 431 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (d, J = 8.2 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.47 (s, 2H), 6.44 (s, 1H), 6.41 (s, 1H), 4.53 (s, 2H), 3.77 - 3.71 (m, 2H), 2.97 - 2.91 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.86 (dd, J = 9.9, 5.7 Hz, 2H), 1.12 (s, 9H). Example 6: N-(2,6-dimethyl-4-(7-(trifluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (006)

[0111] [ka]

[0112] Step 1: 6-hydroxy-3,4-dihydro-2H-1-naphthone (0.8 g, 5 mmol) was dissolved in 10 mL of anhydrous DMF, potassium carbonate (0.83 g, 6 mmol) and S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (2.4 g, 6 mmol) were added, and the mixture was stirred at room temperature for about 12 hours to react. After the reaction was completed, water and ethyl acetate were added for extraction, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 6-(trifluoromethoxy)-3,4-dihydronaphthalene-1(2H)-one (0.52 g), with a yield of 45%. LC-MS (ESI-MS): 231 [M+H] + .

[0113] The subsequent steps were performed according to the synthesis route and method of Example 1, and the target compound 006 (22 mg) was prepared by replacing 6-methoxy-3,4-dihydronaphthalen-1(2H)-one with 6-(trifluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one. LC-MS (ESI-MS): 449[M+H] + .

[0114] Example 7: N-(2,6-dimethyl-4-(7-(2,2,2-trifluoroethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (007)

[0115] [ka]

[0116] Step 1: 6-hydroxy-3,4-dihydro-2H-1-naphthone (2 g, 12.33 mmol) was dissolved in 15 mL of DMF, and then cesium carbonate (20.09 g, 61.66 mmol) and trifluoroethyl p-toluenesulfonate (31.35 g, 123.31 mmol) were added in sequence, and the mixture was reacted at 100 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and filtered by suction. The organic phase was washed twice with saturated sodium bicarbonate, twice with saturated ammonium chloride, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain the product 6-(2,2,2-trifluoroethoxy)-3,4-dihydronaphthalene-1(2H)-one (1.6 g), with a yield of 52%. LC-MS (ESI-MS): 245 [M + H] + .

[0117] The subsequent steps were performed according to the synthesis route and method of Example 1, and the target compound 007 (50 mg) was prepared by replacing 6-methoxy-3,4-dihydronaphthalen-1(2H)-one with 6-(2,2,2-trifluoroethoxy)-3,4-dihydronaphthalen-1(2H)-one. LC-MS (ESI-MS): 463[M+H] + .

[0118] Example 8: N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (008)

[0119] [ka]

[0120] Step 1: 6-fluoro-3,4-dihydronaphthalene-1(2H)-one (420 mg, 2.56 mmol) was dissolved in 10 mL of acetonitrile, and then cesium carbonate (1.67 g, 5.12 mmol) and trifluoroisopropanol (583.61 mg, 5.12 mmol) were added in sequence, and the mixture was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, suction filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain intermediate 008-1: 6-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydronaphthalene-1(2H)-one (340 mg), with a yield of 51%. LC-MS (ESI-MS): 259[M+H] + .

[0121] Step 2: Dissolve intermediate 008-1 (1.47 g, 5.67 mmol) in 10 mL of concentrated hydrochloric acid, slowly add sodium azide (737.86 mg, 11.35 mmol) at 0 ° C, gradually return to room temperature, and react for 6 hours. After the reaction is completed, slowly add saturated potassium carbonate aqueous solution to make the pH value of the reaction system about 8, extract with ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and obtain intermediate 008-2: 7-((1,1,1-trifluoropropan-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one by silica gel column chromatography. LC-MS (ESI-MS): 274 [M + H] + .

[0122] Step 3: Dissolve intermediate 008-2 (274 mg, 1.0 mmol) in 1 mL of tetrahydrofuran, slowly add lithium aluminum hydride (2.6 mL, 5.23 mmol, 2 M in THF) at 0°C, warm to reflux, and react for 4 hours. After the reaction is completed, slowly add water until bubbles no longer appear from the reaction system, concentrate under reduced pressure, dissolve the residue in ethyl acetate, and concentrate under reduced pressure to obtain intermediate 008-3: 7-((1,1,1-trifluoropropan-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine. LC-MS (ESI-MS): 260[M+H]+ .

[0123] Step 4: Dissolve intermediate 008-3 (130 mg, 0.50 mmol) in 2 mL of 4-dioxane and sequentially add N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide (252.38 mg, 0.84 mmol), Pd 2 (dba) 3 (25.83 mg, 0.02 mmol), X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) (26.90 mg, 0.05 mmol), sodium tert-butoxide (162.66 mg, 1.69 mmol) were added, and the mixture was replaced with nitrogen gas, and then reacted at 80°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, suction filtered, and the solid residue was washed with ethyl acetate, and then washed three times with saturated ammonium chloride solution. The organic phase was concentrated, and the target compound 008 (90 mg) was obtained by silica gel column chromatography. LC-MS (ESI-MS): 477 [M + H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.19 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 6.67 (dd, J = 8.2, 2.6 Hz, 1H), 6.47 (s, 2H), 6.41 (s, 1H), 4.61 - 4.53 (m, 1H), 4.49 (s, 2H), 3.72 (s, 2H), 2.96 - 2.88 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.90 - 1.81 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H), 1.12 (s, 9H). Example 9: N-(4-(7-cyclopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (009)

[0124] [ka]

[0125] The target compound 009 (21 mg) was prepared by replacing iodomethane with bromocyclopropane according to the synthesis route and synthesis method of Example 1. LC-MS (ESI-MS): 421 [M+H] + .

[0126] Example 10: N-(4-(7-cyclobutoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (010)

[0127] [ka]

[0128] By referring to the synthesis route and synthesis method of Example 1, the target compound 010 (63 mg) was prepared by replacing methyl iodide with bromocyclobutane. LC-MS (ESI-MS): 435 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.13 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.1, 2.6 Hz, 1H), 6.48 (d, J = 6.6 Hz, 2H), 6.40 (s, 1H), 4.57 (t, J = 7.2 Hz, 1H), 4.48 (d, J = 10.8 Hz, 2H), 3.70 (d, J = 4.8 Hz, 2H), 2.93 - 2.84 (m, 2H), 2.45 - 2.36 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.88 - 1.77 (m, 4H), 1.25 (s, 2H), 1.12 (s, 9H). Example 11: N-(4-(7-(cyclopentoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (011)

[0129] [ka]

[0130] By referring to the synthesis route and synthesis method of Example 1, the target compound 011 (52 mg) was prepared by replacing iodomethane with bromocyclopentane. LC-MS (ESI-MS): 449 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.58 (dd, J = 8.2, 2.6 Hz, 1H), 6.48 (s, 2H), 6.40 (brs, 1H), 4.71 - 4.65 (m, 1H), 4.47 (s, 2H), 3.75 - 3.67 (m, 2H), 2.93 - 2.86 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.89 - 1.81 (m, 6H), 1.62 - 1.54 (m, 4H), 1.12 (s, 9H). Example 12: N-(4-(7-(cyclohexyloxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (012)

[0131] [ka]

[0132] By referring to the synthesis route and synthesis method of Example 1 and replacing iodomethane with bromocyclohexane, the target compound 012 (57 mg) was prepared. LC-MS (ESI-MS): 463 [M+H] + .

