Benzodiazepine compounds and their applications as Rho kinase inhibitors

Abstract

A benzodiazepine compound having a structure represented by formula (I) and functioning as a ROCK II kinase inhibitor, as well as the use of the compound in Rho kinase inhibitor drugs and a method for preparing the same. JPEG2026513014000117.jpg6297

Description

[Technical Field]

[0001] This disclosure relates to the pharmaceutical field, and more particularly to benzodiazepine compounds having Rho kinase inhibitory activity and methods for producing the same. [Background technology]

[0002] Rho kinase (ROCK) is one of the first downstream targets of the Rho protein discovered. It is a type of serine / threonine protein kinase with a relative molecular weight of 160 kDa and includes two subtypes: ROCKI and ROCKII. ROCK plays a crucial role in a range of cellular life activities, including cell mitosis, cytoskeletal regulation, muscle cell contraction, and tumor cell invasion. According to literature reports, ROCK is associated with many diseases, including hypertension, pulmonary arterial hypertension, cardiovascular disease, inflammation, autoimmune diseases, lung diseases, and ophthalmic diseases.

[0003] Current glaucoma medications primarily aim to lower intraocular pressure by promoting aqueous humor outflow. However, normal-tension glaucoma cases are still seen in clinical practice, and the clinical definition of glaucoma is progressive retinal ganglion cell loss due to various causes, progression of optic disc cupping, and visual field defects. These factors suggest that, in the development of glaucoma medications, protecting the optic nerve is even more important than lowering intraocular pressure. Netalusdil is currently the only pan-ROCK inhibitor approved by the U.S. Food and Drug Administration (FDA) and is used to treat open-angle glaucoma and ocular hypertension, but clinical trials have reported conjunctival hyperemia and blepharitis as its main side effects. On the other hand, ROCK II inhibitors can lower intraocular pressure by regulating the actin cytoskeleton, extracellular matrix, and Schlemm's canal endothelial cell function in the trabecular meshwork, while simultaneously effectively reducing the toxic side effects of the drug.

[0004] As research deepens, it has been discovered that ROCK II has a unique function in the developmental processes of the vascular and nervous systems and is mainly distributed in muscle tissue and the brain. On the other hand, the expression distribution of ROCK I is very broad, including the liver, kidneys, spleen, testes, thymus, and blood cells. Although the core functions and related mechanisms that different subtypes play in many organs are still unclear, both play certain biological roles in different organs, and broadly inhibiting both may cause potential toxic side effects. Therefore, designing selective inhibitors targeting a single subtype (ROCK II) can reduce the potential toxic side effects of compounds and lower the risks of drug development. Conversely, using single-subtype selective small molecule inhibitors as probes can also lead to the discovery of specific functions of different subtypes in the developmental processes of diseases. Currently, two ROCK II selective inhibitors are in clinical trials and progressing smoothly. Therefore, from the perspective of drug discovery potential and drug safety, further research and development of highly selective ROCK II inhibitors has good future potential. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] The purpose of this disclosure is to provide the synthesis of novel compounds and their application as ROCK inhibitor drugs, in particular, that the compounds have advantages such as high activity, good selectivity and low toxic side effects as ROCK II selective kinase inhibitors. [Means for solving the problem]

[0006] Specifically, this disclosure provides compounds represented by the following formula (I), or their tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, salts, or solvates. [ka] (In the formula, n is selected from 1 or 2, X1 is selected from CH or N, n R1s may be the same or different, and R1 is hydrogen, an amino group, or a C 1-3 alkyl group, and the amino group is optionally a C 1-6 alkyl group or a C 3-8 cycloalkylalkyl group substituted therewith, A is selected from a 5- to 7-membered monocyclic heteroaryl group containing 1 to 2 atoms selected from N, O, S atoms, or a 9- to 12-membered bicyclic heteroaryl group containing 1 to 3 atoms selected from N, O, S atoms, R2 is a C 1-6 alkyl group, a 5- to 7-membered aryl group, and the C 1-6 alkyl group, the 5- to 7-membered aryl group is optionally substituted with one or more halogens, amino groups or hydroxy groups, R3 is hydrogen, C 1-6 alkoxy group, C 1-6 carboxy group, hydroxy group, halogen, -C(O)NR6R7, or -OC(O)-R 11 where, R6 and R7 are each independently a single bond, hydrogen, C 1-6 alkyl group, C 3-7 cycloalkyl group, C 4-8 cycloalkylalkyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N, O or S, and the C 1-6 alkyl group, C 3-7 cycloalkyl group, C 4-8 cycloalkylalkyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from N, O or S are substituted with one or two groups selected from R8 or -(CH2) p -OC(O)R9, R4 is hydrogen, halogen, -B(OH)2, or a dioxaborolane group substituted with one or more C 1-6 alkyl groups, R5 is a hydrogen atom or a C 1-3 alkyl group. )

[0007] In some specific embodiments, R1 is selected from hydrogen, an amino group, or a methyl group, and the amino group is optionally C 3-8 It is substituted with a cycloalkylalkyl group.

[0008] Preferably, R1 is hydrogen or an amino group, and the amino group is optionally substituted with a cyclopropylmethyl group.

[0009] In some specific embodiments, A is selected from a 5-7 member monocyclic heteroaryl group containing 1-2 atoms selected from N, O, and S atoms, or a 9-12 member bicyclic heteroaryl group containing 1-3 atoms selected from N, O, and S atoms.

[0010] Preferably, A is selected from a 5-7 member monocyclic heteroaryl group containing 1-2 N atoms, or a 9-12 member bicyclic heteroaryl group containing 1-2 N atoms.

[0011] Preferably, A is selected from a pyridyl group, a pyrazolyl group, a benzopyrazolyl group, or a pyrrolopyridyl group.

[0012] Preferably, A is selected from a pyridyl group, a pyrazolyl group, or an indazolyl group.

[0013] Preferably, A is selected from the group represented by the following formula. [ka]

[0014] Preferably, A is selected from the group represented by the following formula. [ka]

[0015] Preferably, the group represented by the following formula is [ka] The base is selected from those shown in the following formula. [ka]

[0016] Preferably, the group represented by the following formula is [ka] The base is selected from those shown in the following formula. [ka]

[0017] In some specific embodiments, R2 is C 1-6 Selected from alkyl groups and 5-7 membered aromatic ring groups, the C 1-6 Alkyl groups and 5- to 7-membered aromatic ring groups may be optionally substituted with one or more halogens, amino groups, or hydroxyl groups.

[0018] Preferably, R2 is C 1-3 Selected from alkyl groups or phenyl groups, the C 1-3 Alkyl and phenyl groups may be optionally substituted with 1 to 3 hydroxyl groups, amino groups, or fluorine.

[0019] Preferably, R2 is selected from a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, -CH2OH, -CH2CH2OH, or a phenyl group.

[0020] Preferably, R2 is selected from a methyl group, an ethyl group, an isopropyl group, a -CH2OH group, or a phenyl group.

[0021] In some specific embodiments, R3 is hydrogen, C 1-6 Alkoxy group, C 1-6 Carboxylate group, hydroxyl group, halogen, -C(O)NR6R7 or -OC(O)-R 11 That is the case.

[0022] Preferably, R3 is hydrogen, C 1-3 Alkoxy group, C 1-3 Carboxylate group, hydroxyl group, halogen, -C(O)NR6R7 or -OC(O)-R 11 That is the case.

