Potassium channel regulator, composition and application

Abstract

The present invention discloses a compound having a structure shown in general formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also discloses a composition, a preparation and an application containing the above compound. The compound of the present invention has a significant activation effect on KCNQ2 / 3 potassium ions, and can be used for treating diseases related to potassium channel ion flow, especially for the application in drugs for treating central nervous system diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and design, and specifically relates to a class of potassium channel regulating compounds or their stereoisomers, or pharmaceutically acceptable salts thereof, pharmaceutical compositions and applications thereof. The compounds have the function of regulating potassium channels and can be used to treat diseases or disorders that benefit from KCNQ channel openers. Background Art

[0002] The treatment of central nervous system diseases has always been a difficult problem in the medical field. Traditional drugs cannot prevent and treat central nervous system diseases such as acute and chronic central nervous system damage, Alzheimer's disease, Parkinson's disease, epilepsy, etc.

[0003] The chemical environment of cells is closely related to ion channels on the cell membrane. Ion channels are the key to regulating neuronal excitability, so ion channels have become the most direct target for treating central nervous system diseases. It is known that more than 10% of potassium ion channel subtypes are related to human central nervous system diseases, which are manifested in many different aspects, such as directly controlling neuronal excitability and the balance of the ion environment in the body to indirect effects through metabolism.

[0004] At present, five types of KCNQ1 to 5 have been discovered. KCNQ potassium channels are an important branch of the potassium channel superfamily, and their gene mutations are associated with many genetic diseases. Among them, KCNQ1 (KvLQT) is mainly distributed in the myocardium, and 50% of hereditary LQT syndromes are related to KCNQ1 mutations. KCNQ2 and KCNQ3 are the molecular basis of the M-type potassium channels in nerve cells. Benign familial neonatal convulsions (BFNC) are related to the downregulation of M current caused by mutations in the KCNQ2 and KCNQ3 genes. KCNQ4 is mostly expressed in the nerve conduction pathways, nerve nuclei and inner ear hair cells related to hearing. Hereditary deafness (DFNA) is related to KCNQ4 gene mutations. KCNQ5 is mostly expressed in muscle tissue.

[0005] KCNQ potassium channel openers have become a new direction in the research of anti-epileptic drugs. Retigabine was approved by the US FDA in June 2011 for the treatment of partial seizures of intractable epilepsy. Its excellent performance in vitro and in vivo and its successful launch have proved that KCNQ potassium channels are of great significance as drug targets. In addition, in vivo and in vitro studies have shown that retigabine also has potential therapeutic effects on anxiety, stroke, neurodegenerative diseases, and pain. At the same time, due to the wide range of physiological functions of KCNQ potassium channels, its openers also have very broad application prospects in the treatment of many diseases. Summary of the invention

[0006] The object of the present invention is to provide a novel compound having the function of regulating potassium channels or a pharmaceutically acceptable salt or solvate thereof.

[0007] The present invention also provides a pharmaceutical composition comprising the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt.

[0008] The present invention also provides a use of the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt in the preparation of a drug for treating a disease, disorder or condition that benefits from a KCNQ channel opener.

[0009] The compounds of the present invention are effective in treating and preventing diseases and disorders affected by potassium ion channel activity and can be used to treat a variety of diseases and disorders.

[0010] To achieve the above object, the present invention provides a compound as shown in formula I,

[0011]

[0012] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0013] in:

[0014] Ring A is a benzene ring or a 5-8 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O or S;

[0015] R1 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkenyl, C1-C8 alkenyloxy, spiroalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, C1-C8 alkylthio, C1-C8 alkanoyl, C1-C8 alkylsulfonyl, aminosulfonyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 alkenyloxy, halogenated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, halogenated C2-C8 heterocycloalkoxy, and the alkyl, alkoxy, alkenyl, alkenyloxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkoxy, alkylthio, alkanoyl, alkylsulfonyl, aminosulfonyl may be further substituted by R8;

[0016] R2 is each independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, halogenated C2-C8 heterocycloalkoxy;

[0017] Or two R2 are connected to the same atom, and the two R2 can be different or the same, and form a 3-6 membered ring or a 3-6 membered heterocyclic ring with the atom to which they are connected;

[0018] R4, R5, R6, R7, and R8 are each independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, halogenated C2-C8 heterocycloalkoxy, and spiroalkyl;

[0019] n is selected from 0, 1, 2;

[0020] m is selected from 0, 1, 2, 3, 4, 5;

[0021] X1 and X2 are each independently selected from -CRaRb, -NRa, -O-, -C(O)-, -S-, -S(O)-, -S(O)2-;

[0022] Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C8 cycloalkyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl;

[0023] ---Indicates the presence or absence of a chemical bond;

[0024] Z is selected from O or (CH2) p , p is an integer from 1 to 6;

[0025] R3 is C 1- C8 alkyl, C 3- C8 cycloalkyl, C 3- C8 cycloalkenyl, C 2- C8 alkenyl or C 2- C8 alkynyl, wherein the C 1- C8 alkyl, C 3- C8 cycloalkyl, C 3- C8 cycloalkenyl, C 2- C8 alkenyl or C 2- The C8 alkynyl group may be substituted by one or more groups selected from halogen, nitro, cyano, amine or hydroxy.

[0026] Furthermore, the preferred compounds of the present invention have the structure of general formula I:

[0027] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0028] in:

[0029] Ring A is a benzene ring or a 5-8 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O or S;

[0030] R1 is each independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, C1-C8 alkylthio, C1-C8 alkanoyl, C1-C8 alkylsulfonyl, aminosulfonyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, halogenated C2-C8 heterocycloalkoxy;

[0031] R2 is each independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, halogenated C2-C8 heterocycloalkoxy;

[0032] R4, R5, R6, and R7 are each independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, and halogenated C2-C8 heterocycloalkoxy;

[0033] n is selected from 0, 1, 2;

[0034] m is selected from 0, 1, 2, 3, 4, 5;

[0035] X1 and X2 are each independently selected from -CRaRb, -NRa, -O-, -C(O)-, -S-, -S(O)-, -S(O)2-;

[0036] Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3C8 cycloalkyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkyl;

[0037] ---Indicates the presence or absence of a chemical bond;

[0038] Z is selected from O or (CH2) p , p is an integer from 1 to 6;

[0039] R3 is C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl or C2-C8 alkynyl, wherein the C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl or C2-C8 alkynyl may be substituted by one or more selected from halogen, nitro, cyano, amino or hydroxyl;

[0040] when It is represented by X1=X2, X1 and X2 are independently selected from -CRa-, -N-;

[0041] when It is represented by X1-X2, and when R4, R5, R6, and R7 are not selected from chlorine, and when X1 is CH or O, R2 is H, and when the A ring is a benzene ring, R1 is selected from C1-C8 alkoxy, C3-C8 cycloalkoxy, C2-C8 heterocycloalkoxy, C1-C8 alkylthio, C1-C8 alkanoyl, C1-C8 alkylsulfonyl, aminosulfonyl, halogenated C1-C8 alkoxy, halogenated C3-C8 cycloalkoxy, and halogenated C2-C8 heterocycloalkoxy;

[0042] when It is represented by X1-X2, and when R4, R5, R6, and R7 are not selected from chlorine, and when ring A is a thiophene ring, m is selected from 2, 3, 4, and 5, and R2 is not selected from hydrogen.

[0043] In the present invention, when n and m are greater than 1, it is a poly-substitution, in which case multiple substituents can be substituted on one carbon atom or on multiple atoms of the corresponding ring structure; and in the case of poly-substitution, multiple substituents can be the same or different. When two substituents are connected to the same carbon atom, the two substituents and the carbon atom to which they are connected can together form a C3-C6 cycloalkyl group.

[0044] Preferably, ring A is a benzene ring or a 5-membered heterocyclic ring containing 1-2 heteroatoms selected from N, O or S.

[0045] Preferably, R1 is selected from H, C 1- C5 alkoxy, C 1- C5 alkenyloxy, halogenated C 1- C5 alkoxy, C 3- C6 cycloalkyl, C 3- C6 cycloalkoxy, C3-C4 heterocycloalkyl, C3-C4 heterocycloalkoxy, C 1- C4 alkylthio, halogen, C 1- C4 alkylsulfonyl, R1 may be further substituted with one or more halogen, C 1- C3 alkyl, halogenated C 1- C3 alkyl, C 1- C3 alkoxy, halogenated C 1-C3 alkoxy, spiroalkyl substitution. Preferably, R1 is selected from H, C 1- C4 alkoxy, halogenated C 1- C4 alkoxy, C 3- C6 cycloalkyl, C3-C4 heterocycloalkyl, C 1- C4 alkylthio, halogen, C 1- C4 alkylsulfonyl. R1 is further preferably H, F, Cl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, hexafluoroisopropoxy, trifluorobutoxy, cyclopropaneoxy, cyclobutaneoxy, cyclopentaneoxy, cyclohexaneoxy, oxetanyloxy, methylthio, methylsulfonyl,

[0046] Preferably, R2 is independently selected from hydrogen, halogen, C 1- C3 alkyl. As further preferred, R2 is H, methyl. As further preferred, R2 is H or a methyl substituent on X1. As more specifically preferred, R2 is H or one methyl or two methyl substituents on X1 or two methyl groups and X1 form a cycloalkyl group.

[0047] Preferably, R3 is C 1- As a further preference, R3 is tert-butyl.

[0048] Preferably, R4, R5, R6, and R7 are each independently H, methyl, or halogen (more preferably Cl). More preferably, R4 and R6 are H or Cl; and R5 and R7 are methyl.

[0049] Preferably, Z is (CH2) p , further preferably -CH2-.

[0050] Furthermore, the preferred compounds of the present invention have the structure of the general formula IIa, IIb, IIc:

[0051]

[0052] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

[0053] In the above general formula, there is a double bond or a single bond between X1 and X2.

[0054] Preferably, X3 is N, O or S.

[0055] Furthermore, the preferred compounds of the present invention have the structure of formula III:

[0056]

[0057] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof;

[0058] R1 is selected from C 1-8 Alkoxy, C 3-8 Cycloalkoxy, C2-C8 heterocycloalkoxy, C 1- C8 alkylthio, C 1- C8 alkylsulfonyl, halogenated C 1-8 Alkoxy, halogenated C 3-8 Cycloalkoxy;

[0059] n is selected from 1.

