Benzonitric heterocyclic compounds and their preparation and use

Abstract

The present invention discloses benzonitric heterocyclic compounds, their preparation methods, and uses. The present invention provides 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 high efficacy, low toxicity, and desirable pharmacokinetic properties. [Formula 1] JPEG2023522058000093.jpg30169

Description

Detailed Description of the Invention

[0001] This application claims priority from Chinese patent application No. 2020103048830, filed on April 17, 2020. This application cites the above Chinese patent application in full.

[0002] [Technical field] The present invention relates to benzonitric heterocyclic compounds and methods for their preparation and use.

[0003] [Background technology] Histone deacetylases (HDACs) can catalyze the deacetylation process of histones and non-histones, and together with histone acetyltransferases (HATs), regulate the acetylation level in cells and thus gene expression. Currently, there are 18 subtypes of mammalian HDACs known, which can be classified into four types: class I (HDAC1, HDAC2, HDAC3, HDAC8); class II, which is further divided into two subfamilies, IIa (HDAC4, HDAC5, HDAC7, HDAC9) and IIb (HDAC6, HDAC10); class III (Sirt1-Sirt7); and class IV (HDAC11).

[0004] There are currently five histone deacetylase inhibitors (HDACi) on the market, namely vorinostat, belinostat, panobinostat, romidepsin and chidamide, the first three of which are broad-spectrum inhibitors, and the latter two act selectively on subtype I. Vorinostat and romidepsin are used to treat cutaneous T-cell lymphoma (CTCL), belinostat and tucidinostat are used to treat relapsed and refractory peripheral T-cell lymphoma (PTCL), and panobinostat and the combination of bortezomib and dexamethasone are used to treat multiple myeloma (MM).

[0005] Although the above HDAC inhibitors have already achieved good clinical results, broad-spectrum HDAC inhibitors generally have the following drawbacks:

[0006] (1) They have severe toxic side effects, such as nausea, vomiting, and bone marrow suppression. (2) It is genotoxic; (3) They have poor pharmacokinetic properties, low bioavailability, short half-lives, etc.

[0007] The above drawbacks not only cause inconvenience to tumor patients, but also hinder the use of broad-spectrum HDAC inhibitors in fields other than tumor therapy.

[0008] At present, HDAC subtype-selective inhibitors have become a hotspot of research in this field, among which HDAC6 subtype inhibitors have attracted great attention. HDAC6 is widely involved in disease fields including tumors, neurodegenerative diseases, inflammation, autoimmune responses, tumors and bacterial infections.

[0009] Pharmacological studies have suggested that HDAC6 selective inhibitors can effectively inhibit the proliferation and induce apoptosis of glioblastoma cells, and can increase the sensitivity of glioblastoma cells to temozolomide by inhibiting HDAC6, suggesting that the two have a synergistic effect. Specifically, HDAC6 regulates the activity of its acetylated substrates such as heat shock proteins, which can participate in the repair of misfolded and unfolded proteins as molecular chaperones, and at the same time, the ZnF-UBP structural domain of HDAC6 protein can bind with high affinity to ubiquitinated misfolded proteins and promote their degradation. p97 / VCP, a molecular chaperone of HDAC6, can separate HDAC6-ubiquitin complexes, and the balance between the two may affect the fate of misfolded and unfolded proteins during endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). Thus, combined treatment with HDAC6 inhibitor Tubastatin A and temozolomide (TMZ) reverses the ratio of HDAC6 and p97 / VCP, attenuates heat shock protein activation, and induces pro-apoptotic signals of unfolded protein response and endoplasmic reticulum stress, ultimately overcoming endoplasmic reticulum stress resistance, reducing the viability and inducing apoptosis in TMZ-resistant glioma cells.

[0010] Alzheimer's disease (AD) also requires the development of effective therapeutic drugs in clinical practice, as does glioma. Studies have revealed that the expression levels of HDAC6 in the hippocampus (91% increase) and cerebral cortex (52% increase) of AD brains are significantly increased, and tubulin acetylation is reduced in neurons containing NFTs. HDAC6 is involved in the process of tau hyperphosphorylation. HDAC6 interacts with tau in human brain tissue, and these interactions are mediated by the microtubule-binding domain of tau and the SE14 domain on HDAC6. Inhibition of HDAC6 does not affect the interaction with tau, but attenuates T231 phosphorylation of tau, and T231 is an important regulatory site for tau function. HDAC6 inhibition improves cognition in AD mice. The above studies showed that centrally targeted HDAC6 inhibitors are expected to be developed as new highly efficient and low-toxicity AD therapeutic drugs.

[0011] A literature study (J. Am. Chem. Soc. 2010, 132, 31, 10842-10846) reported that Tubastatin A, an arylhydroxamic acid HDAC6 inhibitor containing a carbazole structure, has central neuroprotective effects, poor physicochemical properties, and low potential for use as a drug.

[0012] The literature (ACS Chem. Neurosci. 2019, 10, 3, 1679-1695) describes HDAC6 inhibitors (IC 50 = 2.3 nM) has been reported to have a certain cognitive improving effect in mice with cognitive impairment.

[0013] [ka]

[0014] Patent WO2018200608A discloses a class of indoline compounds, in which compound II-ING-39 is IC 50 = 21.5 nM and inhibited HDAC6, and SW-100 (IC 50= 2.3 nM), and the substituents on the benzene ring of the indoline have a significant effect on HDAC6 inhibitory activity, for example, here, the nitro-substituted compound II-ING-57 has significantly better HDAC6 inhibitory activity (IC 50 = 1.4 nM).

[0015] [ka]

[0016] The above publications and patents indicate that differences in the structure of the heterocyclic ring containing a nitrogen atom in the formula and differences in the substituents on the benzene ring affect the inhibitory activity of the compound against HDAC6, but the extent of the effect and the pharmacological effect cannot be predicted and need to be verified by experiments.

[0017] Summary of the Invention The technical problem to be solved by the present invention is to provide a benzonitric heterocyclic compound, its preparation method and use, which overcomes the shortcomings of the single HDAC6 inhibitor in the prior art, particularly its low selectivity.The benzonitric heterocyclic compound provided by the present invention can be used as a histone deacetylase inhibitor, has selective inhibitory effect on HDAC6, and has characteristics such as high efficiency, low toxicity, and ideal pharmacokinetic properties, and is expected to meet clinical needs as an anti-tumor or neurodegenerative disease therapeutic agent.

[0018] The present invention solves the above technical problems through the following technical solutions.

[0019] The present invention provides a compound represented by Formula I, or a pharma- ceutically acceptable salt thereof.

[0020] [ka]

[0021] however, Ring A(

[0022] [ka]

[0023] a side is the benzene ring

[0024] [ka]

[0025] and a fused ring are connected) is a 7-membered heterocycloalkyl, and in the 7-membered heterocycloalkyl, one of the represented N is

[0026] [ka]

[0027] In addition to being linked with, 0 to 2 optional N, O, S, S(=O) and S(=O) 2 and a heteroatom selected from n is 0, 1, 2, 3 or 4; R 2 are independently hydrogen, hydroxy, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkyl-O-, (R a R b )N- or O=, (-CH 2 - is replaced) R 1a , R 1b , R 1c and R 1d are independently hydrogen, halogen, hydroxy, cyano or R 1 -L-, -L- is independently a bond, -(C 1 ~C 4 Alkyl)-, -O-, -C(=O)- or -S(=O) 2 - and R 1is independently C 1 ~C 6 Alkyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, (R c R d ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, or 1 ~C 6 Alkyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, (R c R d ) N-, 3- to 7-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently selected from the group consisting of one or more substituents R e and wherein said 3- to 7-membered heterocycloalkyl and one or more substituents R e In the 3- to 7-membered heterocycloalkyl substituted by, the heteroatom groups are N, O, S, S(=O) and S(=O) 2 The number of heteroatoms is 1 to 3, and the 5- to 10-membered heteroaryl and one or more substituents R e In the 5-10 membered heteroaryl substituted by R, the heteroatom group is selected from one or more of N, O and S, the number of heteroatoms is 1 to 4, and R e are independently hydroxyl, halogen, cyano or C 1 ~C 4 alkyl, and when the substituents are plural, they may be the same or different; R a , R b , R c and R d are independently hydrogen or C 1 ~C 4 is alkyl, R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently hydrogen, halogen, C1 ~C 4 C substituted with alkyl or one or more halogens 1 ~C 4 alkyl, and when the substituents are plural, they may be the same or different; If the carbon atom marked with an "*" is a chiral carbon atom, it may be in the S configuration, the R configuration or a mixture thereof.

[0028] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): In the ring A,

[0029] [ka]

[0030] is located at the ortho, meta or para position of the benzene ring connected to the fused ring, e.g., the ortho or para position, and e.g., the ortho position; In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): In ring A, one N shown is

[0031] [ka]

[0032] and optionally containing 0 to 1 heteroatom selected from N, O, and S, other than being linked to for example,

[0033] [ka]

[0034] ,

[0035] [ka]

[0036] ,

[0037] [ka]

[0038] or

[0039] [ka]

[0040] and the a side is linked to the benzene ring and the fused ring.

[0041] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 2 C 1 ~C 4 Alkyl or C 1 ~C 4 When it is alkyl-O-, 1 ~C 4 Alkyl and C 1 ~C 4 Alkyl-O-C 1 ~C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0042] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1a , R 1b , R 1c and R 1d When is independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example, fluorine, chlorine or bromine, also for example, fluorine.

[0043] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): -L- is independent -(C 1 ~C 4 alkyl)-, the -(C 1 ~C 4 Alkyl)- is methylene, ethylene, propylene, butylene, isopropylidene, isobutylene, sec-butylene or tert-butylene, for example, methylene.

[0044] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 C 1 ~C 6 alkyl, one or more substituents R e C replaced by 1 ~C 6 When it is alkyl, the C 1 ~C 6 Alkyl and one or more substituents R e C replaced by 1 ~C 6 Alkyl C 1 ~C 6 Alkyl is independently C 1 ~C4 Alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example methyl.