[0023] Preferably, R3 is hydrogen, methoxy, -C(O)OH, hydroxy, fluoro, -C(O)NR6R7, or -OC(O)-R 11 That is the case.

[0024] R6 and R7 are independent of each other, consisting of a single bond, hydrogen, and C. 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, C 4-8 A cycloalkylalkyl group is selected from a 5-7 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, or S, and the C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, C 4-8 A 5-7 membered heterocycloalkyl group containing 1-2 heteroatoms selected from cycloalkylalkyl groups, N, O, or S is R8 or -(CH2) p - Replaced with one or two groups selected from OC(O)R9.

[0025] Of these, R6 and R7 are independently single bonds, hydrogen, and C. 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, C 4-8 Selected from cycloalkylalkyl groups and 5-7 member heterocycloalkyl groups containing one N atom, the C 1-3 alkyl group, the C 4-8 A cycloalkylalkyl group, a 5- to 7-membered heterocycloalkyl group containing one N atom, optionally has one or two R8 or -(CH2) p -OC(O)R9 is used as a substitute.

[0026] Preferably, R6 is selected from hydrogen.

[0027] Preferably, R7 is a single bond, C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, C 4-8 A cycloalkylalkyl group is selected from a 5- to 7-membered heterocyclic alkyl group containing one N atom, and the C 1-3 alkyl group, the C 4-8 A cycloalkylalkyl group and a 5- to 7-membered heterocyclic alkyl group containing one N atom are one or two R8 or -(CH2) p -OC(O)R9 can be arbitrarily substituted.

[0028] Preferably, R7 is selected from a single bond, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a neopentyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopropylmethyl group, or a cyclohexylmethyl group, and the methyl group, ethyl group, propyl group, isopropyl group, neopentyl group, cyclobutylmethyl group, cyclopropylmethyl group, or cyclohexylmethyl group may optionally be one or two R8 or -(CH2) p -OC(O)R9 is used as a substitute.

[0029] Alternatively, R6 and R7, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered ring, which may optionally contain 1 to 3 halogens, cyano groups, hydroxyl groups, or -(CH2) p -OC(O)R9 is used as a substitute.

[0030] Preferably, R6 and R7, together with the nitrogen atom to which they are bonded, form a 4-5 membered ring, and the 4-5 membered ring contains 1-2 fluorine, cyano group, hydroxyl group or -(CH2) p -OC(O)R9 can be arbitrarily substituted.

[0031] Preferably, R6 and R7, together with the nitrogen atom to which they are bonded, form an azetidine ring, and the azetidine ring optionally contains 1 to 2 fluorine, cyano, hydroxyl, or -(CH2) p -OC(O)R9 is used as a substitute.

[0032] R8 is C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl groups, halogens, hydroxyl groups, C 1-6 The C is selected from a carboxylic acid group, a 4-7 membered heteroalicyclic group containing 1-2 atoms selected from N, O, or S. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-7 A cycloalkyl group, a 4-7 membered heteroalicyclic group containing 1-2 atoms selected from N, O, or S, contains one or more hydroxyl groups, halogens, and C 1-6 It can be optionally substituted with an alkyl group or a nitro group.

[0033] Preferably, R8 is C 1-3 Alkyl alkyl group, C 1-3 Alkoxy group, C 3-7 Cycloalkyl groups, fluoro groups, hydroxyl groups, C 1-3 A carboxyl group, or a 4-7 membered heterocyclic alkyl group containing 1-2 atoms selected from N or O, where the C 1-3 alkyl group, the C 1-3 Alkoxy group, the C 3-7 A cycloalkyl group and a 4-7 membered heterocyclic alkyl group containing 1-2 atoms selected from N or O may have 1-3 hydroxyl groups, halogens, and C 1-3 It is optionally substituted with an alkyl group or a nitro group.

[0034] Preferably, R8 is selected from a methyl group, methoxy group, fluoro group, hydroxy group, carboxy group, piperidinyl group, cyclopropyl group, cyclobutyl group, isopropyl group, cyclohexyl group, morpholinyl group, azetidinyl group, and tetrahydropyranyl group, where the methyl group, piperidinyl group, cyclopropyl group, cyclobutyl group, isopropyl group, cyclohexyl group, morpholinyl group, azetidinyl group, and tetrahydropyranyl group are optionally substituted with one or two fluoro groups, methyl groups, hydroxy groups, or nitro groups.

[0035] p is selected from 0, 1, or 2.

[0036] R9 is a 5-7 membered aryl group, a 5-7 membered monocyclic heteroaryl group containing one N atom, a 5-7 membered heterocycloalkyl group containing one N atom, C 1-6 Alkyl alkyl group, or C 3-7 Selected from cycloalkyl groups, where the 5-7 membered aryl group, the 5-7 membered monocyclic heteroaryl group containing one N atom, the 5-7 membered heterocycloalkyl group containing one N atom, or C 1-6 Alkyl alkyl groups may have one or more R 10 It will be replaced by this.

[0037] Preferably, R9 is a 5-7 membered aromatic ring group, C 1-6 Alkyl alkyl group or C 3-7 Selected from cycloalkyl groups, where the 5-7 membered aromatic ring group, C 1-6 Alkyl alkyl groups may have one or more R 10 It will be replaced by this.

[0038] Preferably, R9 is a phenyl group, C 1-3 Alkyl alkyl group or C 3-7 Selected from cycloalkyl groups, where the phenyl group, C 1-3 The alkyl group can be any one or two R 10 It will be replaced by this.

[0039] Preferably, R9 is selected from a phenyl group, a cyclopropyl group, a cyclobutyl group, a tert-butyl group, or an n-propyl group, where the phenyl group, the cyclopropyl group, the cyclobutyl group, the tert-butyl group, or the n-propyl group may be one or two R groups of any choice. 10 It is replaced by.

[0040] Each R 10 These may be the same or different from each other, and include a hydroxyl group, a nitro group, and C 1-3 Selected from alkyl groups, halogens, or -ONO2.

[0041] Preferably, R10 C 1-3 Selected from alkyl groups, halogens, and -ONO2.

[0042] Preferably, R 10 The group is selected from fluorine, chlorine, cyano group, and methyl group.

[0043] In some specific embodiments, R9 is selected from the group shown by the following formula. [ka]

[0044] Preferably, R9 is selected from the group represented by the following formula. [ka]

[0045] R 11 The group is selected from a 5- to 7-membered aromatic ring group, and the 5- to 7-membered aromatic ring group is optionally substituted with one or more halogen, hydroxyl, nitro, or amino groups.

[0046] Preferably, R 11 The group is selected from phenyl groups, which are optionally substituted with one or two halogen, hydroxyl, nitro, or amino groups.

[0047] Preferably, R 11 The group is represented by the following formula. [ka]

[0048] Preferably, R3 is selected from hydrogen, a methoxy group, fluorine, a hydroxyl group, -C(O)OH, and a group represented by the following formula. [ka] [ka]

[0049] Preferably, R3 is selected from hydrogen, a methoxy group, fluorine, a hydroxy group, and a group represented by the following formula.

Chemical formula

Chemical formula

[0050] R4 is selected from hydrogen, a halogen, -B(OH)2, or a dioxaborolane group substituted with one or more C 1-6 alkyl groups.

[0051] Preferably, R4 is selected from hydrogen, fluorine, bromine, -B(OH)2, or a group represented by the following formula.