[0060] Furthermore, the preferred compounds of the present invention are those having the general formula IV:

[0061]

[0062] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

[0063] R1 is selected from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C2-C6 heterocycloalkoxy, C 1- C3 alkylthio, C 1- C3 alkylsulfonyl, halo 1-6 Alkoxy, halogenated C 3-6 Cycloalkoxy.

[0064] Furthermore, the preferred compounds of the present invention are those having the general formula IIc-2:

[0065]

[0066] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

[0067] There is a double bond or a single bond between X1 and X2;

[0068] n is selected from 2;

[0069] R1 is selected from: halogen, C 1- C8 alkyl, C 1- C8 alkoxy, C 3- C8 cycloalkyl, C 3- C8 cycloalkoxy, C2-C8 heterocycloalkyl, C2-C8 heterocycloalkoxy, C 1- C8 alkylthio, C 1- C8 alkanoyl, C 1- C8 alkylsulfonyl, aminosulfonyl, halogenated C 1- C8 alkyl, halogenated C 1- C8 alkoxy, halogenated C 3-C8 cycloalkyl, halogenated C 3- C8 cycloalkyloxy, halogenated C2-C8 heterocycloalkyl, halogenated C2-C8 heterocycloalkyloxy.

[0070] Furthermore, the preferred compounds of the present invention are those having the general formula III:

[0071]

[0072] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

[0073] R1 is selected from halogen, C 1-8 Alkoxy, C 3-8 Cycloalkoxy, C2-C8 heterocycloalkoxy, C 1- C8 alkylthio, C 1- C8 alkylsulfonyl, halogenated C 1-8 Alkoxy, halogenated C 3-8 Cycloalkoxy;

[0074] n is selected from 2.

[0075] Furthermore, the preferred compounds of the present invention have a structure shown in Formula V:

[0076]

[0077] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

[0078] R1 is selected from halogen, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C2-C6 heterocycloalkoxy, C 1- C3 alkylthio, C 1- C3 alkylsulfonyl, halo 1-6 Alkoxy, halogenated C 3-6 Cycloalkoxy.

[0079] Furthermore, the preferred compounds of the present invention are those of the general formula IIa to IIc or IIc-2:

[0080] X1 and X2 are CH2, with a single bond between them; R4 and R6 are H; R5 and R7 are methyl groups;

[0081] m is selected from 2, 3, 4, and 5;

[0082] R2 is not selected from hydrogen.

[0083] Furthermore, the preferred compounds of the present invention are those having the general formula IIa to IIc or IIc-2:

[0084] R6 is Cl; at least two of R4, R5 and R7 are not selected from hydrogen.

[0085] Preferably, the compound has a structure shown in the general formula Va:

[0086]

[0087] R1' is H, F;

[0088] R1 is

[0089] Preferably, the compound is selected from the following compounds or their stereoisomers or their stereoisomer mixtures or their pharmaceutically acceptable salts:

[0090]

[0091]

[0092]

[0093] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0094] Preferably, the compound is the following compound:

[0095] N-(4-(7-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (001)

[0096] N-(4-(7-ethoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (002)

[0097] N-(4-(7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (003)

[0098] N-(4-(7-(sec-Butoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (004)

[0099] N-(4-(7-(difluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (005)

[0100] N-(2,6-dimethyl-4-(7-(trifluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (006)

[0101] N-(2,6-dimethyl-4-(7-(2,2,2-trifluoroethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (007)

[0102] N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (008)

[0103] N-(4-(7-cyclopropyloxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (009)

[0104] N-(4-(7-cyclobutyloxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (010)

[0105] N-(4-(7-(Cyclopentyloxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (011)

[0106] N-(4-(7-(cyclohexyloxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (012)

[0107] N-(2,6-dimethyl-4-(7-(oxetan-3-yl-oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (013)

[0108] N-(2,6-dimethyl-4-(7-(methylthio)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (014)

[0109] N-(2,6-dimethyl-4-(7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (015)

[0110] N-(4-(7-Fluoro-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (016)

[0111] N-(4-(5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (017)

[0112] 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-dimethylbutanamide (018)

[0113] N-(4-(8,8-dimethyl-4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepin-5-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (019)

[0114] 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-dimethylbutanamide (020)

[0115] N-(4-(4,4-dimethyl-4,5,6,8-tetrahydro-7H-thieno[2,3-c]azepin-7-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (021)

[0116] N-(4-(7-Fluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (022)

[0117] N-(4-(8-Fluoro-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (023)

[0118] N-(4-(8-Fluoro-1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (024)

[0119] N-(4-(8-Fluoro-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (025)

[0120] N-(4-(8-Fluoro-1,1-dioxo-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (026)

[0121] N-(4-(7-Fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (027)

[0122] N-(4-(7-Fluoro-5-methyl-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (028)

[0123] N-(3-Fluoro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2-methylphenyl)-3,3-dimethylbutanamide (029)

[0124] N-(4-(7-Fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,3,6-trimethylphenyl)-3,3-dimethylbutanamide (030)

[0125] N-(3-Chloro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (031)

[0126] (R)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (032)

[0127] (S)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (033)

[0128] (R)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (032)

[0129] (S)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (033)

[0130] N-(4-(8-Fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (034)

[0131] N-(4-(8-Fluoro-7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (035)

[0132] (S)-N-(4-(8-Fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (036)

[0133] (R)-N-(4-(8-fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (037)

[0134] N-(4-(8-Fluoro-7-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (038)

[0135] N-(4-(7-(sec-Butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (039)

[0136] (S)-N-(4-(7-(sec-Butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (040)

[0137] (R)-N-(4-(7-(sec-Butoxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (041)

[0138] N-(4-(7-cyclopropyloxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (042)

[0139] N-(4-(7-cyclobutyloxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (043)

[0140] N-(4-(7-(Cyclopentyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (044)

[0141] N-(4-(7-(cyclohexyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (045)

[0142] N-(4-(7,8-difluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (046)

[0143] N-(4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (047)

[0144] N-(3-Chloro-4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (048)

[0145] N-(4-(7,8-difluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (049)

[0146] (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-dimethylbutanamide (050)

[0147] 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-dimethylbutanamide (051)

[0148] 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-dimethylbutanamide (052)

[0149] 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-dimethylbutanamide (053)

[0150] N-(2,6-dimethyl-4-(7-((1-(trifluoromethyl)cyclopropyl)methoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (054)

[0151] N-(4-(7-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (055)

[0152] 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-dimethylbutanamide (056)

[0153] 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-dimethylbutanamide (057)

[0154] N-(2,6-dimethyl-4-(7-(3,3,3-trifluoropropoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (058)

[0155] N-(2,6-dimethyl-4-(7-((4-(trifluoromethyl)cyclohexyl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (059)

[0156] N-(2,6-dimethyl-4-(7-(4,4,4-trifluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (060)

[0157] 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-dimethylbutanamide (061)

[0158] 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-dimethylbutanamide (062)

[0159] N-(4-(7-(4-Fluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (063)

[0160] Terminology

[0161] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by professionals in the field. Unless otherwise indicated, all patent documents, publicly disclosed materials, etc. referenced in the present invention are incorporated by reference in their entirety. If there are multiple definitions of the same term in the present invention, the definition in this section shall prevail.

[0162] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not limiting of any claims. It should be noted that in the specification and the appended claims, unless otherwise specified herein, singular references such as "a", "an", "the" include plural references. It should also be noted that, unless otherwise specified, "or" means "and / or". In addition, "include", "comprises", and similar terms are not limiting.

[0163] "Substitution" means that a hydrogen atom is replaced by a substituent. It should be noted that the substituents on a particular atom are limited by their valence state. In the definition section, "C i -C j ”, “C i-j " includes a range of starting points and ending points, where i and j are integers representing the number of carbon atoms. For example, C 1- C4, C 1- C8, C 3- C8, C 1-6 , C 3-6 wait.

[0164] The C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes. At the same time, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds of the present invention may be optionally replaced by one or more of their corresponding isotopes, including but not limited to carbon isotopes. 12 C. 13 C. 14 C, isotopes of hydrogen: protium (H), deuterium (D), tritium (T), isotopes of oxygen 16 O. 17 O.18 O, isotope of sulfur 32 S. 33 S. 34 S. 36 S, isotope of nitrogen 14 N. 15 N, isotope of fluorine 17 F. 19 F, isotope of chlorine 35 Cl, 37 Cl, isotope of bromine 79 Br, 81 Br et al.

[0165] The term "alkyl" as used in the present invention refers to a straight or branched 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, t-pentyl, n-hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, and the like. The alkyl group may be substituted with one or more substituents. When multiple substituents are present, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C 12 Cycloalkyl, halogenated C3-C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C6-C 12 Aryl, C5-C 14 Heteroaryl, C3-C 12 Heterocyclic group.

[0166] The terms "alkenyl" and "alkenyl" as used herein refer to straight or branched hydrocarbon chain groups containing 1 to 8 carbon atoms and at least one C=C double bond, including but not limited to 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-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, etc. The alkenyl group may be substituted with one or more substituents, and in the case of multiple substitutions, the substituents may be the same or different; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, amide, sulfonamide, and spiroalkyl.

[0167] The term "alkynyl" as used in the present invention refers to a straight or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C≡C triple bond, including but not limited to 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-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-butynyl, 2-methyl-3-butynyl, 1-methyl-4-butynyl, 1-hex ... alkynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 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. The alkynyl group may be substituted by one or more substituents, and when multiple substitutions occur, the substituents may be the same or different; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, amide, sulfonamide, and spiroalkyl.

[0168] The terms "halogen" and "halo" as used herein refer to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

[0169] The term "cycloalkyl" as used in the present invention refers to a non-aromatic monovalent hydrocarbon group having a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged or spirocyclic or fused) with 3 to 12 carbon atoms, and one or more chemical bonds may be double bonds or triple bonds. “Cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydroindene, decahydronaphthalene, bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1.1]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.0]heptan ... .2.1]octyl, 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]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.5]nonyl, spiro[3.4]octyl, spiro[3.3]heptyl, spiro[4.5]decyl, spiro[4.4]nonyl, etc. The cycloalkyl group may be substituted with one or more substituents. When multiple substituents are present, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C 12 Cycloalkyl, halogenated C3-C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C6-C 12 Aryl, C5-C 14 Heteroaryl, C3-C 12 Heterocyclic group.

