BENZONITRIC HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Disclosed are a benzonitric heterocyclic compound, a preparation method therefor and the use thereof. Provided in the present invention is a benzonitric heterocyclic compound represented by formula I, or a pharmaceutically acceptable salt thereof, which can be used as a histone deacetylase inhibitor, has a selective inhibitory effect on HDAC6, and has characteristics such as a high efficiency, low toxicity and ideal pharmacokinetic properties.

##STR00001##

Claims

1. A benzonitric heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof: ##STR00049## wherein, ring A is a 7-membered heterocycloalkyl; in the 7-membered heterocycloalkyl, in addition to the N atom which is connected with the ##STR00050## the 7-membered heterocycloalkyl also contains 0 to 2 heteroatoms optionally selected from N, O, S, S(═O) and S(═O).sub.2; n is 0, 1, 2, 3 or 4; R.sup.2 is independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl-O—, (R.sup.aR.sup.b)N— or O═; R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently hydrogen, halogen, hydroxyl, cyano or R.sup.1-L-; -L- is independently a linker bond, —(C.sub.1-C.sub.4 alkyl)-, —O—, —C(═O)— or —S(═O).sub.2—; R.sup.1 is independently C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, or, the C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl and 5- to 10-membered heteroaryl are substituted by one or more substituents of R.sup.e; in the 3- to 7-membered heterocycloalkyl and the 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R.sup.e, the heteroatom is selected from one or more of N, O, S, S(═O) and S(═O).sub.2, and the number of heteroatoms is 1 to 3; in the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl substituted by one or more substituents of R.sup.e, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; R.sup.e is independently hydroxyl, halogen, cyano or C.sub.1-C.sub.4 alkyl; when there are multiple substituents, they are the same or different; R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently hydrogen or C.sub.1-C.sub.4 alkyl; R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl substituted by one or more halogen; when there are multiple substituents, they are the same or different; a carbon atom with “*” indicates that when it is a chiral carbon atom, it is a S configuration, R configuration or a mixture thereof.

2. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, in ring A, the N connected with the ##STR00051## is located at the ortho or para position of the benzene fused with the ring; or, in ring A, in addition to the N atom which is connected with the ##STR00052## and the ring A also contains 0 to 1 heteroatom optionally selected from N, O and S; or, when R.sup.2 is independently C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl-O—, the C.sub.1-C.sub.4 alkyl in the C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl-O— is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, when R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently halogen, the halogen is fluorine, chlorine, bromine or iodine; or, when -L- is independently —(C.sub.1-C.sub.4 alkyl)-, the —(C.sub.1-C.sub.4 alkyl)- is methylene, ethylene, propylene, butylene, isopropylidene, isobutylene, sec-butylene or tert-butylene; or, when R.sup.1 is independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by one or more substituents of R.sup.e, the C.sub.1-C.sub.6 alkyl in the C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkyl substituted by one or more substituents of R.sup.e is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or when R.sup.1 is independently C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7 cycloalkyl substituted by one or more substituents of R.sup.e, the C.sub.3-C.sub.7 cycloalkyl in the C.sub.3-C.sub.7 cycloalkyl and C.sub.3-C.sub.7 cycloalkyl substituted by one or more substituents of R.sup.e is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; or, when R.sup.1 is independently C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 aryl substituted by one or more substituents of R.sup.e, the C.sub.6-C.sub.10 aryl in the C.sub.6-C.sub.10 aryl and C.sub.6-C.sub.10 aryl substituted with one or more substituents of R.sup.e is independently phenyl or naphthyl; or, when R.sup.1 is independently 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R.sup.e, the 3- to 7-membered heterocycloalkyl in the 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R.sup.e is independently 5- to 6-membered heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2; or, when R.sup.1 is independently 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R.sup.e, the 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R.sup.e is independently 5- to 6-membered heteroaryl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2; or, when R.sup.e is independently halogen, the halogen is fluorine, chlorine, bromine or iodine; or, when R.sup.e is independently C.sub.1-C.sub.4 alkyl, the C.sub.1-C.sub.4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, when R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently C.sub.1-C.sub.4 alkyl, the C.sub.1-C.sub.4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, when R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl substituted by one or more halogen, the C.sub.1-C.sub.4 alkyl in the C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl substituted by one or more halogen is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, when R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are independently halogen or C.sub.1-C.sub.4 alkyl substituted by one or more halogen, the halogen in the halogen or C.sub.1-C.sub.4 alkyl substituted by one or more halogen is fluorine, chlorine, bromine or iodine; or, when R.sup.1 is independently C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, and the C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl and 5- to 10-membered heteroaryl are substituted by substituents of R.sup.e, and the R.sup.e is independently halogen, and the number of R.sup.e is 1, 2 or 3; or, when R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.4 alkyl substituted by one or more halogen, the number of halogen substitutions is substituted by 1 to 3 halogens.

3. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, ring A is ##STR00053## Y is a linker bond, methylene or ##STR00054## X is C, N, O or S; or, n is 0 or 1; or, R.sup.2 is independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl, (R.sup.aR.sup.b)N— or O═; or, -L- is independently a linker bond or —O—; or, R.sup.1 is independently C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; or, R.sup.1-L- is C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl or C.sub.1-C.sub.6 alkyl-O—; or, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently hydrogen, halogen or R.sup.1-L-; or, R.sup.4 and R.sup.5 are independently hydrogen or halogen; or, R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently C.sub.1-C.sub.4 alkyl; or, R.sup.3a, R.sup.3b, R.sup.3c and R.sup.3d are independently hydrogen or halogen.

4. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the benzonitric heterocyclic compound represented by formula I is the following scheme 1, scheme 2, scheme 3 or scheme 4: scheme 1, the benzoazepine compound represented by formula I is a benzonitric heterocyclic compound represented by formula I-1 or formula I-2: ##STR00055## wherein, X.sub.1 and X.sub.2 are independently ##STR00056## scheme 2, ring A is 7-membered heterocycloalkyl; the N in ring A connected with the ##STR00057## is located at the ortho or para position of the benzene ring; n is 0 or 1; R.sup.2 is independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl-O—, (R.sup.aR.sup.b)N— or O═; R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently hydrogen, halogen or R.sup.1-L-; -L- is independently a linker bond or —O—; R.sup.1 is independently C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; R.sup.4 and R.sup.5 are independently hydrogen or halogen; R.sup.3a, R.sup.3b, R.sup.3c and R.sup.3d are independently hydrogen or halogen; scheme 3, ring A is 7-membered heterocycloalkyl; in ring A, the N connected with the ##STR00058## is located at the ortho or para position of the benzene; n is 0 or 1; R.sup.2 is independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl-O—, (R.sup.aR.sup.b)N— or O═; R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl-O—, C.sub.3-C.sub.7 cycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 aryl-(C.sub.1-C.sub.4 alkyl)-, (R.sup.cR.sup.d)N—, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.4 and R.sup.5 are independently hydrogen; R.sup.3a, R.sup.3b, R.sup.3c and R.sup.3d are independently hydrogen or halogen; scheme 4, ring A is ##STR00059## X.sup.1 is independently ##STR00060## n is 0 or 1; R.sup.2 is independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl or O═; R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently hydrogen, fluorine or C.sub.1-C.sub.6 alkyl-O—; R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are independently hydrogen.

5. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, ring A is ##STR00061## or, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently hydrogen, fluorine, chlorine, bromine, methoxy, cyclopropyl, phenyl, ##STR00062## or, R.sup.2 is independently hydrogen, hydroxyl, methyl, methoxy, ##STR00063## or O═; or, R.sup.4 and R.sup.5 are independently hydrogen or fluorine; or, R.sup.3a, R.sup.3b, R.sup.3c and R.sup.3d are independently hydrogen or fluorine.

6. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the benzonitric heterocyclic compound represented b formula I is selected from any of the following structures: ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069##

7. A preparation method of benzonitric heterocyclic compound represented by formula I according to claim 1, wherein, in a solvent, performing a hydroxylamine reaction as shown below between a compound represented by formula II with hydroxylamine to obtain the benzonitric heterocyclic compound represented by formula I; ##STR00070## wherein, *, ring A, n, R.sup.2, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are as defined above; R.sup.6 is C.sub.1-C.sub.6 alkyl.

8. A pharmaceutical composition, comprising the benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof as defined in claim 1, and one or more pharmaceutically acceptable carriers.

9. A method of inhibiting HDAC in a subject in need thereof, comprising administering the benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof as defined in, claim 1 into the subject.

10. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 2, wherein, in ring A, the N connected with the ##STR00071## is located at the ortho position of the benzene fused with the ring; or, when R.sup.2 is independently C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl-O—, the C.sub.1-C.sub.4 alkyl in the C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl-O— is methyl; or, when R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently halogen, the halogen is fluorine, chlorine or bromine; or, when R.sup.1 is independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by one or more substituents of R.sup.e, the C.sub.1-C.sub.6 alkyl in the C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkyl substituted by one or more substituents of R.sup.e is independently methyl; or, when R.sup.1 is independently C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7 cycloalkyl substituted by one or more substituents of R.sup.e, the C.sub.3-C.sub.7 cycloalkyl in the C.sub.3-C.sub.7 cycloalkyl and C.sub.3-C.sub.7 cycloalkyl substituted by one or more substituents of R.sup.e is independently cyclopropyl; or, when R.sup.1 is independently C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 aryl substituted by one or more substituents of R.sup.e, the C.sub.6-C.sub.10 aryl in the C.sub.6-C.sub.10 aryl and C.sub.6-C.sub.10 aryl substituted with one or more substituents of R.sup.e is independently phenyl; or, when R.sup.1 is independently 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R.sup.e, the 3- to 7-membered heterocycloalkyl in the 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R.sup.e is independently piperidinyl; or, when R.sup.1 is independently 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R.sup.e, the 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R.sup.e is independently piperidinyl; or, when R.sup.e is independently C.sub.1-C.sub.4 alkyl, the C.sub.1-C.sub.4 alkyl is methyl; or, when R.sup.a, R.sup.b, R and R.sup.d are independently C.sub.1-C.sub.4 alkyl, the C.sub.1-C.sub.4 alkyl is methyl; or, when R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl substituted by one or more halogen, the C.sub.1-C.sub.4 alkyl in the C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkyl substituted by one or more halogen is methyl.

11. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 3, wherein, R.sup.2 is independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl or O═; or, R.sup.1 is independently C.sub.1-C.sub.6 alkyl; or, R.sup.1-L- is C.sub.1-C.sub.6 alkyl-O; or, one or two of R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are independently halogen or R.sup.1-L-, the rest are hydrogen; or, R.sup.4 and R.sup.5 are independently hydrogen; or, R.sup.3a is hydrogen or halogen; R.sup.3b, R.sup.3c and R.sup.3d are independently hydrogen.

12. The benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof according to claim 4, wherein, in scheme 3, in ring A, the N connected with the ##STR00072## is located at the ortho position of the benzene.

13. The preparation method according to claim 7, wherein, R.sup.6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, the solvent is an alcohol solvent; or, the mass-volume ratio of the compound represented by formula II to the solvent is 0.1 g/L to 20 g/L; or, the molar ratio of the compound represented by formula II to hydroxylamine is 1:5 to 1:50; or, the temperature of the hydroxylamine reaction is room temperature to 80° C.; or, the preparation method also comprises a post-treatment; the post-treatment comprises the following steps: after the hydroxylamine reaction is finished, adjusting the pH to neutral, concentrating, adding with the organic solvent, washing with water, drying the organic phase, concentrating, separating and purifying; or, the preparation method also comprises the following steps: in a solvent, under the exist of a base, performing a coupling reaction as shown below between a compound represented by formula III with a compound represented by formula IV to obtain the compound represented by formula II; ##STR00073## wherein, R.sup.6, *, ring A, n, R.sup.2, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.4 and R.sup.5 are as defined above; X is a halogen.

14. The method according to claim 9, wherein, the HDAC is HDAC6.

15. A method of preventing and/or treating cancer, nervous diseases or autoimmune diseases, comprising administering the benzonitric heterocyclic compound represented by formula I or the pharmaceutically acceptable salt thereof as defined in claim 1 into the subject.