Chemical formula

[0052] Preferably, R4 is fluorine or bromine.

[0053] R5 is selected from hydrogen or a C 1-3 alkyl group.

[0054] Preferably, R5 is selected from a hydrogen atom or a methyl group.

[0055] Preferably, R5 is hydrogen.

[0056] According to one aspect of the present disclosure, the compound or a tautomer, enantiomer, diastereomer, mixture of enantiomers and diastereomers, racemate, meso form, mixture of racemate and meso form, pharmaceutically acceptable hydrate, salt or solvate thereof is included, where the compound has a structure represented by the following formula (IIIA), (IIIB), (IIIC) or (IIID): [ka] Here, the definitions of R1, R2, R3, R4, and n are as defined above.

[0057] According to one aspect of the present disclosure, the present invention includes the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, salts or solvates, wherein the compound has the structure represented by formula (IV): [ka] Here, the definitions of X1, R2, R3, and R4 are as defined above.

[0058] According to one aspect of the present disclosure, the following compounds and their tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, salts or solvates. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0059] According to one aspect of the present disclosure, a pharmaceutical composition comprises the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable excipients.

[0060] According to one aspect of the present disclosure, use of the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, mesoforms, mixtures of racemates and mesoforms, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates, and pharmaceutical compositions in the manufacture of agents for the prevention and / or treatment of diseases associated with abnormal ROCK activity.

[0061] According to one aspect of the present disclosure, use of the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates, and pharmaceutical compositions in the manufacture of ROCK inhibitors.

[0062] According to one aspect of the present disclosure, a method is provided for inhibiting ROCK in a patient in need thereof, the method comprising administering to the patient the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts, solvates or pharmaceutical compositions thereof.

[0063] According to one aspect of the present disclosure, a method is provided for inhibiting ROCK in a biological sample, the method comprising contacting the biological sample with the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts, solvates or pharmaceutical compositions thereof.

[0064] According to one aspect of the present disclosure, a method is provided for treating a ROCK-mediated disease in a patient in need thereof, the method comprising administering to the patient the compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts, solvates or pharmaceutical compositions thereof.

[0065] Preferably, ROCK-mediated diseases include, but are not limited to, cardiovascular diseases, smooth muscle-related diseases, fibrous diseases, inflammatory diseases, neurological diseases, neoplastic diseases, diseases that increase intraocular pressure, diabetes, organ transplantation, infectious diseases, and autoimmune diseases. [Modes for carrying out the invention]

[0066] I. Definition Unless otherwise specified in this disclosure, scientific and technical terms used herein have the meanings that are ordinarily understood by those skilled in the art. Furthermore, the terms and laboratory procedures used herein in relation to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology are widely used terms and conventional procedures in their respective fields. At the same time, to better understand this disclosure, definitions and explanations of relevant terms are provided below.

[0067] For the purpose of clear and concise description, features are described in this specification as part of several identical or distinct embodiments; however, it should be understood that the scope of this disclosure may include several embodiments having all or some of the described features.

[0068] Unless otherwise clearly indicated, throughout the specification and claims, the term “includes” or variations thereof, such as “contains” or “possesses,” should be understood to include the described elements or components, but not to exclude other elements or components.

[0069] The compounds of this disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, this includes all stereoisomers, such as enantiomers and diastereomers. Compounds containing an asymmetric carbon atom of this disclosure can be isolated in the form of optically active pures or racemates. Optically active pures can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of this disclosure.

[0070] In this disclosure, the following symbols indicate the positions to which substituents are attached. [ka]

[0071] In this disclosure, the numerical range refers to each integer within a given range. For example, "C 1-6 " means that the group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, and "C 1-3 " means that the group may have one carbon atom, two carbon atoms, or three carbon atoms.

[0072] The terms "arbitrarily" or "at will" mean that the event or situation described thereafter may or may not occur, and that description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "arbitrarily substituted with one or two hydroxyl groups" means that it may be substituted with one hydroxyl group, may be substituted with two hydroxyl groups, or may not be substituted with any hydroxyl groups at all.

[0073] The term "substituted" or "substituted" refers to the substitution of any one or more hydrogen atoms on a particular atom or group with a substituent, provided that the valence of the atom or group remains normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents may be arbitrary, to the extent that it is chemically feasible. The substituents may be substituted with one, two, or more substituents selected from deuterium, halogen groups, cyano groups, nitro groups, -C(=O)R, -C(=O)OR', -OC(=O)R'', imide groups, amide groups, hydroxyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted haloalkyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heteroaryl groups, etc.

[0074] Any variable (e.g., R n If a group appears multiple times in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted with 1 to 3 Rs, the group may be substituted with up to 3 Rs, and the Rs in each case are independent choices. Furthermore, combinations of substituents and / or variations thereof are only permissible if such combinations produce a stable compound.

[0075] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group containing a straight-chain or branched saturated hydrocarbon group, and the hydrocarbon group has the number of carbon atoms indicated. For example, the term "C 1-6The term "alkyl group" includes C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, and C6 alkyl groups. Examples include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, and 3-hexyl group. It may also be a divalent group such as a methylene group or an ethylene group.

[0076] The term "alkoxy group" may be linear, branched, or cyclic. There are no particular restrictions on the number of carbon atoms in an alkoxy group, but it is preferably 1 to 20. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n-nonyloxy, and n-decyloxy groups.

[0077] The term "cycloalkylalkyl group" refers to a cycloalkyl substituent bonded via an alkyl chain. An example of a cycloalkylalkyl substituent is cyclohexylethyl, where cyclohexane is bonded via an ethane linker. Other examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylethyl, cycloheptylethyl, and cyclohexylmethyl. In this disclosure, examples of halogen groups include fluorine, chlorine, bromine, or iodine.

[0078] In this disclosure, the term "cycloalkyl group" refers to a monocyclic saturated hydrocarbon system that does not contain heteroatoms or double bonds. For example, the term "C 3-8Examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0079] In this disclosure, the term "aryl group" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system, which is obtained by removing one hydrogen atom from a single carbon atom of an aromatic ring system. This includes bicyclic groups containing saturated, partially unsaturated rings, or aromatic rings fused with aromatic carbocyclic rings. Specific examples include, but are not limited to, phenyl or naphthyl groups.

[0080] In this disclosure, the term "heterocycloalkyl group" refers to a 5-12 member saturated non-aromatic system having a ring carbon atom and one or two ring heteroatoms. Specific examples of heterocyclic groups include, but are not limited to, the piperidyl group or the tetrahydropyrrolyl group.

[0081] In this disclosure, the term "heteroaryl group" means a monovalent aryl group containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur heteroatoms, where the heteroaryl group may be monocyclic or polycyclic (e.g., bicyclic), and where two or more rings exist in the form of fused rings, bridging rings, or spiro rings, and at least one of these rings contains one or more heteroatoms. Specific examples of heteroaryl groups include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, imidazopyridyl, benzofuranyl, pyridadinyl, and isoindolyl groups.

[0082] The term "heterocyclic" refers to a saturated non-aromatic system with 5 to 12 members, having a ring carbon atom and 1 to 2 ring heteroatoms, where the heteroatoms are independently selected from nitrogen, sulfur, or oxygen atoms. In a heterocyclic group containing one or more nitrogen atoms, the bond sites may be carbon or nitrogen atoms, as long as the valence allows. Heterocyclics may be monocyclic or polycyclic (e.g., bicyclic), where two or more rings exist in the form of fused rings, bridging rings, or spiro-rings, and at least one of these rings contains one or more heteroatoms.