[0170] The term "cycloalkenyl" as used in the present invention refers to a non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms and containing at least one C=C double bond, which is a monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond or are bridged or spirocyclic or fused) ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloalkenyl, spiro[2.2]pent-1-enyl, spiro[2.2]penta-1,4-dienyl, spiro[2.3]hex-1-enyl, spiro[2.3]hex-1,4-dienyl, spiro[3.3]hept-1-enyl, Spiro[3.3]hept-1,5-dienyl, spiro[3.4]oct-1-enyl, spiro[3.4]oct-1,6-dienyl, spiro[3.4]oct-5-enyl, spiro[3.4]oct-6-enyl, spiro[3.4]oct-1-enyl, bicyclo[2.1.1]hex-1-enyl, bicyclo[2.1.1]hex-2-enyl, bicyclo[3.1.1]hept-1-enyl, bicyclo[3.1.1]hept-2-enyl, bicyclo[2.2.1]hept-1-enyl, bicyclo[2.2.1]hept-2-enyl, and the like. Cycloalkenyl and cycloalkenyl groups may be substituted with one or more substituents. In case of multiple substitutions, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C 12 Cycloalkyl, halogenated C3-C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C6-C 12 Aryl, C5-C 12 Heteroaryl, C3-C 12 Heterocyclic group.

[0171] The terms "heterocyclyl" and "heterocycloalkyl" as used in the present invention refer to monocyclic or polycyclic (two monocyclic rings are connected by chemical bonds or bridged or spirocyclic or fused), saturated or unsaturated (having one or more double bonds, conjugated or incompletely conjugated) bivalent cyclic hydrocarbon groups having 3 to 15 ring atoms, and having one or more heteroatoms selected from N, O, and S. Heterocyclyl includes, but is not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, thienyl, furanyl, triazolyl, oxazolyl, imidazolyl, indazolyl, indolizinyl, indolyl, dihydroindolinyl, isoindolinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, dihydro ... , oxadiazole, aziridine, azidoyl, azidothiazol, azido-1, azido-2, azido-3, azido-4, azido-5, azido-6, azido-7, azido-8, azido-9, azido-10, azido-11, azido-12, azido-13, azido-14, azido-15, azido-16, azido-17, azido-18, azido-19, azido-20, azido-21, azido-22, azido-23, azido-24, azido-25, azido-26, azido-27, azido-28, azido-29, azido-30, azido-31, azido-32 Base, diazepine Thiazepine yl, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl, tetrahydroimidazolyl, hexahydropyridazinyl, hexahydropyrimidinyl, thienoazepine, benzazepine, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, benzoxadiazolyl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, imidazothiazolyl, pyrrolopyridinyl, thienopyrrolyl, thienothienyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrrolyl, pyrrolopyrimidinyl, pyrrolopyrrolidinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, 1-azaspiro 1-azaspiro[2.2]pentanyl, 1-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5-azaspiro[2.3]hexanyl, 2-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-azaspiro[2.5]octanyl, 2-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2-azaspiro[3.5]nonanyl, 6-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2- oxa-7-azaspiro[3.5]nonanyl, 1-azaspiro[4.4]nonanyl, 2-azaspiro[4.4]nonanyl, 8-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 1-oxaspiro[2.2]pentanyl, 1-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 2-oxaspiro[3.3]heptanyl, 1-oxaspiro[2.5]octanyl, 2-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 2-oxaspiro[3.5]nonanyl, 6-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5] Spiro[3.5]nonanyl, 1-oxaspiro[4.4]nonanyl, 2-oxaspiro[4.4]nonanyl, 8-oxaspiro[4.5]decanyl, decahydroquinolyl, decahydroisoquinolyl, 2-azabicyclo[1.1.1]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, azabicyclo[2.1.1]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[3.1.1]heptanyl, oxabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[4.1.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl and the like.The heterocyclic group may be substituted by one or more substituents. When multiple substitutions occur, the substituents may be the same or different; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methylsulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C8 12 Cycloalkyl, halogenated C3-C 12 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C6-C 12 Aryl, C5-C 14 Heteroaryl, C3-C 12 Heterocyclyl. As defined herein, the term "heterocyclyl" may include an aromatic heterocyclic ring or a non-aromatic heterocyclic ring or an aliphatic heterocyclic ring having at least one heteroatom.

[0172] The term "spiroalkyl" as used in the present invention refers to two carbon atoms of an alkyl group connected to the same carbon atom of a parent molecular group to form a 3-12 membered carbon ring.

[0173] The term "alkoxy" as used in the present invention refers to alkyl-O-, wherein alkyl is as defined above. Examples of "alkoxy" as used in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. "Alkoxy" also includes substituted alkoxy groups, and the substituents thereof may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 alkylamino, C3-C8 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0174] The term "alkenyloxy" as used herein refers to alkenyl-O-, wherein alkenyl is as defined above. "Alkenyloxy" also includes substituted alkenyloxy, whose substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 alkylamino, C3-C8 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0175] The term "cycloalkyloxy" as used herein refers to cycloalkyl-O-, wherein cycloalkyl is as defined above. Examples of "cycloalkyloxy" as used herein include, but are not limited to, cyclopropaneoxy, cyclobutaneoxy, cyclopentaneoxy, cyclohexaneoxy, cycloheptaneoxy, cyclooctaneoxy, bicyclo[1.1.0]butaneoxy, bicyclo[2.1.0]pentaneoxy, bicyclo[2.2.0]hexaneoxy, bicyclo[1.1.1]pentaneoxy, bicyclo[2.1.1]hexaneoxy, and the like. The term "cycloalkyloxy" also includes substituted cycloalkyloxy, whose substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 alkylamino, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0176] The term "heterocycloalkoxy" used in the present invention refers to heterocycloalkyl-O-, wherein heterocycloalkyl is as defined above. Examples of "heterocycloalkoxy" used in the present invention include, but are not limited to, oxiraneoxy, oxetaneoxy, oxolaneoxy, oxhexaneoxy, aziridineoxy, azetidineoxy, azolidineoxy, azolidineoxy, azideneoxy, and the like. "Heterocycloalkoxy" also includes substituted heterocycloalkoxy, and its substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, sulfonamide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 alkylamino, C3-C8 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12Aryl, C5-C 14 Heteroaryl.

[0177] The term "haloalkyl" as used in the present invention refers to a straight or branched alkyl group substituted by a halogen (preferably fluorine, chlorine, bromine, iodine), wherein "alkyl" is as defined above. Examples of "haloalkyl" used in the present invention 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-trifluoroprop-2-yl, and the like. "Haloalkyl" also includes substituted haloalkyl groups, whose substituents may be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl. The halogen substituents in "haloalkyl" may be one or more and may be substituted on one atom or on different atoms.

[0178] The term "haloalkoxy" used in the present invention refers to haloalkyl-O-, wherein haloalkyl is as defined above. Examples of "haloalkoxy" 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, trifluoroisopentyloxy, monochloromethoxy, dichloromethoxy, monochloroethoxy, dichloroethyl, chloropropyl, etc. The term "haloalkoxy" also includes substituted haloalkoxy, and the substituents thereof may be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0179] The term "halocycloalkyl" as used herein refers to a cycloalkyl group substituted by halogen (preferably fluorine, chlorine, bromine, iodine), wherein the cycloalkyl group is as defined above. The halogen substituent in the "halocycloalkyl" may be one or more, and may be substituted on one atom or on different atoms.

[0180] The term "halocycloalkoxy" as used herein refers to a halocycloalkyl-O-, wherein the halocycloalkyl is as defined above. "Halocycloalkoxy" also includes substituted halocycloalkoxy, whose substituents may be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0181] The term "halogenated heterocycloalkyl" used in the present invention refers to a heterocycloalkyl group substituted by halogen (preferably fluorine, chlorine, bromine, iodine), wherein heterocycloalkyl is as defined above. The halogen substituent in "halogenated heterocycloalkyl" may be one or more, and may be substituted on one atom or on different atoms.

[0182] The term "halogenated heterocycloalkoxy" used in the present invention refers to halogenated heterocycloalkyl-O-, wherein the halogenated heterocycloalkyl is as defined above. "Haloheterocycloalkoxy" also includes substituted "halogenated heterocycloalkoxy", and its substituents can be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amide, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl.

[0183] The term "alkylthio" used in the present invention refers to alkyl-S-, wherein alkyl is as defined above. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

[0184] The term "alkanoyl" as used herein refers to alkyl-C(O)-, wherein alkyl is as defined above.

[0185] The term "alkylsulfonyl" as used herein refers to alkyl-S(O)2-, wherein alkyl is as defined above.

[0186] The term "aminosulfonyl" as used herein refers to amino-S(O)2-.

[0187] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that can be prepared by a method known to those skilled in the art. The salt may be a salt formed with an acid or a base, etc. A preferred salt is a salt formed with an acid of the compound of the present invention. 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, and carbonic acid; 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, citric 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, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred salt is a 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 organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0188] 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 technical solutions above. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any one of the technical solutions above and other compounds, or one or more of the compounds described in any one of the technical solutions above.

[0189] Another object of the present invention is to provide a pharmaceutical preparation comprising one or more of any one of the compounds described above. Preferably, the pharmaceutical preparation comprises tablets, powders, capsules, injection preparations, granular preparations, and sprays. On the other hand, the present invention provides the use of the compounds described in Formula I to Formula V disclosed herein, or their stereoisomers, or their stereoisomer mixtures, or their pharmaceutically acceptable salts, in the treatment of diseases, disorders, or conditions that benefit from KCNQ agonism.

[0190] On the other hand, the present invention provides the use of the compounds of Formula I to Formula V disclosed herein in the preparation of drugs for treating diseases sensitive to increased potassium channel ion flow, especially in the preparation of drugs for treating central nervous system diseases.

[0191] In some embodiments, the subject in need thereof suffers from cancer comprising epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, stroke, complications from cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome, or tinnitus.

[0192] The inventors of the present invention have confirmed through experiments that the compound of the present invention has a significant activation effect on KCNQ2 / 3 potassium ions.

[0193] The inventors of the present invention have verified through experiments that the present invention has the effect of significantly inducing a leftward shift of the half-open voltage.

