Benzodiazepine compounds and their use as Rho kinase inhibitors

Abstract

The present disclosure relates to a benzodiazepine compound having a structure shown in formula (I). The compound, as a ROCKII kinase inhibitor, has the advantages of high activity, good selectivity and low toxicity and side effects. The present disclosure also relates to the application of the compound in Rho kinase inhibitor drugs and a preparation method.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a benzodiazepine having a Rho kinase inhibitory effect. Compounds and preparation methods thereof. Background Art

[0002] Rho kinase (ROCK) is one of the earliest discovered downstream targets of Rho protein. It is a serine / threonine protein kinase with a relative molecular mass of 160kDa, including two subtypes, ROCKI and ROCKII. ROCK kinase plays an important role in a series of cell life activities, such as cell mitosis adhesion, cytoskeleton adjustment, muscle cell contraction, tumor cell infiltration, etc. According to literature reports, ROCK kinase is related to a variety of diseases, including hypertension, pulmonary hypertension, cardiovascular disease, inflammation, autoimmune disease, lung disease and ophthalmic disease.

[0003] Existing drugs for glaucoma mainly promote the outflow of aqueous humor to achieve the effect of lowering intraocular pressure, but there are still some cases of glaucoma with normal intraocular pressure in clinical practice, and the clinical explanation of glaucoma is that different causes cause progressive loss of retinal ganglion cells, progressive depression of the optic disc, and visual field damage. These all suggest that in addition to reducing intraocular pressure, the more important thing for us to develop glaucoma drugs is to protect the optic nerve. Netarsudil is currently the only pan-ROCK inhibitor approved by the FDA for marketing. It is also used to treat open-angle glaucoma and ocular hypertension, but clinical trials report that its main side effects are conjunctival congestion and blepharitis. ROCKII inhibitors can reduce intraocular pressure by regulating the actin cytoskeleton, extracellular matrix, and Schemms tube endothelial cell function in the trabecular meshwork, and at the same time, can effectively reduce the toxic side effects of the drug.

[0004] As the research continues to deepen, scholars have found that ROCKII has unique functions in the development of blood vessels and nervous systems, and is mainly distributed in muscle tissue and brain, while ROCK I is widely expressed, including liver, kidney, spleen, testis, thymus and blood cells. Although the core functions and related mechanisms of different subtypes in many organs are still unclear, the two play certain biological roles in different organs. If they are widely inhibited, potential toxic side effects will occur. Therefore, designing selective inhibitors for a single subtype (ROCK II) can, on the one hand, reduce the potential toxic side effects of the compound and reduce the risk of drug development; on the other hand, using single subtype selective small molecule inhibitors as probes can also discover the special functions of different subtypes in the development of the disease. At present, two ROCKII selective inhibitors have entered clinical trials and are progressing smoothly. Therefore, from the perspective of target drugability and drug safety, further research and development of highly selective inhibitors of ROCK II has good prospects. Summary of the invention

[0005] The purpose of the present disclosure is to provide a synthesis of a novel compound and its application in ROCK kinase inhibitor drugs. In particular, the compound, as a ROCKII selective kinase inhibitor, has the advantages of high activity, good selectivity and low toxicity and side effects.

[0006] Specifically, the present disclosure provides a compound represented by the following formula (I) or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, salt or solvate,

[0007]

[0008] wherein n is selected from 1 or 2;

[0009] X1 is selected from CH or N;

[0010] n R1 may be the same or different; R1 is selected from hydrogen, amino, or C 1-3 Alkyl, the amino group is optionally replaced by C 1-6 Alkyl or C 3-8 substituted with cycloalkylalkyl;

[0011] A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O, and S, or a 9-12 membered bicyclic heteroaryl group containing 1-3 atoms selected from N, O, and S;

[0012] R2 is selected from C 1-6 Alkyl, 5-7 membered aryl, the C 1-6Alkyl, 5-7 membered aryl are optionally substituted by one or more halogen, amino or hydroxyl groups;

[0013] R3 is hydrogen, C 1-6 Alkoxy, C 1-6 Carboxyl, hydroxyl, halogen, -C(O)NR6R7 or -OC(O)-R 11 ;

[0014] R6 and R7 are independently selected from a single bond, hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O or S, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O or S, optionally substituted by one or two R8 or -(CH2) p -OC(O)R9;

[0015] R4 is selected from hydrogen, halogen, -B(OH)2, or dioxaborolanyl, wherein the dioxaborolanyl is replaced by one or more C 1-6 Alkyl substitution;

[0016] R5 is selected from hydrogen or C 1-3 alkyl.

[0017] In some embodiments, R1 is selected from hydrogen, amino, or methyl, wherein the amino group is optionally replaced by C 3-8 substituted with cycloalkylalkyl;

[0018] Preferably, R1 is hydrogen or amino, said amino being optionally substituted by cyclopropylmethyl;

[0019] In some embodiments, A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O, and S, or a 9-12 membered bicyclic heteroaryl group containing 1-3 atoms selected from N, O, and S;

[0020] Preferably, A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 N atoms, or a 9-12 membered bicyclic heteroaryl group containing 1-2 N atoms;

[0021] Preferably, A is selected from pyridyl, pyrazolyl, benzopyrazolyl, or pyrrolopyridinyl;

[0022] Preferably, A is selected from pyridyl, pyrazolyl or benzopyrazolyl;

[0023] Preferably, A is selected from

[0024] Preferably, A is selected from

[0025] Preferably, Selected from

[0026] Preferably, Selected from

[0027] In some embodiments, R2 is selected from C 1-6 Alkyl, 5-7 membered aryl, the C 1-6 Alkyl, 5-7 membered aryl are optionally substituted by one or more halogen, amino or hydroxyl groups:

[0028] Preferably, R2 is selected from C 1-3 Alkyl, or phenyl, the C 1-3 Alkyl, phenyl is optionally substituted with one to three hydroxyl, amino or fluorine groups;

[0029] Preferably, R2 is selected from methyl, ethyl, isopropyl, trifluoromethyl, -CH2OH, -CH2CH2OH, or phenyl;

[0030] Preferably, R2 is selected from methyl, ethyl, isopropyl, -CH2OH or phenyl.