[0083] Pharmaceuticals or pharmaceutical compositions The term "pharmaceutically acceptable" means that, within reasonable medical judgment, these compounds, materials, compositions, and / or dosage forms are suitable for contact with human and animal tissues, free from excessive toxicity, irritation, allergic reactions, or other problems or complications, and represent a reasonable benefit-to-risk ratio.

[0084] The term "tautomer" refers to a functional isomer that arises when one atom in a compound rapidly moves between two positions. The difference between tautomers lies in the rearrangement of protons and the double bonds at the corresponding positions. Specific examples include, but are not limited to, enol and keto tautomers.

[0085] The term "enantiomer" refers to two stereoisomers that are mirror images of each other and cannot be superimposed; one is levorotatory and the other is dextrorotatory. The term "diastereomer" refers to two stereoisomers that are not mirror images of each other and have two or more chiral centers.

[0086] The term "racemate" refers to a mixture in which an optically active chiral molecule and its enantiomer are mixed in equal amounts, and their opposing optical rotational effects cancel each other out. The term "meso compound" refers to a compound that has two or more chiral centers within the molecule but does not exhibit optical activity as a whole due to the presence of other factors such as planes of symmetry. The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, where the parent compound is modified by preparing an acid addition salt or base addition salt of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines and base or organic acid salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, ordinary 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, as well as 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. The pharmaceutically acceptable salts of this disclosure can be synthesized by conventional chemical methods using parent compounds containing acidic or basic groups. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture thereof.

[0087] The pharmaceuticals or pharmaceutical compositions of this disclosure may be administered orally, topically, parenterally, or mucosally (e.g., sublingually, by inhalation, or rectally) as dosage form units comprising a conventional non-toxic, pharmaceutically acceptable carrier.

[0088] When administered orally in tablet or capsule form, the active drug component may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen 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), colorants and flavorings, gelatin, sweeteners, natural and synthetic rubbers (e.g., gum arabic, tragacanth gum, or alginate), buffer salts, carboxymethylcellulose, polyethylene glycol, wax, etc. When administered orally in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), a suspending 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., tonsil oil, oily esters, ethanol, or fractionated vegetable oils), a preservative (e.g., methyl parahydroxybenzoate, propyl parahydroxybenzoate, or sorbic acid), etc. Stabilizers, such as antioxidants (butylated hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), propyl gallate, sodium ascorbate, citric acid), may also be added to stabilize the dosage form.

[0089] Formulations containing tablets as the active compound can be coated by methods well known in the art. The compositions of this disclosure containing the compound of formula I as the active compound can also be introduced into beads, microspheres, or microcapsules constructed from, for example, polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, emulsions, or suspensions, or can be provided as dry products for reconstitution with water or other suitable excipients before use. Oral formulations can be appropriately formulated to control or delay the release of the active compound.

[0090] The pharmaceuticals or pharmaceutical compositions of this disclosure can be delivered parenterally, i.e., by direct injection, for example by bolus injection or continuous infusion, by intravenous (iv), intraventricular (icv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), subcutaneous (sd), or intradermal (id) administration. The injectable formulations can be provided, for example, as unit dosage forms in ampoules or multi-dose containers with added preservatives. The compositions may take the form of excipients, and may take the form of suspensions, solutions, or emulsions in oily or aqueous carriers, and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier (e.g., sterile pyrogen-free water) before use.

[0091] The pharmaceuticals or pharmaceutical compositions of this disclosure may also be formulated for rectal administration, for example, in the form of suppositories or retaining enemas (including conventional suppository bases such as cocoa butter or other glycerides).

[0092] Dosage forms for topical administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds can be mixed under sterile conditions with pharmaceutically acceptable carriers and, if necessary, any preservatives, buffers, or propellants.

[0093] In addition to the active compounds of this disclosure, the ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0094] Ophthalmic preparations, eye ointments, powders, and solutions (e.g., eye drops) are also considered to be within the scope of this disclosure.

[0095] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate fluidity can be maintained, for example, by the use of a coating material (e.g., lecithin), by maintaining a desired particle size in the case of a dispersion, and by the use of a surfactant.

[0096] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. The inclusion of various antimicrobial and antifungal agents, such as parahydroxybenzoic acid esters, chlorobutanol, and phenolsorbic acid, can reliably prevent microbial action on the target compound. It may also be desirable to include isotonic agents (e.g., sugars, sodium chloride) in the composition. Furthermore, extended absorption of injectable drug forms can be achieved by including absorption-delaying agents (e.g., aluminum monostearate and gelatin).

[0097] The term "treatment" includes the inhibition, mitigation, prevention, or elimination of one or more symptoms or side effects associated with the disease, condition, or disorder being treated. The term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, inhibit, or alleviate one or more symptoms of the disease condition being treated, or otherwise provide a desired pharmacological and / or physiological effect. The exact dose varies depending on various factors such as subject-dependent variables (e.g., age, immune system health), the disease or condition, and the treatment administered. The effect of the effective dose can be compared to a control. These controls are known in the art and are discussed herein, and can be compared, for example, to the state of a subject before or without administration of a pharmaceutical or pharmaceutical composition, or, in the case of a pharmaceutical composition, to the combined effect with the effect of administering only one pharmaceutical.

[0098] The term "pharmaceutical composition" means a compound described in this disclosure or a pharmaceutically acceptable salt thereof, and a composition comprising, depending on the method of administration and the nature of the dosage form, at least one pharmaceutically acceptable component selected from carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0099] Based on the above-mentioned content of this disclosure, various other forms of modifications, substitutions, or changes can be made in accordance with ordinary technical knowledge and customary means in the art, without departing from the above-mentioned basic technical concept of this disclosure.

[0100] II. Examples All raw materials and equipment used in the specific embodiments of this disclosure are known products and were obtained by purchasing commercially available products.

[0101] Example 1: Preparation of compounds 1 and 2: [ka] Preparation of Intermediate 1b: 7-Bromo-1,2-dihydro-4H-benzo[d]oxazin-4-one Raw material 1a (2.16 g, 10 mmol of 2-amino-4-bromobenzoic acid) was dissolved in 20 mL of anhydrous tetrahydrofuran. Then, a solution of triphosgene (1.04 g, 3.50 mmol) in tetrahydrofuran was slowly added dropwise at 0 °C. The reaction was stirred at room temperature for 4 hours. After adding ice water to the system, suction filtration was carried out, and the filter cake was washed with dichloromethane to obtain Intermediate 1b. The yield was 80%. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.96 (d, J = 7.4 Hz, 1H), 7.45 (dd, J = 7.3, 1.6 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H); MS (ESI, positive ion) m / z: 241.88, [M + H] + .

[0102] Preparation of Intermediate 1c: 7-Bromo-1-methyl-2H-benzo[d]oxazine-2,4-(1H)-dione Intermediate 1b (1.60 g, 6.70 mmol) was added to 20 mL of anhydrous DMF. Then, sodium hydride (0.30 g, 8.00 mmol) was slowly added at 0 °C. The reaction system was stirred at low temperature for 20 minutes, then 500 μL of methyl iodide was added. After that, the reaction was stirred at room temperature for 2 hours. Then, methanol was added to quench the excess sodium hydride, and it was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the target Intermediate 1c. The yield was 75%. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.49 (dd, J = 7.5, 1.6 Hz, 1H), 3.40 (s, 3H); MS (ESI, positive ion) m / z: 255.96 [M + H] + .