[0194] The inventors of the present invention have confirmed through experiments that the present invention can significantly inhibit the occurrence of hind limb rigidity in mice in MES-induced epilepsy.

[0195] The inventors of the present invention have confirmed through experiments that the compound of the present invention has good brain exposure. DETAILED DESCRIPTION

[0196] The feasibility of the present invention is illustrated below by using embodiments. Those skilled in the art should understand that according to the teachings of the prior art, modifications or replacements of corresponding technical features still fall within the scope of protection claimed by the present invention.

[0197] Example 1: N-(4-(7-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (001)

[0198]

[0199] Step 1, 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (1g, 6.17mmol) was dissolved in 10mL 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 2h. 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 sodium bicarbonate aqueous solution, and a large amount of white solid was precipitated after vacuum concentration. The crude product was filtered and dried by filter cake. The product 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] + . Use directly in the next step.

[0200] Step 2, dissolve the intermediate 001-1 (1g, 5.67mmol) in 10mL concentrated hydrochloric acid, slowly add sodium azide (737.86mg, 11.35mmol) at 0℃, gradually return to room temperature, and react for 6h. After the reaction is completed, slowly add saturated potassium carbonate aqueous solution to make the pH value of the system about 8, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain the intermediate 001-2: 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (0.52mg) by silica gel column chromatography, with a yield of 48%. LC-MS (ESI-MS): 192[M+H] +.

[0201] Step 3, dissolve the intermediate 001-2 (250 mg, 1.31 mmol) in 1 mL of tetrahydrofuran, slowly add lithium aluminum tetrahydride (2.6 mL, 5.23 mmol, 2M in THF) at 0°C, raise the temperature to reflux, and react for 4 hours. After the reaction is completed, slowly add water until the system stops bubbling, concentrate under reduced pressure, dissolve the residue in ethyl acetate, and concentrate under reduced pressure to obtain the intermediate 001-3: 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (200 mg), with a yield of 86%. LC-MS (ESI-MS): 178 [M+H] + .

[0202] Step 4, the intermediate 001-3 (100 mg, 0.56 mmol) was dissolved in 2 mL of 1,4-dioxane, and N-(2,6-dimethyl-4-bromophenyl)-3,3-dimethylbutanamide (252.38 mg, 0.84 mmol), Pd2(dba)3 (25.83 mg, 0.02 mmol), XPhos (2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl) (26.90 mg, 0.05 mmol), sodium tert-butoxide (162.66 mg, 1.69 mmol) were added in sequence, and the reaction was carried out at 80° C. for 2 h after nitrogen replacement. After the reaction was completed, the mixture was cooled to room temperature, 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 (400MHz, CDCl3) δ7.18(d,J=8.2Hz,1H),6.67(d,J=2.4Hz,1H),6.62(dd,J=8.1,2.6Hz,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).

[0203] Example 2: N-(4-(7-ethoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (002)

[0204]

[0205] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with ethyl bromide to prepare the target compound 002 (35 mg), LC-MS (ESI-MS): 409 [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.16(d,J=8.2Hz,1H),6.66(d,J=2.5Hz,1H),6.61(dd,J=8.2,2.6Hz,1H),6.49(d,J=6.1Hz,2H),6.39(brs,1H),4.48(s,2H ),3.97(q,J=7.0Hz,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 = 7.0Hz, 3H), 1.12 (s, 9H).

[0206] Example 3: N-(4-(7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (003)

[0207]

[0208] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with 2-bromopropane to prepare the target compound 003 (46 mg), LC-MS (ESI-MS): 423 [M+H] + , 1 H NMR(400MHz, CDCl3)δ7.15(d,J=8.2Hz,1H),6.65(d,J=2.4Hz,1H),6.60(dd,J=8.2,2.5Hz,1H),6.48(s,2H),6.42(brs,1H),4.51–4.44 (m,3H),3.71(d,J=4.6Hz,2H),2.92–2.85(m,2H),2.23(s,2H),2.14(s,6H),1.85(d,J=4.3Hz,2H),1.30(d,J=6.1Hz,6H),1.12(s,9H).

[0209] Example 4: N-(4-(7-(sec-butoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (004)

[0210]

[0211] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with 2-bromobutane to prepare the target compound 004 (60 mg), LC-MS (ESI-MS): 437 [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.15 (d, J = 8.2Hz, 1H), 6.65 (d, J = 2.4Hz, 1H), 6.60 (dd, J = 8. 2,2.5Hz,1H),6.49(d,J=7.5Hz,2H),6.42(brs,1H),4.49(s,2H),4.22(dd,J=12. 1,6.1Hz,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).

[0212] Example 5: N-(4-(7-(difluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (005)

[0213]

[0214] Step 1, 6-hydroxy-3,4-dihydro-2H-1-naphthalenone (2g, 12.33mmol) was dissolved in 10mL DMF, potassium iodide (2.07g, 12.45mmol), tetrabutylammonium iodide (4.78g, 12.45mmol), sodium difluorobromoacetate (2.45g, 12.45mmol), cesium carbonate (8.04g, 24.66mmol) 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, filtered, and the organic phase was washed twice with saturated sodium bicarbonate and twice with saturated ammonium chloride, concentrated under reduced pressure, and the product 6-(difluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one (1.4g) was obtained by silica gel column chromatography, with a yield of 53%. LC-MS (ESI-MS): 213 [M+H] + .

[0215] The subsequent steps refer to the synthetic route and method of Example 1, and replace 6-methoxy-3,4-dihydronaphthalene-1(2H)-one with 6-(difluoromethoxy)-3,4-dihydronaphthalene-1(2H)-one (1.4 g) to prepare the target compound 005 (28 mg), LC-MS (ESI-MS): 431 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.24(d,J=8.2Hz,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=9.9,5.7Hz,2H),1.12(s,9H).

[0216] Example 6: N-(2,6-dimethyl-4-(7-(trifluoromethoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (006)

[0217]

[0218] Step 1, 6-hydroxy-3,4-dihydro-2H-1-naphthalenone (0.8 g, 5 mmol) was dissolved in 10 mL of anhydrous DMF, potassium carbonate (0.83 g, 6 mmol) and S-(trifluoromethyl) dibenzothiophene trifluoromethylsulfonate (2.4 g, 6 mmol) were added, and the mixture was stirred at room temperature for about 12 hours. After the reaction, water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine and 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-dihydronaphthalen-1(2H)-one (0.52 g), with a yield of 45%, LC-MS (ESI-MS): 231 [M+H] + .

[0219] The subsequent steps refer to the synthetic route and method of Example 1, and replace 6-methoxy-3,4-dihydronaphthalene-1(2H)-one with 6-(trifluoromethoxy)-3,4-dihydronaphthalene-1(2H)-one to prepare the target compound 006 (22 mg), LC-MS (ESI-MS): 449 [M+H] + .

[0220] 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-dimethylbutanamide (007)

[0221]

[0222] Step 1, 6-hydroxy-3,4-dihydro-2H-1-naphthalenone (2g, 12.33mmol) was dissolved in 15mL DMF, cesium carbonate (20.09g, 61.66mmol), trifluoroethyl p-toluenesulfonate (31.35g, 123.31mmol) 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, filtered, and the organic phase was washed twice with saturated sodium bicarbonate and twice with saturated ammonium chloride, concentrated under reduced pressure, and the product 6-(2,2,2-trifluoroethoxy)-3,4-dihydronaphthalen-1(2H)-one (1.6g) was obtained by silica gel column chromatography, with a yield of 52%. LC-MS (ESI-MS): 245[M+H] + .

[0223] The subsequent steps refer to the synthetic route and method of Example 1, and replace 6-methoxy-3,4-dihydronaphthalene-1(2H)-one with 6-(2,2,2-trifluoroethoxy)-3,4-dihydronaphthalene-1(2H)-one to prepare the target compound 007 (50 mg), LC-MS (ESI-MS): 463 [M+H] + .

[0224] Example 8: N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (008)

[0225]

[0226] Step 1, dissolve 6-fluoro-3,4-dihydronaphthalene-1(2H)-one (420 mg, 2.56 mmol) in 10 mL of acetonitrile, add cesium carbonate (1.67 g, 5.12 mmol) and trifluoroisopropanol (583.61 mg, 5.12 mmol) in sequence, and reflux overnight. After the reaction is completed, cool to room temperature, dilute with ethyl acetate, filter, and concentrate under reduced pressure. Silica gel column chromatography is used to obtain intermediate 008-1: 6-((1,1,1-trifluoropropane-2-yl)oxy)-3,4-dihydronaphthalene-1(2H)-one (340 mg), with a yield of 51%. LC-MS (ESI-MS): 259 [M+H] + .

[0227] Step 2, dissolve the 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 system about 8, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Silica gel column chromatography to obtain the intermediate 008-2: 7-((1,1,1-trifluoropropane-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one. LC-MS (ESI-MS): 274 [M+H] + .

[0228] Step 3, dissolve the intermediate 008-2 (274 mg, 1.0 mmol) in 1 mL of tetrahydrofuran, slowly add lithium aluminum tetrahydride (2.6 mL, 5.23 mmol, 2M in THF) at 0°C, raise the temperature to reflux, and react for 4 hours. After the reaction is completed, slowly add water until the system stops bubbling, concentrate under reduced pressure, dissolve the residue in ethyl acetate, and concentrate under reduced pressure to obtain the intermediate 008-3: 7-((1,1,1-trifluoropropane-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, LC-MS (ESI-MS): 260[M+H] + .

[0229] Step 4, the intermediate 008-3 (130 mg, 0.50 mmol) was dissolved in 2 mL of 4-dioxane, and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide (252.38 mg, 0.84 mmol), Pd2(dba)3 (25.83 mg, 0.02 mmol), X-Phos (2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl) (26.90 mg, 0.05 mmol), sodium tert-butoxide (162.66 mg, 1.69 mmol) were added in sequence, and the reaction was carried out at 80° C. for 2 h after nitrogen replacement. After the reaction was completed, the mixture was cooled to room temperature, 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] + . 1HNMR (400MHz, CDCl3) δ7.19(d,J=8.2Hz,1H),6.73(d,J=2.6Hz,1H),6.67(dd,J=8.2,2.6Hz,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=6.4Hz,3H),1.12(s,9H).