[0133] Example 13: N-(2,6-dimethyl-4-(7-(oxetan-3-yl-oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (013)

[0134] [ka]

[0135] By referring to the synthesis route and synthesis method of Example 1, the target compound 013 (22 mg) was prepared by replacing methyl iodide with 3-bromooxetane. LC-MS (ESI-MS): 437 [M+H] + .

[0136] Example 14: N-(2,6-dimethyl-4-(7-(methylthio)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (014)

[0137] [ka]

[0138] Step 1: In a reaction flask, 6-fluoro-3,4-dihydro-2H-1-naphthone (1.6 g) was dissolved in 15 mL of anhydrous DMSO, sodium thiomethoxide (1.1 g) was added, and the mixture was heated to 50° C. and stirred for about 3 hours to react. The reaction was quenched by adding water, and dichloromethane and water were added for extraction. The separated dichloromethane phase was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain 6-(methylthio)-3,4-dihydronaphthalene-1(2H)-one (1.1 g). LC-MS (ESI-MS): 193 [M+H] + .

[0139] The subsequent steps were carried out according to the synthesis route and method of Example 1, and the target compound 014 (78 mg) was prepared by replacing 6-methoxy-3,4-dihydronaphthalene-1(2H)-one with 6-(methylthio)-3,4-dihydronaphthalene-1(2H)-one. LC-MS (ESI-MS): 411 [M+H] + . 1 H NMR (400 MHz, CDCl 3) δ 7.18 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H), 6.47 (s, 2H), 6.41 (s, 1H), 4.50 (s, 2H), 3.74 - 3.69 (m, 2H), 2.95 - 2.89 (m, 2H), 2.44 (s, 3H), 2.23 (s, 2H), 2.14 (s, 6H), 1.88 - 1.83 (m, 2H), 1.12 (s, 9H). Example 15: N-(2,6-dimethyl-4-(7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (015)

[0140] [ka]

[0141] In a reaction flask, compound 014 (30 mg) was dissolved in 3 mL of dichloromethane, mCPBA (35 mg) (3-chloroperbenzoic acid) was added, and the mixture was stirred at room temperature for about 1 hour to react. The reaction was then quenched with an aqueous solution of sodium sulfite, and extracted with dichloromethane and water. The separated dichloromethane phase was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain compound 015 (26 mg). LC-MS (ESI-MS): 443 [M+H] + .

[0142] Example 16: N-(4-(7-fluoro-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (016)

[0143] [ka]

[0144] Step 1: In a reaction flask, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (700 mg, synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227) was dissolved in 7 mL of hydrochloric acid, and sodium azide (473.46 mg, 7.28 mmol) was slowly added at 0°C, and the mixture was gradually returned to room temperature and reacted for 4 hours. After the reaction was completed, a saturated aqueous potassium carbonate solution was slowly added to make the pH of the reaction system about 8, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain intermediate 016-1: 7-fluoro-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (360 mg), with a yield of 36%. LC-MS (ESI-MS): 208[M+H] + .

[0145] Step 2: Dissolve intermediate 016-1 (170 mg, 0.82 mmol) in 3 mL of tetrahydrofuran, slowly add lithium aluminum hydride (1.6 mL, 3.28 mmol, 2 M in THF) at 0°C, warm to reflux, and react for 4 hours. After the reaction is completed, slowly add water until bubbles no longer appear from the reaction system, concentrate under reduced pressure, dissolve the residue in ethyl acetate, and concentrate under reduced pressure to obtain intermediate 016-2: 7-fluoro-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (150 mg), with a yield of 94%. LC-MS (ESI-MS): 194 [M+H] + .

[0146] Step 3: N-(2,6-dimethyl-4-bromophenyl)-3,3-dimethylbutyramide (5 g, 16.77 mmol) was dissolved in 80 mL of 1,4-dioxane and successively added bis-pinacolatodiboron (3.41 g, 13.41 mmol), potassium carbonate (4.94 g, 50.30 mmol), Pd(dppf)Cl 2(614.62 mg, 0.83 mmol) was added, the mixture was purged with nitrogen gas, and the mixture was reacted at 90°C for 3 hours. After the reaction was completed, the mixture was diluted with ethyl acetate, suction filtered, the organic phase was washed once with a saturated aqueous sodium chloride solution, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain intermediate 016-3: (3,5-dimethyl-4-(3,3-dimethylbutyramide))phenylboronic acid pinacol ester (4.30 g), with a yield of 74%. LC-MS (ESI-MS): 346 [M+H] + .

[0147] Step 4: Intermediate 016-3 (3 g, 8.69 mmol) was dissolved in 30 mL of tetrahydrofuran, and 10 mL of water and sodium periodate (11.15 g, 52.13 mmol) were added in sequence, and the mixture was allowed to react at room temperature overnight. After the reaction was completed, water was added until a solid precipitated, and the mixture was filtered and dried to obtain intermediate 016-4: (3,5-dimethyl-4-(3,3-dimethylbutyramido))phenylboronic acid (2.0 g), with a yield of 87%. LC-MS (ESI-MS): 264[M+H] + .

[0148] Step 5: Intermediate 016-2 (100 mg, 0.51 mmol) was dissolved in 5 mL of acetonitrile, and then intermediate 016-4 (204.24 mg, 0.77 mmol), boronic acid (63.99 mg, 1.03 mmol), diisopropylethylamine (133.75 mg, 1.03 mmol), and copper acetate (93.98 mg, 0.51 mmol) were added in sequence, and the mixture was reacted at 70 °C in an oxygen gas atmosphere for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and suction filtered. The organic phase was washed twice with saturated ammonium chloride, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain the target compound 016 (70 mg), with a yield of 32%. LC-MS (ESI-MS): 411 [M + H] + , 1 H NMR (400 MHz, CDCl 3) δ 7.22 - 7.17 (m, 1H), 7.07 (dd, J = 11.7, 2.6 Hz, 1H), 6.82 (td, J = 8.0, 2.6 Hz, 1H), 6.43 - 6.38 (m, 3H), 4.56 (s, 2H), 3.61 - 3.55 (m, 2H), 2.23 (s, 2H), 2.14 (s, 6H), 2.05 - 1.98 (m, 2H), 1.33 (d, J = 4.0 Hz, 6H), 1.12 (s, 9H). Example 17: N-(4-(5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (017)

[0149] [ka]

[0150] By referring to the synthesis route and synthesis method of Example 16, and replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one with 4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227), the target compound 017 (52 mg) could be prepared. LC-MS (ESI-MS): 393 [M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J = 7.0 Hz, 1H), 7.24 - 7.08 (m, 3H), 6.42 (d, J = 5.9 Hz, 3H), 4.59 (s, 2H), 3.60 - 3.54 (m, 2H), 2.23 (s, 2H), 2.14 (s, 6H), 2.05 (t, J = 5.9 Hz, 2H), 1.33 (s, 6H), 1.12 (s, 9H). Example 18: N-(4-(2-chloro-8,8-dimethyl-4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepin-5-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (018)

[0151] [ka]