[0103] Preparation of Intermediate 1d: (S)-8-Bromo-1,3-dimethyl-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione 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, triethylamine (2.4 mL, 17.6 mmol) was added. The reaction system was stirred at 60°C for 2 hours, concentrated under reduced pressure, and 10 mL of acetic acid was added. The mixture was then heated under reflux for 4 hours, and further reduced pressure was used to remove the acetic acid. The mixture was extracted with dichloromethane and water, the organic phase was washed with saturated brine, dried over magnesium sulfate, filtered by Celite, and the filtrate was purified by column 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] + .

[0104] Preparation of intermediate 1e:(S)-8-bromo-4-(3-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: Intermediate 1d (88 mg, 0.22 mmol) was dissolved in tetrahydrofuran, the reaction system was cooled to 0°C, sodium hydride (8 mg, 0.32 mmol) was added, and the mixture was stirred for 10 minutes. 3-benzyl 3-methoxybromide (80 mg, 0.4 mmol) was then added dropwise, and the mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by TLC, excess sodium hydride was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain intermediate 1e as a white solid. The yield was 80%. MS (ESI, positive ion) m / z: 403.20, 405.25. [M+H] + .

[0105] Preparation of Compound 1:(S)-4-(3-methoxybenzyl)-1,3-dimethyl-8-(pyridine-4-yl)-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: Intermediate 1e (48 mg, 0.12 mmol), 4-pyridineboronic acid (18 mg, 0.15 mmol), K2CO3 (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (8 mg, 0.01 mmol) were placed in a two-necked flask. A 1,4-dioxane / water mixture (V / V=5 / 1) was added, and the mixture was reacted at 85°C for 5 hours under an argon gas atmosphere. The completion of the reaction was monitored by TLC, and after cooling the reaction mixture, it was filtered by Celite. The filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate = 1:5) to obtain compound 1 as a white solid. 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) ion)m / z:402.35.[M+H] + .

[0106] Preparation of Compound 2: (S)-4-(3-methoxybenzyl)-1,3-dimethyl-8-(2-aminopyridine-4-yl)-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: The synthesis of compound 2 was the same as that of compound 1, obtained by reacting intermediate 1e with 2-amino-4-pyridineboronic acid, with a yield of 60%.

[0107] 1H 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, MS (ESI, positive ion)m / z:417.40.[M+H] + .

[0108] Example 2: Preparation of compounds 3 and 4: [ka] Preparation of intermediate 3a: (R)-8-bromo-1,3-dimethyl-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: The preparation method for intermediate 3a was the same as for 1d, using intermediate 1c and D-alanine as raw materials, with a yield of 40%. MS(ESI, positive ion)m / z:283.16,285.32.[M+H] + .

[0109] Preparation of intermediate 3b: (R)-8-bromo-4-(3-methoxybenzyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: The preparation method for intermediate 3b was the same as for 1e, using intermediate 3a as the raw material, and the yield was 80%. MS(ESI,positive)m / z:403.23,405.36.[M+H] + .

[0110] Preparation of compound 3:(R)-4-(3-methoxybenzyl)-1,3-dimethyl-8-(pyridine-4-yl)-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: The preparation method for compound 3 was the same as for compound 1, using intermediate 3b and 4-pyridineboronic acid as starting materials, and the yield was 75%.

[0111] 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) ion)m / z:402.33.[M+H] + .

[0112] Preparation of intermediate 3c:(R)-4-(3-hydroxybenzyl)-1,3-dimethyl-8-(pyridine-4-yl)-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: Compound 3 (80 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (48 μL, 0.5 mmol) was added under an ice bath. The reaction was allowed to proceed at room temperature for 1 hour. The completion of the reaction was monitored by TLC, and the reaction mixture was quenched with saturated sodium bicarbonate. The reaction was extracted with ethyl acetate, 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 intermediate 3c as a white solid. The yield was 30%. MS (ESI, positive ion) m / z: 388.23.[M+H] + .

[0113] Compound 4: (R)-3-((1,3-dimethyl-2,5-dioxo-8-(pyridine-4-yl)-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methyl)phenyl 2,4-dimethylbenzoate 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. The mixture was then reacted at room temperature for 2 hours. The completion of the reaction was monitored by TLC, and methanol was added to stop the reaction. The mixture was then concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 4.

[0114] 1 H 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] + .

[0115] The preparation method for compounds 5 and 6 is the same as for compound 3, and is shown in Table 1 below. [Table 1]

[0116] Example 3: Preparation of compounds 7 and 8: [ka] Preparation of intermediate 7a: (R)-8-bromo-4-((6-fluoro-2-pyridyl)methyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: The synthesis of intermediate 7a was similar to that of intermediate 3b, obtained by reacting intermediate 3a with 2-bromomethyl-6-fluoropyridine as a starting material, with a yield of 90%. MS(ESI, positive ion) m / z: 392.25, 394.28.[M+H] + .

[0117] Preparation of compound 7:(R)-4-((6-fluoro-2-pyridyl)methyl)-1,3-dimethyl-8-(2-aminopyridine-4-yl)-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: [ka] The synthesis of compound 7 was similar to that of compound 3, obtained by reacting intermediate 7a with 2-amino-4-pyridineboronic acid as a starting material, with a yield of 70%.

[0118] 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] + .

[0119] Preparation of intermediate 7b: (R)-8-bromo-4-((6-hydroxy-2-pyridyl)methyl)-1,3-dimethyl-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: [ka] Intermediate 7a (60 mg, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL), then aqueous hydrochloric acid (2 mL, 4 mol / L) was added, and 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, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 7b. The yield was 20%. MS (ESI, positive ion) m / z: 390.23, 392.24. [M+H] + .

[0120] Preparation of compound 8:(R)-4-((6-hydroxy-2-pyridyl)methyl)-1,3-dimethyl-8-(2-aminopyridine-4-yl)-3,4-dihydro-1H-benzo[e]diazepine-2,5-dione: [ka] The synthesis of compound 8 was the same as that of compound 1, and it was obtained by reacting intermediate 7b with 2-amino-4-pyridineboronic acid as a starting material, with a yield of 70%.

[0121] 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), MS(ESI, positive ion)m / z:404.41.[M+H] + .

[0122] Example 4: Preparation of compounds 9, 10, and 11: [ka] Preparation of intermediate 9a:(R)-3-((8-bromo-1,3-dimethyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)methyl benzoate: [ka] The synthesis of intermediate 9a was similar to that of intermediate 3b, obtained by reacting intermediate 3a with methyl 3-(bromomethyl)benzoate as a starting material, with a yield of 85%. MS (ESI, positive ion) m / z: 431.18, 433.21 [M+H] + .

[0123] Preparation of intermediate 9b:(R)-3-((8-(pyridine-4-yl)-1,3-dimethyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)methyl benzoate: [ka] The synthesis of intermediate 9b was the same as for compound 3, obtained by reacting intermediate 9a with 4-pyridineboronic acid as a starting material, with a yield of 75%. MS(ESI, positive ion)m / z:430.30.[M+H] + .