[0045] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 But independently, C 3 ~C 7 Cycloalkyl, one or more substituents R e C replaced by 3 ~C 7 When it is cycloalkyl, the C 3 ~C 7 Cycloalkyl and one or more substituents R e C replaced by 3 ~C 7 Cycloalkyl C 3 ~C 7 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, for example, cyclopropyl.

[0046] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 C 6 ~C 10 Aryl, one or more substituents R e C replaced by 6 ~C 10 When it is aryl, 6 ~C 10 Aryl and one or more substituents R e C replaced by 6 ~C 10 Aryl C 6 ~C 10Aryl is independently phenyl or naphthyl, for example phenyl.

[0047] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 are independently 3- to 7-membered heterocycloalkyl, one or more substituents R e When the 3- to 7-membered heterocycloalkyl is substituted by, the 3- to 7-membered heterocycloalkyl and one or more substituents R e The 3-7 membered heterocycloalkyl substituted by is independently a 5-6 membered heterocycloalkyl, where the heteroatom group is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2, such as piperidinyl (also for example,

[0048] [ka]

[0049] ).

[0050] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 are independently 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted with one or more substituents Re, e The 5-10 membered heteroaryl of the 5-10 membered heteroaryl substituted by is independently a 5-6 membered heteroaryl, where the heteroatom group is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2, such as pyridyl (also for example,

[0051] [ka]

[0052] ).

[0053] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R e When is independently a halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0054] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R e C 1 ~C 4 When it is alkyl, the C 1 ~C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0055] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R a , R b , R c and R d C 1 ~C 4 When it is alkyl, the C 1 ~C 4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0056] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 3a , R 3b , R 3c , R 3d , R 4 and R 5 C 1 ~C 4 C substituted with alkyl or one or more halogens 1 ~C 4 When it is alkyl, the C 1 ~C 4 C substituted with alkyl and one or more halogens 1 ~C 4 Alkyl C 1 ~C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0057] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently halogen or C substituted with one or more halogens 1 ~C 4 When it is alkyl, it is C substituted with the halogen and one or more halogens. 1 ~C 4Alkyl halogen is fluorine, chlorine, bromine or iodine, also for example fluorine or chlorine.

[0058] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 C 1 ~C 6 Alkyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, (R c R d ) N-, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and 1 ~C 6 Alkyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, (R c R d )N-, 3- to 7-membered heterocycloalkyl and 5- to 10-membered heteroaryl are substituents R e is replaced by R e are independently halogen, R e The number of is 1, 2 or 3, For example, trifluoromethyl.

[0059] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 3a , R 3b , R 3c , R 3d , R 4 and R 5 C independently substituted with one or more halogens 1 ~C 4When it is alkyl, the number of halogen substitutions is 1 to 3, for example, trifluoromethyl.

[0060] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): Ring A is

[0061] [ka]

[0062] and Y is a bond, methylene or ethylene (

[0063] [ka]

[0064] ) (i.e. ring A is

[0065] [ka]

[0066] ,

[0067] [ka]

[0068] or

[0069] [ka]

[0070] ) where, for example, Y is a bond or

[0071] [ka]

[0072] and X is C, N, O or S, and the a side is connected to the benzene ring and the condensed ring.

[0073] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): n is 0 or 1.

[0074] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 2 are independently hydrogen, hydroxyl, C 1 ~C 4 Alkyl, (R a R b ) N- or O=; For example, hydrogen, hydroxyl, C 1 ~C 4 alkyl or O=; In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): -L- is independently a bond or -O-.

[0075] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 is independently C 1 ~C 6 Alkyl, C 3 ~C 7 Cycloalkyl, C6 ~C 10 Aryl, (R c R d ) N-, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, for example, C 1 ~C 6 It is an alkyl.

[0076] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1 -L- is C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, (R c R d )N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl or C 1 ~C 6 Alkyl-O-, for example, C 1 ~C 6 It is alkyl-O-.

[0077] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1a , R 1b , R 1c and R 1d are independently hydrogen, halogen or R 1 -L-, For example, R 1a , R 1b , R 1c and R 1d One or two of are independently halogen or R 1 -L-, the remainder being hydrogen; For example, R 1a , R 1b , R 1c and R 1d One or two of the following may be independently selected: C1 ~C 6 alkyl-O-, the remainder being hydrogen, or R 1c is a halogen and the remainder are hydrogen, said halogen being preferably fluorine.

[0078] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 4 and R 5 is independently hydrogen or halogen, for example, hydrogen.

[0079] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R a , R b , R c and R d is independently C 1 ~C 4 It is an alkyl.

[0080] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 3a , R 3b , R 3c and R 3d is independently hydrogen or halogen, e.g., hydrogen; For example, R 3a and R 3d are independently hydrogen or halogen; R 3b and R 3c are independently hydrogen; For example, R 3a is hydrogen or halogen, R 3b , R 3c and R3d are independently hydrogen.

[0081] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): The benzazepine compound of formula I is a benzonitric heterocyclic compound of formula I-1 or I-2,

[0082] [ka]

[0083] However, X 1 and X 2 is independently

[0084] [ka]

[0085] (R 2 If =O,

[0086] [ka]

[0087] ),

[0088] [ka]

[0089] ,

[0090] [ka]

[0091] or

[0092] [ka]

[0093] and Preferred is a benzonitric heterocyclic compound represented by formula I-1.

[0094] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): Ring A is a 7-membered heterocycloalkyl; In the ring A,

[0095] [ka]

[0096] and the N linked to is located at the ortho or para position of the benzene ring, e.g., at the ortho position; n is 0 or 1, R 2 are independently hydrogen, hydroxyl, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkyl-O-, (R a R b ) N- or O=, e.g., hydrogen, hydroxyl, C 1 ~C 4 Alkyl, (R a R b ) N- or O=, and also includes, for example, hydrogen, hydroxyl, C 1 ~C 4 alkyl or O=; R 1a , R 1b , R 1c and R 1d are independently hydrogen, halogen or R 1 -L-, -L- is independently a bond or -O-; R 1 is independently C 1 ~C 6 Alkyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, (R c R d ) N-, 3- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; R 4 and R 5 are independently hydrogen or halogen; R 3a , R 3b , R 3c and R 3d are independently hydrogen or halogen; Preferably, R 1 -L- is C 1 ~C 6 Alkyl-O-, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, C 6 ~C 10 Aryl-(C 1 ~C 4 (RcRd)N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl.

[0097] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): Ring A is

[0098] [ka]

[0099] and Y is a bond or

[0100] [ka]

[0101] and X is C, N, O or S; n is 0 or 1, R 2 are independently hydrogen, hydroxyl, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkyl-O-, (R a R b ) N- or O=, e.g., hydrogen, hydroxyl, C 1 ~C 4 Alkyl, (R a R b ) N- or O=, and also includes, for example, hydrogen, hydroxyl, C 1 ~C 4 alkyl or O=; R 1a , R 1b , R 1c and R 1d are independently hydrogen, halogen, C 1 ~C 6 Alkyl-O-, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, C 6 ~C 10 Aryl-(C 1 ~C 4 alkyl)-, (R c R d ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, for example, hydrogen, fluorine or C 1 ~C 6 alkyl-O-; R 4 and R 5 are independently hydrogen; R 3a , R 3b , R 3c and R 3d are independently hydrogen or halogen, e.g., R 3a and R 3d are independently hydrogen or halogen; R 3b and R3c are independently hydrogen, and for example, R 3a is hydrogen or halogen, R 3b , R 3c and R 3d are independently hydrogen.

[0102] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): Ring A is

[0103] [ka]

[0104] and X 1 is independently

[0105] [ka]

[0106] ,

[0107] [ka]

[0108] ,

[0109] [ka]

[0110] or

[0111] [ka]

[0112] and n is 0 or 1, R 2 are independently hydrogen, hydroxyl, C 1 ~C 4 alkyl or O=; R 1a , R 1b , R 1c and R 1d are independently hydrogen, fluorine or C 1 ~C 6 alkyl-O-, for example, R 1a , R 1b , R 1c and R 1d One or two of are independently fluorine or C 1 ~C 6 alkyl-O-, the remainder being hydrogen; For example, R 1a , R 1b , R 1c and R 1d One or two of the following may be independently selected: C 1 ~C 6 alkyl-O-, the remainder being hydrogen, or R 1c is fluorine and the remainder is hydrogen, R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently hydrogen.

[0113] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): Ring A is

[0114] [ka]

[0115] ,

[0116] [ka]

[0117] ,

[0118] [ka]

[0119] ,

[0120] [ka]

[0121] or

[0122] [ka]

[0123] and the a side is a connection between the benzene ring and the condensed ring.

[0124] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 1a , R 1b , R 1c and R 1d are independently hydrogen, fluorine, chlorine, bromine, methoxy, cyclopropyl, phenyl,

[0125] [ka]

[0126] ,

[0127] [ka]

[0128] or

[0129] [ka]

[0130] and is, for example, hydrogen, fluorine, or methoxy.

[0131] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 2 are independently hydrogen, hydroxyl, methyl, methoxy,

[0132] [ka]

[0133] Or O=.

[0134] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 4 and R 5 is independently hydrogen or fluorine, for example, hydrogen.

[0135] In some preferred embodiments of the present invention, certain groups of the benzonitric heterocyclic compounds of formula I are defined as follows (groups not mentioned are as described in any one of the schemes of the present application): R 3a , R 3b , R 3c and R 3d are independently hydrogen or fluorine; For example, R 3a is hydrogen or fluorine, R 3b, R 3c and R 3d are independently hydrogen.

[0136] In some embodiments of the present invention, the benzonitric heterocyclic compound of formula I is selected from the following structures:

[0137] [ka]

[0138] In the present invention, the benzonitric heterocyclic compound represented by formula I or its pharma- ceutically acceptable salt has one or more chiral carbon atoms, and therefore can be separated to obtain optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization of salts, or chiral preparative column separation.