[0031] In some embodiments, R3 is hydrogen, C 1-6 Alkoxy, C 1-6 Carboxyl, hydroxyl, halogen, -C(O)NR6R7 or -OC(O)-R 11 ;

[0032] Preferably, R3 is hydrogen, C 1-3 Alkoxy, C 1-3 Carboxyl, hydroxyl, halogen, -C(O)NR6R7 or -OC(O)-R 11 ;

[0033] Preferably, R3 is hydrogen, methoxy, -C(O)OH, hydroxy, fluorine, -C(O)NR6R7 or -OC(O)-R 11 ;

[0034] R6 and R7 are independently selected from a single bond, hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O or S, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O or S, optionally substituted by one or two R8 or -(CH2) p -OC(O)R9;

[0035] Wherein, R6 and R7 are each independently selected from a single bond, hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1 N atom, the C 1-3 Alkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1 N atom is optionally replaced by one or two R8 or -(CH2) p -OC(O)R9;

[0036] Preferably, R6 is selected from hydrogen;

[0037] Preferably, R7 is selected from a single bond, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1 N atom, the C 1-3 Alkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1 N atom is optionally replaced by one or two R8 or -(CH2) p -OC(O)R9;

[0038] Preferably, R7 is selected from a single bond, methyl, ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclobutyl, cyclobutane methyl, cyclopropane methyl or cyclohexane methyl, wherein the methyl, ethyl, propyl, isopropyl, neopentyl, cyclobutane methyl, cyclopropane methyl or cyclohexane methyl is optionally replaced by one or two R8 or -(CH2) p -OC(O)R9;

[0039] Or R6, R7 and the nitrogen atom to which they are attached together form a 3-7 membered ring, wherein the 3-7 membered ring is optionally substituted by 1 to 3 halogen, cyano, hydroxyl or -(CH2) p -OC(O)R9;

[0040] Preferably, R6, R7 and the nitrogen atom to which they are attached together form a 4-5 membered ring, wherein the 4-5 membered ring is optionally substituted by 1 to 2 fluorine, cyano, hydroxyl or -(CH2) p -OC(O)R9;

[0041] Preferably, R6, R7 together with the nitrogen atom to which they are attached form azetidine, which is optionally substituted by 1 to 2 fluorine, cyano, hydroxyl or -(CH2)p -OC(O)R9;

[0042] R8 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogen, hydroxyl, C 1-6 carboxyl, a 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O or S; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O or S, optionally substituted by one or more hydroxyl, halogen, C 1-6 Alkyl, or nitro substituted;

[0043] Preferably, R8 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, fluorine, hydroxyl, C 1-3 carboxyl, a 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N or O, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O, optionally substituted by one to three hydroxyl, halogen, C 1-3 Alkyl, nitro substituted;

[0044] Preferably, R8 is selected from methyl, methoxy, fluoro, hydroxy, carboxyl, piperidinyl, cyclopropyl, cyclobutyl, isopropyl, cyclohexyl, morpholinyl, azetidinyl, tetrahydropyranyl, wherein the methyl, piperidinyl, cyclopropyl, cyclobutyl, isopropyl, cyclohexyl, morpholinyl, azetidinyl, tetrahydropyranyl is optionally substituted with one or two fluoro, methyl, hydroxyl, or nitro groups;

[0045] p is selected from 0, 1 or 2;

[0046] R9 is selected from 5-7 membered aryl, 5-7 membered monocyclic heteroaryl containing 1 N atom, 5-7 membered heterocycloalkyl containing 1 N atom, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the 5-7 membered aryl, the 5-7 membered monocyclic heteroaryl containing 1 N atom, the 5-7 membered heterocycloalkyl containing 1 N atom or C 1-6 The alkyl group is optionally substituted with one or more R 10 replaced by;

[0047] Preferably, R9 is selected from 5-7 membered aryl, C 1-6 Alkyl or C 3-7Cycloalkyl, wherein the 5-7 membered aryl, C 1-6 The alkyl group is optionally substituted with one or more R 10 replaced by;

[0048] Preferably, R9 is selected from phenyl, C 1-3 Alkyl or C 3-7 Cycloalkyl, wherein the phenyl, C 1-3 The alkyl group is optionally substituted by one or two R 10 replaced by;

[0049] Preferably, R9 is selected from phenyl, cyclopropane, cyclobutane, tert-butyl, or n-propyl, wherein the phenyl, cyclopropane, cyclobutane, tert-butyl, or n-propyl is optionally replaced by one or two R 10 replaced by;

[0050] Every R 10 are the same as or different from each other and are selected from hydroxyl, nitro, C 1-3 Alkyl, halogen or -ONO2;

[0051] Preferably, R 10 Selected from C 1-3 Alkyl, halogen, -ONO2;

[0052] Preferably, R 10 is selected from fluorine, chlorine, cyano, methyl;

[0053] In some embodiments, R9 is selected from

[0054] Preferably, R9 is selected from

[0055] R 11 is selected from 5-7 membered aryl, wherein the 5-7 membered aryl is optionally substituted by one or more halogen, hydroxyl, nitro or amino;

[0056] Preferably, R 11 is selected from phenyl, which is optionally substituted by one or two halogen, hydroxy, nitro or amino groups;

[0057] Preferably, R 11 for

[0058] Preferably, R3 is selected from hydrogen, methoxy, fluorine, hydroxyl, -C(O)OH,

[0059]

[0060] Preferably, R3 is selected from hydrogen, methoxy, fluorine, hydroxyl,

[0061]

[0062]

[0063] R4 is selected from hydrogen, halogen, -B(OH)2, or dioxaborolanyl, wherein the dioxaborolanyl is replaced by one or more C 1-6 Alkyl substitution;

[0064] Preferably, R4 is selected from hydrogen, fluorine, bromine, -B(OH)2, or

[0065] Preferably, R4 is fluorine or bromine;

[0066] R5 is selected from hydrogen, or C 1-3 alkyl;

[0067] Preferably, R5 is selected from hydrogen, or methyl;

[0068] Preferably, R5 is hydrogen.

[0069] According to one aspect of the present disclosure, the compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, salt or solvate is included, wherein the compound has a structure shown by the following formula (IIIA), (IIIB) or (IIIC) or (IIID):

[0070]

[0071] Wherein, R1, R2, R3, R4 and n are as defined above.

[0072] According to one aspect of the present disclosure, the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, salt or solvate is included, wherein the compound has a structure shown in formula (IV):

[0073]

[0074] Wherein, X1, R2, R3 and R4 are as defined above.

[0075] According to one aspect of the present disclosure, the following compounds and their tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, mesomers, mixtures of racemates and mesomers, pharmaceutically acceptable hydrates, salts or solvates are included:

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] According to one aspect of the present disclosure, a pharmaceutical composition is included, which comprises the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate and pharmaceutically acceptable excipients.

[0086] According to one aspect of the present disclosure, the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate and pharmaceutical composition are used in the preparation of a medicament for preventing and / or treating a disorder associated with abnormal Rho kinase activity.

[0087] According to one aspect of the present disclosure, the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate and pharmaceutical composition are used in the preparation of Rho kinase inhibitors.

[0088] According to one aspect of the present disclosure, there is provided a method for inhibiting Rho kinase in a patient in need thereof, comprising administering to the patient the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof.

[0089] According to one aspect of the present disclosure, there is provided a method for inhibiting Rho kinase in a biological sample, comprising contacting the biological sample with the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof.