[0124] Preparation of intermediate 9c:(R)-3-((8-(2-aminopyridine-4-yl)-1,3-dimethyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzoic acid: [ka] Intermediate 9b (500 mg, 1.16 mmol) was dissolved in methanol / water (5 mL, V / V, 4 / 1), then sodium hydroxide (120 mg, 3.0 mmol) was added. The mixture was reacted at room temperature for 4 hours, and the completion of the reaction was monitored by TLC. Dilute hydrochloric acid was added to adjust the pH to neutral, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 9c. The yield was 90%. MS (ESI, positive ion) m / z: 416.33.[M+H] + .

[0125] Preparation of compound 9:(R)-3-((8-(pyridine-4-yl)-1,3-dimethyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)-N-((3-hydroxycyclobutyl)methyl)benzamide: [ka] Intermediate 9c (50 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL), then 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, and the mixture was stirred at room temperature for 10 minutes. Then 3-(aminomethyl)cyclobutanol (24 mg, 0.24 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After confirming that the reaction of the starting materials was complete by TLC, the reaction mixture was purified directly over reversed-phase silica gel C-18 to obtain compound 9. The yield was 60%.

[0126] 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] + .

[0127] Preparation of compound 10:(R)-3-((8-(pyridine-4-yl)-1,3-dimethyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzamide)methyl)cyclobutyl 2,4-dimethylbenzoate: [ka] Compound 9 (50 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL), then 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. After confirming that the reaction of the starting materials was complete by TLC, the reaction solution was purified directly over reversed-phase silica gel C-18 to obtain compound 10. The yield was 60%.

[0128] 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] + .

[0129] Preparation of Compound 11:(R)-3-((8-(pyridine-4-yl)-1,3-dimethyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzamide)methylene)cyclobutyl 3,3-difluorocyclobutane carboxylate: [ka] Compound 9 (50 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then N,N-diisopropylethylamine (46 μL, 0.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), and 3,3-difluorocyclobutanecarboxylic acid (36 mg, 0.24 mmol) were added. The mixture was reacted at room temperature for 2 hours. After confirming that the reaction of the starting materials was complete by TLC, the reaction solution was purified directly using reverse-phase silica gel C-18 to obtain compound 11. The yield was 60%.

[0130] 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] + .

[0131] The preparation methods for the compounds in the table below are the same as those for compounds 9~11. Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

[0132] Example 5: Preparation of Compound 53:

Chem.

[0133] Intermediate 53b: Methyl (R)-3-((8-bromo-3-(hydroxymethyl)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)methylene)benzoate:

Chem.

[0134] Intermediate 53c: (R)-3-((8-(4-aminopyridyl)-3-(hydroxymethyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)methyl benzoate: [ka] The synthesis of intermediate 53c was the same as for compound 3, and it was obtained by reacting intermediate 53b with 4-amino-2-pyridineboronic acid as a starting material, with a yield of 70%. MS(ESI, positive ion)m / z:461.22[M+H] + .

[0135] Intermediate 53d: (R)-3-((8-(4-aminopyridyl)-3-(hydroxymethyl)-1-methyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzoic acid: [ka] The synthesis of intermediate 53d was the same as that of compound 8, obtained by reacting intermediate 21c as a starting material, with a yield of 80%. MS(ESI, positive ion) m / z: 447.31[M+H] + .

[0136] Compound 53: (R)-3-((8-(4-aminopyridyl)-3-(hydroxymethyl)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-4H-benzo[e]diazepin-4-yl)methylene)-N-((1-methyl-4-piperidyl)methyl)benzamide

Chem.

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.54 (m, 1H), 9.74 - 9.59 (m, 1H), 8.08 (d, J = 6.9 Hz, 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] + .

[0138] The preparation methods of Compounds 54 - 59 in the following table are the same as that of Compound 53.

Table 3

[0139] Example 6: Preparation of Compound 60

Chem.

[0140] Intermediate 60b: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)methyl benzoate: [ka] Intermediate 60a (93 mg, 0.2 mmol) was dissolved in anhydrous toluene (3 mL), and then 4,5-bis(diphenylphosphin)-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. The mixture was reacted at 100°C for 12 hours under a nitrogen atmosphere. After monitoring the completion of the reaction by TLC, the reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0:1) to obtain intermediate 60b as a white solid. MS (ESI, positive ion) m / z: 499.33 [M+H] + .

[0141] Intermediate 60c: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzoic acid: [ka] The synthesis of intermediate 60c was similar to that of intermediate 9c, obtained by reacting intermediate 60b as a starting material, with a yield of 80%. MS(ESI, positive ion) m / z: 485.31[M+H] + .

[0142] Intermediate 60d: tert-butyl(R)-3-((3-((8-(2-((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzamide)methyl)-3-hydroxyazetidine-1-carboxylate: [ka] The synthesis of intermediate 60d was the same as for compound 9, and it was obtained by reacting intermediate 60c with tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate as a starting material, with a yield of 75%. MS(ESI, positive ion)m / z:669.50[M+H] + .

[0143] Compound 60: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)-N-((3-hydroxyazetidine-3-yl)methyl)benzamide. [ka] Intermediate 60d (60 mg, 0.1 mmol) was dissolved in methanol (1 mL), hydrogen chloride (0.1 mL, 4 mol / L 1,4-dioxane solution) was added, and the mixture was reacted at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the mixture was concentrated under reduced pressure, and then purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 60 as a white solid. 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+H] + .

[0144] The preparation methods for compounds 112-116 in the table below are the same as for compound 60. [Table 4]

[0145] Example 7: Preparation of compounds 61 and 62 [ka] Compound 61:(R)-1-(3-((8-((2-((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzoyl)azetidine-3-carbonitrile: [ka] The synthesis of compound 61 was the same as that of compound 21, and it was obtained by reacting intermediate 60b as a starting material, with a yield of 75%. 1 H NMR(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] + .

[0146] Intermediate 62a: (R)-3-((8-(2-((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)-N-((3-hydroxycyclobutyl)methyl)benzamide: [ka] The synthesis of intermediate 62a was the same as that of compound 61, obtained by reacting intermediate 60b as a starting material, with a yield of 75%. MS(ESI, positive ion) m / z: 568.45[M+H] + .

[0147] Compound 62:(R)-3-((3-((8-(2-(((cyclopropylmethyl)amino-4-pyridyl)-1,3-dimethyl-2,5-dione-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)benzamide)methyl)cyclobutyl3,4-dichlorobenzoate: [ka] The synthesis of compound 62 was similar to that of compound 10, obtained by reacting intermediate 62a with 3,4-dichlorobenzoyl chloride as a starting material, with a yield of 75%.

[0148] 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] + .

[0149] Example 8: Preparation of Compound 117 [ka] Preparation of intermediate 117a: 2-bromoacetic acid (R)-3-((3-((1,3-dimethyl-2,5-dioxo-8-(pyridine-4-yl)-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)-5-fluorobenzamide)methyl)cyclobutyl ester [ka] The synthesis of intermediate 117a was the same as that of compound 10, prepared using 2-bromopropionyl chloride and compound 96 as starting materials, with a yield of 82%. MS(ESI, positive ion) m / z: 637.37, 639.36[M+H] + .