[0152] Referring to the synthesis route and synthesis method of Example 16, the target compound 018 (28 mg) was prepared by replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 2-chloro-7,7-dimethyl-6,7-dihydrobenzo[b]thiophene-4(5H)-one (synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227). LC-MS (ESI-MS): 433[M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 6.71 (s, 1H), 6.45 - 6.40 (m, 3H), 4.37 (s, 2H), 3.76 - 3.70 (m, 2H), 2.25 (s, 2H), 2.16 (s, 6H), 1.90 - 1.84 (m, 2H), 1.33 (s, 6H), 1.13 (s, 9H). Example 19: N-(4-(8,8-dimethyl-4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepin-5-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (019)

[0153] [ka]

[0154] By referring to the synthesis route and synthesis method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 7,7-dimethyl-6,7-dihydrobenzo[b]thiophene-4(5H)-one (synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227), the target compound 019 (41 mg) could be prepared. LC-MS (ESI-MS): 399[M+H] + , 1H NMR (400 MHz, CDCl 3 ) δ 6.97 (d, J = 5.1 Hz, 1H), 6.90 (d, J = 5.1 Hz, 1H), 6.47 (s, 2H), 6.42 (brs, 1H), 4.48 (s, 2H), 3.81 - 3.76 (m, 2H), 2.24 (s, 2H), 2.15 (s, 6H), 1.91 - 1.86 (m, 2H), 1.38 (s, 6H), 1.12 (s, 9H). Example 20: N-(4-(2-chloro-4,4-dimethyl-4,5,6,8-tetrahydro-7H-thieno[2,3-c]azepin-7-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (020)

[0155] [ka]

[0156] Referring to the synthesis route and synthesis method of Example 16, the target compound 020 (29 mg) was prepared by replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 2-chloro-4,4-dimethyl-5,6-dihydrobenzo[b]thiophene-7(4H)-one (synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227). LC-MS (ESI-MS): 433[M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 6.73 (s, 1H), 6.49 (s, 2H), 6.44 (brs, 1H), 4.44 (s, 2H), 3.72 - 3.68 (m, 2H), 2.25 (s, 2H), 2.17 (s, 6H), 1.89 - 1.83 (m, 2H), 1.24 (s, 6H), 1.13 (s, 9H). Example 21: N-(4-(4,4-dimethyl-4,5,6,8-tetrahydro-7H-thieno[2,3-c]azepin-7-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (021)

[0157] [ka]

[0158] By referring to the synthesis route and synthesis method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 4,4-dimethyl-5,6-dihydrobenzo[b]thiophene-7(4H)-one (synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227), the target compound 021 (18 mg) could be prepared. LC-MS (ESI-MS): 399[M+H] + , 1 H NMR (400 MHz, CDCl 3 ) δ 6.98 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 5.2 Hz, 1H), 6.53 (s, 2H), 6.42 (brs, 1H), 4.57 (s, 2H), 3.77 - 3.72 (m, 2H), 2.24 (s, 2H), 2.16 (s, 6H), 1.92 - 1.88 (m, 2H), 1.28 (s, 6H), 1.12 (s, 9H). Example 22: N-(4-(7-fluoro-3,4-dihydrospiro[benzo[c]azepine-5,1′-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (022)

[0159] [ka]

[0160] By referring to the synthesis route and synthesis method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 7'-fluoro-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one (synthesized with reference to Adv. Synth. Catal. 2019, 361, 3223-3227), and the target compound 022 (33 mg) was prepared. LC-MS (ESI-MS): 409[M+H] + , 1 H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 7.48 (dd, J = 8.1, 6.2 Hz, 1H), 6.93 (ddd, J = 11.0, 9.5, 2.6 Hz, 2H), 6.54 (s, 2H), 4.67 (s, 2H), 3.78 (s, 2H), 2.15 (s, 2H), 2.05 (s, 6H), 1.65 - 1.46 (m, 2H), 1.05 (s, 9H), 0.96 - 0.83 (m, 4H). Example 23: N-(4-(8-fluoro-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (023)

[0161] [ka]

[0162] By referring to the synthetic route and synthetic method of Example 16, and replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 7-fluoro-2,3-dihydroquinolin-4(1H)-one (synthesized with reference to Bioorganic Chemistry, 2020, 99, 103800), the target compound 023 (44 mg) could be prepared. LC-MS (ESI-MS): 384 [M + H] + , 1 H NMR (400 MHz, CDCl 3) δ 7.16 (dd, J = 8.2, 6.5 Hz, 1H), 6.53 - 6.49 (m, 2H), 6.48 (s, 2H), 6.39 (dd, J = 10.3, 2.4 Hz, 1H), 4.46 (s, 2H), 3.71 - 3.66 (m, 2H), 3.26 - 3.21 (m, 2H), 2.22 (s, 2H), 2.13 (s, 6H), 1.11 (s, 9H). Example 24: N-(4-(8-fluoro-1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (024)

[0163] [ka]

[0164] Referring to the synthesis route and synthesis method of Example 16, the target compound 024 (52 mg) was prepared by replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 7-fluoro-1-methyl-2,3-dihydroquinolin-4(1H)-one. LC-MS (ESI-MS): 398 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (dd, J = 8.9, 6.8 Hz, 1H), 6.56 (s, 1H), 6.55 - 6.50 (m, 3H), 6.44 (brs, 1H), 4.44 (s, 2H), 3.66 - 3.61 (m, 2H), 3.15 (dd, J = 5.9, 3.7 Hz, 2H), 2.88 (s, 3H), 2.24 (s, 2H), 2.16 (s, 6H), 1.12 (s, 9H). Example 25: N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (025)

[0165] [ka]

[0166] By referring to the synthesis route and synthesis method of Example 16, the target compound 025 (47 mg) could be prepared by replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 7-fluorothiochroman-4-one. LC-MS (ESI-MS): 401 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (dd, J = 8.2, 5.9 Hz, 1H), 7.23 (dd, J = 8.8, 2.5 Hz, 1H), 6.86 (td, J = 8.3, 2.5 Hz, 1H), 6.49 - 6.41 (m, 3H), 4.71 (s, 2H), 4.03 - 3.96 (m, 2H), 2.97 - 2.91 (m, 2H), 2.23 (s, 2H), 2.15 (s, 6H), 1.11 (s, 9H). Example 26: N-(4-(8-fluoro-1,1-dioxo-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (026)

[0167] [ka]

[0168] In a reaction flask, compound 025 (25 mg) was dissolved in 2 mL of dichloromethane, mCPBA (30 mg) was added, and the mixture was stirred at room temperature for about 1 hour to react. The reaction was then quenched using an aqueous solution of sodium sulfite, and extracted with dichloromethane and water. The separated dichloromethane phase was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain the target compound 026 (21 mg). LC-MS (ESI-MS): 433 [M+H] + .