[0090] According to one aspect of the present disclosure, there is provided a method for treating a disorder mediated by Rho kinase in a patient in need thereof, comprising administering to the patient the above-mentioned compound or its tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, mesomer, mixture of racemate and mesomer, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof;

[0091] Preferably, the Rho kinase-mediated disorders include, but are not limited to, cardiovascular and cerebrovascular disorders, smooth muscle-related disorders, fibrotic diseases, inflammatory diseases, neurological disorders, oncological disorders, elevated intraocular pressure disorders, diabetes, organ transplantation, infection and autoimmune disorders. DETAILED DESCRIPTION

[0092] I. Definitions

[0093] In the present disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In addition, the protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology and laboratory operation procedures used herein are terms and routine procedures widely used in the corresponding fields. At the same time, in order to better understand the present disclosure, the definitions and explanations of the relevant terms are provided below.

[0094] For purposes of clarity and concise description, features are described herein as part of the same or separate embodiments, however, it will be understood that the scope of the present disclosure may include embodiments having a combination of all or some of the described features.

[0095] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0096] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0097] In this disclosure, It refers to the position where a substituent is bonded.

[0098] In this disclosure, numerical ranges refer to each integer in the given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 1-3 ” means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0099] The term "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "optionally substituted with one or two hydroxy groups" means that it may be substituted with one hydroxy group, it may be substituted with two hydroxy groups, or it may not be substituted with hydroxy groups.

[0100] The term "substituted" or "substituted" means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence state of the specific atom or group is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical achievable. The substituent can be selected from one, two or more of the following substituents: deuterium, halogen group, cyano group, nitro group, -C(=O)R, -C(=O)OR', -OC(=O)R", imide group, amide group, hydroxyl group, substituted or unsubstituted amine group, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted haloalkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aryloxy group, substituted or unsubstituted heteroaryl group, etc., but are not limited thereto.

[0101] When any variable (such as R n ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with one to three R, the group may be optionally substituted with up to three R, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0102] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups, having the indicated number of carbon atoms. 1-6 "Alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It may be divalent, such as methylene, ethylene.

[0103] The term "alkoxy" may be linear, branched or cyclic. The number of carbon atoms of the alkoxy group is not particularly limited, but is preferably 1 to 20. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, neopentoxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n-nonyloxy, n-decyloxy, etc., but are not limited thereto.

[0104] The term "cycloalkylalkyl" refers to a cycloalkyl substituent connected by an alkyl chain. Examples of cycloalkylalkyl substituents include cyclohexylethyl, wherein cyclohexane is connected by an ethane joint. Other examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylethyl, cycloheptylethyl, cyclohexylmethyl. In the present disclosure, examples of halogen groups may include fluorine, chlorine, bromine or iodine.

[0105] In this disclosure, the term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system without heteroatoms and double bonds. For example, the term "C 3-8 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0106] In the present disclosure, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system, which is obtained by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. It includes a bicyclic group containing an aromatic ring fused to a saturated, partially unsaturated ring, or an aromatic carbocyclic ring. Specific examples thereof include phenyl or naphthyl, but are not limited thereto.

[0107] In the present disclosure, the term "heterocycloalkyl" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms. Specific examples of the heterocyclic group include piperidinyl or tetrahydropyrrolyl, but are not limited thereto.

[0108] In the present disclosure, the term "heteroaryl" refers to a monovalent aromatic group containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur. The heteroaryl group may be a monocyclic ring or a polycyclic ring system, such as a bicyclic ring, wherein two or more rings exist in the form of a cyclic ring, a bridged ring or a spirocyclic ring, wherein at least one ring contains one or more heteroatoms. Specific examples of heteroaryl groups include pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furanyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, imidazopyridinyl, benzofuranyl, pyridazinyl, isoindolyl, but are not limited thereto.

[0109] The term "heterocycle" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. The heterocycle may be a monocyclic or polycyclic system, such as a bicyclic ring, wherein two or more rings are present in the form of a cyclic ring, a bridged ring or a spirocyclic ring, wherein at least one ring contains one or more heteroatoms.

[0110] Drug or drug composition

[0111] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0112] The term "tautomer" refers to functional group isomers produced by the rapid movement of an atom in two positions in a compound. The difference between tautomers lies in the migration of protons and double bonds in corresponding positions. Specific examples include but are not limited to tautomers of enol and keto forms.

[0113] The term "enantiomers" refers to two non-superimposable stereoisomers that are mirror images of each other, one being levorotatory and the other dextrorotatory, and the term "diastereomers" refers to two stereoisomers that are not mirror images of each other and have two or more chiral centers.

[0114] The term "racemate" refers to a mixture in which an optically active chiral molecule and its enantiomer are mixed in equal proportions, and their opposite optical effects cancel each other out; the term "mesomorph" refers to a compound that has two or more chiral centers in the molecule, but due to the presence of other factors, such as symmetry planes, the molecule as a whole does not show optical activity. The term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound, in which the parent compound is modified by preparing its acid salt or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkaline or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid. Pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are prepared by reacting with a stoichiometric amount of an appropriate base or acid.

[0115] The medicaments or pharmaceutical compositions of the present disclosure may be administered orally, topically, parenterally or mucosally (eg, buccally, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers.

[0116] For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose): fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate): lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.): disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0117] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present disclosure containing the compound of formula I as the active compound can also introduce beads, microspheres or microcapsules, such as those constructed from polyglycolic acid / lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.

[0118] The medicine or pharmaceutical composition of the present disclosure can be delivered parenterally, that is, administered intravenously (iv), intracerebroventricularly (icv), subcutaneously (sc), intraperitoneally (ip), intramuscularly (im), subcutaneously (sd) or intradermally (id), by direct injection, for example, by bolus injection or continuous infusion. The formulation for injection can be presented in unit dosage form, for example, in an ampoule or multi-dose container with an added preservative. The composition can be in the shape of an excipient, in the form of a suspension, solution or emulsion in an oil or aqueous vehicle, and can include formulation agents such as anti-settling agents, stabilizers and / or dispersants. Alternatively, the active ingredient can be reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use in powder form.

[0119] The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as a suppository or retention enema (eg, containing a conventional suppository base such as cocoa butter or other glycerides).

[0120] Dosage forms for topical administration of the disclosed compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0121] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0122] Ophthalmic formulations, eye ointments, powders, solutions (eg, eye drops), etc. are also contemplated as being within the scope of this disclosure.

[0123] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Appropriate fluidity can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0124] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents may be included, such as parabens, chlorobutanol, phenol sorbic acid, etc. to ensure that microorganisms are prevented from acting on the subject compound. It may also be desirable to include isotonic agents (such as sugar, sodium chloride, etc.) in the composition. In addition, the extended absorption of injectable drug forms may be achieved by including agents (such as aluminum monostearate and gelatin) that delay absorption.