[0139] In the present invention, the benzonitric heterocyclic compound represented by formula I or its pharma- ceutically acceptable salt can exist in crystalline or amorphous form. The term "crystalline form" refers to the fact that the ions or molecules therein are arranged in a strictly periodic manner in three-dimensional space in a definite manner and have a regularity that repeats periodically at regular intervals, and there may be multiple crystalline forms, i.e., crystal polymorphism, due to differences in the periodic arrangement. The term "amorphous" refers to the fact that the ions or molecules are in a disordered distribution state, i.e., there is no periodic arrangement regularity between the ions or molecules.

[0140] In the present invention, the benzonitric heterocyclic compound represented by formula I or a pharma- ceutically acceptable salt thereof, when stereoisomers exist, may exist in the form of a single stereoisomer or a mixture thereof (e.g., racemate). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and concentrated by asymmetric synthesis or chiral separation methods (including, but not limited to, thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution by combining with other chiral compounds (e.g., chemical bonding) and salt formation (e.g., physical bonding). The term "single stereoisomer" refers to the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound being 95% or more.

[0141] In the present invention, when the benzonitric heterocyclic compound represented by the formula I or a pharma- ceutically acceptable salt thereof is a tautomer, it may exist in the form of a single tautomer or a mixture thereof, and preferably exists mainly in the form of a relatively stable tautomer.

[0142] The present invention also includes isotopically labeled benzonitric heterocyclic compounds of formula I according to the present invention or pharma- ceutically acceptable salts thereof, in which one or more atoms are replaced by one or more atoms of a particular atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur and chlorine (e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 18 F, 35 S and 36 Isotopically labeled compounds of the present invention can be used to measure the tissue distribution of the compounds, their prodrugs and metabolites, and the isotope used in such measurements is preferably3 H and 14 C. Additionally, in some cases, substitution with heavier isotopes, such as deuterium (2H or D), can provide therapeutic advantages such as increased metabolic stability, increased half-life in the body, or reduced dosage requirements.

[0143] Isotopically labeled compounds of the invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0144] In the present invention, the benzonitric heterocyclic compound represented by formula I or its pharma- ceutically acceptable salt can be synthesized by a method similar to a conventional method in the chemical field, and the steps and conditions can refer to the similar reaction steps and conditions in the art, and are particularly synthesized according to the description in the specification. Starting materials are usually commercially available, and can be easily prepared using methods known to those skilled in the art, for example, from Aldrich or by methods known from SciFinder, Reaxys online database.

[0145] In the present invention, the benzonitric heterocyclic compound represented by formula I or a pharma- ceutically acceptable salt thereof can be obtained by peripherally modifying the already prepared benzonitric heterocyclic compound represented by formula I or a pharma- ceutically acceptable salt thereof using a conventional method in the art.

[0146] The raw materials or reagents required for preparing the benzonitric heterocyclic compounds of formula I or their pharma- ceutically acceptable salts are commercially available or can be prepared by conventional synthetic methods in the art. The compounds of the present invention, either as free bases or as acid addition salts thereof, can be prepared by the methods described in the experimental section below. The term pharma- ceutically acceptable salts refers to pharma- ceutically acceptable salts as defined herein, which have all the effects of the parent compound. The pharma- ceutically acceptable salts can be prepared by adding the corresponding acid to an appropriate organic solvent of an organic base and treating according to conventional methods.

[0147] Illustrative examples of salt formation include, in the case of base addition salts, the preparation of alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., aluminum, magnesium, calcium, zinc or bismuth) salts by treating a compound of the invention having a suitable acidic proton with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., ethoxide or methoxide) or a suitable basic organic amine (e.g., diethanolamine, choline or meglumine) in an aqueous medium.

[0148] Alternatively, in the case of acid addition salts, they are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, mucofuranic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid, or trimethylacetic acid.

[0149] "Compounds of the invention" or "compounds according to the invention" include any benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof. The compounds of the invention may also exist in the form of hydrates or solvates.

[0150] The present invention also provides a method for preparing the benzonitric heterocyclic compound represented by formula I, which comprises the steps of: reacting a compound represented by formula II with hydroxylamine in a solvent to obtain the benzonitric heterocyclic compound represented by formula I by hydroxylation as shown below;

[0151] [ka]

[0152] where *, ring A, n, R 2 , R 1a , R 1b , R 1c , R 1d , R 3a , R 3b , R 3c , R 3d , R 4 and R 5 The definitions of are as described above, and R 6 is C 1 ~C 6 Alkyl (e.g., C 1 ~C 4 It is alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl).

[0153] In the preparation method of the benzonitric heterocyclic compound represented by formula I, the conditions and operations of the hydroxylation reaction can be the usual conditions and operations of the reaction in the art, and in the present invention, the conditions and operations are preferably as follows:

[0154] However, the solvent may also be an alcoholic solvent, for example methanol and / or ethanol.

[0155] The amount of the solvent may be within a range that does not affect the reaction, and for example, the mass / volume ratio of the compound represented by formula II to the solvent is 0.1 g / L to 20 g / L (e.g., 5 g / L to 15 g / L).

[0156] The molar ratio of the compound represented by formula II to the hydroxylamine may be 1:5 to 1:50 (eg, 1:40 to 1:48).

[0157] The temperature of the hydroxylation reaction may be from room temperature to 80° C. (eg, 10 to 30° C.).

[0158] The process of the hydroxylation reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC or NMR), and the reaction is generally terminated when the compound represented by formula II disappears or does not react.

[0159] The preparation method may also include a post-treatment, which includes the steps of adjusting the pH to neutral after the hydroxylation reaction is completed, concentrating, adding an organic solvent, washing with water (to remove hydroxylamine), drying the organic phase, concentrating, and isolating and purifying, and when adjusting the pH to neutral, a common acid such as 1N hydrochloric acid may be used, and the organic solvent may be an ester solvent, for example, ethyl acetate. The separation and purification is preferably column chromatography separation or crystallization, and the solvent for the crystallization may be a mixed solvent of an alcohol solvent (for example, ethanol) and water.

[0160] The method further includes the steps of: coupling a compound represented by formula III with a compound represented by formula IV in a solvent in the presence of a base to obtain a compound represented by formula II;

[0161] [ka]

[0162] However, R 6 , *, ring A, n, R 2 , R 1a , R 1b , R 1c , R 1d , R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are all as defined above, and X is a halogen (e.g., bromine or chlorine).

[0163] In the preparation method of the benzonitric heterocyclic compound represented by formula I, the conditions and operations of the coupling reaction may be the usual conditions and operations of the reaction in the art, and in the present invention, they are preferably as follows: However, the solvent may also be an amide solvent, for example, N,N-dimethylformamide (DMF).

[0164] The amount of the solvent may be within a range that does not affect the reaction, and for example, the mass / volume ratio of the compound represented by formula II to the solvent is 1 g / L to 50 g / L (e.g., 35 g / L to 45 g / L).

[0165] The molar ratio of the compound represented by formula III to the compound represented by formula IV may be 0.8:1 to 1:0.8 (eg, 1:1).

[0166] The base may be an inorganic base and / or an organic base, and the inorganic base may be an alkali metal carbonate, such as one or more of sodium carbonate, potassium carbonate, and lithium carbonate.

[0167] The molar ratio of the base to the compound represented by formula IV may be 0.8:1 to 3:1 (for example, 1:1 to 2:1, and also, for example, 1.5:1).

[0168] The temperature of the coupling reaction may be from room temperature to 150° C. (for example, from 80 to 120° C., or for example, 100° C.).

[0169] The process of the coupling reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC or NMR), and generally, the end point of the reaction is the disappearance or non-reaction of the compound represented by formula III or the compound represented by formula IV.

[0170] The preparation method may also include a post-treatment, which may include adding water after the coupling reaction is completed, extracting with an organic solvent, drying the organic phase, concentrating, and isolating and purifying, and the organic solvent may be an ester solvent such as ethyl acetate. The separation and purification is preferably column chromatographic separation or crystallization, and the packing material for the column chromatography may be a silica gel packing material.

[0171] The present invention also provides a compound of formula II,

[0172] [ka]

[0173] However, R 6 , *, ring A, n, R 2 , R 1a , R 1b , R 1c , R 1d , R 3a , R 3b , R 3c , R 3d , R 4 and R 5 The definitions of are as described above.

[0174] In some embodiments, the compound of formula II may have any of the following structures:

[0175] [ka]

[0176] The present invention provides a pharmaceutical composition comprising the benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, wherein the amount of the benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition may be a therapeutically effective amount.

[0177] The pharma- ceutically acceptable carrier (pharmaceutical excipient) may be an excipient that is widely used in the field of pharmaceutical manufacturing. Excipients are primarily used to provide a safe, stable and functional pharmaceutical composition, and may also provide a way to allow the active ingredient to dissolve at a desired rate after administration to a subject, or to facilitate effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient may be an inert filler, or may provide a specific function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient of the composition. The pharmaceutical excipient may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners.

[0178] The pharmaceutical compositions of the present invention can be prepared according to the disclosure by any method known to those skilled in the art, for example, conventional mixing, dissolving, granulating, emulsifying, precipitating, encapsulating, entrapping or lyophilizing processes.

[0179] The pharmaceutical compositions of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration, etc. The pharmaceutical compositions of the present invention may also be in controlled release or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, tablets, etc. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, solutions, etc. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations, etc. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharma- ceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations, aerosols, nasal sprays or inhalants, liquid dosage forms suitable for parenteral administration, suppositories, and tablets.

[0180] The present invention also provides a use of the benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition, in the manufacture of an HDAC inhibitor, wherein the HDAC is preferably HDAC6.

[0181] In the above-mentioned uses, the HDAC inhibitors can be used in a mammalian body, and can also be used in vitro, mainly in experiments, for example to provide a comparison as a standard or control sample, or to prepare a kit according to conventional methods in the art to rapidly detect the inhibitory effect of HDAC6.