[0169] Example 27: N-(4-(7-fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (027)

[0170] [ka]

[0171] By referring to the synthesis route and synthesis method of Example 16, the target compound 027 (37 mg) could be prepared by replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 6-fluoronaphthalene-1(2H)-one. LC-MS (ESI-MS): 381 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 - 7.20 (m, 1H), 6.83 (t, J = 8.0 Hz, 2H), 6.47 (s, 2H), 6.42 - 6.33 (m, 2H), 6.03 - 5.96 (m, 1H), 4.49 (s, 2H), 4.27 (s, 2H), 2.23 (s, 2H), 2.13 (s, 6H), 1.12 (s, 9H). Example 28: N-(4-(7-fluoro-5-methyl-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (028)

[0172] [ka]

[0173] By referring to the synthesis route and synthesis method of Example 16, the target compound 028 (23 mg) could be prepared by replacing 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one with 6-fluoro-4-methylnaphthalene-1(2H)-one. LC-MS (ESI-MS): 395 [M+H] + . 1 H NMR (400 MHz, CDCl3 ) δ 7.34 - 7.31 (m, 1H), 7.11 (dd, J = 10.2, 2.6 Hz, 1H), 6.97 (td, J = 8.3, 2.7 Hz, 1H), 6.60 (s, 2H), 6.53 (s, 1H), 6.07 (t, J = 5.8 Hz, 1H), 4.18 (s, 2H), 3.66 (d, J = 6.3 Hz, 2H), 2.31 (s, 2H), 2.24 (s, 6H), 2.20 (s, 3H), 1.19 (s, 9H). Example 29: N-(3-fluoro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2-methylphenyl)-3,3-dimethylbutyramide (029)

[0174] [ka]

[0175] Step 1: N-(2-methyl-3-fluoro-4-bromophenyl)-3,3-dimethylbutyramide (5 g, 16.77 mmol) was dissolved in 80 mL of 1,4-dioxane and successively added bis-pinacolatodiboron (3.41 g, 13.41 mmol), potassium acetate (4.94 g, 50.30 mmol), PdDPPFCl 2 (614.62 mg, 0.83 mmol) was added, the atmosphere was replaced with nitrogen gas, and the reaction was carried out at 90°C for 3 hours. After the reaction was completed, the mixture was diluted with ethyl acetate, suction filtered, and the organic phase was washed once with a saturated aqueous sodium chloride solution, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain oily (3-methyl-2-fluoro-4-(3,3-dimethylbutyramido))phenylboronic acid pinacol ester (4 g), with a yield of 69%. LC-MS (ESI-MS): 350 [M+H] + .

[0176] Step 2: 7-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (90 mg, 0.54 mmol) was dissolved in 5 mL of acetonitrile, and (3-methyl-2-fluoro-4-(3,3-dimethylbutyramide))phenylboronic acid pinacol ester (190 mg, 0.54 mmol), boronic acid (70 mg, 1.09 mmol), and copper acetate (100 mg, 0.54 mmol) were added in sequence, and the mixture was reacted at 80 °C in an oxygen gas atmosphere for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and suction filtered. The organic phase was washed twice with saturated ammonium chloride, dried, concentrated under reduced pressure, and subjected to column chromatography to obtain the target compound 029 (36 mg), with a yield of 17%. LC-MS (ESI-MS): 387 [M + H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (d, J = 8.8 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.85 (dd, J = 9.6, 2.3 Hz, 1H), 6.82 - 6.70 (m, 3H), 4.35 (s, 2H), 3.60 - 3.55 (m, 2H), 3.00 - 2.94 (m, 2H), 2.23 (s, 2H), 2.15 (d, J = 2.2 Hz, 3H), 1.98 - 1.91 (m, 2H), 1.11 (s, 9H). Example 30: N-(4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,3,6-trimethylphenyl)-3,3-dimethylbutyramide (030)

[0177] [ka]

[0178] 7-Fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (100 mg, 0.60 mmol) was dissolved in 5 mL of acetonitrile, and (2,3,5-trimethyl-4-(3,3-dimethylbutyramide))phenylboronic acid pinacol ester (260 mg, 0.72 mmol), boronic acid (75 mg, 1.21 mmol), copper acetate (109 mg, 0.60 mmol), and pyridine (50 μL, 1.21 mmol) were added in sequence, and the mixture was reacted at 80 ° C. in an oxygen gas atmosphere for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and filtered by suction. The organic phase was washed twice with saturated ammonium chloride, dried, concentrated under reduced pressure, and the target compound 030 (38 mg) was obtained by column chromatography, with a yield of 16%. LC-MS (ESI-MS): 397 [M + H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.02 (dd, J = 8.2, 5.8 Hz, 1H), 6.89 - 6.85 (m, 2H), 6.79 (td, J = 8.4, 2.6 Hz, 1H), 6.58 (brs, 1H), 4.01 (s, 2H), 3.26 - 3.21 (m, 2H), 2.96 - 2.90 (m, 2H), 2.30 (s, 2H), 2.22 (s, 3H), 2.15 (s, 6H), 1.94 - 1.87 (m, 2H), 1.16 (s, 9H). Example 31: N-(3-chloro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (031)

[0179] [ka]

[0180] 7-Fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (100 mg, 0.60 mmol) was dissolved in 5 mL of acetonitrile, and (2-chloro-3,5-dimethyl-4-(3,3-dimethylbutyramide))phenylboronic acid pinacol ester (282 mg, 0.66 mmol) (synthesized in the same manner as in Example 16), boronic acid (75 mg, 1.21 mmol), copper acetate (110 mg, 0.60 mmol), and pyridine (50 μL, 1.21 mmol) were added in sequence, and the mixture was reacted at 80 ° C. in an oxygen gas atmosphere for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, suction filtered, and the organic phase was washed twice with saturated ammonium chloride, dried, concentrated under reduced pressure, and the target compound 031 (52 mg) was obtained by column chromatography, with a yield of 20%. LC-MS (ESI-MS): 417 [M + H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 (dd, J = 8.3, 5.9 Hz, 1H), 6.89 - 6.85 (m, 2H), 6.80 (td, J = 8.5, 2.7 Hz, 1H), 6.63 (brs, 1H), 4.13 (s, 2H), 3.41 - 3.36 (m, 2H), 2.98 - 2.92 (m, 2H), 2.32 - 2.27 (m, 2H), 2.30 (s, 3H), 2.19 (s, 3H), 1.99- 1.92 (m, 2H), 1.15 (s, 9H). Example 32: (R)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (032)

[0181] [ka]

[0182] By referring to the synthesis route and synthesis method of Example 8, the target compound 032 (50 mg) was prepared by replacing trifluoroisopropanol with (R)-1,1,1-trifluoropropan-2-ol. LC-MS (ESI-MS): 477 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.19 (d, J = 8.2 Hz, 1H), 6.72 - 6.73 (m, 1H), 6.65 - 6.68 (m, 1H), 6.46 - 6.48 (m, 2H), 6.41 (brs, 1H), 4.53 - 4.59 (m, 1H), 4.49 (s, 2H), 3.71 - 3.73 (m, 2H), 2.89 - 2.92 (m, 2H), 2.22 (s, 2H), 2.14 (s, 6H), 1.83 - 1.86 (m, 2H), 1.46 (d, J = 6.5 Hz, 3H), 1.12 (s, 9H). Example 33: (S)—N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (033)

[0183] [ka]