[0125] The term "treatment" includes suppressing, alleviating, preventing or eliminating one or more symptoms or side effects associated with the treated disease, illness or disorder. The term "effective amount" or "therapeutically effective amount" refers to a dosage that is enough to treat, suppress or alleviate one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effects. The precise dosage will vary according to a variety of factors, such as the variable (e.g., age, immune system health, etc.) that the subject depends on, the disease or illness, and the treatment applied. The effect of the effective amount can be relative to a control. These controls are known in the art and discussed in this article, and can be, for example, the condition of the subject before or when the drug or drug combination is not applied, or in the case of a drug combination, the combined effect can be compared with the effect of only applying a drug.

[0126] The term "pharmaceutical composition" means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0127] According to the above contents of the present disclosure, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present disclosure, other various forms of modifications, replacements or changes may be made.

[0128] II. Embodiment

[0129] The raw materials and equipment used in the specific embodiments of the present disclosure are all known products, which are obtained by purchasing commercially available products.

[0130] Example 1: Preparation of Compounds 1 and 2:

[0131]

[0132] Intermediate 1b: Preparation of 7-bromo-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-one:

[0133] The raw material 1a (2.16 g of 2-amino-4-bromobenzoic acid, 10 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and then a tetrahydrofuran solution of triphosgene (1.04 g, 3.50 mmol) was slowly dripped into it at 0°C. The reaction was stirred at room temperature for 4 hours. After adding ice water to the system, it was filtered with suction, and the filter cake was washed with dichloromethane to obtain the intermediate 1b. The yield was 80%, 1HNMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 7.96 (dJ=7.4Hz, 1H), 7.45 (dd, J=7.3, 1.6Hz, 1H), 7.34 (d, J=1.3Hz, 1H); MS (ESI, positive ion) m / z: 241.88, [M+H] + .

[0134] Intermediate 1c: Preparation of 7-bromo-1-methyl-2H-benzo[d][1,3]oxazine-2,4-(1H)-dione:

[0135] Add intermediate 1b (1.60 g, 6.70 mmol) to 20 mL of anhydrous DMF, then slowly add sodium hydride (0.30 g, 8.00 mmol) at 0°C, stir the reaction system at low temperature for 20 minutes, add 500 μL of iodomethane, stir the reaction at room temperature for 2 hours, then add methanol to quench the excess sodium hydride, concentrate and mix the sample, and perform column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the target intermediate 1c. The yield is 75%. 1 H NMR (400MHz, DMSO-d6) δ7.92 (d, J=7.5Hz, 1H), 7.70 (d, J=1.5Hz, 1H), 7.49 (dd, J=7.5, 1.6Hz, 1H), 3.40 (s, 3H); MS (ESI, positive ion) m / z: 255.96 [M+H] + .

[0136] Intermediate 1d: (S)-8-Bromo-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0137] Triethylamine (2.4 mL, 17.6 mmol) was added to a mixture of intermediate 1c (1.5 g, 5.86 mmol) and L-alanine (0.57 g, 6.45 mmol) in DME and water. The reaction system was stirred at 60°C for 2 h, concentrated under reduced pressure, and 10 mL of acetic acid was added. The mixture was then heated under reflux for 4 h. The acetic acid was further removed under reduced pressure, and the mixture was extracted with dichloromethane and water. The organic phase was washed with saturated brine, dried with magnesium sulfate, filtered with diatomaceous earth, and the filtrate was mixed with a sample column for chromatography (dichloromethane / methanol = 20:1) to obtain intermediate 1d. The yield was 40%. MS (ESI, positive ion) m / z: 283.12, 285.30. [M+H] + .

[0138] Intermediate 1e: (S)-8-Bromo-4-(3-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0139] The intermediate 1d (88 mg, 0.22 mmol) was dissolved in tetrahydrofuran, and then the reaction system was cooled to 0°C, sodium hydride (8 mg, 0.32 mmol) was added, stirred for 10 min, and then 3-methoxybenzyl bromide (80 mg, 0.4 mmol) was added dropwise, and the reaction was moved to room temperature for 1 h. The reaction was monitored by TLC. The excess sodium hydride was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then column chromatography (petroleum ether / ethyl acetate = 2:1) was performed to obtain a white solid as the intermediate 1e. The yield was 80%. MS (ESI, positive ion) m / z: 403.20, 405.25. [M+H]+.

[0140] Compound 1: (S)-4-(3-methoxybenzyl)-1,3-dimethyl-8-(pyridin-4-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0141] The intermediate 1e (48 mg, 0.12 mmol), 4-pyridine boronic acid (18 mg, 0.15 mmol), K2CO3 (50 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (8 mg, 0.01 mmol) were placed in a two-necked bottle, and a mixture of 1,4-dioxane / water (V / V=5 / 1) was added thereto. The mixture was reacted at 85°C for 5 h under argon protection. The reaction was completed by TLC monitoring. After cooling, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate=1:5) to obtain a white solid, which was compound 1. The yield was 80%. 1 H NMR (400MHz, DMSO-d6) δ8.74-8.67(m, 1H), 7.95-7.73(m, 4H), 7.67-7.53(m, 3H), 7.23(t, J=7.8Hz, 1H), 6.84-6.77(m, 2H), 4.80-4.63 (m, 2H), 4.45 (d, J=6.9Hz, 1H), 3.75-3.70 (s, 3H), 3.41 (s, 3H), 1.27 (d, J=6.9Hz, 3H); MS (ESI, positive ion)m / z:402.35.[M+H] + .

[0142] Compound 2: (S)-4-(3-methoxybenzyl)-1,3-dimethyl-8-(2-aminopyridin-4-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0143] The synthesis of compound 2 is similar to that of compound 1, and is obtained by reacting intermediate 1e with 2-amino-4-pyridineboronic acid with a yield of 60%.

[0144] 1 H NMR (400MHz, DMSO-d6) δ8.02 (d, J=5.4Hz, 1H), 7.86 (dd, J=8.2, 6.6Hz, 1H), 7.63-7.57 (m, 2H), 7.23 (q, J=7.9Hz, 1H), 6.87 (dd, J=5.4, 1.7Hz, 1H), 6.84-6.73 (m, 4H), 4.80-4.62 (m, 2H), 4.44 (q, J=6.6Hz, 1H), 3.73 (d, J=5.0Hz, 3H), 3.38 (s, 3H), 1.27 (d, J=6.9Hz, 3H); MS (ESI, positive ion)m / z:417.40.[M+H] + .

[0145] Example 2: Preparation of compounds 3 and 4:

[0146]

[0147] Intermediate 3a: (R)-8-Bromo-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0148] The preparation method of intermediate 3a is similar to that of 1d, using intermediate 1c and D-alanine as raw materials, and the yield is 40%. MS (ESI, positive ion) m / z: 283.16, 285.32. [M+H]+.

[0149] Intermediate 3b: (R)-8-bromo-4-(3-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0150] The preparation method of intermediate 3b is similar to that of 1e, and the intermediate 3a is used as the raw material to obtain the intermediate 3b with a yield of 80%. MS (ESI, positive ion) m / z: 403.23, 405.36. [M+H]+.