16. The method according to claim 15, wherein, the cancers are selected from ovarian cancer, colon cancer, breast cancer, liver cancer, pancreatic cancer, gallbladder cancer, gastrointestinal cancer, head and neck cancer, cervical cancer, prostate cancer, lung cancer, melanoma, germ cell tumor, gestational trophoblastic tumor, glioblastoma, myeloma, neuroblastoma-derived CNS tumor, monocytic leukemia, B-cell-derived leukemia, T-cell-derived leukemia, B-cell-derived lymphoma, T-cell-derived lymphoma and mast cell-derived tumors, and combinations thereof; or, the nervous diseases are selected from neurodegenerative disease, peripheral neuropathy, and combinations thereof; or, the autoimmune diseases are selected from psoriasis, inflammatory diseases, and symptoms that are able to treat by immunomodulation.

17. The method according to claim 16, wherein, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Spinocerebellar degeneration, Rett syndrome; or, the peripheral neuropathy is selected from peroneal muscular atrophy, giant axonal neuropathy; or, the inflammatory diseases are selected from osteoarthritis, rheumatoid arthritis and colitis; or, the symptoms that are able to treat by immunomodulation are selected from multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergy, asthma, allergic rhinitis and inflammatory bowel disease.

18. A method of inhibiting HDAC in a subject in need thereof, comprising administering the pharmaceutical composition as defined in claim 8 into the subject.

19. A method of preventing and/or treating cancer, nervous diseases or autoimmune diseases, comprising administering the pharmaceutical composition as defined in claim 8 into the subject.

20. The method according to claim 19, wherein, the cancers are selected from ovarian cancer, colon cancer, breast cancer, liver cancer, pancreatic cancer, gallbladder cancer, gastrointestinal cancer, head and neck cancer, cervical cancer, prostate cancer, lung cancer, melanoma, germ cell tumor, gestational trophoblastic tumor, glioblastoma, myeloma, neuroblastoma-derived CNS tumor, monocytic leukemia, B-cell-derived leukemia, T-cell-derived leukemia, B-cell-derived lymphoma, T-cell-derived lymphoma and mast cell-derived tumors, and combinations thereof; or, the nervous diseases are selected from neurodegenerative disease, peripheral neuropathy, and combinations thereof; or, the autoimmune diseases are selected from psoriasis, inflammatory diseases, and symptoms that are able to treat by immunomodulation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0224] FIG. 1 is the cell survival rate in the HCA-induced neuronal toxicity model

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0225] The present disclosure is further described below by way of embodiments, but the present disclosure is not thereby limited to the scope of the described embodiments. The experimental methods not specified in the specific conditions in the following embodiments are selected according to the conventional methods and conditions, or according to the commodity instructions.

[0226] In the following embodiments, the abbreviations are explained:

[0227] DCM: dichloromethane; PE: petroleum ether; EA: ethyl acetate; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; MeOH: methanol; p-TsCl: p-toluenesulfonyl chloride; t-BuOK: potassium tert-butoxide; pyridine: pyridine; toluene: toluene; concd: concentrated; PPA: polyphosphoric acid; DIBALH: diisobutylaluminum hydride.

[0228] In the following embodiments, room temperature refers to 10 to 30° C.; overnight refers to 8 to 15 hours, for example, 12 hours; eq refers to equivalent; and solvent ratios (for example, PE/EA) refer to volume ratios.

[0229] The compounds of the present disclosure can be prepared by the following synthetic general method:

[0230] General method I:

##STR00039## ##STR00040##

[0231] General method II:

##STR00041##

[0232] General method III:

##STR00042##

[0233] A compound comprising a structure represent by formula I was obtained by the described synthesis general method, which could further react with inorganic acid and organic acid in a solvent, and the corresponding salt of the compound represent by formula I was precipitated by cooling.

[0234] The raw materials, compounds and reagents used in the above preparation methods could be purchased through commercial channels.

Embodiment 1: Preparation of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-1)

[0235] Prepared according to the synthesis general method I, the synthesis route was as follows:

##STR00043## ##STR00044##

Synthesis of methyl 4-chloro-2-((4-methylphenyl)sulfonamido)benzoate (1-2)

[0236] Methyl 4-chloro-2-aminobenzoate (25 g, 134.69 mmol, 1 eq), p-toluenesulfonyl chloride (30.81 g, 1.2 eq), and pyridine (117.20 g, 11 eq) were sequentially added to a 500 mL three-necked flask, and the reaction was carried out at room temperature for 12 hours. The mixture was filtered to obtain a yellow solid, dissolved to clear with 200 mL of dichloromethane, washed twice with 100 mL of 5% hydrochloric acid and washed once with 100 mL of water; the organic phase was dried and then slurried with 150 mL of 50% ethanol to obtain a white solid with a drying weight of 40.50 g and a yield of 88.49%.

Synthesis of methyl 4-chloro-2-((N-(4-ethoxy-4-oxobutyl)-4-methylphenyl)sulfonamido)benzoate (1-3)

[0237] Intermediate 1-2 (36.40 g, 107.12 mmol, 1 eq) was added to a 1 L three-necked flask, then dissolved in 300 mL of DMF, and then ethyl 4-bromobutyrate (22.98 g, 1.1 eq) and potassium carbonate (41.45 g, 2.8 eq) were added, and the reaction mixture was stirred at 120° C. for 5 hours. The reaction mixture was cooled to room temperature, and 500 mL of water was added thereto, extracted with 500 mL of ethyl acetate; the organic phase was separated and concentrated to dryness, and separated by column chromatography to obtain 35.32 g of white solid with a yield of 72.63%.

Synthesis of ethyl 8-chloro-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (1-4)

[0238] Potassium tert-butoxide (16.81 g, 149.80 mmol, 2 eq) and 400 mL of toluene were added to a 1 L three-necked flask, heated to 75° C., and stirred well; intermediate 1-3 (34.00 g, 74.90 mmol, 1eq) was dissolved in 200 mL of toluene, slowly added dropwise to the reaction solution for 1 hour; after the dropwise addition was completed, the reaction solution was heated to 115° C. and refluxed for 1 hour. After cooling to room temperature, the mixture was poured into the ice-water mixture, and the organic phase was separated, and then the aqueous phase was extracted with 200 mL of dichloromethane once. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 32 g of red oil, and directly used in the next step without purification.

Synthesis of 8-chloro-1-tosyl-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (1-5)

[0239] 32 g of the crude product of intermediate 1-4, 45 mL of concentrated hydrochloric acid, 80 mL of acetic acid, and 10 mL of water were added to a 500 mL three-necked flask, and the mixture was heated to 105° C. and refluxed for 6 hours. After cooling to room temperature, the mixture was poured into ice-water mixture, adjusted to neutral with 10% NaOH, extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography to obtain 16.35 g of colorless oil with a two-step yield of 62.49%.