[0184] By referring to the synthesis route and synthesis method of Example 8, the target compound 033 (63 mg) was prepared by replacing trifluoroisopropanol with (S)-1,1,1-trifluoropropan-2-ol. LC-MS (ESI-MS): 477[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 7.19 (d, J = 8.2 Hz, 1H), 6.72 - 6.73 (m, 1H), 6.65 - 6.68 (m, 1H), 6.46 - 6.49 (m, 2H), 6.42 (brs, 1H), 4.52 - 4.60 (m, 1H), 4.49 (s, 2H), 3.71 - 3.73 (m, 2H), 2.90 - 2.93 (m, 2H), 2.22 (s, 2H), 2.14 (s, 6H), 1.82 - 1.88 (m, 2H), 1.45 - 1.46 (m, 3H), 1.12 (s, 9H). Example 34: N-(4-(8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (034)

[0185] [ka]

[0186] Step 1, 6,7-difluoro-3,4-dihydronaphthalene-1(2H)-one (2.0 g, 10.98 mmol) was dissolved in 30 mL of acetonitrile, trifluoroisopropanol (2.5 mL, 27.45 mmol) and cesium carbonate (10.7 g, 32.94 mmol) were added to the reaction system in sequence, the tube was sealed, and the reaction was carried out at 80 ° C for 4 hours. After the reaction was completed, the mixture was concentrated to remove acetonitrile, ethyl acetate was added, the mixture was dissolved in water, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 034-1: 7-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydronaphthalene-1(2H)-one (3.12 g), with a yield of 94%. The mixture was used directly in the next reaction. ESI-MS (M + H) + =277. 1H-NMR (400 MHz, CCl3D) δ 7.76 (d, J = 11.6 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 4.66 - 4.74 (m, 1H), 2.88 - 2.91 (m, 2H), 2.58 - 2.61 (m, 2H), 2.09 - 2.15 (m, 2H), 1.57 (dd, J = 6.5, 0.9 Hz, 3H). Step 2: Intermediate 034-1 (3.12 g, 11.30 mmol) was dissolved in 40 mL of concentrated hydrochloric acid, and sodium azide (1.47 g, 22.60 mmol) was slowly added under ice bath, and the mixture was reacted at room temperature for 48 hours. After the reaction was completed, ice water and aqueous sodium carbonate solution were slowly added at low temperature to adjust the pH of the reaction system to basic, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE / EA elution) to obtain intermediate 034-2: 8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (750 mg), the yield was 23%. ESI-MS (M+H) + =292.

[0187] Step 3: Intermediate 034-2 (400 mg, 1.44 mmol) was dissolved in 100 mL of tetrahydrofuran, lithium aluminum hydride (1 mmol / mL, 13 mL) was added, and the mixture was reacted at 60° C. for 2 hours. After the reaction was completed, water was added to quench the reaction (until no bubbles were generated), and the mixture was concentrated under reduced pressure to remove water. The mixture was then dissolved in ethyl acetate (1 g of product in 1 L of EA), suction filtered, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain intermediate 034-3: 8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine 350 mg, with a yield of 92%. ESI-MS (M+H)+=278.

[0188] Step 4: Dissolve intermediate 034-3 (230 mg, 0.83 mmol) in 10 mL of 1,4-dioxane, and add N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide (370 mg, 1.24 mmol), sodium tert-butoxide (244 mg, 2.49 mmol), cesium carbonate (811 mg, 2.49 mmol), palladium acetate (19 mg, 0.08 mmol), and Pd 2 (dba) 3 (76 mg, 0.08 mmol), X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) (79 mg, 0.17 mmol) were added, and the mixture was replaced with nitrogen gas and reacted at 105 ° C for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove dioxane, dichloromethane was added, the mixture was dissolved in water, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE / EA elution) to obtain the target compound 034 (170 mg), the yield was 41%. ESI-MS (M + H) + =495. 1 H-NMR (400 MHz, CCl 3 D) δ 7.02 (d, J = 11.2 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.43 - 6.47 (m, 3H), 4.45 - 4.49 (m, 3H), 3.67 - 3.75 (m, 2H), 2.87 - 2.90 (m, 2H), 2.23 (s, 2H), 2.16 (s, 6H), 1.82 - 1.85 (m, 2H), 1.50 (d, J = 6.5 Hz, 3H), 1.12 (s, 9H). Example 35: N-(4-(8-fluoro-7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (035)

[0189] [ka]

[0190] Step 1: Refer to the synthetic route and synthetic method of Steps 1, 2, and 3 of Example 34, and replace trifluoroisopropanol with isopropanol to prepare 8-fluoro-7-isopropoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine. ESI-MS (M+H) + =224.

[0191] Step 2: 8-fluoro-7-isopropoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (540 mg, 2.42 mmol) was dissolved in 15 mL of acetonitrile, and (4-(3,3-dimethylbutyramido)-3,5-dimethylphenyl)boronic acid (1.3 g, 4.84 mmol), copper acetate (440 mg, 2.42 mmol), boronic acid (300 mg, 4.84 mmol), and DIPEA (940 mg, 7.26 mmol) were added to the reaction system in sequence, and the mixture was replaced with oxygen gas and reacted at 60 ° C for 2 hours. After the reaction was completed, the mixture was washed with an aqueous solution of saturated ammonium chloride, extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE / EA elution) to obtain the target compound 035 (150 mg), with a yield of 14%. ESI-MS (M+H) + =441. 1 H-NMR (400 MHz, CCl 3 D) δ 6.97 - 7.00 (m, 1H), 6.71 - 6.74 (m, 1H), 6.42 - 6.48 (m, 3H), 4.40 - 4.45 (m, 3H), 3.67 - 3.73 (m, 2H), 2.85 - 2.89 (m, 2H), 2.21 (s, 2H), 2.14 (s, 6H), 1.81 - 1.85 (m, 2H), 1.32 (d, J = 6.1 Hz, 6H), 1.12 (s, 9H). Example 36: (S)—N-(4-(8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (036)

[0192] [ka]

[0193] Referring to the synthesis route and synthesis method of Example 34, the target compound 036 (58 mg) could be prepared by replacing trifluoroisopropanol in step 1 with (S)-1,1,1-trifluoropropan-2-ol. LC-MS (ESI-MS): 495 [M+H] + .

[0194] Example 37: (R)-N-(4-(8-fluoro-7-((1,1,1-trifluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (037)

[0195] [ka]

[0196] Referring to the synthesis route and synthesis method of Example 34, the target compound 037 (50 mg) could be prepared by replacing trifluoroisopropanol in step 1 with (S)-1,1,1-trifluoropropan-2-ol. LC-MS (ESI-MS): 495 [M+H] + .

[0197] Example 38: N-(4-(8-fluoro-7-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (038)

[0198] [ka]

[0199] By referring to the synthesis route and synthesis method of Example 34, the target compound 038 (47 mg) could be prepared by replacing trifluoroisopropanol with methanol in step 1. LC-MS (ESI-MS): 413 [M+H] + .

[0200] Example 39: N-(4-(7-(sec-butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (039)

[0201] [ka]

[0202] By referring to the synthesis route and synthesis method of Example 34, the target compound 039 (62 mg) could be prepared by replacing trifluoroisopropanol with butan-2-ol in step 1. LC-MS (ESI-MS): 455 [M+H] + .