[0151] Compound 3: (R)-4-(3-methoxybenzyl)-1,3-dimethyl-8-(pyridin-4-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0152] The preparation method of compound 3 is similar to that of 1, using intermediate 3b and 4-pyridine boronic acid as raw materials, and the yield is 75%.

[0153] 1 H NMR (400MHz, DMSO-d6) δ8.74-8.67(m, 1H), 7.95-7.73(m, 4H), 7.67-7.53(m, 3H), 7.23(t, J=7.8Hz, 1H), 6.84-6.77(m, 2H), 4.80-4.63 (m, 2H), 4.45 (d, J=6.9Hz, 1H), 3.75-3.70 (s, 3H), 3.41 (s, 3H), 1.27 (d, J=6.9Hz, 3H); MS (ESI, positive ion)m / z:402.33.[M+H] + .

[0154] Intermediate 3c: (R)-4-(3-hydroxybenzyl)-1,3-dimethyl-8-(pyridin-4-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0155] Compound 3 (80 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (48 μL, 0.5 mmol) was added under ice-water bath, and the reaction was allowed to react at room temperature for 1 hour. TLC monitored the reaction to be complete, and the reaction solution was quenched with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate = 1:10) to obtain a white solid, which was intermediate 3c, with a yield of 30%. MS (ESI, positive ion) m / z: 388.23.[M+H] + .

[0156] Compound 4: (R)-3-((1,3-dimethyl-2,5-dicarbonyl-8(pyridin-4-yl)-1,2,3,5-tetrahydro-4-hydro-benzo[e][1,4]diazepine -4-yl)phenyl 2,4-dimethylbenzoic acid methyl ester

[0157] Intermediate 3c (38 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL), and triethylamine (30 mg, 0.3 mmol), 2,4-dimethylbenzoyl chloride (32 mg, 0.2 mmol), and 4-dimethylaminopyridine (5 mg, 0.04 mmol) were added and reacted at room temperature for two hours. TLC monitored the reaction to be complete, methanol was added to terminate the reaction, and the mixture was directly concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 4.

[0158] 1H NMR (400MHz, Methanol-d4) δ8.94-8.88(m, 2H), 8.45-8.38(m, 2H), 8.08-8.01 (m, 2H), 7.95-7.88 (m, 2H), 7.41 (t, J=7.9Hz, 1H), 7.24 (d, J=8.1Hz, 1H), 7.20 -7.09(m, 4H), 5.01-4.93(m, 1H), 4.83(s, 1H), 4.55-4.49(m, 1H), 3.48(d, J=4 .6Hz, 3H), 2.59 (s, 3H), 2.38 (s, 3H), 1.45 (d, J=6.9Hz, 3H).MS (ESI, positive ion)m / z:520.32[M+H] + .

[0159] The preparation method of compound 5-6 is similar to that of compound 3, as shown in Table 1 below.

[0160] Table 1: Preparation methods of compounds 5-6

[0161]

[0162] Example 3: Preparation of Compounds 7 and 8:

[0163]

[0164] Intermediate 7a: (R)-8-Bromo-4-((6-fluoro-2-pyridyl)methyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0165] The synthesis of intermediate 7a is similar to that of intermediate 3b, and is obtained by reacting intermediate 3a with 2-bromomethyl-6-fluoropyridine as raw materials, with a yield of 90%. MS (ESI, positive ion) m / z: 392.25, 394.28. [M+H]+.

[0166] Compound 7: (R)-4-((6-fluoro-2-pyridinyl)methyl)-1,3-dimethyl-8-(2-aminopyridin-4-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0167]

[0168] The synthesis of compound 7 is similar to that of compound 3, and is obtained by reacting intermediate 7a with 2-amino-4-pyridineboronic acid as raw materials, with a yield of 70%.

[0169] 1 H NMR (400MHz, DMSO-d6) δ8.02 (d, J=5.3Hz, 1H), 7.98-7.90 (m, 1H), 7.84 (d, J=8 .0Hz, 1H), 7.64-7.56 (m, 2H), 7.27-7.20 (m, 1H), 7.06-7.00 (m, 1H), 6.90-6.8 5 (m, 1H), 6.77 (s, 1H), 6.07 (s, 2H), 4.97 (d, J = 16.6Hz, 1H), 4.60 (d, J = 16.8Hz , 1H), 4.50-4.42 (m, 1H), 3.38 (s, 2H), 1.28 (d, J=6.9Hz, 3H); MS (ESI, positive ion)m / z:406.41.[M+H]+.

[0170] Intermediate 7b: (R)-8-Bromo-4-((6-hydroxy-2-pyridinyl)methyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0171]

[0172] Intermediate 7a (60 mg, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL) and then added with aqueous hydrochloric acid solution (2 mL, 4 mol / L). The mixture was reacted at 50°C for 5 hours. After the reaction was complete, sodium bicarbonate was added to adjust the pH to neutral. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 7b was obtained after silica gel column chromatography with a yield of 20%. MS (ESI, positive ion) m / z: 390.23, 392.24. [M+H]+.

[0173] Compound 8: (R)-4-((6-hydroxy-2-pyridinyl)methyl)-1,3-dimethyl-8-(2-aminopyridin-4-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepine -2,5-dione preparation:

[0174]

[0175] The synthesis of compound 8 is similar to that of compound 1, and is obtained by reacting intermediate 7b with 2-amino-4-pyridineboronic acid as raw materials, with a yield of 70%.

[0176] 1 H NMR (400MHz, DMSO-d6) δ8.02 (d, J=5.3Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.76-7.56 (m, 4H), 7.37 (dd, J=9.0, 6.8Hz, 1H), 6.87 (dd, J=5.4, 1.7Hz, 1H), 6.77 (s, 1H), 6.21 (d, J=9.1Hz, 1H), 6.07 (s, 2H), 4.59 (d, J=17.2Hz, 1H), 4.50-4.39 (m, 2H), 3.42 (s, 3H), 1.30 (d, J=3.2Hz, 2H); MS (ESI, positive ion)m / z:404.41.[M+H]+.

[0177] Example 4: Preparation of compounds 9, 10, and 11:

[0178]

[0179] Intermediate 9a: (R)-3-((8-bromo-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of methyl 4-(4-yl)methylene)benzoate:

[0180]

[0181] The synthesis of intermediate 9a is similar to that of intermediate 3b, and is obtained by reacting intermediate 3a with methyl 3-bromomethylbenzoate as raw materials, with a yield of 85%. MS (ESI, positive ion) m / z: 431.18, 433.21. [M+H]+.

[0182] Intermediate 9b: (R)-3-((8-(pyridin-4-yl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of methyl 4-(4-yl)methylene)benzoate:

[0183]

[0184] The synthesis of intermediate 9b is similar to compound 3, and is obtained by reacting intermediate 9a with 4-pyridine boronic acid as raw materials, with a yield of 75%. MS (ESI, positive ion) m / z: 430.30.[M+H]+.