[0182] The present invention also provides the use of the benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition described above, in the manufacture of a medicament, which may be for preventing and / or treating cancer, a neurological disease or an autoimmune disease, or which may be for preventing and / or treating a disease or condition associated with HDAC.

[0183] The present invention also provides a use of the benzonitric heterocyclic compound of formula I or a pharma- ceutical acceptable salt thereof, or the pharmaceutical composition, in the manufacture of a medicament for preventing and / or treating a disease or condition associated with HDAC, wherein the HDAC is preferably HDAC6, and the disease or condition associated with HDAC may be cancer, a neurological disease or an autoimmune disease, and the medicament can prevent and / or treat the cancer, neurological disease or autoimmune disease by regulating the expression and / or activity of HDAC.

[0184] The present invention also provides a method for preventing and / or treating cancer, neurological disease or autoimmune disease (e.g., HDAC-associated, preferably HDAC6), comprising administering to an individual, e.g., a human, in need thereof a therapeutically effective amount of a benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition.

[0185] The present specification also provides a method for inhibiting cell proliferation or cancer in vitro or in vivo, the method comprising contacting a cell with an effective amount of a benzonitric heterocyclic compound of formula I as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0186] The cancer may be 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 tumors, gestational trophoblastic tumors, glioblastoma, myeloma, CNS tumors derived from neuroblastoma, 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.

[0187] The neurological disease may be a neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar degeneration, Rett syndrome), a peripheral neuropathy (e.g., peroneal muscular atrophy, giant axonal neuropathy (GAN)), or a combination thereof.

[0188] The autoimmune disease may be psoriasis, an inflammatory disease (e.g., osteoarthritis, rheumatoid arthritis, colitis), a disease treatable by immunomodulation (e.g., multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergy, asthma, allergic rhinitis, inflammatory bowel disease).

[0189] When used as a pharmaceutical, the benzonitric heterocyclic compounds of formula I or pharma- ceutically acceptable salts thereof may be administered in the form of pharmaceutical compositions. These compositions may be prepared according to methods known in the pharmaceutical art and may be administered by various routes depending on the need for local or systemic treatment and the area to be treated. Administration may be in the form of topical (including epidermal and transdermal, ocular and mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (including, for example, inhalation or insufflation by powder or aerosol, intratracheal or intranasal administration by sprayer), oral or parenteral administration. Oral administration may include dosage forms prepared for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion, or intracranial or intraventricular administration, such as intrathecal. Parenteral administration may be in the form of a single bolus dose or by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, salves, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners and the like may be necessary or required.

[0190] The term "treatment" as used herein refers to a curative or palliative measure. Beneficial or desirable clinical results include, but are not limited to, alleviating all or some of the symptoms associated with a disease or disorder or condition, reducing the extent of the disease, stabilizing the condition (i.e., not worsening), delaying or slowing the progression of the disease, palliating or alleviating the disease state (e.g., one or more symptoms of a disease), and detectable or undetectable alleviation (partial or total), etc. "Treatment" may also mean prolonging survival as compared to expected survival in the absence of treatment.

[0191] In some embodiments, the benzonitric heterocyclic compounds of formula I or pharma- ceutically acceptable salts thereof, or the pharmaceutical compositions may be used to prevent diseases and conditions as defined herein (e.g., autoimmune diseases, neurological diseases, and cancer). As used herein, the term "prevention" refers to preventing, in whole or in part, the onset, recurrence, or spread of a disease or condition or symptoms thereof as described herein.

[0192] The term "pharmaceutical auxiliary" or "excipient" refers to a pharma- ceutically acceptable chemical, e.g., a reagent to aid in the administration of a drug, known to those skilled in the art of pharmacy. It is a compound that may be used in the preparation of a pharmaceutical composition, and includes excipients that are generally safe, non-toxic, and biologically or otherwise undesirable and are acceptable for veterinary and human medicine. Common excipients include binders, surfactants, diluents, disintegrants, and lubricants.

[0193] Unless otherwise stated, the following definitions are used herein. For purposes of the present invention, the chemical elements are consistent with the CAS Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. General principles of organic chemistry may also be found in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito:1999, and March's Advanced Organic Chemistry by Michael B. Smith and Jerry March, John Wiley&Sons, New York:2007, the entire contents of which are incorporated herein by reference.

[0194] In this specification, groups and their substituents may be selected by one skilled in the art to provide stable structural moieties and compounds. When a substituent is depicted in a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left.

[0195] Certain chemical groups defined herein are preceded by a shorthand symbol indicating the total number of carbon atoms present in that group. For example, C 1 ~C 6 Alkyl refers to an alkyl, as defined below, having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the shorthand symbol does not include carbons that may be present in substituents of said group.

[0196] In this specification, the numerical ranges defined for substituents, for example, 0 to 4, 1 to 4, 1 to 3, etc., represent integers within the range; for example, 1 to 6 is 1, 2, 3, 4, 5, 6.

[0197] In addition to the above, as used in the specification and claims of this application, unless specifically stated otherwise, the following terms have the meanings set forth below.

[0198] The terms "one or more" or "one or more" refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0199] The term "comprises" is open-ended, i.e. includes the subject matter specified in the present invention but does not exclude other aspects.

[0200] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the compound after substitution is stable.

[0201] In general, the term "substituted" refers to one or more hydrogen atoms in a given structure being replaced with a specific substituent. Furthermore, when the substituent is replaced with one or more of the aforementioned substituents, the aforementioned substituents are independent of each other, i.e., the aforementioned one or more substituents may be different from each other or may be the same. Unless otherwise stated, a substituent may be replaced at each substitutable position of the substituent. When multiple positions of a given structural formula may be replaced with one or more substituents selected from a specific group, the substituent may be replaced at each position in the same or different manner.

[0202] At various places in the present specification, substituents of the compounds disclosed herein are disclosed according to radical types or ranges. In particular, the present invention includes each independent subcombination of each member of these radical types and ranges. x ~C y "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "C 1 ~C 6 Alkyl" or "C 16 "Alkyl" refers to any of the independently disclosed methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 Refers to alkyl, and "C 1 - 4 "Alkyl" refers to any of the independently disclosed methyl, ethyl, C 3 Alkyl (i.e., propyl, including n-propyl and isopropyl), C 4 Refers to alkyl (ie, butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0203] The term "halogen" is selected from F, Cl, Br or I and particularly refers to F or Cl.

[0204] The term "alkoxy" refers to the group -OR X Here, R X is alkyl as defined above.

[0205] As used herein, the term "alkyl" as a group or part of another group (e.g., groups such as alkyl substituted with halogen) refers to a branched or straight-chain saturated aliphatic hydrocarbon containing a specified number of carbon atoms, such as a straight or branched saturated hydrocarbon chain containing 1 to 20 carbon atoms, and also includes, for example, C 1 ~C 6 It is an alkyl group. 1 ~C 6 As defined by "alkyl," it includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain configuration. 3 Alkyl (including isomers such as n-propyl or isopropyl), butyl is C 4 Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, and tert-butyl), and pentyl is C 5 Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-amyl or neopentyl), hexyl is C 6 Alkyl (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2,3-dimethylbutyl). Heptyl is C 7 Alkyl (including isomers such as n-heptyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, and 3-ethylpentyl). Octyl is C 8 Alkyl (including isomers such as n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, and 2-methyl-3-ethylpentyl). Nonyl is C 9Alkyl (including isomers such as n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, and 2,2-diethylpentyl). Decyl is C 10 In some embodiments, the "alkyl" is preferably a straight or branched chain alkyl having 1 to 6 carbon atoms. In some embodiments, the "alkyl" is preferably a straight or branched chain alkyl having 1 to 6 carbon atoms. 1 ~C 6 In some embodiments, the "alkyl" refers to C 1 ~C 4 Refers to alkyl.

[0206] As used herein, the terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally recognized as a chemical entity embedded in or attached to a molecule.

[0207] In cases where a recited substituent does not specify through which atom it is attached to a compound contained in a general formula but not specifically mentioned, such substituent may be attached through any of the atoms. Combinations of substituents and / or isomers thereof are permissible only if such combinations result in stable compounds.

[0208] If a recited group is not specified to have substituents, then such group refers only to the unsubstituted form. For example, "C 1 ~C 4 If "alkyl" is not qualified by "substituted or unsubstituted," then "C 1 ~C 4 Alkyl" by itself or "unsubstituted C 1 ~C 4 Refers only to "alkyl."

[0209] In various parts of the present invention, linking substituents are described. If the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and "alkyl" is listed in the definition of the Markush group for this variable, then "alkyl" should be understood to represent a linked alkylene.

[0210] In some particular structures, where an alkyl group is explicitly depicted as the linking group, the alkyl group represents a linked alkylene, e.g., "halo-C 1 ~C 6 "Alkyl" C 1 ~C 6 Alkyl is C 1 ~C 6 It should be understood as alkylene.

[0211] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. An illustrative example of an alkylene is methylene (-CH 2 -), ethylene {-CH 2 CH 2 -or-CH(CH 3 )-}, isopropylidene {-CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -contains} and so on.