[0203] Example 40: (S)-N-(4-(7-(sec-butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (040)

[0204] [ka]

[0205] Referring to the synthesis route and synthesis method of Example 34, the target compound 040 (40 mg) could be prepared by replacing trifluoroisopropanol with (S)-butan-2-ol in step 1. LC-MS (ESI-MS): 455 [M+H] + .

[0206] Example 41: (R)-N-(4-(7-(sec-butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (041)

[0207] [ka]

[0208] Referring to the synthesis route and synthesis method of Example 34, the target compound 041 (46 mg) could be prepared by replacing trifluoroisopropanol with (R)-butan-2-ol in step 1. LC-MS (ESI-MS): 455 [M+H] + .

[0209] Example 42: N-(4-(7-cyclopropoxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (042)

[0210] [ka]

[0211] Referring to the synthesis route and synthesis method of Example 34, the target compound 042 (35 mg) could be prepared by replacing trifluoroisopropanol with cyclopropanol in step 1. LC-MS (ESI-MS): 439 [M+H] + .

[0212] Example 43: N-(4-(7-cyclobutoxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (043)

[0213] [ka]

[0214] By referring to the synthesis route and synthesis method of Example 34, the target compound 043 (34 mg) could be prepared by replacing trifluoroisopropanol with cyclobutanol in step 1. LC-MS (ESI-MS): 453 [M+H] + .

[0215] Example 44: N-(4-(7-(cyclopentoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (044)

[0216] [ka]

[0217] Referring to the synthesis route and synthesis method of Example 34, the target compound 044 (41 mg) could be prepared by replacing trifluoroisopropanol with cyclopentanol in step 1. LC-MS (ESI-MS): 467 [M+H] + .

[0218] Example 45: N-(4-(7-(cyclohexyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (045)

[0219] [ka]

[0220] Referring to the synthesis route and synthesis method of Example 34, the target compound 045 (48 mg) could be prepared by replacing trifluoroisopropanol with cyclohexanol in step 1. LC-MS (ESI-MS): 481 [M+H] + .

[0221] Example 46: N-(4-(7,8-difluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (046)

[0222] [ka]

[0223] Referring to the synthesis route and synthesis method of steps 2, 3, and 4 of Example 34, the target compound 046 (38 mg) was prepared by replacing 7-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one with 6,7-difluoronaphthalen-1(2H)-one. LC-MS (ESI-MS): 399 [M+H] + .

[0224] Example 47: N-(4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (047)

[0225] [ka]

[0226] Referring to the synthesis route and synthesis method of steps 2, 3, and 4 of Example 34, the target compound 047 (63 mg) was prepared by replacing 7-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one in step 2 with 6,7-difluoro-3,4-dihydronaphthalen-1(2H)-one. LC-MS (ESI-MS): 401 [M+H] + .

[0227] Example 48: N-(3-chloro-4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (048)

[0228] [ka]

[0229] By referring to the synthesis route and synthesis method of Example 31, the target compound 048 (37 mg) could be prepared by replacing 7-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine with 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine. LC-MS (ESI-MS): 435 [M+H] + .

[0230] Example 49: N-(4-(7,8-difluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (049)

[0231] [ka]

[0232] Referring to the synthesis route and synthesis method of steps 2, 3, and 4 of Example 34, the target compound 049 (38 mg) was prepared by replacing 7-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one with 6',7'-difluoro-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalen]-4'-one. LC-MS (ESI-MS): 427 [M+H] + .

[0233] Example 50: (E)-N-(2,6-dimethyl-4-(7-((4,4,4-trifluorobut-2-en-1-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (050)

[0234] [ka]

[0235] Referring to the synthesis route and synthesis method of Example 8, the target compound 050 (50 mg) could be prepared by replacing trifluoroisopropanol in step 1 with (E)-4,4,4-trifluorobut-2-en-1-ol. LC-MS (ESI-MS): 489 [M+H] + .

[0236] Example 51: N-(4-(7-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (051)

[0237] [ka]

[0238] Referring to the synthesis route and synthesis method of Example 8, the target compound 051 (42 mg) was prepared by replacing trifluoroisopropanol in step 1 with 3-(difluoromethyl)bicyclo[1.1.1]pentan-1-ol. LC-MS (ESI-MS): 497 [M+H] + .

[0239] Example 52: N-(2,6-dimethyl-4-(7-(2,2,2-trifluoro-1-methoxyethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl))phenyl)-3,3-dimethylbutyramide (052)

[0240] [ka]

[0241] Referring to the synthesis route and synthesis method of Example 8, the target compound 052 (52 mg) could be prepared by replacing trifluoroisopropanol in step 1 with 2,2,2-trifluoro-1-methoxyethan-1-ol. LC-MS (ESI-MS): 493 [M+H] + .

[0242] Example 53: N-(2,6-dimethyl-4-(7-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (053)

[0243] [ka]

[0244] Referring to the synthesis route and synthesis method of Example 8, the target compound 053 (46 mg) was prepared by replacing trifluoroisopropanol in step 1 with 3,3,3-trifluoro-2-methylpropan-1-ol. LC-MS (ESI-MS): 491 [M+H] + .

[0245] Example 54: N-(2,6-dimethyl-4-(7-((1-(trifluoromethyl)cyclopropyl)methoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (054)

[0246] [ka]

[0247] Referring to the synthesis route and synthesis method of Example 8, the target compound 054 (34 mg) could be prepared by replacing trifluoroisopropanol in step 1 with (1-(trifluoromethyl)cyclopropyl)methanol. LC-MS (ESI-MS): 503 [M+H] + .

[0248] Example 55: N-(4-(7-((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (055)

[0249] [ka]

[0250] Referring to the synthesis route and synthesis method of Example 8, the target compound 055 (49 mg) was prepared by replacing trifluoroisopropanol with hexafluoroisopropanol in step 1. LC-MS (ESI-MS): 531 [M+H] + .

[0251] Example 56: N-(2,6-dimethyl-4-(7-(2-(2,2,2-trifluoroethoxy)ethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (056)

[0252] [ka]

[0253] Referring to the synthesis route and synthesis method of Example 8, the target compound 056 (62 mg) was prepared by replacing trifluoroisopropanol in step 1 with 2-(2,2,2-trifluoroisoethoxy)ethanol. LC-MS (ESI-MS): 507 [M+H] + .

[0254] Example 57: N-(2,6-dimethyl-4-(7-(2,2,3,3-tetrafluoropropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (057)

[0255] [ka]

[0256] Referring to the synthesis route and synthesis method of Example 8, the target compound 057 (53 mg) was prepared by replacing trifluoroisopropanol with tetrafluoropropanol in step 1. LC-MS (ESI-MS): 495 [M+H] + .

[0257] Example 58: N-(2,6-dimethyl-4-(7-(3,3,3-trifluoropropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (058) Referring to the synthesis route and synthesis method of Example 8, the target compound 058 (48 mg) was prepared by replacing trifluoroisopropanol with trifluoropropanol in step 1. LC-MS (ESI-MS): 477 [M+H] + .

[0258] Example 59: N-(2,6-dimethyl-4-(7-((4-(trifluoromethyl)cyclohexyl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (059)

[0259] [ka]

[0260] Referring to the synthesis route and synthesis method of Example 8, the target compound 059 (50 mg) could be prepared by replacing trifluoroisopropanol in step 1 with 4-(trifluoromethyl)cyclohexanol. LC-MS (ESI-MS): 531 [M+H] + .