[0185] Intermediate 9c: (R)-3-((8-(2-aminopyridin-4-yl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of 4-(4-yl)methylene)benzoic acid:

[0186]

[0187] Intermediate 9b (500 mg, 1.16 mmol) was dissolved in methanol / water (5 mL, V / V, 4 / 1) and sodium hydroxide (120 mg, 3.0 mmol) was added. The mixture was reacted at room temperature for 4 hours. TLC monitored the reaction to be complete. Dilute hydrochloric acid was added to adjust the pH to neutral, and the mixture was concentrated under reduced pressure. Intermediate 9c was obtained by purification by silica gel column chromatography with a yield of 90%. MS (ESI, positive ion) m / z: 416.33.[M+H]+.

[0188] Compound 9: (R)-3-((8-(pyridin-4-yl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of N-((3-hydroxycyclobutyl)methyl)benzamide:

[0189]

[0190] Intermediate 9c (50 mg, 0.12 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (46 μL, 0.3 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol) were added. After stirring at room temperature for 10 minutes, 3-(aminomethyl)cyclobutanol (24 mg, 0.24 mmol) was added and reacted at room temperature for 2 hours. TLC showed that the raw material reacted completely, and the reaction solution was directly purified by reverse silica gel C-18 to obtain compound 9 with a yield of 60%.

[0191] 1H NMR (400MHz, Methanol-d4) δ8.82 (s, 2H), 8.19 (d, J = 5.6Hz, 2H), 8.06 (d, J = 8.6Hz, 1 H), 7.90-7.84(m, 2H), 7.75-7.68(m, 2H), 7.49-7.40(m, 2H), 5.05-4.87(m, 2H), 4.5 7-4.48(m, 1H), 4.08-4.01(m, 1H), 3.46(s, 3H), 3.39(d, J=6.6Hz, 2H), 2.46-2.32(m , 1H), 2.10-1.98 (m, 2H), 1.72-1.59 (m, 2H), 1.41 (d, J=6.9Hz, 3H).MS (ESI, positive ion)m / z:499.43.[M+H]+.

[0192] Compound 10: (R)-3-((8-(pyridin-4-yl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of methyl 2,4-dimethylbenzoate:

[0193]

[0194] Compound 9 (50 mg, 0.12 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (46 μL, 0.3 mmol), 2, 4-dimethylbenzoyl chloride (40 mg, 0.24 mmol) and 4-dimethylaminopyridine (3 mg, 0.02 mmol) were added, and the mixture was reacted at room temperature for 2 hours. TLC showed that the raw material was completely reacted, and the reaction solution was directly purified by reverse silica gel C-18 to obtain compound 10 with a yield of 60%.

[0195] 1H NMR (400MHz, DMSO-d6) δ8.91 (d, J=5.7Hz, 2H), 8.55 (t, J=5.7Hz, 1H), 8.24 (d, J=5.6Hz, 2H), 8.00-7 .86 (m, 3H), 7.74-7.69 (m, 3H), 7.39 (s, 2H), 7.15-7.04 (m, 2H), 4.98 (t, J=7.3Hz, 1H), 4.90 (d, J=15 .9Hz, 1H), 4.70 (d, J=16.3Hz, 1H), 4.45 (t, J=6.7Hz, 1H), 3.40 (s, 3H), 3.35 (t, J=6.2Hz, 3H), 2.45 ( s, 3H), 2.30 (s, 3H), 2.30-2.22 (m, 2H), 1.94-1.87 (m, 2H), 1.26 (d, J=6.8Hz, 3H).MS (ESI, positive ion)m / z: 631.31.[M+H]+.

[0196] Compound 11: (R)-3-((8-(pyridin-4-yl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of cyclobutyl 3,3-difluorocyclobutyrate:

[0197]

[0198] Compound 9 (50 mg, 0.12 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (46 μL, 0.3 mmol) and 2-(7-azobenzotriazole)-N, N, N′, N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), 3,3-difluorocyclobutanecarboxylic acid (36 mg, 0.24 mmol) were added, and the mixture was reacted at room temperature for 2 hours. TLC showed that the raw material was completely reacted, and the reaction solution was directly purified by reverse silica gel C-18 to obtain compound 11 with a yield of 60%.

[0199] 1H NMR (400MHz, DMSO-d6) δ9.03-8.83 (m, 2H), 8.52 (t, J = 5.8Hz, 1H), 8.24 (d, J = 5.5Hz, 2H), 8.05-7.86 (m , 3H), 7.78-7.63 (m, 2H), 7.49-7.32 (m, 2H), 4.91 (d, J=16.1Hz, 1H), 4.85-4.78 (m, 1H), 4.69 (d, J=16. 2Hz, 1H), 4.49-4.44 (m, 1H), 3.41 (d, J=2.7Hz, 3H), 3.33-3.29 (m, 2H), 3.10-2.99 (m, 1H), 2.90-2.63 ( m, 5H), 2.40 (d, J=7.1Hz, 1H), 2.20 (s, 1H), 1.87-1.71 (m, 2H), 1.27 (d, J=6.9Hz, 3H).MS (ESI, positive ion)m / z: 617.44.[M+H]+.

[0200] The preparation methods of the compounds in the following table are similar to those of compounds 9-11.

[0201] Table 2: Preparation methods of Examples 12-52, 94-111

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] Example 5: Preparation of Compound 53:

[0213]

[0214] The synthesis of intermediate 53a is similar to that of intermediate 3a, and is obtained by reacting intermediate 1c with D-serine as raw materials, with a yield of 30%. MS (ESI, positive ion) m / z: 299.23, 301.30 [M+H]+.

[0215] Intermediate 53b: (R)-3-((8-bromo-3-(hydroxymethyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoic acid methyl ester:

[0216]

[0217] Intermediate 53a (95 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide, and then the reaction system was cooled to 0°C, cesium carbonate (117 mg, 0.36 mmol) and 3-bromomethylbenzoate (82 mg, 0.36 mmol) were added, and the reaction was moved to room temperature for 5 h. The reaction was completed under TLC monitoring, and the organic phase was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then column chromatographed (petroleum ether / ethyl acetate = 2:1) to obtain a white solid as intermediate 53b. The yield was 60%. MS (ESI, positive ion) m / z: 447.23, 449.25 [M+H]+.

[0218] Intermediate 53c: (R)-3-((8-(4-aminopyridinyl)-3-(hydroxymethyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoic acid methyl ester:

[0219]

[0220] The synthesis of intermediate 53c is similar to compound 3, and is obtained by reacting intermediate 53b with 4-amino-2-pyridine boronic acid as raw materials, with a yield of 70%. MS (ESI, positive ion) m / z: 461.22 [M+H]+.

[0221] Intermediate 53d: (R)-3-((8-(4-aminopyridinyl)-3-(hydroxymethyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoic acid:

[0222]

[0223] The synthesis of intermediate 53d is similar to compound 8, and is obtained from intermediate 21c with a yield of 80%. MS (ESI, positive ion) m / z: 447.31 [M+H]+.