[0230] Example 9: N-(4-(7-cyclopropyloxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (009)

[0231]

[0232] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with cyclopropane bromide to prepare the target compound 009 (21 mg), LC-MS (ESI-MS): 421 [M+H] + .

[0233] Example 10: N-(4-(7-cyclobutyloxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (010)

[0234]

[0235] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with cyclobutane bromide to prepare the target compound 010 (63 mg), LC-MS (ESI-MS): 435 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.13(d,J=8.2Hz,1H),6.59(d,J=2.4Hz,1H),6.52(dd,J =8.1,2.6Hz,1H),6.48(d,J=6.6Hz,2H),6.40(s,1H),4.57(t,J=7.2Hz,1H),4 .48(d,J=10.8Hz,2H),3.70(d,J=4.8Hz,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).

[0236] Example 11: N-(4-(7-(cyclopentyloxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (011)

[0237]

[0238] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with cyclopentyl bromide to prepare the target compound 011 (52 mg), LC-MS (ESI-MS): 449 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.14(d,J=8.2Hz,1H),6.63(d,J=2.5Hz,1H),6.58(dd,J=8.2,2.6Hz,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).

[0239] Example 12: N-(4-(7-(cyclohexyloxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (012)

[0240]

[0241] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with cyclohexyl bromide to prepare the target compound 012 (57 mg), LC-MS (ESI-MS): 463 [M+H] + .

[0242] Example 13: N-(2,6-dimethyl-4-(7-(oxetane-3-yl-oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (013)

[0243]

[0244] Referring to the synthetic route and method of Example 1, methyl iodide was replaced with 3-bromobutylene oxide to prepare the target compound 013 (22 mg), LC-MS (ESI-MS): 437 [M+H] +.

[0245] Example 14: N-(2,6-dimethyl-4-(7-(methylthio)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (014)

[0246]

[0247] Step 1, dissolve 6-fluoro-3,4-dihydro-2H-1-naphthalenone (1.6 g) in 15 mL of anhydrous DMSO in a reaction flask, add sodium thiomethoxide (1.1 g), heat to 50°C and stir to react for about 3 hours. Add water to quench the reaction, add dichloromethane and water to extract, and the separated dichloromethane phase is dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography to obtain 6-(methylthio)-3,4-dihydronaphthalen-1(2H)-one (1.1 g), LC-MS (ESI-MS): 193 [M+H] + .

[0248] The subsequent steps refer to the synthetic route and method of Example 1, and replace 6-methoxy-3,4-dihydronaphthalene-1(2H)-one with 6-(methylthio)-3,4-dihydronaphthalene-1(2H)-one to prepare the target compound 014 (78 mg), LC-MS (ESI-MS): 411 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.18(d,J=7.6Hz,1H),7.00(d,J=8.2Hz,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).

[0249] Example 15: N-(2,6-dimethyl-4-(7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (015)

[0250]

[0251] Compound 014 (30 mg) was dissolved in 3 mL of dichloromethane in a reaction flask, and mCPBA (35 mg) (3-chloroperbenzoic acid) was added, and the reaction was stirred at room temperature for about 1 hour. The reaction was then quenched with an aqueous sodium sulfite solution, and dichloromethane and water were added for extraction. The separated dichloromethane phase was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography to obtain compound 015 (26 mg), LC-MS (ESI-MS): 443 [M+H] + .

[0252] 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-dimethylbutanamide (016)

[0253]

[0254] Step 1: Dissolve 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one (700 mg, synthesized according to Adv.Synth.Catal.2019,361,3223–3227) in 7 mL of hydrochloric acid in a reaction flask, slowly add sodium azide (473.46 mg, 7.28 mmol) at 0°C, gradually return to room temperature, and react for 4 hours. After the reaction is completed, slowly add saturated potassium carbonate aqueous solution to make the system pH about 8, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain intermediate 016-1: 7-fluoro-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (360 mg) by silica gel column chromatography, with a yield of 36%. LC-MS (ESI-MS): 208 [M+H] + .

[0255] Step 2, dissolve the intermediate 016-1 (170 mg, 0.82 mmol) in 3 mL of tetrahydrofuran, slowly add lithium aluminum tetrahydride (1.6 mL, 3.28 mmol, 2 M in THF) at 0°C, raise the temperature to reflux, and react for 4 hours. After the reaction is completed, slowly add water until the system stops bubbling, concentrate under reduced pressure, dissolve the residue in ethyl acetate, and concentrate under reduced pressure to obtain the 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] + .

[0256] Step 3, dissolve N-(2,6-dimethyl-4-bromophenyl)-3,3-dimethylbutanamide (5g, 16.77mmol) in 80mL 1,4-dioxane, add boronic acid pinacol ester (3.41g, 13.41mmol), potassium acetate (4.94g, 50.30mmol), Pd(dppf)Cl2 (614.62mg, 0.83mmol) in sequence, replace with nitrogen, and react at 90°C for 3h. After the reaction is completed, dilute with ethyl acetate, filter, wash the organic phase with saturated sodium chloride aqueous solution once, dry and concentrate under reduced pressure, and obtain intermediate 016-3: (3,5-dimethyl-4-(3,3-dimethylbutanamido))phenylboronic acid pinacol ester (4.30g) by column chromatography, with a yield of 74%. LC-MS (ESI-MS): 346[M+H] + .

[0257] Step 4, dissolve the intermediate 016-3 (3 g, 8.69 mmol) in 30 mL of tetrahydrofuran, add 10 mL of water and sodium periodate (11.15 g, 52.13 mmol) in sequence, and react at room temperature overnight. After the reaction is completed, add water until solid precipitates, filter, and dry to obtain the 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] + .

[0258] Step 5, the intermediate 016-2 (100 mg, 0.51 mmol) was dissolved in 5 mL of acetonitrile, and the intermediate 016-4 (204.24 mg, 0.77 mmol), boric 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 atmosphere for 3 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and filtered. The organic phase was washed twice with saturated ammonium chloride, dried, and concentrated under reduced pressure. The target compound 016 (70 mg) was obtained by column chromatography with a yield of 32%. LC-MS (ESI-MS): 411 [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.22–7.17(m,1H),7.07(dd,J=11.7,2.6Hz,1H),6.82(td,J=8.0,2.6Hz,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=4.0Hz,6H),1.12(s,9H).

[0259] Example 17: N-(4-(5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (017)

[0260]

[0261] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one (synthesized by reference Adv.Synth.Catal.2019,361,3223–3227), and the target compound 017 (52 mg) was prepared. LC-MS (ESI-MS): 393 [M+H] + , 1 H NMR(400MHz, CDCl3) δ7.39(d,J=7.0Hz,1H),7.24–7.08(m,3H),6.42(d,J=5.9Hz,3H),4.59(s,2H ),3.60–3.54(m,2H),2.23(s,2H),2.14(s,6H),2.05(t,J=5.9Hz,2H),1.33(s,6H),1.12(s,9H).

[0262] 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-dimethylbutanamide (018)

[0263]

[0264] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one was replaced with 2-chloro-7,7-dimethyl-6,7-dihydrobenzo[b]thiophene-4(5H)-one (synthesized by reference to Adv.Synth.Catal.2019,361,3223–3227), and the target compound 018 (28 mg) was prepared. LC-MS (ESI-MS): 433 [M+H] + , 1H NMR(400MHz, CDCl3)δ6.71(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).

[0265] 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-dimethylbutanamide (019)

[0266]

[0267] Referring to the synthetic route and 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 by reference Adv.Synth.Catal.2019,361,3223–3227), and the target compound 019 (41 mg) was prepared. LC-MS (ESI-MS): 399 [M+H] + , 1 HNMR(400MHz, CDCl3)δ6.97(d,J=5.1Hz,1H),6.90(d,J=5.1Hz,1H),6.47(s,2H),6.42(brs,1H),4.4 8(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).

[0268] 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-dimethylbutanamide (020)

[0269]

[0270] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 2-chloro-4,4-dimethyl-5,6-dihydrobenzo[b]thiophene-7(4H)-one (synthesized by reference to Adv.Synth.Catal.2019,361,3223–3227), and the target compound 020 (29 mg) was prepared. LC-MS (ESI-MS): 433 [M+H] + , 1 H NMR(400MHz, CDCl3)δ6.73(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).

[0271] 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-dimethylbutanamide (021)

[0272]

[0273] Referring to the synthetic route and 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 by reference Adv.Synth.Catal.2019,361,3223–3227), and the target compound 021 (18 mg) was prepared. LC-MS (ESI-MS): 399 [M+H] + , 1 HNMR(400MHz, CDCl3)δ6.98(d,J=5.2Hz,1H),6.91(d,J=5.2Hz,1H),6.53(s,2H),6.42(brs,1H),4.5 7(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).

[0274] Example 22: N-(4-(7-fluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (022)

[0275]

[0276] Referring to the synthetic route and 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 by 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 (400MHz, DMSO) δ8.72(s,1H),7.48(dd,J=8.1,6.2Hz,1H),6.93(ddd,J=11.0,9.5,2.6Hz,2H),6.54(s,2 H),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).

[0277] Example 23: N-(4-(8-Fluoro-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (023)

[0278]

[0279] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one was replaced with 7-fluoro-2,3-dihydroquinolin-4(1H)-one (synthesized by reference to Bioorganic Chemistry, 2020, 99, 103800), and the target compound 023 (44 mg) was prepared. LC-MS (ESI-MS): 384 [M+H] + , 1 H NMR(400MHz, CDCl3)δ7.16(dd,J=8.2,6.5Hz,1H),6.53–6.49(m,2H),6.48(s,2H),6.39(dd,J=10.3,2 .4Hz,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).

[0280] 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-dimethylbutanamide (024)

[0281]

[0282] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one was replaced with 7-fluoro-1-methyl-2,3-dihydroquinolin-4(1H)-one to prepare the target compound 024 (52 mg), LC-MS (ESI-MS): 398 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.16(dd,J=8.9,6.8Hz,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=5.9,3.7Hz,2H),2.88(s,3H),2.24(s,2H),2.16(s,6H),1.12(s,9H).

[0283] Example 25: N-(4-(8-fluoro-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (025)

[0284]

[0285] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one was replaced with 7-fluorothiochroman-4-one to prepare the target compound 025 (47 mg). LC-MS (ESI-MS): 401 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.33 (dd, J=8.2, 5.9Hz, 1H), 7.23 (dd, J=8.8, 2.5Hz, 1H), 6.86 (td, J=8.3, 2.5Hz, 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).

