Benzonitric heterocyclic compound, preparation method therefor and use thereof

1 . A benzonitric heterocyclic compound represented by formula I-1 or a pharmaceutically acceptable salt thereof,

X 1 is

R 2 is independently hydrogen, hydroxyl, 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, hydroxyl, cyano or R 1 -L-;

-L- is independently a linker bond, —(C 1 -C 4 alkyl)-, —O—, —C(═O)— or —S(═O) 2 —;

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, the 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 and 5- to 10-membered heteroaryl are substituted by one or more substituents of R e ; in the 3- to 7-membered heterocycloalkyl and the 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R e , the heteroatom is selected from one or more of N, O, S, S(═O) and S(═O) 2 , and the number of heteroatoms is 1 to 3; in the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl substituted by one or more substituents of R e , the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; R e is independently hydroxyl, halogen, cyano or C 1 -C 4 alkyl; when there are multiple substituents, they are the same or different;

R a , R b , R c and R d are independently hydrogen or C 1 -C 4 alkyl;

R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more halogen; when there are multiple substituents, they are the same or different;

a carbon atom with “*” indicates that when it is a chiral carbon atom, it is a S configuration, R configuration or a mixture thereof.

2 . The benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof according to claim 1 , wherein,

when R 2 is independently C 1 -C 4 alkyl or C 1 -C 4 alkyl-O—, the C 1 -C 4 alkyl in the C 1 -C 4 alkyl and C 1 -C 4 alkyl-O— is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

or, when R 1a , R 1b , R 1c and R 1d are independently halogen, the halogen is fluorine, chlorine, bromine or iodine;

or, when -L- is independently —(C 1 -C 4 alkyl)-, the —(C 1 -C 4 alkyl)- is methylene, ethylene, propylene, butylene, isopropylidene, isobutylene, sec-butylene or tert-butylene;

or, when R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more substituents of R e , the C 1 -C 6 alkyl in the C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted by one or more substituents of R e is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

or when R 1 is independently C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted by one or more substituents of R e , the C 3 -C 7 cycloalkyl in the C 3 -C 7 cycloalkyl and C 3 -C 7 cycloalkyl substituted by one or more substituents of R e is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

or, when R 1 is independently C 6 -C 10 aryl, C 6 -C 10 aryl substituted by one or more substituents of R e , the C 6 -C 10 aryl in the C 6 -C 10 aryl and C 6 -C 10 aryl substituted with one or more substituents of R e is independently phenyl or naphthyl;

or, when R 1 is independently 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R e , the 3- to 7-membered heterocycloalkyl in the 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R e is independently 5- to 6-membered heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2;

or, when R 1 is independently 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R e , the 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R e is independently 5- to 6-membered heteroaryl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2;

or, when R e is independently halogen, the halogen is fluorine, chlorine, bromine or iodine;

or, when R e is independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

or, when R a , R b , R c and R d are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

or, when R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more halogen, the C 1 -C 4 alkyl in the C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more halogen is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

or, when R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently halogen or C 1 -C 4 alkyl substituted by one or more halogen, the halogen in the halogen or C 1 -C 4 alkyl substituted by one or more halogen is fluorine, chlorine, bromine or iodine;

or, when 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 the 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 and 5- to 10-membered heteroaryl are substituted by substituents of R e , and the R e is independently halogen, and the number of R e is 1, 2 or 3;

or, when R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently C 1 -C 4 alkyl substituted by one or more halogen, the number of halogen substitutions is substituted by 1 to 3 halogens.

3 . The benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof according to claim 1 , wherein,

R 2 is independently hydrogen, hydroxyl, C 1 -C 4 alkyl, (R a R b )N— or O═;

or, -L- is independently a linker bond or —O—;

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;

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, 5- to 10-membered heteroaryl or C 1 -C 6 alkyl-O—;

or, R 1a , R 1b , R 1c and R 1d are independently hydrogen, halogen or R 1 -L-;

or, R 4 and R 5 are independently hydrogen or halogen;

or, R a , R b , R c and R d are independently C 1 -C 4 alkyl;

or, R 3a , R 3b , R 3c and R 3d are independently hydrogen or halogen.