[0261] Example 60: N-(2,6-dimethyl-4-(7-(4,4,4-trifluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (060)

[0262] [ka]

[0263] Referring to the synthesis route and synthesis method of Example 8, the target compound 060 (63 mg) was prepared by replacing trifluoroisopropanol with trifluorobutanol in step 1. LC-MS (ESI-MS): 491 [M+H] + .

[0264] Example 61: N-(2,6-dimethyl-4-(7-((4,4,5,5,5-pentafluoropentyl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (061)

[0265] [ka]

[0266] By referring to the synthesis route and synthesis method of Example 8, 4,4,5,5,5-pentafluoropentanol (49 mg) was prepared from trifluoroisopropanol in step 1. LC-MS (ESI-MS): 541 [M+H] + .

[0267] Example 62: N-(2,6-dimethyl-4-(7-(2,2,4,4,4-pentafluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutyramide (062)

[0268] [ka]

[0269] By referring to the synthesis route and synthesis method of Example 8, 2,2,4,4,4-pentafluorobutanol (57 mg) was prepared from trifluoroisopropanol in step 1. LC-MS (ESI-MS): 527 [M+H] + .

[0270] Example 63: N-(4-(7-(4-fluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (063)

[0271] [ka]

[0272] Referring to the synthesis route and synthesis method of Example 8, the target compound 063 (45 mg) was prepared by replacing trifluoroisopropanol with 4-fluorobutanol in step 1. LC-MS (ESI-MS): 455 [M+H] + .

[0273] Biological testing Example 64: KCNQ2 / 3 potassium ion channel activity test Steps 1. Cell Culturing hKCNQ-CHO cells were incubated at 5% CO 2 The cells were cultured at 37°C in a humidified atmosphere.

[0274] 2. Solution 2.1. Extracellular fluid (mM): NaCl 145, KCl 4, CaCl 2 2. MgCl 2 1, Glucose 10, HEPES 10. The pH value of the extracellular fluid was adjusted to 7.4 with NaOH, and the osmolarity was adjusted to approximately 295 mOsm.

[0275] 2.2. Intracellular solution (mM (mmol / L)): KOH 31.25, KCl 120, EGTA 10, MgCl 2 1.75, CaCl 2 The pH of the intracellular fluid was adjusted to 7.4 with HCl, and the osmolarity was adjusted to approximately 285 mOsm.

[0276] 2.3. Extracellular solution should be prepared once a week, and intracellular solution should be stored at -20°C after preparation.

[0277] 3. Preparation of Working Solutions The model positive reference compound, Retigabine (RTG), was dissolved in 100% DMSO and prepared and stored at a working solution of 10 mM. Test compounds were dissolved in 100% DMSO and prepared and stored at a working solution of 10 mM. The final concentration of DMSO in the test solutions should be less than 0.3%.

[0278] 4. Whole-cell Voltage Clamp Recordings Whole-cell patch clamping was performed at room temperature. Electrical signals recorded using an EPC 10 USB amplifier (HEKA Elektronik, Germany) were filtered by a 3 kHz low pass and finally recorded in PatchMaster 2x90.5 software (HEKA Elektronik, Germany). The quality control criteria in this step are a high resistance seal of the cells greater than 500 MOhms and a detection current greater than 0.4 nA.

[0279] Recording electrodes were pulled and polished through a vertical puller (NARISHIGE PC-10, Japan) using borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK). At this step, the quality control criterion is that the electrode resistance is between 2 and 5 MΩ.

[0280] During whole-cell patch-clamp recordings, extracellular fluid was continuously perfused using a continuous perfusion system (BT100-2J, LongerPump, China). The perfusion system was installed on the stage of an upright microscope (FN-S2N, Nikon, Japan), and the perfusion head was manually positioned under the microscope.

[0281] Voltage command for hKCNQ current amplitude detection: cells were stepped up from a clamp potential of -80 mV to -30 mV for 1500 ms; then the clamp voltage was decreased to -120 mV for 500 ms; finally the voltage was returned to the clamp potential of -80 mV. The detection voltage command was repeated every 15,000 ms, and this command was executed continuously during the compound test. The quality control criterion for the stability of the compound effect was the current amplitude under five consecutive voltage commands, the coefficient of variation of which was <5%. If the compound did not have any effect on the hKCNQ current amplitude, 5 min of continuous monitoring was required.

[0282] 5. Data Analysis Data analysis was performed using PatchMaster 2×90.5 software (HEKA Elektronik, Germany) and Excel 2013 software (Microsoft, USA). Patch clamp recordings of each cell were required to obtain the hKCNQ channel current amplitude (Itest) corresponding to the concentration of the test compound. The enhanced channel current was obtained by subtracting the original channel current (Icontrol) of the cell from Itest, and then divided by Icontrol to obtain the current enhancement coefficient. That is, the current enhancement coefficient (enhancement%) = (Itest-Icontrol) / Icontrol*100%. The experimental results are shown in Table 1.

[0283]

Table 2

[0284] In the table, "0.05 μM" and "3 μM" represent the test concentrations of the test compounds. A > 100%, 50% < B < 100%, C < 50%. "-" indicates that the corresponding test has not been performed.

[0285] Here, compound a is a control compound, and its structure is

[0286]

Chemical formula

[0287] as follows.

[0288] a represents the activation activity of retigabine on the KCNQ2 / 3 potassium ion channel at a concentration of 10 μM.

[0289] The results in Table 1 show that the activities of compound a at a concentration of 3 μM and retigabine at a concentration of 10 μM on KCNQ2 / 3 potassium ion channel activation are less than 50%, and the activity of the compound of the present invention at a concentration of 3 μM on KCNQ2 / 3 potassium ion channel activation exceeds 50%.

[0290] Example 65: Half-open voltage left shift test Steps 1. Cell culture hKCNQ-CHO cells were cultured at 37 °C in a humidified atmosphere of 5% CO 2 2.

[0291] 2. Solution a) Extracellular fluid (mM): NaCl 145, KCl 4, CaCl 2 2, MgCl 21, Glucose 10, HEPES 10. The pH value of the extracellular fluid was adjusted to 7.4 with NaOH, and the osmolarity was adjusted to approximately 295 mOsm.

[0292] b) Intracellular solution (mM): KOH 31.25, KCl 120, EGTA 10, MgCl 2 1.75, CaCl 2 The pH of the intracellular fluid was adjusted to 7.4 with HCl, and the osmolarity was adjusted to approximately 285 mOsm.

[0293] c) Extracellular solution should be prepared once a week, and intracellular solution should be prepared and then aliquoted and stored at -20°C.

[0294] 3. Preparation of Working Solutions The model positive reference compound Retigabine (RTG) was dissolved in 100% DMSO and stored at a working solution of 10 mM. The compounds to be tested were dissolved in 100% DMSO and stored at a working solution of 10 mM. The final concentration of DMSO in the test solution should be less than 0.3%.