[0150] Preparation of Compound 117: 2-((R)-2-methylpyrrolidine-1-yl)acetic acid (R)-3-((3-((1,3-dimethyl-2,5-dioxo-8-(pyridine-4-yl)-1,2,3,5-tetrahydro-4H-benzo[e]diazepine-4-yl)methylene)-5-fluorobenzamide)methyl)cyclobutyl ester [ka] Intermediate 117a (100 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2 mL), then potassium carbonate (52 mg, 0.38 mmol) and (R)-2-methylpyrrolidine (21 mg, 0.25 mmol) were added. The mixture was reacted at room temperature for 2 hours and purified using C-18 reversed-phase silica gel to obtain compound 117. The yield was 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] + .

[0151] Test Example 1: In vitro kinase test of benzodiazepinone derivatives In vitro kinase testing was performed using the Kinase Profiler service provided by Eurofins. The experimental procedure was summarized as follows: Test small molecules (0.001-10 μM), test protein kinase, substrate, 10 mM magnesium acetate and [γ- 33 The reaction was initiated by incubating the mixture with a buffer containing P-ATP and adding Mg\ATP mix. After incubation at room temperature for a certain period, the reaction was stopped by adding a 3% phosphoric acid solution to the buffer. Subsequently, 10 μL of the reaction mixture was added dropwise onto P30 filter paper, washed three times with 75 mM phosphoric acid solution, and then once with methanol. After drying the P30 filter paper, scintillation solution was added and scintillation counts were performed. The inhibitory activity of the compound was measured at the half-number inhibitory concentration (IC). 50 ) is represented as IC 50 The values ​​were obtained by fitting the inhibition rates corresponding to each concentration gradient, and the results are shown in Table 5 below. The combined results in the table indicate that the compound of the present invention exhibits good selective inhibitory activity against ROCK II kinase compared to ROCK I kinase. [Table 5]

Claims

1. Compounds represented by formula (I), or their tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso compounds, mixtures of racemates and meso compounds, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates. 【Chemistry 1】 (In the formula, n is selected from 1 or 2, X １ is selected from CH or N, n R １ They may be the same or different, R １ is hydrogen, amino group, or C １－３ Selected from alkyl groups, the amino group is optionally C １－６ Alkyl alkyl group or C ３－８ Substituted with a cycloalkylalkyl group, A is selected from a 5-7 member monocyclic heteroaryl group containing 1-2 atoms selected from N, O, and S atoms, or a 9-12 member bicyclic heteroaryl group containing 1-3 atoms selected from N, O, and S atoms. R ２ is selected from a C １－６ alkyl group and a 5- to 7-membered aryl group, and the C １－６ alkyl group and the 5- to 7-membered aryl group are optionally substituted with one or more halogen, amino or hydroxy groups, R ３ is hydrogen, C １－６ Alkoxy group, C １－６ Carboxy group, hydroxyl group, halogen, -C(O)NR ６ R ７ , or -OC(O)-R １１ And, R ６ , R ７ These are, independently, single bonds, hydrogen, and C. １－６ Alkyl alkyl group, C ３－７ Cycloalkyl groups, C ４－８ A cycloalkylalkyl group is selected from a 5-7 membered heterocycloalkyl group containing one or two heteroatoms selected from N, O, or S, and the C １－６ Alkyl alkyl group, C ３－７ Cycloalkyl groups, C ４－８ A 5-7 membered heterocycloalkyl group containing one or two heteroatoms selected from cycloalkylalkyl groups, N, O, or S is R ８ or - (CH ２ ) ｐ -OC(O)R ９ Substituted with one or two bases selected from, R ４ is hydrogen, halogen, -B(OH) ２ , or one or more C １－６ Selected from dioxaborolane groups substituted with alkyl groups, R ５ is a hydrogen atom or C １－３ (Selected from alkyl groups.)

2. R １ The group is selected from hydrogen, an amino group, or a methyl group, and the amino group is optionally C ３－８ Substituted with a cycloalkylalkyl group, Preferably, R １ is a hydrogen atom or an amino group, and the amino group is optionally substituted with a cyclopropylmethyl group. Preferably, A is selected from a 5-7 member monocyclic heteroaryl group containing 1-2 N atoms, or a 9-12 member bicyclic heteroaryl group containing 1-2 N atoms. Preferably, A is selected from a pyridyl group, a pyrazolyl group, a benzopyrazolyl group, or a pyrrolopyridyl group. Preferably, A is selected from a pyridyl group, a pyrazolyl group, or an indazolyl group. Preferably, A is selected from the group shown by the following formula, 【Chemistry 2】 Preferably, the group represented by the following formula is 【Transformation 3】 Selected from the elements shown in the following formula, 【Chemistry 4】 Preferably, R ２ C １－３ Selected from alkyl groups or phenyl groups, the C １－３ Alkyl and phenyl groups may be optionally substituted with 1 to 3 hydroxyl groups, amino groups, or fluorine. Preferably, R ２ These are methyl group, ethyl group, isopropyl group, trifluoromethyl group, and -CH ２ OH, -CH ２ CH ２ Selected from OH or phenyl group, A compound represented by formula (I) as described in claim 1.