[0224] Compound 53: (R)-3-((8-(4-aminopyridinyl)-3-(hydroxymethyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)-N-((1-methyl-4-piperidinyl)methyl)benzamide:

[0225]

[0226] The synthesis of compound 53 is similar to that of compound 9. It is obtained by reacting intermediate 53d with (1-methyl-4-piperidinyl)methylamine with a yield of 60%.

[0227] 1 H NMR (400MHz, DMSO-d6) δ8.63-8.54 (m, 1H), 9.74-9.59 (m, 1H), 8.08 (d, J=6.9Hz, 1H), 8.02 -7.62(m, 5H), 7.51-7.31(m, 2H), 7.24(s, 2H), 5.37-5.28(m, 1H), 4.67-4.49(m, 1H), 4.32 -4.19(m, 1H), 3.88-3.73(m, 2H), 3.33(s, 3H), 3.21-3.13(m, 3H), 2.96-2.83(m, 2H), 2.80 -2.66(m, 4H), 1.89-1.74(m, 2H), 1.49-1.27(m, 2H), 0.87-0.80(m, 1H); MS (ESI, positive ion)m / z: 557.52[M+H]+.

[0228] The preparation methods of compounds 54-59 in the following table are similar to that of compound 53.

[0229] Table 3: Preparation methods of compounds 54-59

[0230]

[0231]

[0232] Example 6: Preparation of Compound 60

[0233]

[0234] Intermediate 60a: (R)-3-((8-(4-chloropyridinyl)-3-methyl-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoic acid methyl ester:

[0235]

[0236] The synthesis of intermediate 60a is similar to that of 9b, and is obtained by reacting intermediate 9a with 2-chloro-4-pyridineboronic acid as raw materials, with a yield of 88%. MS (ESI, positive ion) m / z: 464.22 [M+H]+.

[0237] Intermediate 60b: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridyl)-3-methyl-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoic acid methyl ester:

[0238]

[0239] The intermediate 60a (93 mg, 0.2 mmol) was dissolved in anhydrous toluene (3 mL), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), potassium tert-butoxide (67 mg, 0.6 mmol), palladium acetate (5 mg, 0.02 mmol), and cyclopropylmethylamine (42 mg, 0.6 mmol) were added, and the mixture was reacted at 100°C for 12 hours under nitrogen protection. After the reaction was completed as monitored by TLC, the reaction solution was directly concentrated under reduced pressure and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 0:1) to obtain a white solid as the intermediate 60b. MS (ESI, positive ion) m / z: 499.33 [M+H]+.

[0240] Intermediate 60c: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridinyl)-3-methyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoic acid:

[0241]

[0242] The synthesis of intermediate 60c is similar to that of intermediate 9c, and is obtained from intermediate 60b with a yield of 80%. MS (ESI, positive ion) m / z: 485.31 [M+H]+.

[0243] Intermediate 60d: tert-butyl-(R)-3-((3-((8-(2-((cyclopropylmethyl)amino-4-pyridinyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzamide)methyl)-3-hydroxyazetidin-1-carboxylate:

[0244]

[0245] The synthesis of intermediate 60d is similar to compound 9, and is obtained by reacting intermediate 60c and tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate as raw materials, with a yield of 75%. MS (ESI, positive ion) m / z: 669.50 [M+H]+.

[0246] Compound 60: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridinyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)-N-((3-hydroxyazetidin-3-yl)methyl)benzamide.

[0247]

[0248] Intermediate 60d (60 mg, 0.1 mmol) was dissolved in methanol (1 mL), and hydrogen chloride (0.1 mL, 4 mol / L 1,4-dioxane solution) was added and reacted at room temperature for 2 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure and then purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain a white solid as compound 60. 1 H NMR (400MHz, Methanol-d4) δ8.05-7.99 (m, 2H), 7.94-7.90 (m, 1H), 7.82-7.74 (m, 3H), 7.52-7. 46(m, 2H), 7.41-7.38(m, 1H), 7.28-7.24(m, 1H), 5.13-4.99(m, 1H), 4.83-4.71(m, 1H), 4.56(s , 2H), 4.27-4.19(m, 3H), 4.15-4.07(m, 1H), 3.99-3.93(m, 1H), 3.75-3.67(m, 2H), 3.45(s, 3H) , 1.45-1.38(m, 3H), 1.33-1.17(m, 2H), 0.74-0.62(m, 2H), 0.43-0.35(m, 2H).MS(ESI, positive ion)m / z: 569.36[M+H1+.

[0249] The preparation methods of compounds 112-116 in the following table are similar to that of compound 60.

[0250] Table 4: Preparation methods of compounds 112-116

[0251]

[0252]

[0253] Example 7: Preparation of Compounds 61 and 62

[0254]

[0255] Compound 61: (R)-1-(3-((8-(2-((cyclopropylmethyl)amino-4-pyridinyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzoyl)azetidinyl-3-carbonitrile:

[0256]

[0257] The synthesis of compound 61 is similar to that of compound 21, and is obtained from intermediate 60b with a yield of 75%. 1 HNMR (400MHz, Methanol-d4) δ8.03 (d, J=8.6Hz, 1H), 7.91 (d, J=6.8Hz, 1H), 7.76-7.72 (m, 2H), 7.56-7.52 (m, 2H), 7.49-7.44 (m, 2H), 7.31 (d, J=1.7Hz, 1H), 7.25-7.21 (m, 1H), 5.01 (d, J=16. 1Hz, 1H), 4.79 (d, J=16.3Hz, 1H), 4.66-4.41 (m, 4H), 4.35-4.25 (m, 2H), 3.83-3.72 (m, 1H), 3.4 8-3.43 (m, 5H), 1.40 (d, J=6.9Hz, 3H), 0.74-0.65 (m, 2H), 0.42-0.35 (m, 2H).MS (ESI, positive ion)m / z: 549.33[M+H]+.

[0258] Intermediate 62a: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridinyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)-N-((3-hydroxycyclobutyl)methylene)benzamide:

[0259]

[0260] The synthesis of intermediate 62a is similar to compound 61, and is obtained from intermediate 60b with a yield of 75%. MS (ESI, positive ion) m / z: 568.45 [M+H]+.

[0261] Compound 62: (R)-3-((3-((8-(2-((cyclopropylmethyl)amino-4-pyridinyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine -4-yl)methylene)benzamide)methyl)cyclobutyl 3,4-dichlorobenzoate:

[0262]

[0263] The synthesis of compound 62 is similar to that of compound 10, and is obtained by reacting intermediate 62a and 3,4-dichlorobenzoyl chloride as raw materials, with a yield of 75%.