[0295] 4. Whole-cell Voltage Clamp Recordings Whole-cell patch clamping was performed at room temperature. Electrical signals recorded using an EPC 10 USB amplifier (HEKA Elektronik, Germany) were filtered by a 3 kHz low pass and finally recorded in PatchMaster 2x90.5 software (HEKA Elektronik, Germany). The quality control criteria in this step are a high resistance seal of the cells greater than 500 MOhms and a detection current greater than 0.4 nA.

[0296] Recording electrodes were pulled and polished through a vertical puller (NARISHIGE PC-10, Japan) using borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK). At this step, the quality control criterion is that the electrode resistance is between 2 and 5 MΩ.

[0297] During whole-cell patch-clamp recordings, extracellular fluid was continuously perfused using a continuous perfusion system (BT100-2J, LongerPump, China). The perfusion system was installed on the stage of an upright microscope (FN-S2N, Nikon, Japan), and the perfusion head was manually positioned under the microscope.

[0298] Voltage commands for hKCNQ current amplitude detection: the cell was clamped continuously for 1500ms to +60mV with a clamp potential of -80mV down to -120mV and an increment of 10mV per sweep; then the clamp voltage was reduced to -120mV for 500ms; and finally the voltage was returned to the clamp potential of -80mV. The test voltage command was repeated every 15000ms and was executed continuously during compound testing. The half voltage of the cell hKCNQ should be obtained by nonlinear fitting of the cell's current amplitude at various clamp potentials (-120mV to +60mV).

[0299] 5. Data Analysis Data analysis was performed using PatchMaster 2×90.5 software (HEKA Elektronik, Germany) and Excel 2013 software (Microsoft, USA). For each cell, patch clamp recordings should obtain the hKCNQ half voltage (V1 / 2-test) corresponding to the concentration of the test compound. The V1 / 2-test minus the hKCNQ half voltage before the compound action (V1 / 2-control) is the left-shifted half voltage value ΔV1 / 2 (V 1 / 2 Shift (mV).

[0300] The experimental results are shown in Table 2.

[0301] [Table 3]

[0302] In the table: "50 nM", "300 nM" are the test concentrations of the test compounds. "-" indicates that the corresponding test was not performed.

[0303] The compound Xen-1101 is a control compound and has the structure:

[0304] [ka]

[0305] (WO2008024398A2).

[0306] The test results in Table 2 show that the compounds designed in the present invention have the effect of inducing a significant left shift in the half-open voltage.

[0307] Example 66: Mouse brain experiments Experimental steps 1. Drug Preparation Dosage: 5mg / kg Drugs were prepared into solutions with a concentration of 0.5 mg / mL according to proportionality (solvent: 5% DMSO + 5% Solutol + 90% saline) and administered intragastrically to mice at 0.1 mL / 10 g, with three mice run in parallel at each time point.

[0308] 2. Take Brain Tissue at Time Points After administration to the mice, the mice were anesthetized, the hearts were perfused with saline, the brain tissues were dissected, washed with saline, wiped dry, weighed, and transferred to 2 mL EP tubes, saline was added at a ratio of brain tissue:saline = 1:1 (g / mL), 3 steel balls were placed in each tube on a tissue grinder, and the tissue was homogenized at 60 Hz for 60 s. The tissue was centrifuged at 15,000 rpm and 4°C for 10 minutes, and the supernatant was collected, which was the brain tissue homogenate.

[0309] 3. Sample Processing 3.1. Preparation and Processing of Standard Curve and Quality Control Samples Drug stock solutions (0.5 mg / mL) were taken and diluted with acetonitrile to prepare standard curve working solutions at concentrations of 50, 100, 200, 500, 1000, 2000, 5000, 10000, and 20000 ng / mL, and quality control working solutions at concentrations of 100, 2000, and 10000 ng / mL, respectively. Take 47.5μL of blank matrix, add 2.5μL of standard curve working solution and quality control working solution to prepare standard curve samples with concentrations of 2.5, 5, 10, 25, 50, 100, 250, 500, 1000ng / mL, and quality control samples with concentrations of 5, 100, 500ng / mL, add 200μL of acetonitrile (containing internal standard loratadine 5ng / mL), vortex for 3 minutes, centrifuge at 15000rpm, 4℃ for 10 minutes, take the supernatant and perform LC-MS / MS analysis to obtain the standard curve.

[0310] 3.2 Sample preparation and processing 50 μL of brain tissue homogenate sample was taken, 200 μL of acetonitrile (containing internal standard loratadine 5 ng / mL) was added, vortexed for 3 min, and then centrifuged at 15000 rpm and 4 °C for 10 min, and the supernatant was taken for LC-MS / MS analysis, which was combined with the standard curve to obtain the corresponding brain concentration.

[0311] The experimental results are shown in Table 3.

[0312] [Table 4]

[0313] The test results in Table 3 show that there was a certain increase in the brain concentration of the compound in mice after intragastric administration.

[0314] Example 67: MES Mouse Epilepsy Model Experimental steps: 1. Mice (10 per group) were transferred to the operating room for adaptation to the environment 30 min before the experiment.

[0315] 2. Test compound or positive drug (sodium valproate, Valproate) was administered at a specific time. 30 minutes after administration of valproic acid or 30 minutes after administration of test compound, electrical stimulation was given by ear electrodes, and the stimulation parameters were square wave of total duration: 0.8 s, frequency: 50 Hz, amplitude: 50 mA, and the interval between square waves was 10 msec.

[0316] 3. Within 1 min after the completion of electrical stimulation, the number and time to onset of hind limb stiffening of the animals, as well as possible mortality and time to death, were recorded.

[0317] 4. After administration, possible side effects induced by the drug were observed and recorded and classified into the following four levels: None: Normal Mild sedation Moderate sedation Severe sedation The experimental results are shown in Table 4.

[0318] [Table 5]

[0319] The test results in Table 4 show that the compounds can significantly inhibit the development of hind limb stiffness in mice with MES-induced epilepsy.

Claims

1. A compound having a structure represented by general formula IV or V, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 【Chemistry 2】 (In the general formula IV, R １ is C １－６ Alkoxy, C ３－６ Cycloalkoxy, C ２ ~C ６ Heterocycloalkoxy, C １ ~C ３ Alkylthio, C １ ~C ３ Alkylsulfonyl, C １－６ Haloalkoxy, C ３－６ halocycloalkoxy, 【Chemistry 3】 is selected from In general formula V, R 1 is independently selected from halogen, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 2 -C 6 heterocycloalkoxy, C 1 -C 3 alkylthio, C 1 -C 3 alkylsulfonyl, C 1-6 haloalkoxy, and C 3-6 halocycloalkoxy.

2. It has a structure represented by general formula Va, 【Chemistry 4】 R 1 is H or F; R 1 ' is 【Chemistry 5】 The compound according to claim 1, characterized in that

3. 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the following compounds: 【Table 1】

4. A pharmaceutical composition, characterized in that it comprises one or more of the compounds according to any one of claims 1 to 3.

5. A pharmaceutical formulation, characterized in that it contains one or more compounds according to any one of claims 1 to 3.

6. A pharmaceutical for treating a disease benefiting from activation of a potassium ion channel, comprising a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

7. The pharmaceutical composition described in claim 6, wherein the disease is a central nervous system disease.

8. The pharmaceutical composition according to claim 6, characterized in that the disease is selected from epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, depression, stroke, complications from cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome, or tinnitus.

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