Synthesis of 8-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (1-6)

[0240] Intermediate 1-5 (8 g, 22.87 mmol) and 60 g of polyphosphoric acid were added to a 250 mL three-necked flask, and the mixture was heated to 90° C. and reacted for 2 hours. The mixture was adjusted to neutral with saturated NaHCO.sub.3 solution, extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography to obtain 4.13 g of yellow solid with a yield of 92.31%.

Synthesis of 8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1-7)

[0241] Intermediate 1-6 (3.00 g, 15.33 mmol, 1 eq) and 50 mL of anhydrous tetrahydrofuran were added to a 100 mL three-necked flask, and the mixture was cooled in an ice-water bath, and then lithium aluminum hydride (1.16 g, 2 eq) was added in portions, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was slowly poured into the ice-water mixture, stirred for 30 min, filtered with diatomite, and the filtrate was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the purified by column chromatography to obtain 2.15 g of yellow solid with a yield of 77.18%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.51-1.57 (m, 2H), 1.64-1.70 (m, 2H), 2.61-2.64 (m, 2H), 2.92 (dt, J=5.8, 3.5 Hz, 2H), 5.48 (t, J=3.6 Hz, 1H), 6.67 (dd, J=8.0, 2.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H). ESI-MS(+) m/z=182.00 [M+H]+.

Synthesis of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)benzoate (1-8)

[0242] Intermediate 1-7 (2.00 g, 11.01 mmol, 1 eq), methyl 4-(bromomethyl)benzoate (2.52 g, 1 eq), potassium carbonate (2.28 g, 1.5 eq) and 50 mL of DMF were added to a 100 mL three-necked flask, and reacted at 100° C. for 4 hours. The mixture was cooled to room temperature, and 100 mL of water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried, and separated by column chromatography to obtain 2.90 g of white solid with a yield of 79.86%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.55-1.61 (m, 4H), 2.78-2.81 (m, 2H), 2.89-2.91 (m, 2H), 3.84 (s, 3H), 4.41 (s, 2H), 6.84 (dd, J=8.0, 2.1 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.92-7.95 (m, 2H). ESI-MS(+) m/z=330.10 [M+H].sup.+.

Synthesis of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-1)

[0243] 20 g of hydroxylamine hydrochloride was dissolved in 200 mL of methanol, and 19 g potassium hydroxide (purity of 85%) was dissolved in 200 mL of methanol, and then the mixture was slowly and evenly mixed in an ice-water bath, stirred at room temperature for 2 hours, and filtered to obtain a filtrate as a hydroxylamine methanol solution. Intermediate 1-8 (2 g, 6.06 mmol) and 50 mL of hydroxylamine methanol solution were added to a 100 mL three-necked flask, and the reaction was carried out at room temperature overnight. The pH was adjusted to neutral with 1 N hydrochloric acid. The mixture was concentrated, followed by addition of ethyl acetate, washed with water to remove hydroxylamine, and the organic phase was dried then concentrated to dryness, and then 20 mL of ethanol/water was added to crystallize, and 1.13 g of white solid was obtained by filtration, and the yield was 56.33%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.53-1.61 (m, 4H), 2.78-2.80 (m, 2H), 2.89 (t, J=4.9 Hz, 2H), 4.36 (s, 2H), 6.83 (dd, J=8.0, 2.1 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 10.13 (s, 2H). ESI-MS(+) m/z=331.00 [M+H].sup.+.

Embodiment 2: Preparation of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-2)

[0244] ##STR00045##

[0245] The preparation was carried out according to general method I. White solid, .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.52-1.60 (m, 4H), 2.79-2.87 (m, 4H), 4.34 (s, 2H), 6.92 (d, J=8.6 Hz, 1H), 7.08 (dd, J=8.5, 2.6 Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.70-7.72 (m, 2H), 9.04 (s, 1H), 11.18 (s, 1H). ESI-MS(+) m/z=331.00 [M+H].sup.+.

Embodiment 3: Preparation of 4-((8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-3)

[0246] Prepared according to the synthesis general method II, the specific synthesis route was as follows:

##STR00046##

Synthesis of 7-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (3-2)

[0247] 7-Bromo-tetralone (10 g, 44.43 mmol, 1 eq), hydroxylamine hydrochloride (6.17 g, 2 eq) and 100 mL of pyridine were added to a 250 mL three-necked flask, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and evaporated under reduced pressure to remove pyridine, and 100 mL of water was added thereto. The mixture was extracted with 100 mL of dichloromethane, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 9.23 g of white solid with a yield of 86.53%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.71-1.77 (m, 2H), 2.62-2.69 (m, 4H), 7.16 (d, J=8.2 Hz, 1H), 7.42 (dd, J=8.2, 2.2 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 11.31 (s, 1H).

Synthesis of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (3-3)

[0248] 3-2 (9.00 g, 47.06 mmol) and 200 mL of dichloromethane were added to a 250 mL three-necked flask under the protection of nitrogen, and the mixture was cooled down to −5° C., then diisobutylaluminium hydride (DIBALH, 1 M/hexane, 280 mL, 6 eq) was slowly added dropwise for 40 min; after the dropwise addition was completed, the mixture was stirred for 4 hours at room temperature. The reaction was quenched by slowly adding 50 mL of water dropwise, stirred for 1 hour at room temperature, filtered with diatomite, and the filtrate was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and then purified by column chromatography to obtain 5.64 g of white solid with a yield of 67.61%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.51-1.57 (m, 2H), 1.63-1.68 (m, 2H), 2.59-2.62 (m, 2H), 2.90-2.93 (m, 2H), 5.49 (t, J=3.6 Hz, 1H), 6.80 (dd, J=8.0, 2.1 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H).

Synthesis of methyl 4-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)benzoate (3-4)

[0249] Intermediate 3-3 (2.00 g, 11.28 mmol, 1 eq), methyl 4-(bromomethyl)benzoate (2.58 g, 1 eq), potassium carbonate (2.34 g, 1.5 eq) and 50 mL of DMF were added to a 100 mL three-necked flask, and reacted at 100° C. for 4 hours. The mixture was cooled to room temperature, and 100 mL of water was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried, and separated by column chromatography to obtain 3.12 g of white solid with a yield of 84.97%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.54-1.60 (m, 4H), 2.77-2.80 (m, 2H), 2.89 (t, J=5.1 Hz, 2H), 3.84 (s, 3H), 4.41 (s, 2H), 6.97 (dd, J=7.9, 2.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 7.52-7.55 (m, 2H), 7.93-7.95 (m, 2H).