[0212] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic carbocyclic substituent composed solely of carbon and hydrogen atoms, and may be attached to the remainder of the molecule by a single bond through any suitable carbon atom, or, if polycyclic, may be a fused, bridged, or spiro-bonded (i.e., two geminal hydrogens at a carbon atom are replaced by alkylene) fused, bridged, or spiro ring system. In some embodiments, typical monocyclic cycloalkyls are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0213] The term "heterocycloalkyl" refers to a saturated cyclic group containing heteroatoms, and independently includes N, O, S, S(=O) and S(=O) 2and the remainder is a stable 3- to 10-membered saturated heterocyclic group containing one or more heteroatoms selected from: Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiacyclopropyl, or stereoisomers thereof, and the like; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, epoxypropyl, thiacyclobutyl, or isomers and stereoisomers thereof, and the like; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofryl, dithiofryl, or isomers and stereoisomers thereof, and the like. Exemplary 6-membered heterocyclyls include, but are not limited to, piperidinyl, tetrahydropyranyl, thiocyclopentyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof, and exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxacycloheptyl, thiocycloheptyl, and diazecycloheptyl, or isomers and stereoisomers thereof. Also, in some embodiments, it is tetrahydroquinolyl, tetrahydrotriazolopyrazinyl, or diazepanyl. In some embodiments, it is a 5-6 membered monocyclic heterocyclyl containing one or more heteroatoms independently selected from N, O, and S. In some embodiments, "heterocycloalkyl" is a 4-6 membered heterocycloalkyl, where the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0214] The term "aryl" refers to an all-carbon aromatic group having a completely conjugated pi-electron system, which may be monocyclic or fused ring, and typically has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Illustrative examples of aryl include, but are not limited to, phenyl, naphthyl, anthracyl, and the like.

[0215] The term "heteroaryl" refers to an aromatic group containing heteroatoms, which may be monocyclic or fused rings, preferably containing 1 to 4 heteroatoms independently selected from N, O and S, including, but not limited to, pyrrolyl, furyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolinyl, (benzo)oxazolyl, (benzo)furanyl, (benzo)thienyl, (benzo)thiazolyl, triazolyl, etc. In some embodiments, the typical heteroaryl is a 5-6 membered monocyclic heteroaryl containing one or more heteroatoms independently selected from N, O and S. In some embodiments, the "heteroaryl" is a 5-6 membered heteroaryl, where the heteroatom is one or more selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0216] Unless otherwise explained, all technical and scientific terms used herein have standard meanings within the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for a term, those set forth in the specification prevail.

[0217] Unless otherwise stated, singular forms such as "a" and "an" as used herein should be understood to include plural referents. Also, the term "comprising" is an open rather than closed limitation, i.e., includes the subject matter specified in the present invention but does not exclude other aspects.

[0218] Unless otherwise stated, the present invention employs conventional methods of mass spectrometry and elemental analysis, and each step and condition may refer to conventional operating steps and conditions in the art.

[0219] Unless otherwise explained, this invention uses standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used for chemical syntheses, chemical analyses, and performance testing of light emitting devices.

[0220] In addition, unless otherwise specified, the description method "independently ..." used in the present invention should be understood in a broad sense, and each described individual is independent of each other, and may be the same or different specific groups independently. More specifically, the description method "independently ..." refers to specific options represented by the same symbol in different groups not affecting each other, and also represents that specific options represented by the same symbol in the same group not affecting each other.

[0221] Those skilled in the art will recognize, in accordance with conventions used in the art, the " " used in the structural formulas of groups described in this application.

[0222] [ka]

[0223] " indicates that the corresponding group is connected to other fragments and groups within the compound through this site.

[0224] Without violating the common knowledge of the art, the above preferred conditions can be combined in any manner to obtain each preferred embodiment of the present invention.

[0225] The reagents and materials used in the present invention are commercially available.

[0226] Positive progressive effects of the present invention: Pharmacological experiments have shown that the benzonitric heterocyclic compounds described in the present invention have the beneficial effects shown below.

[0227] 1) The compounds of the present invention have higher inhibitory activity against HDAC6 (almost half of the compounds have IC 50 <10 nM) and showed more selective inhibitory activity against HDAC1 (IC 50 All of these are >250 nM, and their selectivity against HDAC1 / HDAC6 is >30-fold in most cases, and >50-fold in some cases), superior to the Phase I / II clinical drug Rocilinostat (ACY-1215), an HDAC6 inhibitor, and superior to SW-100 in selectivity.

[0228] 2) The compounds described in the present invention effectively inhibit multiple tumor cells, while at the same time exhibiting weak inhibitory effects on normal cells, thus exhibiting good cell-selective inhibitory activity.

[0229] 3) The compounds of the present invention exhibit a dose-dependent protective effect against oxidative stress in HCA-induced neuronal cells in a cell model, demonstrating that they have specific neuroprotective effects.

[0230] 4) The compounds described in the present invention have weak inhibitory activity against hERG, low potential for cardiotoxicity, and are well tolerated and have low acute toxicity when administered intragastricly in a single dose in rats.

[0231] 5) In particular, in vivo drug metabolism tests have shown that the compounds of the present invention have ideal pharmacokinetic properties, higher blood-brain barrier permeability properties, and superior brain permeability to the 6-membered ring positive control compound SW-100 and the 5-membered ring positive control compound II-ING-39.

[0232] In summary, the advantages of the benzonitric heterocyclic compounds described in the present invention are that the compounds have selective and high inhibitory activity against HDAC6, have low potential risk of affecting the heart, have high animal tolerance, and show better antiproliferative activity against multiple tumor cells in vitro, while at the same time have low toxicity against normal human cells, so they are expected to be used as highly efficient and low-toxic targeted antitumor drugs. At the same time, the benzonitric heterocyclic compounds of the present invention have protective effect on nerve cells in vitro, and their pharmacokinetics in vivo show high blood-brain barrier permeability properties, so they can also be used as therapeutic drugs for neurodegenerative diseases.

[0233] The compounds described in the present invention have a novel structure, and the efficacy and safety of the compounds show excellent inventiveness. The present invention has significant novelty and substantial scientific progress.

[0234] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows cell viability in the HCA-induced neurotoxicity model.

[0235] [Mode for carrying out the invention] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods for which no specific conditions are described are selected according to the usual methods and conditions or product instructions.

[0236] In the following examples, the abbreviations are explained.

[0237] 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: diisobutylaluminium hydride.

[0238] In the following examples, room temperature refers to 10 to 30° C., overnight refers to 8 to 15 hours, for example, 12 hours, eq refers to equivalents, and solvent ratios such as PE / EA refer to volume ratios.

[0239] The compounds of the invention may be prepared by the following general synthetic methods.

[0240] Common method 1:

[0241] [ka]

[0242] Common method 2:

[0243] [ka]

[0244] Common method 3:

[0245] [ka]

[0246] The compound having the structure of formula I can be obtained by the general synthesis method described above, and can be further reacted with an inorganic acid or an organic acid in a solvent, and then cooled to precipitate the corresponding salt of the compound having the structure of formula I.

[0247] The raw materials, compounds and reagents used in the above-mentioned preparation methods can be purchased commercially.

[0248] Example 1: Preparation of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-1) It was prepared according to general synthesis method 1, and the synthesis scheme is shown below.

[0249] [ka]

[0250] Synthesis of methyl 4-chloro-2-((4-methylphenyl)sulfonamido)benzoate (1-2) 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 added to a 500 mL three-neck flask in that order and reacted at room temperature for 12 hours. The yellow solid was obtained by filtration, clarified by dissolving in 200 mL of dichloromethane, washed twice with 100 mL of 5% hydrochloric acid, washed once with 100 mL of water, and the organic phase was dried and then slurried in 150 mL of 50% ethanol to obtain a white solid with a dry weight of 40.50 g and a yield of 88.49%.

[0251] Synthesis of methyl 4-chloro-2-((N-(4-ethoxy-4-oxobutyl)-4-methylphenyl)sulfonamido)benzoate (1-3) Add intermediate 1-2 (36.40g, 107.12mmol, 1eq) to a 1L three-neck flask, dissolve in 300ml of DMF, add ethyl 4-bromobutyrate (22.98g, 1.1eq) and potassium carbonate (41.45g, 2.8eq), and stir at 120°C for 5 hours. Cool to room temperature, add 500ml of water, extract with 500ml of ethyl acetate, separate the organic phase, concentrate and dry, and separate by column chromatography to obtain 35.32g of a white solid, with a yield of 72.63%.

[0252] Synthesis of ethyl 8-chloro-5-oxo-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (1-4) Potassium tert-butoxide (16.81g, 149.80mmol, 2eq) and 400ml of toluene were added to a 1L three-neck flask, heated to 75℃, and stirred uniformly. Intermediate 1-3 (34.00g, 74.90mmol, 1eq) was dissolved in 200ml of toluene and slowly added dropwise to the reaction solution, and the addition was completed over 1 hour. The temperature was raised to 115℃ and refluxed for 1 hour. After cooling to room temperature, the mixture was poured into ice water, the organic phase was separated, the aqueous phase was extracted once with 200ml of dichloromethane, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 32g of red oily matter, which was used directly in the next step without purification.

[0253] Synthesis of 8-chloro-1-tosyl-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (1-5) In a 500ml three-neck flask, 32g of intermediate 1-4 crude product, 45ml of concentrated hydrochloric acid, 80ml of acetic acid, and 10ml of water were added, and the mixture was refluxed at 105°C for 6 hours. After cooling to room temperature, the mixture was poured into an ice-water mixture, neutralized with 10% NaOH, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 16.35g of a colorless oily product, with a two-step yield of 62.49%.

[0254] Synthesis of 8-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (1-6) In a 250 ml three-neck flask, intermediate 1-5 (8 g, 22.87 mmol) and 60 g of polyphosphoric acid were added, heated to 90 ° C., and reacted for 2 hours. 3 The solution was adjusted to neutrality and extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 4.13 g of a yellow solid, the yield was 92.31%.

[0255] Synthesis of 8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1-7) In a 100ml three-neck flask, intermediate 1-6 (3.00g, 15.33mmol, 1eq) and 50ml of anhydrous tetrahydrofuran were added, cooled in an ice-water bath, lithium aluminum hydride (1.16g, 2eq) was added in batches, and stirred at room temperature for 2 hours after the addition was complete. The reaction solution was slowly poured into an ice-water mixture, stirred for 30 minutes, filtered through diatomaceous earth, the filtrate was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness, and purified by column chromatography to give 2.15g of a yellow solid, with a yield of 77.18%. 1 H NMR (400 MHz, DMSO-d6) 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 = ESI-MS(+) m / z=182.00 [M+H] + .