[0286] Example 26: N-(4-(8-fluoro-1,1-dioxo-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (026)

[0287]

[0288] Compound 025 (25 mg) was dissolved in 2 mL of dichloromethane in a reaction flask, and mCPBA (30 mg) was added, and the reaction was stirred at room temperature for about 1 hour. The reaction was then quenched with an aqueous sodium sulfite solution, and dichloromethane and water were added for extraction. The separated dichloromethane phase was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography to obtain the target compound 026 (21 mg), LC-MS (ESI-MS): 433 [M+H] + .

[0289] Example 27: N-(4-(7-Fluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (027)

[0290]

[0291] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 6-fluoronaphthalene-1(2H)-one to prepare the target compound 027 (37 mg). LC-MS (ESI-MS): 381 [M+H] + . 1 HNMR(400MHz, CDCl3)δ7.25–7.20(m,1H),6.83(t,J=8.0Hz,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).

[0292] Example 28: N-(4-(7-Fluoro-5-methyl-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (028)

[0293]

[0294] Referring to the synthetic route and method of Example 16, 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one was replaced with 6-fluoro-4-methylnaphthalene-1(2H)-one to prepare the target compound 028 (23 mg), LC-MS (ESI-MS): 395 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.34–7.31(m,1H),7.11(dd,J=10.2,2.6Hz,1H),6.97(td,J=8.3,2.7Hz,1H),6.60(s,2H),6.53( s,1H),6.07(t,J=5.8Hz,1H),4.18(s,2H),3.66(d,J=6.3Hz,2H),2.31(s,2H),2.24(s,6H),2.20(s,3H),1.19(s,9H).

[0295] Example 29: N-(3-Fluoro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2-methylphenyl)-3,3-dimethylbutanamide (029)

[0296]

[0297] Step 1, dissolve N-(2-methyl-3-fluoro-4-bromophenyl)-3,3-dimethylbutanamide (5g, 16.77mmol) in 80mL 1,4-dioxane, add boronic acid pinacol ester (3.41g, 13.41mmol), potassium acetate (4.94g, 50.30mmol), PdDPPFCl2 (614.62mg, 0.83mmol) in sequence, replace with nitrogen, and react at 90°C for 3h. After the reaction is completed, dilute with ethyl acetate, filter, wash the organic phase with saturated sodium chloride solution once, dry and concentrate under reduced pressure, and obtain oily (3-methyl-2-fluoro-4-(3,3-dimethylbutanamido))phenylboronic acid pinacol ester (4g) by column chromatography, with a yield of 69%. LC-MS (ESI-MS): 350[M+H] + .

[0298] Step 2, 7-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (90 mg, 0.54 mmol) was dissolved in 5 mL of acetonitrile, (3-methyl-2-fluoro-4-(3,3-dimethylbutyramide))phenylboronic acid pinacol ester (190 mg, 0.54 mmol), boric acid (70 mg, 1.09 mmol), copper acetate (100 mg, 0.54 mmol) were added in sequence, and the mixture was reacted at 80°C in an oxygen atmosphere for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was washed twice with saturated ammonium chloride, dried and concentrated under reduced pressure. The target compound 029 (36 mg) was obtained by column chromatography with a yield of 17%. , LC-MS (ESI-MS): 387 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.23(d,J=8.8Hz,1H),7.17–7.11(m,1H),6.85(dd,J=9.6,2.3Hz,1H),6.82–6.70(m,3H),4.3 5(s,2H),3.60–3.55(m,2H),3.00–2.94(m,2H),2.23(s,2H),2.15(d,J=2.2Hz,3H),1.98–1.91(m,2H),1.11(s,9H).

[0299] Example 30: N-(4-(7-Fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,3,6-trimethylphenyl)-3,3-dimethylbutanamide (030)

[0300]

[0301] 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-dimethylbutyramido))phenylboronic acid pinacol ester (260 mg, 0.72 mmol), boric acid (75 mg, 1.21 mmol), copper acetate (109 mg, 0.60 mmol), pyridine (50 μL, 1.21 mmol) were added in sequence, and the mixture was reacted at 80°C in an oxygen atmosphere for 6 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was washed twice with saturated ammonium chloride, dried and concentrated under reduced pressure. The target compound 030 (38 mg) was obtained by column chromatography with a yield of 16%. LC-MS (ESI-MS): 397 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.02 (dd, J=8.2, 5.8Hz, 1H), 6.89–6.85 (m, 2H), 6.79 (td, J=8.4, 2.6Hz, 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).

[0302] Example 31: N-(3-chloro-4-(7-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (031)

[0303]

[0304] 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-dimethylbutyramido))phenylboronic acid pinacol ester (282 mg, 0.66 mmol) (which can be synthesized by a method similar to Example 16), boric acid (75 mg, 1.21 mmol), copper acetate (110 mg, 0.60 mmol), pyridine (50 μL, 1.21 mmol) were added in sequence, and the mixture was reacted at 80°C in an oxygen atmosphere for 6 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered, and the organic phase was washed twice with saturated ammonium chloride, dried and concentrated under reduced pressure. 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 (400MHz, CDCl3) δ7.14(dd,J=8.3,5.9Hz,1H),6.89–6.85(m,2H),6.80(td,J=8.5,2.7Hz,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).

[0305] Example 32: (R)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (032)

[0306]

[0307] Referring to the synthetic route and method of Example 8, trifluoroisopropanol was replaced with (R)-1,1,1-trifluoropropane-2-ol to prepare the target compound 032 (50 mg). LC-MS (ESI-MS): 477 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.19(d,J=8.2Hz,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=6.5Hz,3H),1.12(s,9H).

[0308] Example 33: (S)-N-(2,6-dimethyl-4-(7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)phenyl)-3,3-dimethylbutanamide (033)

[0309]

[0310] Referring to the synthetic route and method of Example 8, trifluoroisopropanol was replaced with (S)-1,1,1-trifluoropropane-2-ol to prepare the target compound 033 (63 mg). LC-MS (ESI-MS): 477 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.19(d,J=8.2Hz,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).

[0311] Example 34: N-(4-(8-fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (034)

[0312]

[0313] Step 1, dissolve 6,7-difluoro-3,4-dihydronaphthalene-1(2H)-one (2.0 g, 10.98 mmol) in 30 mL of acetonitrile, add trifluoroisopropanol (2.5 mL, 27.45 mmol) and cesium carbonate (10.7 g, 32.94 mmol) to the system in turn, and react at 80°C for 4 h. After the reaction is completed, concentrate to remove acetonitrile, add ethyl acetate and water to dissolve, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain intermediate 034-1: 7-fluoro-6-((1,1,1-trifluoropropane-2-yl)oxy)-3,4-dihydronaphthalene-1(2H)-one (3.12 g), yield: 94%. Directly proceed to the next step. ESI-MS (M+H) + =277. 1 H-NMR(400MHz,CCl3D)δ7.76(d,J=11.6Hz,1H),6.89(d,J=7.5Hz,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=6.5,0.9Hz,3H).

[0314] Step 2, the intermediate 034-1 (3.12 g, 11.30 mmol) was dissolved in 40 mL of concentrated hydrochloric acid, sodium azide (1.47 g, 22.60 mmol) was slowly added under an ice bath, and the reaction was carried out at room temperature for 48 h. After the reaction was completed, ice water and sodium carbonate aqueous solution were slowly added at low temperature to adjust the pH of the system to alkaline, and ethyl acetate was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE / EA elution) was performed to obtain the intermediate 034-2: 8-fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (750 mg) yield: 23%. ESI-MS (M+H) + =292.

[0315] Step 3, the intermediate 034-2 (400 mg, 1.44 mmol) was dissolved in 100 mL of tetrahydrofuran, and lithium aluminum hydride (1 mmol / mL, 13 mL) was added, and the mixture was reacted at 60°C for 2 h. After the reaction was completed, water was added to quench (until no bubbles were generated), and the mixture was concentrated under reduced pressure to remove water, and ethyl acetate (1 g product 1 L EA) was used to dissolve the mixture, and the mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the intermediate 034-3: 8-fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine 350 mg, yield: 92%. ESI-MS (M+H)+=278.

[0316] Step 4, the intermediate 034-3 (230 mg, 0.83 mmol) was dissolved in 10 mL of 1,4-dioxane, and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (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), Pd2(dba)3 (76 mg, 0.08 mmol), X-Phos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) (79 mg, 0.17 mmol) were added to the system in sequence, and the mixture was replaced with nitrogen and reacted at 105° C. for 4 h. After the reaction was completed, dioxane was removed under reduced pressure, dichloromethane and water were added to dissolve the mixture, and dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The target compound 034 (170 mg) was obtained by column chromatography (PE / EA elution), with a yield of 41%. ESI-MS (M+H) + =495. 1 H-NMR (400MHz, CCl3D) δ7.02(d,J=11.2Hz,1H),6.82(d,J=8.1Hz,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=6.5Hz,3H),1.12(s,9H).

[0317] Example 35: N-(4-(8-Fluoro-7-isopropoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (035)

[0318]

[0319] Step 1, referring to the synthetic route and method of steps 1, 2, and 3 of Example 34, replacing trifluoroisopropanol with isopropanol, 8-fluoro-7-isopropoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine can be prepared. ESI-MS (M+H) + =224.

[0320] 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-dimethylbutyramide)-3,5-dimethylphenyl)boric acid (1.3 g, 4.84 mmol), copper acetate (440 mg, 2.42 mmol), boric acid (300 mg, 4.84 mmol), DIPEA (940 mg, 7.26 mmol) were added to the system in sequence, and the mixture was replaced with oxygen and reacted at 60° C. for 2 h. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added for washing, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE / EA elution) was performed to obtain the target compound 035 (150 mg), with a yield of 14%. ESI-MS (M+H) + =441. 1 H-NMR(400MHz,CCl3D)δ6.97-7.00(m,1H),6.71-6.74(m,1H),6.42-6.48(m,3H),4.40-4.45(m,3H),3.67-3.7 3(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=6.1Hz,6H),1.12(s,9H).