Synthesis of 4-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-3)

[0250] Intermediate 3-4 (2 g, 5.34 mmol) and 50 mL of hydroxylamine methanol solution were added to a 100 mL three-necked flask, and the reaction was carried out at room temperature overnight. The pH was adjusted to neutral with 1 N hydrochloric acid. The mixture was concentrated, followed by addition of ethyl acetate, washed with water to remove hydroxylamine. The organic phase was dried then concentrated to dryness, and 20 mL of ethanol/water was added to crystallize, and 1.27 g of white solid was obtained by filtration, the yield was 63.33%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.52-1.60 (m, 4H), 2.76-2.79 (m, 2H), 2.88 (t, J=4.9 Hz, 2H), 4.36 (s, 2H), 6.97 (dd, J=7.9, 1.9 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 9.10 (s, 1H), 11.20 (s, 1H). ESI-MS(+) m/z=375.00 [M+H].sup.+.

Embodiment 4: Preparation of 4-((7-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-4)

[0251] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.51-1.62 (m, 4H), 2.71-2.79 (m, 2H), 2.88 (t, J=4.9 Hz, 2H), 4.35 (s, 2H), 6.96 (dd, J=7.9, 1.9 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.2 Hz, 2H), 9.12 (s, 1H), 11.21 (s, 1H). ESI-MS(+) m/z=315.00 [M+H].sup.+.

Embodiment 5: Preparation of 4-((7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-5)

[0252] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.51-1.58 (m, 4H), 2.73-2.80 (m, 4H), 3.67 (s, 3H), 4.28 (s, 2H), 6.63 (dd, J=8.7, 3.0 Hz, 1H), 6.73 (d, J=3.0 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H), 7.69-7.71 (m, 2H), 9.06 (s, 1H), 11.16 (s, 1H). ESI-MS(+) m/z=327.14 [M+H].sup.+.

Embodiment 6: Preparation of 4-((8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-6)

[0253] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.49-1.60 (m, 4H), 2.72-2.75 (m, 2H), 2.84-2.87 (m, 2H), 3.65 (s, 3H), 4.34 (s, 2H), 6.38 (dd, J=8.2, 2.4 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.70-7.72 (m, 2H), 9.09 (s, 1H), 11.14 (s, 1H). ESI-MS(+) m/z=327.10 [M+H].sup.+.

Embodiment 7: Preparation of 4-((6-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-7)

[0254] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.47-1.51 (m, 2H), 1.55-1.59 (m, 2H), 2.87 (t, J=5.3 Hz, 4H), 3.73 (s, 3H), 4.34 (s, 2H), 6.57 (dd, J=10.7, 8.2 Hz, 2H), 6.99 (t, J=8.1 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 9.20 (s, 1H), 10.98 (s, 1H). ESI-MS(+) m/z=327.10 [M+H].sup.+.

Embodiment 8: Preparation of 4-((9-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-8)

[0255] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.47-1.51 (m, 2H), 1.55-1.59 (m, 2H), 2.87 (t, J=5.3 Hz, 4H), 3.73 (s, 3H), 4.34 (s, 2H), 6.57 (dd, J=10.7, 8.2 Hz, 2H), 6.99 (t, J=8.1 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 9.20 (s, 1H), 10.98 (s, 1H). ESI-MS(+) m/z=327.10 [M+H].sup.+.

Embodiment 9: Preparation of 4-((7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-9)

[0256] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.63-1.80 (m, 4H), 2.84 (td, J=6.9, 1.0 Hz, 4H), 3.83 (d, J=7.1 Hz, 6H), 4.43 (t, J=1.0 Hz, 2H), 6.43 (s, 1H), 6.68 (t, J=0.9 Hz, 1H), 7.30 (dt, J=7.4, 1.0 Hz, 2H), 7.85-7.91 (m, 2H), 9.25 (s, 1H), 11.09 (s, 1H). ESI-MS(+) m/z=357.20 [M+H].sup.+.

Embodiment 10: Preparation of 4-((8-phenyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-10)

[0257] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.53-1.60 (m, 4H), 2.83 (dt, J=19.4, 4.8 Hz, 4H), 4.35 (s, 2H), 6.89 (d, J=1.5 Hz, 1H), 7.17 (dt, J=7.7, 1.0 Hz, 1H), 7.32-7.41 (m, 4H), 7.42-7.49 (m, 2H), 7.52-7.58 (m, 2H), 7.85-7.91 (m, 2H), 9.04 (s, 1H), 11.15 (s, 1H). ESI-MS(+) m/z=373.25 [M+H].sup.+.

Embodiment 11: Preparation of 4-((8-(pyridin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-11)

[0258] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.53-1.60 (m, 4H), 2.83 (dt, J=19.4, 4.8 Hz, 4H), 4.35 (s, 2H), 7.02 (d, J=7.5 Hz, 1H), 7.21 (q, J=1.2 Hz, 1H), 7.35 (dt, J=7.5, 1.1 Hz, 2H), 7.49 (dd, J=7.5, 1.5 Hz, 1H), 7.64-7.70 (m, 2H), 7.85-7.91 (m, 2H), 8.76-8.81 (m, 2H), 9.04 (s, 1H), 11.15 (s, 1H). ESI-MS(+) m/z=374.25 [M+H].sup.+.

Embodiment 12: Preparation of 4-((8-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-12)

[0259] The preparation was carried out according to general method II. .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 0.55 (dt, J=6.5, 3.2 Hz, 2H), 0.78-0.91 (m, 2H), 1.42-1.66 (m, 4H), 2.78 (dt, J=41.5, 5.1 Hz, 4H), 4.34 (s, 2H), 6.50 (dd, J=7.6, 1.8 Hz, 1H), 6.64 (d, J=1.9 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 9.03 (s, 1H), 11.16 (s, 1H). ESI-MS(+) m/z=337.19 [M+H].sup.+.