[0264] 1 H NMR (400MHz, Methanol-d4) δ8.08-8.00 (m, 2H), 7.93-7.84 (m, 2H), 7.75-7.23 (m, 4H), 7.63 (d, J=8.4Hz, 1H), 7.49-7 .38 (m, 2H), 7.33 (d, J = 1.8Hz, 1H), 7.25-7.23 (m, 1H), 5.14-5.05 (m, 1H), 5.01 (d, J = 16.0Hz, 1H), 4.80 (d, J = 16.0Hz, 1 H), 4.53-4.44(m, 1H), 3.49-3.47(m, 2H), 3.44(d, J=2.5Hz, 3H), 3.28(s, 2H), 2.64-2.58(m, 2H), 2.40-2.33(m, 1H), 2.05-1.97 (m, 2H), 1.40 (d, J=6.9Hz, 3H), 1.24-1.14 (m, 1H), 0.72-0.64 (m, 2H), 0.40-0.37 (m, 2H).MS (ESI, positive ion)m / z: 740.55[M+H]+.

[0265] Example 8: Preparation of Compound 117

[0266]

[0267] Intermediate 117a: 2-bromoacetic acid (R)-3-((3-((1,3-dimethyl-2,5-dioxa-8-(pyridin-4-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of cyclobutyl ester

[0268]

[0269] The synthesis of intermediate 117a was similar to that of compound 10, using 2-bromopropionyl chloride and compound 96 as raw materials, with a yield of 82%, MS (ESI, positive ion) m / z: 637.37, 639.36 [M+H]+.

[0270] Compound 117: 2-((R)-2-methylpyrrolidin-1-yl)-acetic acid (R)-3-((3-((1,3-dimethyl-2,5-dioxa-8-(pyridin-4-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine Preparation of cyclobutyl ester

[0271]

[0272] Intermediate 117a (100 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (52 mg, 0.38 mmol) and (R)-2-methyltetrahydropyrrole (21 mg, 0.25 mmol) were added. The mixture was reacted at room temperature for 2 hours and purified by C-18 reverse silica gel to obtain compound 117 with a yield of 52%. 1 H NMR (400MHz, DMSO-d6) δ8.75-8.66 (m, 2H), 8.60 (s, 1H), 7.98-7.87 (m, 1H), 7.87-7.73 (m, 4H), 7.53 (s, 2H), 7.23 (d, J=9.5Hz, 1H), 4.91 (d, J=16.8Hz, 1H), 4.88-4.75 (m, 1H), 4.70 (d, J=16.4H z, 1H), 4.54-4.44 (m, 1H), 3.39 (s, 3H), 3.14-2.96 (m, 2H), 2.46-2.30 (m, 4H), 2.30-2.11 (m, 1H) , 1.94-1.71(m, 5H), 1.71-1.54(m, 2H), 1.32-1.21(m, 5H), 1.01-0.92(m, 3H).MS(ESI, positive ion)m / z: 642.50[M+H]+.

[0273] Test Example 1: Benzodiazepine In vitro kinase assay of ketone derivatives

[0274] The in vitro kinase assay was performed using the Kinase Profiler service provided by Eurofins. The experimental method is briefly described as follows: the small molecule to be tested (0.001-10 μM), the protein kinase to be tested, and a mixture containing substrate, 10 mM magnesium acetate and [γ- 33 P-ATP] buffer was incubated together, and the reaction was started by adding Mg\ATPmix. After incubation at room temperature for a period of time, 3% phosphate solution was added to the buffer to terminate the reaction. Then 10μL of the reaction mixture was quantitatively drawn and dropped on P30 filter paper, and washed with 75mM phosphate solution three times, and then washed with methanol once. After the P30 filter paper was dried, scintillation liquid was added for scintillation counting. The inhibitory activity of the compound was measured by the half inhibitory concentration IC 50 To indicate that IC 50 The values ​​were obtained by fitting the inhibition rates corresponding to each concentration gradient, and the results are shown in Table 5. Based on the results in the table, relative to ROCKI kinase, the compounds of the present invention have good selective inhibitory activity against ROCKII kinase.

[0275] Table 5: Kinase inhibition data of individual compounds

[0276]

[0277] Note: “ / ” means not tested.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, n is selected from 1 or 2; X1 is selected from CH; n R1 may be the same or different; R1 is selected from hydrogen, amino or C 1-3 Alkyl, the amino group is optionally substituted by cyclopropylmethyl, methyl, ethyl, isopropyl; A is selected from , , , or ; R2 is selected from methyl, ethyl, isopropyl, trifluoromethyl, -CH2OH, -CH2CH2OH or phenyl; R3 is selected from hydrogen, methoxy, fluorine, hydroxyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R4 is selected from hydrogen, fluorine, bromine; R5 is selected from hydrogen or methyl.

2. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Selected from , , , , , , , , or .

3. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R4 is hydrogen or fluorine.

4. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R5 is hydrogen.

5. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in formula (IIIA), (IIIB), (IIIC) or (IIID): Wherein, R1, R2, R3, R4 and n are defined as in formula (I) in claim 1.

6. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in formula (IV): Wherein, X1, R2, R3 and R4 are defined as in formula (I) in claim 1.

7. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: n is selected from 1 or 2; X1 is selected from CH; n R1 may be the same or different; R1 is selected from hydrogen, amino or C 1-3 Alkyl, the amino group is optionally substituted by cyclopropylmethyl, methyl, ethyl, isopropyl; A is selected from or ; R2 is selected from methyl, ethyl, -CH2OH or -CH2CH2OH; R3 is selected from methoxy, , , , , , , , , , , , , , , , , ; R4 is selected from hydrogen or fluorine; R5 is selected from hydrogen.

8. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: n is selected from 1 or 2; X1 is selected from CH; n R1 may be the same or different; R1 is selected from hydrogen, amino or C 1-3 Alkyl, the amino group is optionally substituted by cyclopropylmethyl, methyl, ethyl, isopropyl; A is selected from ; R2 is selected from methyl; R3 is selected from , , , methoxy, , , ; R4 is selected from hydrogen or fluorine; R5 is selected from hydrogen.

9. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: n is selected from 1 or 2; X1 is selected from CH; n R1 may be the same or different; R1 is selected from hydrogen, amino or C 1-3 Alkyl, the amino group is optionally substituted by cyclopropylmethyl, methyl, ethyl, isopropyl; A is selected from ; R2 is selected from methyl; R3 is selected from , , ; R4 is selected from hydrogen or fluorine; R5 is selected from hydrogen.

10. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: n is selected from 1 or 2; X1 is selected from CH; n R1 may be the same or different; R1 is selected from hydrogen, amino or C 1-3 Alkyl, the amino group is optionally substituted by cyclopropylmethyl, methyl, ethyl, isopropyl; A is selected from ; R2 is selected from methyl; R3 is selected from methoxy, , , ; R4 is selected from hydrogen or fluorine; R5 is selected from hydrogen.

11. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 。 12. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 13. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 、 、 、 、 、 、 、 、 、 。 14. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 、 、 、 、 。 15. A pharmaceutical composition, characterized in that The composition comprises the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

16. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the preparation of a medicament for preventing and / or treating a disorder associated with abnormal Rho kinase activity.

17. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a Rho kinase inhibitor.

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