3. R ３ is hydrogen, C １－３ Alkoxy group, C １－３ Carboxy group, hydroxyl group, halogen, -C(O)NR ６ R ７ or -OC(O)-R １１ And, Here, R １１ The group is selected from a 5- to 7-membered aromatic ring group, and the 5- to 7-membered aromatic ring group is optionally substituted with one or more halogen, hydroxyl, nitro, or amino groups. Of these, R ６ , R ７ These are, independently, single bonds, hydrogen, and C. １－６ Alkyl alkyl group, C ３－７ Cycloalkyl groups, C ４－８ Selected from cycloalkylalkyl groups and 5- to 7-membered heterocycloalkyl groups containing one N atom, the C １－３ alkyl group, the C ４－８ A cycloalkylalkyl group, a 5- to 7-membered heterocycloalkyl group containing one N atom, optionally contains one or two R atoms. ８ or - (CH ２ ) ｐ -OC(O)R ９ Replaced by, Alternatively, R ６ , R ７ These, together with the nitrogen atom to which they are bonded, form a 3- to 7-membered ring, and this 3- to 7-membered ring may optionally contain 1 to 3 halogens, cyano groups, hydroxyl groups, or -(CH ２ ) ｐ -OC(O)R ９ Replaced by, R ８ C １－６ Alkyl alkyl group, C １－６ Alkoxy group, C ３－７ Cycloalkyl groups, halogens, hydroxyl groups, C １－６ A carboxylic acid group, a 4-7 membered heteroalicyclic group containing 1-2 atoms selected from N, O, or S, where the C １－６ Alkyl alkyl group, C １－６ Alkoxy group, C ３－７ A cycloalkyl group, a 4-7 membered heteroalicyclic group containing one or two atoms selected from N, O, or S, is one or more hydroxyl groups, halogens, and C １－６ Optionally substituted with an alkyl group or a nitro group, R ９ This includes a 5-7 membered aryl group, a 5-7 membered monocyclic heteroaryl group containing one N atom, a 5-7 membered heterocycloalkyl group containing one N atom, and C １－６ Alkyl alkyl group, or C ３－７ Selected from cycloalkyl groups, where the 5-7 membered aryl group, the 5-7 membered monocyclic heteroaryl group containing one N atom, the 5-7 membered heterocycloalkyl group containing one N atom, or C １－６ Alkyl alkyl groups may have one or more R １０ Replaced by, Each R １０ These may be the same or different from each other, and include a hydroxyl group, a nitro group, a cyano group, and C １－３ Alkyl alkyl groups, halogens, or -ONO ２ Selected from, Preferably, R ３ is hydrogen, methoxy, -C(O)OH, hydroxy, fluoro, -C(O)NR ６ R ７ or -OC(O)-R １１ And, Preferably, R ６ It is selected from hydrogen, Preferably, R ７ is a single bond, C １－６ alkyl group, C ３－７ cycloalkyl group, C ４－８ cycloalkylalkyl group, a 5- to 7-membered heterocyclic alkyl group containing one N atom, and the C １－３ alkyl group, the C ４－８ cycloalkylalkyl group, and the 5- to 7-membered heterocyclic alkyl group containing one N atom are optionally substituted with one or two R ８ or -(CH ２ ) ｐ -OC(O)R ９ and are optionally substituted with Preferably, R ７ The R group is selected from a single bond, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a neopentyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopropylmethyl group, or a cyclohexylmethyl group, and the methyl group, ethyl group, propyl group, isopropyl group, neopentyl group, cyclobutylmethyl group, cyclopropylmethyl group, or cyclohexylmethyl group may have one or two R groups. ８ or - (CH ２ ) ｐ -OC(O)R ９ Replaced by, Preferably, R ６ , R ７ These, together with the nitrogen atom to which they are bonded, form a 4-5 membered ring, and the 4-5 membered ring contains 1-2 fluorine, cyano group, hydroxyl group, or -(CH ２ ) ｐ -OC(O)R ９ It is arbitrarily replaced with, Preferably, R ６ , R ７ These, together with the nitrogen atom to which they are bonded, form an azetidine ring, and the azetidine ring optionally contains one to two fluorine, cyano, hydroxyl, or -(CH ２ ) ｐ -OC(O)R ９ Replaced by, Preferably, R ８ C １－３ Alkyl alkyl group, C １－３ Alkoxy group, C ３－７ Cycloalkyl groups, fluoro groups, hydroxyl groups, C １－３ Selected from a carboxyl group or a 4-7 membered heterocyclic alkyl group containing 1-2 atoms selected from N or O, where the C １－３ alkyl group, the C １－３ Alkoxy group, the C ３－７ A cycloalkyl group and a 4-7 membered heterocyclic alkyl group containing 1-2 atoms selected from N or O may have 1-3 hydroxyl groups, halogens, and C １－３ Optionally substituted with an alkyl group or a nitro group, Preferably, R ８ The group is selected from a methyl group, methoxy group, fluoro group, hydroxy group, carboxy group, piperidinyl group, cyclopropyl group, cyclobutyl group, isopropyl group, cyclohexyl group, morpholinyl group, azetidinyl group, and tetrahydropyranyl group, where the methyl group, piperidinyl group, cyclopropyl group, cyclobutyl group, isopropyl group, cyclohexyl group, morpholinyl group, azetidinyl group, and tetrahydropyranyl group are optionally substituted with one or two fluoro groups, methyl groups, hydroxy groups, or nitro groups. p is selected from 0, 1, or 2. Preferably, R ９ is a phenyl group, C １－３ Alkyl alkyl group or C ３－７ Selected from cycloalkyl groups, where the phenyl group, C １－３ The alkyl group can be any one or two R １０ Replaced by, Preferably, R ９ R is selected from a phenyl group, a cyclopropyl group, a cyclobutyl group, a tert-butyl group, or an n-propyl group, where the phenyl group, the cyclopropyl group, the cyclobutyl group, the tert-butyl group, or the n-propyl group may be one or two R groups of any choice. １０ Replaced by, Preferably, R １０ C １－３ Alkyl groups, halogens, cyano groups, -ONO ２ Selected from, Preferably, R １０ is selected from fluorine, chlorine, cyano group, and methyl group, preferably R ９ It is selected from the base shown in the following formula, 【Transformation 5】 Preferably, R １１ The group is selected from phenyl groups, and the phenyl group is optionally substituted with one or two halogens, hydroxyl groups, nitro groups, or amino groups. Preferably, R １１ The group is represented by the following formula, 【Transformation 6】 Preferably, R ３ It is selected from hydrogen, methoxy group, fluorine, hydroxyl group, -C(O)OH, and the group represented by the following formula. 【Transformation 7】 【Transformation 8】 【Chemistry 9】 Preferably, R ４ It consists of hydrogen, fluorine, bromine, and -B(OH) ２ , or selected from the bases shown in the following formula, 【Chemistry 10】 Preferably, R ４ It is fluorine or bromine, Preferably, R ５ This is selected from a hydrogen atom or a methyl group. Preferably, R ５ It is hydrogen. A compound represented by formula (I) according to claim 1 or 2.

4. The aforementioned compound has a structure represented by formula (IIIA), (IIIB), (IIIC), or (IIID), 【Chemistry 11】 Here, R １ , R ２ , R ３ , R ４ The definition of n is as defined in equation (I). A compound represented by formula (I) as described in claim 1.

5. The aforementioned compound has a structure represented by formula (IV), 【Chemistry 12】 Here, X １ , R ２ , R ３ , R ４ The definition is as defined in claim 1. A compound represented by formula (I) as described in claim 1.

6. A compound represented by formula (I) according to claim 1, selected from the following compounds. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】

7. A pharmaceutical composition characterized by comprising a compound or tautomer thereof according to any one of claims 1 to 6, an enantiomer, a diastereomer, a mixture of an enantiomer and a diastereomer, a racemic mixture, a meso compound, a mixture of a racemic mixture and a meso compound, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable excipient.

8. The compound according to any one of claims 1 to 6 or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemic mixtures, meso-forms, mixtures of racemic mixtures and meso-forms, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates, and the use of the pharmaceutical composition of claim 7 in the manufacture of agents for the prevention and / or treatment of diseases associated with abnormal Rho kinase activity.

9. The compound according to any one of claims 1 to 6 or its tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate, or the use of the pharmaceutical composition of claim 7 in the manufacture of a Rho kinase inhibitor.

10. A method for inhibiting Rho kinase in a biological sample, comprising contacting the biological sample with a compound or tautomer thereof described in any one of claims 1 to 6, an enantiomer, a diastereomer, a mixture of an enantiomer and a diastereomer, a racemate, a meso, a mixture of a racemate and a meso, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable salt, a solvate, or the pharmaceutical composition of claim 7.

11. A method for inhibiting Rho kinase in a patient requiring such inhibition, comprising administering to the patient a compound or tautomer thereof according to any one of claims 1 to 6, an enantiomer, a diastereomer, a mixture of an enantiomer and a diastereomer, a racemate, a meso, a mixture of a racemate and a meso, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable salt, a solvate, or the pharmaceutical composition of claim 7.

12. A method for treating a Rho kinase-mediated disease in a patient requiring such treatment, comprising administering to the patient a compound or tautomer thereof according to any one of claims 1 to 6, an enantiomer, a diastereomer, a mixture of an enantiomer and a diastereomer, a racemate, a meso, a mixture of a racemate and a meso, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable salt, a solvate, or the pharmaceutical composition of claim 7, Preferably, the Rho kinase-mediated disease is selected from cardiovascular disease, smooth muscle-related disease, fibrous disease, inflammatory disease, neurological disease, neoplastic disease, intraocular pressure elevation disease, diabetes, organ transplantation, infectious disease, and autoimmune disease. A method characterized by the following features.

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