Embodiment 13: Preparation of 4-((8-dimethylamino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-13)

[0260] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.64 (pd, J=7.1, 0.9 Hz, 2H), 1.76 (pd, J=7.0, 0.8 Hz, 2H), 2.75 (td, J=7.0, 1.0 Hz, 2H), 2.95 (s, 6H), 3.35 (t, J=7.0 Hz, 2H), 4.43 (t, J=1.0 Hz, 2H), 6.14 (d, J=1.5 Hz, 1H), 6.47 (dd, J=7.5, 1.5 Hz, 1H), 6.99 (dt, J=7.5, 1.1 Hz, 1H), 7.31 (dt, J=7.5, 1.1 Hz, 2H), 7.84-7.90 (m, 2H), 9.26 (s, 1H), 10.96 (s, 1H). ESI-MS(+) m/z=340.20 [M+H].sup.+.

Embodiment 14: Preparation of 4-((8-(piperidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-14)

[0261] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.58-1.81 (m, 10H), 2.77 (td, J=7.0, 1.0 Hz, 2H), 3.34 (t, J=7.0 Hz, 2H), 3.43 (t, J=7.0 Hz, 4H), 4.43 (t, J=1.0 Hz, 2H), 6.14 (d, J=1.5 Hz, 1H), 6.54 (dd, J=7.5, 1.5 Hz, 1H), 7.06 (dt, J=7.5, 1.1 Hz, 1H), 7.34 (dt, J=7.6, 1.0 Hz, 2H), 7.86-7.92 (m, 2H), 9.26 (s, 1H), 10.96 (s, 1H). ESI-MS(+) m/z=380.25 [M+H].sup.+.

Embodiment 15: Preparation of 4-((3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-N-hydroxybenzamide (15)

[0262] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.90 (p, J=5.8 Hz, 2H), 3.19-3.22 (m, 2H), 4.09 (t, J=5.8 Hz, 2H), 4.44 (s, 2H), 6.68-6.73 (m, 1H), 6.77-6.79 (m, 1H), 6.82-6.85 (m, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 9.26 (s, 1H), 10.96 (s, 1H). ESI-MS(+) m/z=299.09 [M+H].sup.+.

Embodiment 16: Preparation of 4-((3,4-dihydrobenzo[b][1,4]thiazepin-5(2H)-yl)methyl)-N-hydroxybenzamide (T-16)

[0263] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.85 (t, J=5.8 Hz, 2H), 2.92 (t, J=5.8 Hz, 2H), 3.28 (t, J=5.4 Hz, 2H), 4.45 (s, 2H), 6.76 (t, J=7.4 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 7.03-7.08 (m, 1H), 7.26 (dd, J=7.7, 1.6 Hz, 1H), 7.43 (d, J=7.9 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 9.11 (s, 1H), 11.10 (s, 1H). ESI-MS(+) m/z=315.10 [M+H].sup.+.

Embodiment 17: Preparation of 4-((5-methyl-2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepin-1-yl)methyl-N-hydroxybenzamide (T-17)

[0264] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.96 (dp, J=28.4, 7.1 Hz, 2H), 2.96 (s, 3H), 3.36 (t, J=7.1 Hz, 2H), 3.44 (t, J=7.1 Hz, 2H), 4.41 (s, 2H), 6.76 (t, J=7.4 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 7.03-7.08 (m, 1H), 7.26 (dd, J=7.7, 1.6 Hz, 1H), 7.43 (d, J=7.9 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 9.15 (s, 1H), 11.16 (s, 1H). ESI-MS(+) m/z=312.20 [M+H].sup.+.

Embodiment 18: Preparation of 4-((5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-18)

[0265] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.91 (p, J=7.1 Hz, 2H), 2.62-2.68 (m, 2H), 3.43 (t, J=7.1 Hz, 2H), 4.47 (t, J=1.0 Hz, 2H), 6.89 (dd, J=7.4, 1.6 Hz, 1H), 7.28-7.35 (m, 3H), 7.39 (td, J=7.5, 1.6 Hz, 1H), 7.59 (dd, J=7.4, 1.6 Hz, 1H), 7.84-7.89 (m, 2H), 9.11 (s, 1H), 11.10 (s, 1H). ESI-MS(+) m/z=311.15 [M+H].sup.+.

Embodiment 19: Preparation of 4-((5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-19)

[0266] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.75-1.81 (m, 1H), 1.81-1.89 (m, 3H), 3.34-3.42 (m, 2H), 3.51 (d, J=7.5 Hz, 1H), 4.43 (t, J=1.0 Hz, 2H), 4.74-4.82 (m, 1H), 6.72 (dd, J=7.5, 1.5 Hz, 1H), 6.83 (td, J=7.5, 1.5 Hz, 1H), 7.08 (td, J=7.5, 1.6 Hz, 1H), 7.32 (dddd, J=13.5, 7.5, 1.8, 0.8 Hz, 3H), 7.84-7.89 (m, 2H), 9.11 (s, 1H), 11.10 (s, 1H). ESI-MS(+) m/z=313.20 [M+H].sup.+.

Embodiment 20: Preparation of 4-((5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-20)

[0267] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.78-2.03 (m, 4H), 3.23 (d, J=1.5 Hz, 3H), 3.36 (t, J=6.9 Hz, 2H), 4.36 (dt, J =12.3, 0.9 Hz, 1H), 4.51 (dt, J=12.5, 1.1 Hz, 1H), 4.61 (ddt, J=7.4, 5.8, 1.1 Hz, 1H), 6.72 (dd, J=7.5, 1.5 Hz, 1H), 6.83 (td, J=7.5, 1.5 Hz, 1H), 7.08 (td, J=7.5, 1.6 Hz, 1H), 7.32 (dddd, J=13.5, 7.5, 1.8, 0.8 Hz, 3H), 7.84-7.89 (m, 2H), 9.11 (s, 1H), 11.10 (s, 1H). ESI-MS(+) m/z=327.30 [M+H].sup.+.

Embodiment 21: Preparation of 4-((5-dimethylamino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-21)

[0268] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.77-1.91 (m, 4H), 2.31 (d, J=1.5 Hz, 6H), 3.28-3.37 (m, 2H), 3.65-3.72 (m, 1H), 4.43 (t, J=1.0 Hz, 2H), 6.67 (dd, J=7.5, 1.5 Hz, 1H), 6.75 (td, J=7.5, 1.5 Hz, 1H), 7.04 (td, J=7.5, 1.6 Hz, 1H), 7.31 (dt, J=7.5, 1.1 Hz, 2H), 7.36-7.42 (m, 1H), 7.84-7.90 (m, 2H), 9.26 (s, 1H), 10.96 (s, 1H). ESI-MS(+) m/z=340.20 [M+H].sup.+.