[0256] Synthesis of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)benzoic acid (1-8) In a 100ml three-neck flask, intermediate 1-7 (2.00g, 11.01mmol, 1eq), methyl 4-(bromomethyl)benzoate (2.52g, 1eq), potassium carbonate (2.28g, 1.5eq), and 50ml of DMF were added and reacted at 100°C for 4 hours. The mixture was cooled to room temperature, 100ml of water was added, and the mixture was extracted with 100ml of ethyl acetate. The organic phase was dried and then separated by column chromatography to obtain 2.90g of a white solid, with a yield of 79.86%. 1H NMR (400 MHz, DMSO-d6) 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, ESI-MS(+) m / z=330.10 [M+H] + .

[0257] Synthesis of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-1) 20g of hydroxylamine hydrochloride was dissolved in 200ml of methanol, and 19g of potassium hydroxide (85% purity) was dissolved in 200ml of methanol. The mixture was slowly mixed uniformly under cooling conditions in an ice-water bath, stirred at room temperature for 2 hours, and filtered to obtain a methanol solution of hydroxylamine as the filtrate. Intermediate 1-8 (2g, 6.06mmol) and 50ml of a methanol solution of hydroxylamine were added to a 100ml three-neck flask and reacted at room temperature overnight. The pH was adjusted to neutral with 1N hydrochloric acid, and after concentration, ethyl acetate was added, and the mixture was washed with water to remove hydroxylamine. The organic phase was dried, then concentrated to dryness, and 20ml of ethanol / water was added to crystallize, and filtered to obtain 1.13g of a white solid, with a yield of 56.33%. 1H NMR (400 MHz, DMSO-d6) 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, ESI-MS(+) m / z=331.00 [M+H] + .

[0258] Example 2: Preparation of 4-((8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-2)

[0259] [ka]

[0260] Prepared according to general method 1. White solid, 1 H NMR (400 MHz, DMSO-d6) 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, ESI-MS(+) m / z=331.00 [M+H] + .

[0261] Example 3: Preparation of 4-((8-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-3) It was prepared according to general synthesis method 2, and the specific synthesis scheme is shown below.

[0262] [ka]

[0263] Synthesis of 7-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (3-2) 7-Bromo-tetralone (10g, 44.43mmol, 1eq), hydroxylamine hydrochloride (6.17g, 2eq), and 100ml pyridine were added to a 250ml three-neck flask and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, evaporated to remove pyridine, added with 100ml water, extracted with 100ml dichloromethane, 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 9.23g of a white solid, with a yield of 86.53%. 1 H NMR (400 MHz, DMSO-d6) 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 = 2.1Hz, 1H), 11.31 (s, 1H).

[0264] Synthesis of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine (3-3) In a 250ml three-neck flask, 3-2 (9.00g, 47.06mmol) and 200ml of dichloromethane were added, and the mixture was cooled to -5℃ under nitrogen gas protection. Then, diisobutylaluminum hydride (DIBALH, 1M / hexane, 280ml, 6eq) was slowly added dropwise, and the addition was completed over 40 minutes, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by slowly adding 50ml of water, and the mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filtrate was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 5.64g of a white solid, with a yield of 67.61%. 1 H NMR (400 MHz, DMSO-d6) 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).

[0265] Synthesis of methyl 4-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)benzoate (3-4) In a 100ml three-neck flask, intermediate 3-3 (2.00g, 11.28mmol, 1eq), methyl 4-(bromomethyl)benzoate (2.58g, 1eq), potassium carbonate (2.34g, 1.5eq), and 50ml of DMF were added and reacted at 100°C for 4 hours. The mixture was cooled to room temperature, 100ml of water was added, and the mixture was extracted with 100ml of ethyl acetate. The organic phase was dried and then separated by column chromatography to obtain 3.12g of a white solid, with a yield of 84.97%. 1H NMR (400 MHz, DMSO-d6) 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).

[0266] Synthesis of 4-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-3) In a 100ml three-neck flask, add intermediate 3-4 (2g, 5.34mmol) and 50ml of hydroxylamine methanol solution, and react overnight at room temperature. Adjust pH to neutral with 1N hydrochloric acid, concentrate, add ethyl acetate, wash with water to remove hydroxylamine, dry the organic phase, concentrate to dryness, add 20ml of ethanol / water to crystallize, and filter to obtain 1.27g of white solid, yield 63.33%. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0267] Example 4: Preparation of 4-((7-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-4) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0268] Example 5: Preparation of 4-((7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-5) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0269] Example 6: Preparation of 4-((8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-6) Prepared according to general method 2. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0270] Example 7: Preparation of 4-((6-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-7) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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 = ESI-MS(+) m / z=327.10 [M+H] + .

[0271] Example 8: Preparation of 4-((9-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-8) Prepared according to general method 2. 1H NMR (400 MHz, DMSO-d6) 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 = ESI-MS(+) m / z=327.10 [M+H] + .

[0272] Example 9: Preparation of 4-((7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-9) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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). m / z=357.20 [M+H] + .

[0273] Example 10: Preparation of 4-((8-phenyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-10) Prepared according to general method 2. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0274] Example 11: Preparation of 4-((8-(pyridin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-11) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0275] Example 12: Preparation of 4-((8-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-12) Prepared according to general method 2. 1 H NMR (600 MHz, DMSO-d6 ) 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] + .

[0276] Example 13: Preparation of 4-((8-dimethylamino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-13) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0277] Example 14: Preparation of 4-((8-(piperidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-14) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0278] Example 15: Preparation of 4-((3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-N-hydroxybenzamide (15) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0279] Example 16: Preparation of 4-((3,4-dihydrobenzo[b][1,4]thiazepin-5(2H)-yl)methyl)-N-hydroxybenzamide (T-16) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0280] Example 17: Preparation of 4-((5-methyl-2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepin-1-yl)methyl-N-hydroxybenzamide (T-17) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0281] Example 18: Preparation of 4-((5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-18) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0282] Example 19: Preparation of 4-((5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-19) Prepared according to general method 2. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0283] Example 20: Preparation of 4-((5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-20) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0284] Example 21: Preparation of 4-((5-dimethylamino-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-N-hydroxybenzamide (T-21) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0285] Example 22: Preparation of 4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)fluoromethyl)-N-hydroxybenzamide (T-22) Prepared according to general method 2. 1 H NMR (400 MHz, DMSO-d6) 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]+ .

[0286] Example 23: Preparation of 4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)difluoromethyl)-N-hydroxybenzamide (T-23) Prepared according to general method 2. 1 H NMR (600 MHz, DMSO-d6) 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] + .

[0287] Example 24: Preparation of 4-((2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)-2-fluoro-N-hydroxybenzamide (T-24) Prepared according to general method 2. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0288] Example 25: Preparation of 4-((7-Methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-25) It was prepared according to general synthesis method 3, and the synthesis scheme is shown below.

[0289] [ka]

[0290] The product is a white solid. 1H NMR (400 MHz, DMSO-d6) 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] + .

[0291] Example 26: Preparation of 4-((6-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-26) Prepared according to general method 3. 1 H NMR (400 MHz, DMSO-d6) 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, ESI-MS(+) m / z=327.15 [M+H] + .

[0292] Example 27: Preparation of 4-((6-bromo-9-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-27) Prepared according to general method 3. 1H NMR (400 MHz, DMSO-d6) 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 = ESI-MS(+) m / z=405.13 [M+H] + .

[0293] Example 28: Preparation of 4-((6-cyclopropyl-9-methoxy-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)methyl)-N-hydroxybenzamide (T-28) Prepared according to general method 3. 1 H NMR (400 MHz, DMSO-d6) 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] + .

[0294] Example 29 Inhibitory activity of compounds against HDAC The in vitro histone deacetylase inhibitory activity of the compounds was measured according to the instructions of the HDAC1 and HDAC6 inhibitor screening kit (Biovision). Clinical-stage HDAC6 inhibitor Rocilinostat (ACY-1215)

[0295] [ka]

[0296] and compound SW-100 were used as positive controls.

[0297] The experimental results are shown in the table.

[0298] [Table 1]

[0299] From the above table, it can be seen that the compounds of the present invention have superior inhibitory activity against HDAC6 (almost IC 50 <100 nM), and some compounds had inhibitory activity equivalent to or superior to the positive controls Rocilinostat (ACY-1215) and SW-100. Furthermore, the inhibitory activity IC 50 were all >250 nM, and compared with HDAC1, the compounds of the present invention could selectively inhibit HDAC6, with most of the selectivity being >30-fold, and even >50-fold, and the selectivity was superior to that of Rocilinostat and SW-100.

[0300] Example 30 In vitro antiproliferative activity test against tumor cells and human normal cells The anti-proliferative activity of some compounds of the present invention is measured in glioma cell line U-87MG, myeloma cell line RPMI8226, human liver cancer cell line HepG2, human lung cancer cell line A549, and MRC-5 human normal embryonic lung fibroblasts under single concentration (10μM), and Rocilinostat (ACY-1215) is selected as control.The specific results are shown in the table below (unit: Inh% in 10μM).

[0301] Test method: Tumor cells in the logarithmic growth phase with good growth were taken and 4 x 10 cells were cultured per well. 3 Each well was inoculated into a 96-well plate, and eight replicate wells were set up for each group, which were then placed in a cell culture incubator for incubation. After the cells attached to the wall, the corresponding plasmid was transfected. After 48 hours of incubation, the medium containing the drug was discarded, and 10 μL of freshly prepared CCK8 containing toxicity detection solution was added to each well. After 4 hours of incubation in the incubator, the OD value at a wavelength of 450 nm was measured using a microplate reader. The experiment was repeated three times, and the average value of the experimental results was used as the final experimental result, and the inhibition rate was calculated.

