CN116178337A - Benzodiazepine compounds and their use as Rho kinase inhibitors - Google Patents

Benzodiazepine compounds and their use as Rho kinase inhibitors Download PDF

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CN116178337A
CN116178337A CN202211486877.7A CN202211486877A CN116178337A CN 116178337 A CN116178337 A CN 116178337A CN 202211486877 A CN202211486877 A CN 202211486877A CN 116178337 A CN116178337 A CN 116178337A
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杨胜勇
黄维
谢佳雨
胡海
李升�
熊益好
吴孝全
黄奇
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Chengdu Aorui Pharmaceutical Co ltd
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Abstract

The present disclosure relates to a benzodiazepine having a structure represented by formula (I)
Figure DDA0003962015080000012
The compound is used as a ROCKII kinase inhibitor, has the advantages of high activity, good selectivity, low toxic and side effects and the like, and also relates to application and a preparation method of the compound in Rho kinase inhibitor medicines.

Description

Benzodiazepine compounds and their use as Rho kinase inhibitors
Technical Field
The present disclosure relates to the field of medicine, and in particular to a benzodiazepine with Rho kinase inhibition
Figure SMS_1
A compound and its preparation method are provided.
Background
Rho kinase (ROCK) is one of the earliest discovered downstream targets of Rho protein, and is a serine/threonine protein kinase with a relative molecular mass of 160kDa, and comprises two subtypes of ROCK ki and ROCK ii, and ROCK kinase plays an important role in a series of cell vital activities such as cell mitosis adhesion, cytoskeletal adjustment, muscle cell contraction, tumor cell infiltration and the like. ROCK kinase has been reported in the literature to be associated with a variety of diseases including hypertension, pulmonary hypertension, cardiovascular disease, inflammation, autoimmune disease, pulmonary disease, and ophthalmic disease, among others.
The existing medicine for glaucoma mainly surrounds the glaucoma case which promotes the outflow of aqueous humor so as to achieve the effect of reducing intraocular pressure, but still has some normal intraocular pressure in clinic, and clinically elucidation of glaucoma is caused by progressive retinal ganglion cell loss, progressive depression of optic disc and visual field damage of different reasons. These suggest that our development of glaucoma drugs can reduce ocular tension and, more importantly, protect the optic nerve. Netarsudil is currently the only approved marketed pan-ROCK inhibitor by the FDA and is also used in open angle glaucoma and ocular hypertension treatment, but clinical trials report its major side effects as conjunctival congestion and blepharitis. The ROCKII inhibitor can reduce intraocular pressure by regulating actin cytoskeleton, extracellular matrix and Schemms tube endothelial cell functions in trabecular meshwork, and can effectively reduce toxic and side effects of the medicament.
Along with the continuous and intensive research, students find that ROCKII has unique functions in the development process of blood vessels and nervous systems, and is mainly distributed in muscle tissues and brains, while the expression distribution of ROCK I is very wide, including liver, kidney, spleen, testis, thymus, blood cells and the like. Although the core functions and related mechanisms of the different subtypes in various organs are not clear, the different subtypes play a certain biological role in different organs, and potential toxic and side effects can be caused if the different subtypes are widely inhibited. Therefore, the design of the selective inhibitor aiming at a single subtype (ROCK II) can weaken potential toxic and side effects of the compound and reduce the risk of drug development; on the other hand, the specific functions of different subtypes in the disease occurrence and development process can be also discovered by using a single subtype selective small molecule inhibitor as a probe. Two ROCKII selective inhibitors have been shown to enter clinical trials and progress smoothly. Therefore, from the aspects of target drug formulation and drug safety, further research and development of ROCK II high-selectivity inhibitors have good prospects.
Disclosure of Invention
The purpose of the present disclosure is to provide a synthesis of a novel compound and an application thereof in a ROCK kinase inhibitor drug, in particular, the compound has the advantages of high activity, good selectivity, low toxic and side effects and the like as a ROCK ii selective kinase inhibitor.