Embodiment 22: Preparation of 4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)fluoromethyl)-N-hydroxybenzamide (T-22)

[0269] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.53-1.60 (m, 4H), 2.83 (dt, J=19.4, 4.8 Hz, 4H), 5.85 (s, 1H), 6.81 (t, J=7.3 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.06 (td, J=7.7, 1.7 Hz, 1H), 7.10 (d, J=7.1 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 9.04 (s, 1H), 11.15 (s, 1H). ESI-MS(+) m/z=315.20 [M+H].sup.+.

Embodiment 23: Preparation of 4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)difluoromethyl)-N-hydroxybenzamide (T-23)

[0270] The preparation was carried out according to general method II. .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 1.53-1.60 (m, 4H), 2.83 (dt, J=19.4, 4.8 Hz, 4H), 6.81 (t, J=7.3 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.06 (td, J=7.7, 1.7 Hz, 1H), 7.10 (d, J=7.1 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 9.04 (s, 1H), 11.15 (s, 1H). ESI-MS(+) m/z=333.20 [M+H].sup.+.

Embodiment 24: Preparation of 4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-2-fluoro-N-hydroxybenzamide (T-24)

[0271] The preparation was carried out according to general method II. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.65 (pd, J=7.1, 0.9 Hz, 2H), 1.77 (pd, J=6.9, 0.8 Hz, 2H), 2.78 (td, J=7.1, 1.0 Hz, 2H), 3.33 (t, J=7.1 Hz, 2H), 4.42 (dt, J=12.3, 1.0 Hz, 1H), 4.51 (dt, J=12.5, 0.9 Hz, 1H), 6.52 (dd, J=7.4, 1.5 Hz, 1H), 6.64 (td, J=7.5, 1.5 Hz, 1H), 6.84 (dq, J=7.5, 1.1 Hz, 1H), 6.95 (td, J=7.4, 1.6 Hz, 1H), 7.14 (tt, J=8.0, 1.3 Hz, 2H), 7.79 (dd, J=7.4, 5.0 Hz, 1H), 8.82 (d, J=4.9 Hz, 1H), 9.09 (s, 1H), 11.25 (s, 1H). ESI-MS(+) m/z=315.20 [M+H].sup.+.

Embodiment 25: Preparation of 4-((7-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-25)

[0272] The preparation was carried out according to general method III, and the synthetic route was as follows:

##STR00047##

[0273] The product was a white solid, .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.49 (s, 2H), 2.53 (s, 2H), 2.78 (dd, J=6.3, 3.8 Hz, 2H), 2.81 (dd, J=6.2, 3.7 Hz, 2H), 3.62 (s, 2H), 3.69 (s, 3H), 6.63 (dd, J=8.2, 2.7 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.65-7.81 (m, 2H), 9.09 (s, 1H), 11.25 (s, 1H). ESI-MS(+) m/z=327.15 [M+H].sup.+.

Embodiment 26: Preparation of 4-((6-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-26)

[0274] The preparation was carried out according to general method III. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.48 (m, 4H), 2.83 (m, 2H), 2.93 (m, 2H), 3.60 (s, 2H), 6.65-6.74 (m, 1H), 6.76-6.83 (m, 1H), 7.04 (m, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.68-7.80 (m, 2H), 9.11 (s, 1H), 11.25 (s, 1H). ESI-MS(+) m/z=327.15 [M+H].sup.+.

Embodiment 27: Preparation of 4-((6-bromo-9-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-27)

[0275] The preparation was carried out according to general method III. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.46-2.50 (m, 2H), 2.97-3.00 (m, 2H), 3.08-3.11 (m, 2H), 3.59 (s, 2H), 3.74 (s, 3H), 6.79 (d, J=8.9 Hz, 1H), 7.36-7.39 (m, 3H), 7.73 (d, J=8.0 Hz, 2H), 9.09 (s, 1H), 11.20 (s, 1H). ESI-MS(+) m/z=405.13 [M+H].sup.+.

Embodiment 28: Preparation of 4-((6-cyclopropyl-9-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-28)

[0276] The preparation was carried out according to general method III. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.37-0.51 (m, 2H), 0.73-0.89 (m, 2H), 1.79 (tt, J=8.4, 5.4 Hz, 1H), 2.47 (q, J =4.7 Hz, 4H), 2.94 (dd, J=7.0, 3.1 Hz, 2H), 3.11 (dd, J=6.8, 3.1 Hz, 2H), 3.58 (s, 2H), 3.69 (s, 3H), 6.69 (d, J=8.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.63-7.82 (m, 2H), 9.08 (s, 1H), 11.20 (s, 1H). ESI-MS(+) m/z=366.88 [M+H].sup.+.

[0277] Embodiment 29 Inhibitory activity of compounds against HDAC

[0278] The in vitro inhibitory activity of histone deacetylase of the compound was determined according to the instructions of HDAC1 and HDAC6 inhibitor screening kit (Biovision Company). HDAC6 inhibitor Rocilinostat (ACY 1215)

##STR00048##

in the clinical stage and compound SW-100 were used as positive controls.

[0279] The experimental results are shown in the table:

TABLE-US-00001 IC.sub.50 (nM) Compd. HDAC6 HDAC1 Rocilinostat (ACY-1215) 6.8 19 SW-100 2.4 69 T-1 37 >500 T-2 14 406 T-3 43 400 T-4 8.2 414 T-5 5.6 257 T-6 8.2 294 T-7 6.5 277 T-8 9.2 287 T-9 8.6 269 T-10 129 >500 T-11 14.3 >500 T-12 45 >500 T-13 85 >500 T-14 142 >500 T-15 6.2 367 T-16 1.2 254 T-17 7.4 >500 T-18 7.2 421 T-19 6.4 442 T-24 12 >500 T-25 17 >500 T-26 97 >500 T-27 29 431 T-28 22 >500

[0280] It can be seen from the above table that the compounds of the present disclosure show better inhibitory activity against HDAC6 (most IC.sub.50<100 nM), and some compounds have comparable or better inhibitory activity to the positive controls Rocilinostat (ACY-1215) and SW-100. In addition, the inhibitory activity IC.sub.50 against HDAC1 are all >250 nM; compared with HDAC1, the compounds of the present disclosure can selectively inhibit HDAC6, most of the selectivity are >30 times, or even 50 times, and the selectivity is better than Rocilinostat and SW-100.