[0302] [Table 2]

[0303] A:100≧~>90;B:80<~≦90;C:70<~≦80;D:50<~≦70E:<50 As can be seen from the above table, compared with the positive control Rocilinostat, the compounds of the present invention all showed good in vitro antitumor cell proliferation activity against multiple tumor cells, and showed higher inhibitory activity against glioma cell line U-87MG, myeloma cell line RPMI8226, and human hepatoma cell line HepG2, and the antitumor cell proliferation activity of some compounds was superior to that of the positive control drug.

[0304] At the same time, compared with rocilinostat, the compounds of the present invention have weaker inhibitory activity against MRC-5 human normal embryonic lung fibroblasts and less toxic side effects, indicating that the compounds of the present invention have better selectivity in inhibiting the proliferation of tumor cells and normal cells, and may have less toxic side effects when used as antitumor drugs.

[0305] Example 31 Protective effect of compounds against HCA-induced neuronal damage HCA (5 mmol / L) was used to induce injury in rat cortical mixed cells and primary neurons, and the effects of different concentrations (test concentrations: 0.1 μM, 1.0 μM and 10.0 μM) of the compounds on the injury were observed, and the changes in activity, number, morphology and necrosis of neurons and glial cells were detected, and the effects of the compounds on normal neurons were observed, and the similar neuroprotective HDAC6 inhibitor compound Tubastatin A was used as a control. The results showed that all of the compounds of the present invention have a certain protective effect against anti-HCA-induced neuronal excitotoxicity. Here, the in vitro activity of compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 showed stronger protective activity and a certain dose-effect relationship compared with the HDAC6 inhibitor compound Tubastatin A with neuroprotective effect, suggesting that the compounds of the present invention have neuroprotective effect and can be used to treat neurodegeneration-related diseases. The results are shown in Figure 1.

[0306] Example 32 Experiments on the effect of compounds on the hERG potassium channel Using the whole-cell patch clamp technique, changes in hERG current (I) were recorded after exposure to different concentrations of compounds in HEK293 cells expressing the hERG potassium channel (hERG-HEK293 steady-state cells) and the half-inhibitory concentrations (IC) of the compounds acting on the I were measured. 5 0) was studied.

[0307] The potential cardiotoxic side effects of some compounds of the present invention, T-2, T-5, T-15, T-16, T-19, T-21 and T-28, were preliminarily investigated in vitro.

[0308] The experimental results are shown in the table below.

[0309] [Table 3]

[0310] The results of the hERG experiment showed that the inhibitory activity of the test compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 against the hERG potassium channel was all greater than 10 μM, suggesting that the compounds of the present invention have low potential cardiotoxicity.

[0311] Example 33: Maximum tolerated dose toxicity test of compounds administered intragastrically Forty ICR mice were taken, half male and half female, weighing 18-20g, and divided into four groups, 10 mice per group. After six hours of fasting, samples were extracted from each group using a sterile plastic syringe and administered orally at a volume of 0.3ml / 10g. General signs and death of the animals were recorded at 1, 2, and 4 hours after administration. Observations were continued for 14 days after administration, and the weight, signs, and death of the animals were observed and recorded daily. The deceased animals were dissected, and the organs of the animals were observed for visible pathological changes, and pathological examinations were performed on suspicious tissues and organs.

[0312] The experimental results showed that the compounds T-2, T-5, T-15, T-16, T-19, T-21 and T-28 of the present invention had a maximum tolerated dose of more than 1000 mg / kg when administered intragastrically to mice, and showed excellent animal tolerance.

[0313] Example 34 PK study of compounds Some compounds of the present invention, T-2, T-5, T-15, T-16, T-19, T-21 and T-28, are intraperitoneally administered once to male SD rats, and the drug concentration of the compounds in the brain and plasma of rats is measured using LC-MS / MS method, and the brain / blood drug concentration ratio of test compound at t=1.0h is calculated to evaluate the brain permeability of active compound.Compound SW-100 is used as control, and the test results are shown in Table.

[0314] [Table 4]

[0315] The test results showed that compared with the positive controls II-ING-39 and SW-100, all of the compounds of the present invention showed superior blood-brain permeability.

[0316] Although the specific embodiments of the present invention have been described above, those skilled in the art will recognize that these are merely illustrative and may make various changes or modifications to these embodiments without violating the principles and substance of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims. [Brief description of the drawings]

[0317] [Figure 1] Cell viability in HCA-induced neurotoxicity model.

Claims

1. A benzonitric heterocyclic compound represented by formula I or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (however, Ring A is a 7-membered heterocycloalkyl, and in the 7-membered heterocycloalkyl, one of the N's is 【Chemistry 2】 In addition to linking with, optionally 0 to 2 N, O, S, S(=O) and S(=O) ２ and a heteroatom selected from n is 0, 1, 2, 3 or 4; R ２ are independently hydrogen, hydroxy, C １ ~C ４ Alkyl, C １ ~C ４ Alkyl-O-, (R ａ R ｂ ) N— or O═; R １ａ , R １ｂ , R １ｃ and R １ｄ are independently hydrogen, halogen, hydroxy, cyano or R １ -L-, -L- is independently a bond, -(C １ ~C ４ Alkyl)-, -O-, -C(=O)- or -S(=O) ２ - and R １ is independently C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, or １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently selected from the group consisting of one or more substituents R ｅ and wherein said 3- to 7-membered heterocycloalkyl and one or more substituents R ｅ In the 3- to 7-membered heterocycloalkyl substituted by, the heteroatom groups are N, O, S, S(=O) and S(=O) ２ wherein the number of heteroatoms is 1 to 3, and the 5- to 10-membered heteroaryl and one or more substituents R ｅ In the 5-10 membered heteroaryl substituted by, the heteroatom group is selected from one or more of N, O and S, the number of heteroatoms is 1 to 4, and R ｅ are independently hydroxy, halogen, cyano or C １ ~C ４ alkyl, and when the substituents are plural, they may be the same or different; R ａ , R ｂ , R ｃ and R ｄ are independently hydrogen or C １ ~C ４ is alkyl, R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ and R ５ are independently hydrogen, halogen, C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ alkyl, and when the substituents are plural, they may be the same or different; When a carbon atom marked with "*" represents a chiral carbon atom, it may have the S configuration, the R configuration, or a mixture thereof.

2. In the ring A, 【Chemistry 3】 and the N linked to is located at the ortho or para position of the benzene ring to which the fused ring is bonded; And / or, in ring A, one N is 【Chemistry 4】 and optionally containing 0 to 1 heteroatom selected from N, O and S, other than being linked to And / or R ２ became independent and C １ ~C ４ Alkyl or C １ ~C ４ When it is alkyl-O-, １ ~C ４ Alkyl and C １ ~C ４ Alkyl-O-C １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And / or R １ａ , R １ｂ , R １ｃ and R １ｄ is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or -L- is independently -(C １ ~C ４ When the -(C １ ~C ４ alkyl)- is methylene, ethylene, propylene, butylene, isopropylidene, isobutylene, sec-butylene or tert-butylene; And / or R １ became independent and C １ ~C ６ is alkyl, and one or more substituents R ｅ C substituted with １ ~C ６ When it is alkyl, １ ~C ６ Alkyl and one or more substituents R ｅ C substituted with １ ~C ６ Alkyl C １ ~C ６ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or R １ became independent and C ３ ~C ７ cycloalkyl, and one or more substituents R ｅ C substituted with ３ ~C ７ When it is cycloalkyl, the C ３ ~C ７ Cycloalkyl and one or more substituents R ｅ C substituted with ３ ~C ７ Cycloalkyl C ３ ~C ７ Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; And / or R １ became independent and C ６ ~C １０ aryl, with one or more substituents R ｅ C substituted with ６ ~C １０ When it is aryl, ６ ~C １０ Aryl and one or more substituents R ｅ C substituted with ６ ~C １０ Aryl C ６ ~C １０ Aryl is independently phenyl or naphthyl; And / or R １ is independently 3- to 7-membered heterocycloalkyl, and one or more substituents R ｅ When the 3- to 7-membered heterocycloalkyl is substituted by, the 3- to 7-membered heterocycloalkyl and one or more substituents R ｅ the 3- to 7-membered heterocycloalkyl substituted by is independently a 5- to 6-membered heterocycloalkyl, where the heteroatom group is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2; And / or R １ is independently 5-10 membered heteroaryl, and one or more substituents R ｅ When the 5- to 10-membered heteroaryl is a 5- to 10-membered heteroaryl substituted by ｅ The 5-10 membered heteroaryl of the 5-10 membered heteroaryl substituted by is independently a 5-6 membered heteroaryl, where the heteroatom group is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2; And / or R ｅ is independently a halogen, said halogen is fluorine, chlorine, bromine or iodine; And / or R ｅ became independent and C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And / or R ａ , R ｂ , R ｃ and R ｄ became independent and C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And / or R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ and R ５ became independent and C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ When it is alkyl, １ ~C ４ C substituted with alkyl and one or more halogens １ ~C ４ Alkyl C １ ~C ４ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And / or R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ and R ５ are independently halogen or C substituted with one or more halogens １ ~C ４ When it is alkyl, it is C substituted with one or more halogens. １ ~C ４ Alkyl halogen is fluorine, chlorine, bromine or iodine; And / or R １ became independent and C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl, and １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl and 5- to 10-membered heteroaryl are substituents R ｅ is substituted by R ｅ is independently halogen, R ｅ is one, two or three, And / or R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ and R ５ C independently substituted with one or more halogens １ ~C ４ The benzonitric heterocyclic compound represented by formula I according to claim 1 or a pharma- ceutically acceptable salt thereof, characterized in that when alkyl, the number of halogens substituted is 1 to 3.