In particular, the present disclosure provides compounds represented by the following formula (I) or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, salt or solvate thereof,
Figure SMS_2
wherein n is selected from 1 or 2;
X 1 selected from CH or N;
n R 1 May be the same or different; r is R 1 Selected from hydrogen, amino, or C 1-3 Alkyl, said amino optionally being C 1-6 Alkyl or C 3-8 Cycloalkyl alkyl substituted;
a is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O, S, or a 9-12 membered bicyclic heteroaryl group containing 1-3 atoms selected from N, O, S;
R 2 selected from C 1-6 Alkyl, 5-7 membered aryl, said C 1-6 Alkyl, 5-7 membered aryl optionally substituted with one or more halo, amino or hydroxy;
R 3 is hydrogen, C 1-6 Alkoxy, C 1-6 Carboxyl, hydroxyl, halogen, -C (O) NR 6 R 7 or-OC (O) -R 11 ；
R 6 、R 7 Are independently selected from 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, said 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 with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
R 4 selected from hydrogen, halogen, -B (OH) 2 Or a dioxaborolan group, said dioxaborolan group being substituted with one to more C' s 1-6 Alkyl substitution;
R 5 selected from hydrogen or C 1-3 An alkyl group.
In some embodiments, R 1 Selected from hydrogen, amino, or methyl, the amino optionally being C 3-8 Cycloalkyl alkyl substituted;
preferably, R 1 Is hydrogen or amino optionally substituted with cyclopropylmethyl;
in some embodiments, A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O, S, or a 9-12 membered bicyclic heteroaryl group containing 1-3 atoms selected from N, O, S;
preferably, A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2N atoms, or a 9-12 membered bicyclic heteroaryl group containing 1-2N atoms;
preferably, a is selected from pyridinyl, pyrazolyl, benzopyrazolyl, or pyrrolopyridinyl;
Preferably, a is selected from pyridinyl, pyrazolyl or benzopyrazolyl;
preferably, A is selected from
Figure SMS_3
Preferably, A is selected from
Figure SMS_4
Preferably, the method comprises the steps of,
Figure SMS_5
selected from->
Figure SMS_6
Figure SMS_7
Preferably, the method comprises the steps of,
Figure SMS_8
selected from the group consisting of
Figure SMS_9
Figure SMS_10
In some embodiments, R 2 Selected from C 1-6 Alkyl, 5-7 membered aryl, said C 1-6 Alkyl, 5-7 membered aryl optionally substituted with one or more halogen, amino or hydroxy:
preferably, R 2 Selected from C 1-3 Alkyl, or phenyl, the C 1-3 Alkyl, phenyl optionally substituted with one to three hydroxy, amino or fluoro;
preferably, R 2 Selected from methyl, ethyl, isopropyl, trifluoromethyl, -CH 2 OH、-CH 2 CH 2 OH, or phenyl;
preferably, R 2 Selected from methyl, ethyl, isopropyl, -CH 2 OH or phenyl.
In some embodiments, R 3 Is hydrogen, C 1-6 Alkoxy, C 1-6 Carboxyl, hydroxyl, halogen,-C(O)NR 6 R 7 or-OC (O) -R 11 ；
Preferably, R 3 Is hydrogen, C 1-3 Alkoxy, C 1-3 Carboxyl, hydroxyl, halogen, -C (O) NR 6 R 7 or-OC (O) -R 11 ；
Preferably, R 3 Is hydrogen, methoxy, -C (O) OH, hydroxy, fluoro, -C (O) NR 6 R 7 or-OC (O) -R 11 ；
R 6 、R 7 Are independently selected from 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, said 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 with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
wherein R is 6 、R 7 Each independently selected from single bond, hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, said C 1-3 Alkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, optionally substituted with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 6 Selected from hydrogen;
preferably, R 7 Selected from single bonds, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, said C 1-3 Alkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, optionally substituted with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 7 Selected from single bond, methyl, ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclobutyl, cyclobutanylmethyl, cyclopropanylmethyl or cyclohexane-a methyl group, said methyl, ethyl, propyl, isopropyl, neopentyl, cyclobutanylmethyl, cyclopropanylmethyl or cyclohexaanylmethyl group optionally being substituted with one or two R groups 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