[0321] Example 36. (S)-N-(4-(8-fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (036)

[0322]

[0323] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with (S)-1,1,1-trifluoropropane-2-ol to prepare the target compound 036 (58 mg). LC-MS (ESI-MS): 495 [M+H] + .

[0324] Example 37. (R)-N-(4-(8-fluoro-7-((1,1,1-trifluoropropane-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (037)

[0325]

[0326] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with (R)-1,1,1-trifluoropropane-2-ol to prepare the target compound 037 (50 mg). LC-MS (ESI-MS): 495 [M+H] + .

[0327] Example 38. N-(4-(8-fluoro-7-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (038)

[0328]

[0329] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with methanol to prepare the target compound 038 (47 mg). LC-MS (ESI-MS): 413 [M+H] + .

[0330] 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-dimethylbutanamide (039)

[0331]

[0332] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with butane-2-ol to prepare the target compound 039 (62 mg). LC-MS (ESI-MS): 455 [M+H] + .

[0333] 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-dimethylbutanamide (040)

[0334]

[0335] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with (S)-butane-2-ol to prepare the target compound 040 (40 mg). LC-MS (ESI-MS): 455 [M+H] + .

[0336] Example 41. (R)-N-(4-(7-(sec-Butyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (041)

[0337]

[0338] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with (R)-butane-2-ol to prepare the target compound 041 (46 mg). LC-MS (ESI-MS): 455 [M+H] + .

[0339] Example 42. N-(4-(7-cyclopropyloxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (042)

[0340]

[0341] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with cyclopropanol to prepare the target compound 042 (35 mg). LC-MS (ESI-MS): 439 [M+H] + .

[0342] Example 43. N-(4-(7-cyclobutyloxy-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (043)

[0343]

[0344] Referring to the synthetic route and method of Example 34, the target compound 043 (34 mg) can be prepared by replacing trifluoroisopropanol in step 1 with cyclobutanol. LC-MS (ESI-MS): 453 [M+H] + .

[0345] Example 44. N-(4-(7-(Cyclopentyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (044)

[0346]

[0347] Referring to the synthetic route and method of Example 34, the trifluoroisopropanol in step 1 was replaced with cyclopentanol to prepare the target compound 044 (41 mg). LC-MS (ESI-MS): 467 [M+H] + .

[0348] Example 45. N-(4-(7-(cyclohexyloxy)-8-fluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide (045)

[0349]

[0350] Referring to the synthetic route and method of Example 34, the target compound 045 (48 mg) can be prepared by replacing trifluoroisopropanol in step 1 with cyclohexanol. LC-MS (ESI-MS): 481 [M+H] + .

[0351] Example 46. N-(4-(7,8-difluoro-1,3-dihydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (046)

[0352]

[0353] Referring to the synthetic route and method of steps 2, 3, and 4 of Example 34, 7-fluoro-6-((1,1,1-trifluoropropane-2-yl)oxy)-3,4-dihydronaphthalene-1(2H)-one was replaced with 6,7-difluoronaphthalene-1(2H)-one to prepare the target compound 046 (38 mg). LC-MS (ESI-MS): 399 [M+H] + .

[0354] Example 47. N-(4-(7,8-difluoro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (047)

[0355]

[0356] Referring to the synthetic routes and methods 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-trifluoropropane-2-yl)oxy)-3,4-dihydronaphthalene-1(2H)-one in step 2 with 6,7-difluoro-3,4-dihydronaphthalene-1(2H)-one. LC-MS (ESI-MS): 401 [M+H] + .

[0357] 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-dimethylbutanamide (048)

[0358]

[0359] Referring to the synthetic route and method of Example 31, 7-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine was replaced with 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine to prepare the target compound 048 (37 mg). LC-MS (ESI-MS): 435 [M+H] + .

[0360] Example 49. N-(4-(7,8-difluoro-3,4-dihydrospiro[benzo[c]azepine-5,1'-cyclopropane]-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (049)

[0361]

[0362] Referring to the synthetic route and method of steps 2, 3, and 4 of Example 34, 7-fluoro-6-((1,1,1-trifluoropropane-2-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one was replaced with 6',7'-difluoro-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one to prepare the target compound 049 (38 mg). LC-MS (ESI-MS): 427 [M+H] + .

[0363] 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-dimethylbutanamide (050)

[0364]

[0365] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with (E)-4,4,4-trifluorobut-2-en-1-ol to prepare the target compound 050 (50 mg). LC-MS (ESI-MS): 489 [M+H] + .

[0366] 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-dimethylbutanamide (051)

[0367]

[0368] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 3-(difluoromethyl)bicyclo[1.1.1]pentan-1-ol to prepare the target compound 051 (42 mg). LC-MS (ESI-MS): 497 [M+H] + .

[0369] 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-dimethylbutanamide (052)

[0370]

[0371] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 2,2,2-trifluoro-1-methoxyethane-1-ol to prepare the target compound 052 (52 mg). LC-MS (ESI-MS): 493 [M+H] + .

[0372] 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-dimethylbutanamide (053)

[0373]

[0374] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 3,3,3-trifluoro-2-methylpropan-1-ol to prepare the target compound 053 (46 mg). LC-MS (ESI-MS): 491 [M+H] + .

[0375] 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-dimethylbutanamide (054)

[0376]

[0377] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with (1-(trifluoromethyl)cyclopropyl)methanol to prepare the target compound 054 (34 mg). LC-MS (ESI-MS): 503 [M+H] + .

[0378] Example 55. N-(4-(7-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (055)

[0379]

[0380] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with hexafluoroisopropanol to prepare the target compound 055 (49 mg). LC-MS (ESI-MS): 531 [M+H] + .

[0381] 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-dimethylbutanamide (056)

[0382]

[0383] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 2-(2,2,2-trifluoroethoxy)ethanol to prepare the target compound 056 (62 mg). LC-MS (ESI-MS): 507 [M+H] + .

[0384] 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-dimethylbutanamide (057)

[0385]

[0386] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with tetrafluoropropanol to prepare the target compound 057 (53 mg). LC-MS (ESI-MS): 495 [M+H] + .

[0387] 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-dimethylbutanamide (058)

[0388]

[0389] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with trifluoropropanol to prepare the target compound 058 (48 mg). LC-MS (ESI-MS): 477 [M+H] + .

[0390] 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-dimethylbutanamide (059)

[0391]

[0392] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 4-(trifluoromethyl)cyclohexanol to prepare the target compound 059 (50 mg). LC-MS (ESI-MS): 531 [M+H] + .

[0393] 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-dimethylbutanamide (060)

[0394]

[0395] Referring to the synthetic route and method of Example 8, the target compound 060 (63 mg) can be prepared by replacing trifluorobutanol with trifluoroisopropanol in step 1. LC-MS (ESI-MS): 491 [M+H] + .

[0396] 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-dimethylbutanamide (061)

[0397]

[0398] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 4,4,5,5,5-pentafluoropentanol (49 mg). LC-MS (ESI-MS): 541 [M+H] + .

[0399] 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-dimethylbutanamide (062)

[0400]

[0401] Referring to the synthetic route and method of Example 8, the trifluoroisopropanol in step 1 was replaced with 2,2,4,4,4-pentafluorobutanol (57 mg). LC-MS (ESI-MS): 527 [M+H] + .

[0402] Example 63. N-(4-(7-(4-fluorobutoxy)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (063)

[0403]

[0404] Referring to the synthetic route and method of Example 8, the target compound 063 (45 mg) can be prepared by replacing trifluoroisopropanol in step 1 with 4-fluorobutanol. LC-MS (ESI-MS): 455 [M+H] + .

[0405] Biological tests

[0406] Example 64: KCNQ2 / 3 potassium channel activation assay

[0407] step

[0408] 1. Cell Culture

[0409] hKCNQ-CHO cells were cultured at 37°C in a humidified environment with 5% CO2.

[0410] 2. Solution

[0411] 2.1. Extracellular fluid (mM): NaCl 145, KCl 4, CaCl2 2, MgCl2 1, Glucose 10, HEPES 10. The pH of the extracellular fluid was adjusted to 7.4 using NaOH, and the osmotic pressure was adjusted to about 295 mOsm.

[0412] 2.2. Intracellular solution (mM (mmol / L)): KOH 31.25, KCl 120, EGTA 10, MgCl2 1.75, CaCl2 5.374, HEPES 10, Na-ATP 4. The pH of the intracellular solution was adjusted to 7.4 using HCl, and the osmotic pressure was adjusted to about 285 mOsm.

[0413] 2.3. Extracellular fluid needs to be prepared once a week, and intracellular fluid needs to be stored at -20℃ after preparation.

[0414] 3. Preparation of Working Solution

[0415] The model positive reference compound Retigabine (RTG) was dissolved in 100% DMSO and stored as a 10mM working solution. The test compound was dissolved in 100% DMSO and stored as a 10mM working solution. The final DMSO concentration in the test solution must be less than 0.3%.

[0416] 4. Whole-cell Voltage Clamp Recording

[0417] Whole-cell patch clamp was performed at room temperature. The electrical signals recorded by EPC 10USB amplifier (HEKA Elektronik, Germany) were low-pass filtered at 3kHz and finally recorded in PatchMaster 2×90.5 software (HEKA Elektronik, Germany). At this step, the quality control standard was that the cell high-resistance seal was greater than 500MOhms and the detection current was greater than 0.4nA.

[0418] The recording electrodes were pulled and polished using borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK) using a vertical puller (NARISHIGE PC-10, Japan). At this step, the quality control standard was an electrode resistance between 2 and 5 MΩ.

[0419] During the whole-cell patch clamp recording, a continuous perfusion system (BT100-2J, LongerPump, China) was used to continuously perfuse the extracellular fluid. 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.

[0420] The voltage commands for detecting the hKCNQ current amplitude are as follows: The cell is stepped from a clamping potential of -80 mV to -30 mV for 1500 ms; then the clamping voltage is decreased to -120 mV for 500 ms; finally, the voltage returns to the clamping potential of -80 mV. The detection voltage commands are repeated every 15000 milliseconds and are continuously executed during the compound test. The quality control standard for the stability of the compound's effect is the current amplitude under 5 consecutive voltage commands, and its coefficient of variation < 5%. If the compound has no effect on the hKCNQ current amplitude, it needs to be continuously monitored for 5 minutes.