3. In ring A, 【Chemistry 5】 and the N bonded to the fused ring is located at the ortho position of the benzene ring to which the fused ring is bonded. and / or, when R 2 is independently C 1 -C 4 alkyl or C 1 -C 4 alkyl-O—, the C 1 -C 4 alkyl of said C 1 -C 4 alkyl and C 1 -C 4 alkyl-O— is methyl; and / or, when R 1a , R 1b , R 1c and R 1d are independently halogen, said halogen is fluorine, chlorine or bromine; and / or when R 1 is independently C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted by one or more substituents R e , the C 1 -C 6 alkyl of said C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted by one or more substituents R e is methyl; and / or when R 1 is independently C 3 -C 7 cycloalkyl and C 3 -C 7 cycloalkyl substituted by one or more substituents R e , the C 3 -C 7 cycloalkyl of said C 3 -C 7 cycloalkyl and C 3 -C 7 cycloalkyl substituted by one or more substituents R e is cyclopropyl; and / or when R 1 is independently C 6 -C 10 aryl and C 6 -C 10 aryl substituted by one or more substituents R e , the C 6 -C 10 aryl of said C 6 -C 10 aryl and C 6 -C 10 aryl substituted by one or more substituents R e is phenyl; and / or, when R 1 is independently 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents R e , the 3- to 7-membered heterocycloalkyl of said 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents R e is piperidinyl; and / or, when R 1 is independently 5-10 membered heteroaryl and 5-10 membered heteroaryl substituted by one or more substituents R e , the 5-10 membered heteroaryl of said 5-10 membered heteroaryl and 5-10 membered heteroaryl substituted by one or more substituents R e is piperidinyl; and / or, when R e is independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is methyl; and / or, when R a , R b , R c and R d are independently C 1 -C 4 alkyl, said C 1 -C 4 alkyl is methyl; and / or the benzonitric heterocyclic compound of formula I or a pharma- ceutically acceptable salt thereof according to claim 1, characterized in that, when R3a, R3b, R3c, R3d, R4 and R5 are independently C1-C4 alkyl or C1-C4 alkyl substituted with one or more halogens, the C1-C4 alkyl of the C1-C4 alkyl and C1-C4 alkyl substituted with one or more halogens is methyl.

4. Ring A is 【Chemistry 6】 and Y is a bond, methylene or 【Chemistry 7】 and X is C, N, O or S; and / or n is 0 or 1, And / or R ２ are independently hydrogen, hydroxy, C １ ~C ４ Alkyl, (R ａ R ｂ ) N— or O═; and / or -L- is independently a bond or -O-; And / or R １ is independently C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl; And / or R １ -L- is C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl or C １ ~C ６ alkyl-O-; And / or R １ａ , R １ｂ , R １ｃ and R １ｄ are independently hydrogen, halogen or R １ -L-, And / or R ４ and R ５ are independently hydrogen or halogen; And / or R ａ , R ｂ , R ｃ and R ｄ is independently C １ ~C ４ is alkyl, And / or R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ 2. The benzonitric heterocyclic compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, characterized in that: are independently hydrogen or halogen.

5. R 2 is independently hydrogen, hydroxy, C 1 -C 4 alkyl or O=; and / or R 1 is independently C 1 -C 6 alkyl; and / or R 1 -L- is C 1 -C 6 alkyl-O-; and / or one or two of R 1a , R 1b , R 1c and R 1d are independently hydrogen or R 1 -L-, and the rest are hydrogen; and / or R 4 and R 5 are hydrogen; and / or R 3a is hydrogen or halogen, and R 3b , R 3c and R 3d are independently hydrogen, or a pharma- ceutically acceptable salt thereof, of formula I according to claim 1 .

6. The benzonitric heterocyclic compound represented by formula I is represented by the following scheme 1 or scheme 2: Scheme 1. The benzazepine compound of formula I is a benzonitric heterocyclic compound of formula I-1 or I-2, 【Chemistry 8】 However, X １ and X ２ is independently 【Chemistry 9】 、 【Chemistry 10】 、 【Chemistry 11】 or 【Chemistry 12】 and Scheme 2, Ring A is a 7-membered heterocycloalkyl; In the ring A, 【Chemistry 13】 and the N linked to is located at the ortho or para position of the benzene ring; n is 0 or 1; R ２ are independently hydrogen, hydroxy, C １ ~C ４ Alkyl, C １ ~C ４ Alkyl-O-, (R ａ R ｂ ) N— or O═; R １ａ , R １ｂ , R １ｃ and R １ｄ are independently hydrogen, halogen or R １ -L-, -L- is independently a bond or -O-; R １ is independently C １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R ４ and R ５ are independently hydrogen or halogen; R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ are independently hydrogen or halogen; Scheme 3, Ring A is a 7-membered heterocycloalkyl; In the ring A, 【Chemistry 14】 and the N linked to is located at the ortho or para position of the benzene ring; n is 0 or 1; R ２ are independently hydrogen, hydroxy, C １ ~C ４ Alkyl, C １ ~C ４ Alkyl-O-, (R ａ R ｂ ) N— or O═; R １ａ , R １ｂ , R １ｃ and R １ｄ are independently hydrogen, halogen, C １ ~C ６ Alkyl-O-, C ３ ~C ７ Cycloalkyl, C ６ ~C １０ Aryl, C ６ ~C １０ Aryl-(C １ ~C ４ alkyl)-, (R ｃ R ｄ ) N-, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R ４ and R ５ are independently hydrogen; R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ are independently hydrogen or halogen; Scheme 4, Ring A is 【Chemistry 15】 And X １ is independently 【Chemistry 16】 、 【Chemistry 17】 、 【Chemistry 18】 or 【Chemistry 19】 and n is 0 or 1; R ２ are independently hydrogen, hydroxy, C １ ~C ４ alkyl or O=; R １ａ , R １ｂ , R １ｃ and R １ｄ are independently hydrogen, fluorine or C １ ~C ６ alkyl-O-, R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ and R ５ 2. The benzonitric heterocyclic compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, characterized in that: are independently hydrogen.

7. Ring A is a 7-membered heterocycloalkyl; In the ring A, 【Chemistry 20】 is located at the ortho position of the benzene ring; n is 0 or 1; R2 is independently hydrogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl-O—, (R a R b )N—, or O═; R 1a , R 1b , R 1c and R 1d are independently hydrogen, halogen, C 1 -C 6 alkyl-O—, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl-(C 1 -C 4 alkyl)-, (R c R d )N—, 3- to 7-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R 4 and R 5 are independently hydrogen; 2. The benzonitric heterocyclic compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, characterized in that R3a, R3b, R3c and R3d are independently hydrogen or halogen.

8. Ring A is 【Chemistry 21】 、 【Chemical 22】 、 【Chemistry 23】 、 【Chemistry 24】 or 【Chemistry 25】 and And / or R １ａ , R １ｂ , R １ｃ and R １ｄ are independently hydrogen, fluorine, chlorine, bromine, methoxy, cyclopropyl, phenyl, 【Chemistry 26】 、 【Chemistry 27】 or 【Chemistry 28】 and And / or R ２ are independently hydrogen, hydroxy, methyl, methoxy, 【Chemical 29】 or O=, And / or R ４ and R ５ are independently hydrogen or fluorine; And / or R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ 2. The benzonitric heterocyclic compound of formula I according to claim 1, or a pharma- ceutically acceptable salt thereof, characterized in that: are independently hydrogen or fluorine.

9. The benzonitric heterocyclic compound of formula I according to claim 1 or a pharma- ceutically acceptable salt thereof, wherein the benzonitric heterocyclic compound of formula I is selected from any of the following structures: 【Chemistry 30】

10. A method for producing a benzonitric heterocyclic compound of formula I according to any one of claims 1 to 9, characterized in that a compound of formula II is reacted with hydroxylamine in a solvent to give a benzonitric heterocyclic compound of formula I, 【Chemistry 31】 (where *, ring A, n, R ２ , R １ａ , R １ｂ , R １ｃ , R １ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ and R ５ The definitions of R are as defined in any one of claims 1 to 9. ６ is C １ ~C ６ It is alkyl.

11. R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and / or the solvent is an alcohol-based solvent; and / or the mass volume ratio of the compound represented by formula II to the solvent is 0.1 g / L to 20 g / L; and / or the molar ratio of the compound of formula II and the hydroxylamine is from 1:5 to 1:50; and / or the temperature of the hydroxylation reaction is between room temperature and 80° C. And / or the preparation method also includes post-treatment, which includes the steps of adjusting pH to neutral, concentrating, adding organic solvent, washing with water, drying the organic phase, concentrating, separating and purifying after the hydroxylation reaction is completed; And / or, the method also includes a step of subjecting a compound represented by formula III and a compound represented by formula IV to a coupling reaction represented by the following formula in a solvent in the presence of a base to obtain a compound represented by formula II: 【Chemistry 32】 The method according to claim 10, wherein R 6 , *, ring A, n, R 2 , R 1a , R 1b , R 1c , R 1d , R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are defined as in any one of claims 1 to 9, and X is halogen.

12. A pharmaceutical composition comprising a benzonitric heterocyclic compound of formula I according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable carriers.

13. Use of a benzonitric heterocyclic compound of formula I according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a HDAC inhibitor or medicament, comprising: The medicament is for preventing and / or treating cancer, a neurological disease, or an autoimmune disease, Or, the medicament is a medicament for the prevention and / or treatment of a disease or condition associated with HDAC.

14. The method of claim 1, wherein the HDAC is HDAC6. And / or the use according to claim 13, wherein the HDAC-associated disease or condition is cancer, a neurological disease or an autoimmune disease.

15. The cancer is selected from the group consisting of 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 tumors, gestational trophoblastic tumors, glioblastoma, myeloma, neuroblastoma-derived CNS tumors, 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; and / or the neurological disorder is a neurodegenerative disease, a peripheral neuropathy, or a combination thereof; And / or the use according to claim 13 or 14, wherein the autoimmune disease is psoriasis, an inflammatory disease and a disease treatable by immune modulation.

16. The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar degeneration, or Rett syndrome, And / or, the peripheral neuropathy is peroneal muscular dystrophy, giant axial neuropathy, and / or the inflammatory disease is osteoarthritis, rheumatoid arthritis, or colitis; And / or the use according to claim 15, wherein the diseases treatable by immunomodulation are multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma, allergic rhinitis and inflammatory bowel disease.

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