[0281] Embodiment 30 In Vitro Anti-Proliferative Activity Test on Tumor Cells and Human Normal Cells

[0282] The anti-proliferative activities of some compounds of the present disclosure under the condition of single concentration (10 μM) on glioma cell line U-87MG, myeloma cell line RPMI 8226, human liver cancer cell line HepG2, human lung cancer cell line A549 and MRC-5 human normal embryo lung fibroblast were measured, and Rocilinostat (ACY-1215) was selected as a control. The specific results are shown in the table (unit: Inh % in 10 μM).

[0283] Test method: The tumor cells in the logarithmic growth phase with good growth status were inoculated into 96-well plates at 4×10.sup.3 per well, and 8 duplicate wells were set up in each group. The cells were cultured in a cell incubator, after the cells adhered to the wall, the corresponding plasmids were transfected. After 48 hours of continuous culture, the drug-containing culture medium was discarded, 10 tt L of freshly prepared toxicity detection solution CCK8 was added to each well, and the mixture was placed and cultured in an incubator for 4 hours, and the OD value was measured at a wavelength of 450 nm with a microplate reader. The experiment was repeated 3 times, and the average of the experimental results was taken as the final experimental result, and the inhibition rate was calculated.

TABLE-US-00002 Hep G2 A549 MRC-5 U-87MG RPMI 8226 (Liver (Lung (Normal Compound (Glioma) (Myeloma) cancer) cancer) cell line) Ricolinostat 42.1 99.3 93.4 51.6 46.7 T-2 B A A C E T-5 B A A C E T-15 B A A D E T-16 A A A C E T-19 A A A D E T-21 B A A C E T-28 B A A D E A 100≥ to >90; B: 80< to ≤90; C: 70< to ≤80; D: 50< to ≤70 E: <50

[0284] It can be seen from the above table that, compared with the positive control Rocilinostat, the compound of the present disclosure has good in vitro anti-tumor cell proliferation activity for various tumor cells, and has higher inhibitory activity for glioma cell line U-87MG, myeloma cell line RPMI 8226 and human liver cancer cell line HepG2, the anti-tumor cell proliferation activity of some compounds is better than that of positive control drugs.

[0285] At the same time, compared with Rocilinostat, the compound of the present disclosure has weaker inhibitory activity on MRC-5 human normal embryo lung fibroblasts and lower toxic and side effects, which reveals that the compound of the present disclosure has better selectivity in inhibiting the proliferation of tumor cells and normal cells, and indicates that it may have lower toxic and side effects when used as an anti-tumor drug.

[0286] Embodiment 31 Protective Effect of Compounds on HCA-Induced Neuronal Cell Damage

[0287] HCA (5 mmol/L) was used to induce the injury of mixed cells and primary neurons in rat cortex, and the effects of different concentrations (test concentration: 0.1 μM, 1.0 μM and 10.0 μM) of the compound on the injury were observed, and the activity, quantity, morphology and necrosis of neurons and glial cells were detected, and the effect of compounds on normal neurons was observed; Tubastatin A, a similar HDAC6 inhibitor compound with neuroprotective effect, was used as a control. The results show that the compounds of the present disclosure have a certain protective effect against HCA-induced neuronal excitotoxicity. Among them, the in vitro activity of compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 is stronger than that of the HDAC6 inhibitor compound Tubastatin A with neuroprotective effect at the same dose, and shows a certain dose-effect relationship, suggesting that the compound of the present disclosure has neuroprotective effect and can be used for the treatment of neurodegenerative-related diseases. The results are as shown in FIG. 1.

[0288] Embodiment 32 Experiment of the Effect of Compounds on hERG Potassium Channel

[0289] Whole-cell patch clamp technique was used to record the changes of hERG current (IKr) after different concentrations of compounds acted on HEK293 cells (hERG-HEK293 steady-state cells) expressing hERG potassium channels to study the half inhibitory concentration (IC.sub.50) of the above compounds on IKr.

[0290] The potential cardiac toxicity and side effects in vitro of some compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 of the present disclosure were preliminarily investigated. The experimental results are as follows:

TABLE-US-00003 Compd hERG IC.sub.50 (μM) T-2 >10 T-5 >10 T-15 >10 T-16 >10 T-19 >10 T-21 >10 T-28 >10

[0291] The results of the hERG experiment shows that the inhibitory activities of the test compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 on hERG potassium channels are all greater than 10 μM, suggesting that the potential cardiotoxicity of the compounds of the present disclosure is low.

[0292] Embodiment 33 Toxicity Test of Maximum Tolerance Dose of Compound by Intragastric Administration

[0293] 40 ICR mice, half male and half male, weighing 18 to 20 g, were divided into 4 groups with 10 animals in each group. After 6 hours of fasting, the test samples in each group were taken with sterilized plastic syringe and orally gavaged at a volume of 0.3 mL/10 g. The general physical signs of animals and the death of animals were recorded at 1, 2 and 4 hours after administration. The animals were observed for 14 consecutive days after administration, and the body weights and physical signs and death were observed and recorded daily. The dead animals were dissected to observe whether there were any visible pathological changes in the organs of the animals, and pathological examinations were carried out on suspicious tissues and organs.

[0294] The experimental results show that the maximum tolerated doses of the compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 of the present disclosure to mice by intragastric administration are greater than 1000 mg/kg, and the tolerance of animals is better.

[0295] Embodiment 34 PK Test of Compounds

[0296] Some of compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 of the present disclosure were administered to male SD rats by single intraperitoneal administration, and the drug concentrations of the compounds in rat brain and plasma were determined by LC-MS/MS method, and the brain/plasma drug concentration ratio of the test compound t=1.0 h was calculated to evaluate the brain permeability of the active compound. With compound SW-100 as the control, the test results are as shown in the table:

TABLE-US-00004 Compound Blood-brain barrier permeability (B/P) II-ING-39 0.77 SW-100 1.82 T-2 >2.0 T-5 >2.0 T-15 >2.0 T-16 >2.0 T-19 >2.0 T-21 >2.0 T-28 >2.0

[0297] The test results show that compared with the positive controls II-ING-39 and SW-100, the compounds of the present disclosure show better blood-brain permeability.

[0298] Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present disclosure. Accordingly, the scope of protection of the present disclosure is defined by the claims.