[0421] 5. Data analysis

[0422] Data analysis was performed using PatchMaster 2×90.5 software (HEKA Elektronik, Germany) and Excel 2013 (Microsoft, USA) software. For each cell's patch clamp recording, the hKCNQ channel current amplitude (Itest) corresponding to the test compound concentration needs to be obtained. Itest minus the cell's original channel current (Icontrol) is the enhanced channel current, and dividing by Icontrol gives the current enhancement multiple. That is, the current enhancement multiple (Enhancment%) = (Itest - Icontrol) / Icontrol * 100%. The experimental results are shown in Table 1

[0423] Table 1 Activation activity of compounds on KCNQ2 / 3 potassium channels

[0424]

[0425]

[0426] In the table: "0.05 μM" and "3 μM" represent the test concentrations of the compounds to be tested. A > 100%, 50% < B < 100%, C < 50%. "-" indicates that the corresponding test was not performed.

[0427] Among them, compound a is a control compound, and its structure is

[0428] a Indicates the activation activity of retigabine on KCNQ2 / 3 potassium channels at a concentration of 10 μM.

[0429] The results in Table 1 show that the activation activities of compound a at a concentration of 3 μM and retigabine at a concentration of 10 μM on KCNQ2 / 3 potassium channels are less than 50%, and the activation activity of the compound of the present invention on KCNQ2 / 3 potassium channels at a concentration of 3 μM is greater than 50%.

[0430] Example 65: Half-open voltage left shift test

[0431] step

[0432] 1. Cell Culture

[0433] hKCNQ-CHO cells were cultured at 37°C in a humidified environment with 5% CO2.

[0434] 2. Solution

[0435] a) Extracellular fluid (mM): NaCl 145, KCl 4, CaCl2 2, MgCl2 1, Glucose 10, HEPES 10. The pH of the extracellular fluid was adjusted to 7.4 using NaOH, and the osmotic pressure was adjusted to about 295 mOsm.

[0436] b) Intracellular solution (mM): KOH 31.25, KCl 120, EGTA 10, MgCl2 1.75, CaCl2 5.374, HEPES10, Na-ATP 4. The pH of the intracellular solution was adjusted to 7.4 using HCl, and the osmotic pressure was adjusted to about 285 mOsm.

[0437] c) Extracellular fluid needs to be prepared once a week, and intracellular fluid needs to be aliquoted and stored at -20°C after preparation.

[0438] 3. Preparation of Working Solution

[0439] The model positive reference compound Retigabine (RTG) was dissolved in 100% DMSO and stored as a 10mM working solution. The test compound was dissolved in 100% DMSO and stored as a 10mM working solution. The final DMSO concentration in the test solution must be less than 0.3%.

[0440] 4. Whole-cell Voltage Clamp Recording

[0441] Whole-cell patch clamp was performed at room temperature. The electrical signals recorded by EPC 10USB amplifier (HEKA Elektronik, Germany) were low-pass filtered at 3kHz and finally recorded in PatchMaster 2×90.5 software (HEKA Elektronik, Germany). At this step, the quality control standard was that the cell high-resistance seal was greater than 500MOhms and the detection current was greater than 0.4nA.

[0442] The recording electrodes were pulled and polished using borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK) using a vertical puller (NARISHIGE PC-10, Japan). At this step, the quality control standard was that the electrode resistance was between 2 and 5 MΩ.

[0443] During the whole-cell patch clamp recording, a continuous perfusion system (BT100-2J, LongerPump, China) was used to continuously perfuse the extracellular fluid. 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.

[0444] The voltage command for hKCNQ current amplitude detection is as follows: the cell is clamped from -80mV to -120mV, and the voltage is increased by 10mV per sweep to continuously clamp the cell until it reaches +60mV for 1500ms; then the clamp voltage is reduced to -120mv for 500ms; finally, the voltage is returned to the clamp potential of -80mV. The detection voltage command is repeated every 15000ms and is executed continuously during the compound test. The half-value voltage of the cell hKCNQ needs to be nonlinearly fitted by the current amplitude of the cell at different clamping potentials (-120mV to +60mV).

[0445] 5. Data Analysis

[0446] Data analysis was performed using PatchMaster 2×90.5 software (HEKA Elektronik, Germany) and Excel 2013 (Microsoft, USA). For each cell patch clamp recording, the half-value voltage of hKCNQ corresponding to the test compound concentration (V1 / 2-test) was obtained. V1 / 2-test minus the half-value voltage of hKCNQ before the compound effect (V1 / 2-control) was the left-shifted half-value voltage ΔV1 / 2 (V 1 / 2 Shift(mV)).

[0447] The experimental results are shown in Table 2:

[0448] Table 2 Effect of compounds on left shift of half-open voltage of KCNQ2 / 3

[0449]

[0450] In the table, "50nM" and "300nM" are the test concentrations of the test compounds. "-" means that the corresponding test was not performed.

[0451] Compound Xen-1101 is a control compound, and its structure is: (WO2008024398A2)

[0452] The test results in Table 2 show that the compounds designed in the present invention have the effect of significantly inducing a leftward shift in the half-open voltage.

[0453] Example 66: Mouse brain transfection experiment

[0454] Experimental procedures

[0455] 1. Drug preparation

[0456] Dosage: 5 mg / kg

[0457] The drug was prepared into a solution with a concentration of 0.5 mg / mL according to the proportion (solvent: 5% DMSO+5% Solutol+90% saline), and the mice were gavaged at 0.1 mL / 10 g, with 3 mice in parallel at each point.

[0458] 2. Obtain brain tissue from specific locations

[0459] After the mice were administered the drug, they were anesthetized and cardiac perfused with normal saline. The brain tissue was dissected and washed with normal saline, then dried and weighed before being transferred to a 2 mL EP tube. Normal saline was added at a ratio of brain tissue: normal saline = 1:1 (g / mL). Three steel balls were placed in each tube on a tissue grinder, homogenized at 60 Hz for 60 s, and centrifuged at 15,000 rpm at 4°C for 10 min. The supernatant was the brain tissue homogenate.

[0460] 3. Sample Processing

[0461] 3.1. Preparation and processing of standard curve and quality control samples

[0462] The drug stock solution (0.5 mg / mL) was diluted with acetonitrile to prepare standard curve working solutions with concentrations of 50, 100, 200, 500, 1000, 2000, 5000, 10000, and 20000 ng / mL, and quality control working solutions with concentrations of 100, 2000, and 10000 ng / mL. 47.5 uL of blank matrix was added with 2.5 μL 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, and 1000 ng / mL and quality control samples with concentrations of 5, 100, and 500 ng / mL. 200 μL of acetonitrile (containing internal standard loratadine 5 ng / mL) was added to each sample, vortexed for 3 min, centrifuged at 15000 rpm and 4 °C for 10 min, and the supernatant was analyzed by LC-MS / MS to obtain the standard curve.

[0463] 3.2 Sample preparation and processing

[0464] Take 50 μL of brain tissue homogenate sample, add 200 μL of acetonitrile (containing internal standard loratadine 5 ng / mL), vortex for 3 minutes, centrifuge at 15000 rpm and 4°C for 10 minutes, take the supernatant for LC-MS / MS analysis, and combine with the standard curve to obtain the corresponding brain concentration.

[0465] The experimental results are shown in Table 3:

[0466] Table 3 Brain concentrations of compounds after intragastric administration

[0467]

[0468] The test results in Table 3 show that after oral administration to mice, the concentration of the compound in the brain increased to a certain extent.

[0469] Example 67: MES mouse epilepsy model

[0470] Experimental steps:

[0471] 1. 30 minutes before the experiment, transfer the mice (10 mice per group) to the operating room to adapt to the environment.

[0472] 2. Administer the test compound or positive drug (sodium valproate, Valproate) at a specific time. 30 minutes after the administration of Valproate or the test compound, apply electrical stimulation using ear electrodes, with stimulation parameters of a total duration of 0.8 seconds, a frequency of 50 Hz, an amplitude of 50 mA, and a square wave interval of 10 msec.

[0473] 3. Record the number of hind limb rigidity episodes and the duration of the episodes within 1 minute after the completion of the electrical stimulation, as well as any possible deaths and the time of death.

[0474] 4. After administration, observe and record the possible side effects induced by the drug, which are divided into four levels:

[0475] None: Normal

[0476] Mild sedation

[0477] Moderate sedation

[0478] Severe sedation

[0479] The experimental results are shown in Table 4:

[0480] Table 4 Protective effect of compounds on MES-induced epilepsy in mice (mpk: mg / kg)

[0481] Compound No. dose Ankylosing protection rate Embodiment 003 5mpk 100％ Embodiment 008 5mpk 90％ Embodiment 011 5mpk 90％ Embodiment 032 5mpk 100％ Embodiment 033 5mpk 100％ Embodiment 035 5mpk 100％

[0482] The test results in Table 4 show that the compound can significantly inhibit the occurrence of hind limb rigidity in mice in MES-induced epilepsy.

Claims

1. A compound, characterized in that It has a structure shown in Formula IV or Formula V: or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; Wherein, in the general formula IV, R1 is selected from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C2-C6 heterocycloalkoxy, C 1- C3 alkylthio, C 1- C3 alkylsulfonyl, halo 1-6 Alkoxy, halogenated C 3-6 Cycloalkoxy, In the general formula V, R1 is selected from halogen, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C2-C6 heterocycloalkoxy, C 1- C3 alkylthio, C 1- C3 alkylsulfonyl, halo 1-6 Alkoxy and halogenated C 3-6 Cycloalkoxy.

2. The compound according to claim 1, characterized in that It has the structure shown in the general formula Va: R1 is H or F; R1' is 3. The compound according to claim 1, characterized in that Selected from the following compounds: or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition, characterized in that The method comprises one or more compounds as described in any one of claims 1 to 3.

5. A pharmaceutical preparation, characterized in that The method comprises one or more compounds according to any one of claims 1 to 3.

6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease that benefits from potassium ion channel activation.

7. The use according to claim 6, characterized in that: The disease is a central nervous system disease.

8. The use according to claim 6, characterized in that: The disease is selected from the group consisting of epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative diseases, anxiety disorders, depression, stroke, complications caused by cocaine abuse, nicotine withdrawal syndrome, alcohol withdrawal syndrome or tinnitus.

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