4 . The benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof according to claim 1 , wherein,

R 1a , R 1b , R 1c and R 1d are independently hydrogen, fluorine, chlorine, bromine, methoxy, cyclopropyl, phenyl,

or, R 2 is independently hydrogen, hydroxyl, methyl, methoxy,

or O═;

or, R 4 and R 5 are independently hydrogen or fluorine;

or, R 3a , R 3b , R 3c and R 3d are independently hydrogen or fluorine.

5 . The benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof according to claim 1 , wherein, the benzonitric heterocyclic compound represented b formula I-1 is selected from any of the following structures:

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

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

8 . The benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof according to claim 2 , wherein, R 2 is independently C 1 -C 4 alkyl or C 1 -C 4 alkyl-O—, the C 1 -C 4 alkyl in the C 1 -C 4 alkyl and C 1 -C 4 alkyl-O— is methyl;

or, when R 1a , R 1b , R 1c and R 1d are independently halogen, the halogen is fluorine, chlorine or bromine;

or, when R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more substituents of R e , the C 1 -C 6 alkyl in the C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted by one or more substituents of R e is independently methyl;

or, when R 1 is independently C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted by one or more substituents of R e , the C 3 -C 7 cycloalkyl in the C 3 -C 7 cycloalkyl and C 3 -C 7 cycloalkyl substituted by one or more substituents of R e is independently cyclopropyl;

or, when R 1 is independently C 6 -C 10 aryl, C 6 -C 10 aryl substituted by one or more substituents of R e , the C 6 -C 10 aryl in the C 6 -C 10 aryl and C 6 -C 10 aryl substituted with one or more substituents of R e is independently phenyl;

or, when R 1 is independently 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R e , the 3- to 7-membered heterocycloalkyl in the 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkyl substituted by one or more substituents of R e is independently piperidinyl;

or, when R 1 is independently 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R e , the 5- to 10-membered heteroaryl in the 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl substituted by one or more substituents of R e is independently pyridyl;

or, when R e is independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl;

or, when R a , R b , R c and R d are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl;

or, when R 3a , R 3b , R 3c , R 3d , R 4 and R 5 are independently C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more halogen, the C 1 -C 4 alkyl in the C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted by one or more halogen is methyl.

9 . The benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof according to claim 3 , wherein, R 2 is independently hydrogen, hydroxyl, C 1 -C 4 alkyl or O═;

or, R 1 is independently C 1 -C 6 alkyl;

or, R 1 -L- is C 1 -C 6 alkyl-O;

or, one or two of R 1a , R 1b , R 1c and R 1d are independently halogen or R 1 -L-, the rest are hydrogen;

or, R 4 and R 5 are independently hydrogen;

or, R 3a is hydrogen or halogen; R 3b , R 3c and R 3d are independently hydrogen.

10 . The method according to claim 7 , wherein, the HDAC is HDAC6.

11 . A method of treating cancer or nervous diseases, comprising administering the benzonitric heterocyclic compound represented by formula I-1 or the pharmaceutically acceptable salt thereof as defined in claim 1 into the subject, wherein

the cancers are selected from the group consisting of ovarian cancer, breast cancer, liver cancer, prostate cancer, lung cancer, glioblastoma, and myeloma; and

the nervous diseases are selected from the group consisting of Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

12 . A method of inhibiting HDAC in a subject in need thereof, comprising administering the pharmaceutical composition as defined in claim 6 into the subject.

13 . A method of treating cancer or nervous diseases, comprising administering the pharmaceutical composition as defined in claim 6 into the subject, wherein

the cancers are selected from the group consisting of ovarian cancer, breast cancer, liver cancer, prostate cancer, lung cancer, glioblastoma, and myeloma; and

the nervous diseases are selected from the group consisting of Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.