or R is 6 、R 7 Together with the nitrogen atom to which they are attached form a 3-7 membered ring, said 3-7 membered ring optionally being substituted with 1 to 3 halogen, cyano, hydroxy or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 6 、R 7 Together with the nitrogen atom to which they are attached form a 4-5 membered ring, said 4-5 membered ring optionally being substituted with 1 to 2 fluorine, cyano, hydroxy or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 6 、R 7 Together with the nitrogen atom to which they are attached, form an azetidine, optionally substituted with 1 to 2 fluorine, cyano, hydroxy or- (CH) 2 ) p -OC(O)R 9 Substituted;
R 8 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogen, hydroxy, C 1-6 A carboxyl group, a 4-7 membered heterocycloalkyl group 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 with one or more hydroxy, halogen, C 1-6 Alkyl, or nitro;
preferably, R 8 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, fluoro, hydroxy, C 1-3 A carboxyl group, a 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N or O, wherein said 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 with one to three hydroxy, halogen, C 1-3 Alkyl, nitro substituted;
preferably, R 8 Selected from methyl, methoxy, fluoro, hydroxy, carboxyl, piperidine A group, 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, hydroxy, or nitro groups;
p is selected from 0, 1 or 2;
R 9 selected from the group consisting of 5-7 membered aryl, 5-7 membered monocyclic heteroaryl containing 1N atom, 5-7 membered heterocycloalkyl containing 1N atom, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the 5-7 membered aryl, 5-7 membered monocyclic heteroaryl containing 1N atom, 5-7 membered heterocycloalkyl containing 1N atom or C 1-6 Alkyl is optionally substituted with one or more R 10 Substituted;
preferably, R 9 Selected from 5-7 membered aryl, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the 5-7 membered aryl, C 1-6 Alkyl is optionally substituted with one or more R 10 Substituted;
preferably, R 9 Selected from phenyl, C 1-3 Alkyl or C 3-7 Cycloalkyl, wherein the phenyl, C 1-3 Alkyl is optionally substituted with one or two R 10 Substituted;
preferably, R 9 Selected from phenyl, cyclopropanyl, cyclobutyl, t-butyl, or n-propyl, wherein the phenyl, cyclopropanyl, cyclobutyl, t-butyl, or n-propyl is optionally substituted with one or two R 10 Substituted;
each R is 10 Identical to or different from each other, selected from hydroxy, nitro, C 1-3 Alkyl, halogen or-ONO 2 ；
Preferably, R 10 Selected from C 1-3 Alkyl, halogen, -ONO 2 ；
Preferably, R 10 Selected from fluorine, chlorine, cyano, methyl;
in some embodiments, R 9 Selected from the group consisting of
Figure SMS_11
/>
Figure SMS_12
Preferably, R 9 Selected from the group consisting of
Figure SMS_13
R 11 Selected from 5-7 membered aryl, said 5-7 membered aryl optionally substituted with one or more halogen, hydroxy, nitro or amino groups;
preferably, R 11 Selected from phenyl optionally substituted with one or two halogen, hydroxy, nitro or amino groups;
preferably, R 11 Is that
Figure SMS_14
Preferably, R 3 Selected from the group consisting of hydrogen, methoxy, fluoro, hydroxy, -C (O) OH,
Figure SMS_15
Figure SMS_16
/>
Figure SMS_17
Preferably, R 3 Selected from hydrogen, methoxy, fluoro, hydroxy,
Figure SMS_18
Figure SMS_19
/>
Figure SMS_20
/>
Figure SMS_21
R 4 Selected from hydrogen, halogen, -B (OH) 2 Or a dioxaborolan group, said dioxaborolan group being substituted with one to more C' s 1-6 Alkyl substitution;
preferably, R 4 Selected from hydrogen, fluorine, bromine, -B (OH) 2 Or (b)
Figure SMS_22
Preferably, R 4 Fluorine and bromine;
R 5 selected from hydrogen, or C 1-3 An alkyl group;
preferably, R 5 Selected from hydrogen, or methyl;
preferably, R 5 Is hydrogen.
According to one aspect of the present disclosure, including the above compounds or tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso, mixtures of racemates and meso, pharmaceutically acceptable hydrates, salts or solvates thereof, wherein the compounds have the structure shown in the following formulae (IIIA), (IIIB) or (IIIC) or (IIID):
Figure SMS_23
Wherein R is 1 、R 2 、R 3 、R 4 The definition of n is as defined above.
According to one aspect of the present disclosure, including the above compounds or tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso, mixtures of racemates and meso, pharmaceutically acceptable hydrates, salts or solvates thereof, wherein the compounds have the structure shown in formula (IV):
Figure SMS_24
wherein X is 1 、R 2 、R 3 、R 4 Is defined as above.
According to one aspect of the disclosure, the following compounds, as well as tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso, mixtures of racemates and meso, pharmaceutically acceptable hydrates, salts or solvates thereof are included:
Figure SMS_25
/>
Figure SMS_26
/>
Figure SMS_27
/>
Figure SMS_28
/>
Figure SMS_29
/>
Figure SMS_30
/>
Figure SMS_31
/>
Figure SMS_32
/>
Figure SMS_33
according to one aspect of the present disclosure, a pharmaceutical composition comprising the above compound or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable adjuvant is included.
According to one aspect of the present disclosure, the use of the above-described compounds or tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso, mixtures of racemates and meso, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions for the manufacture of a medicament for the prevention and/or treatment of a condition associated with abnormal Rho kinase activity.
According to one aspect of the present disclosure, the use of the above-described compounds or tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, meso, mixtures of racemates and meso, pharmaceutically acceptable hydrates, pharmaceutically acceptable salts or solvates thereof, in the preparation of a Rho kinase inhibitor, or a pharmaceutical composition.
According to one aspect of the present disclosure there is provided a method of inhibiting Rho kinase in a patient in need thereof, comprising administering to the patient a compound as described above or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof.
According to one aspect of the present disclosure there is provided a method of inhibiting Rho kinase in a biological sample comprising contacting the biological sample with a compound described above or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof.
According to one aspect of the present disclosure there is provided a method for treating a Rho kinase mediated disorder in a patient in need thereof, comprising administering to the patient a compound described above or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof;
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, oncologic disorders, ocular pressure elevation disorders, diabetes, organ transplantation, infections, and autoimmune disorders.
Detailed Description
I. Definition of the definition
In this disclosure, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology-related terms and laboratory procedures as used herein are terms and conventional procedures that are widely used in the corresponding arts. Meanwhile, in order to better understand the present disclosure, definitions and explanations of related terms are provided below.
For purposes of clarity and conciseness of 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 some embodiments having a combination of all or some of the features described.
Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.
The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.
In the context of the present disclosure of the present invention,
Figure SMS_34
refers to the position where the substituent is bonded.
In this disclosure, numerical ranges refer to individual integers in a 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 may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not occur, e.g., "optionally substituted with one or two hydroxyl groups" means that it may be substituted with one hydroxyl group, it may be substituted with two hydroxyl groups, or it may not be substituted with hydroxyl groups.
The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom or group is substituted with a substituent, provided that the valence of the particular atom or group is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o), it means that two hydrogen atoms are substituted. The kind and number of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified. The substituents may be substituted with one, two or more substituents selected from the group consisting of: deuterium, halogen group, cyano, nitro, -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, and the like, but are not limited thereto.
When any variable (e.g. R n ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. Thus, for example, if a group is substituted with one to three R, the group may optionally be substituted with up to three R, and R in each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms. Such as the term "C 1-6 Alkyl "includes C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like. It may be divalent, e.g. methylene, ethylene.
The term "alkoxy" may be straight chain, 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, t-butoxy, sec-butoxy, n-pentoxy, neopentoxy, isopentoxy, n-hexoxy, 3-dimethylbutoxy, 2-ethylbutoxy, n-octoxy, n-nonoxy, n-decyloxy and the like, but are not limited thereto.
The term "cycloalkylalkyl" refers to cycloalkyl substituents attached through an alkyl chain. Examples of cycloalkylalkyl substituents include cyclohexylethyl, wherein the cyclohexanes are linked through an ethane linker. Other examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylethyl, cycloheptylethyl, cyclohexylmethyl. In the present disclosure, examples of the halogen group may include fluorine, chlorine, bromine, or iodine.
In the present disclosure, the term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system, free of heteroatoms and double bonds. For example, the term "C 3-8 Examples of cycloalkyl "include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
In the present disclosure, the term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system, which is obtained by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. It includes bicyclic groups comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Specific examples thereof include phenyl or naphthyl, but are not limited thereto.
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 a piperidyl group or a tetrahydropyrrole group, but are not limited thereto.
In the present disclosure, the term "heteroaryl" refers to a monovalent aryl group comprising at least one heteroatom independently selected from nitrogen, oxygen and sulfur, and the heteroaryl group may be a single ring or may be a polycyclic ring system, such as a bicyclic ring, in which two or more rings are present in the form of a fused, bridged or spiro ring, wherein at least one ring contains one or more heteroatoms. Specific examples of heteroaryl groups include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, imidazopyridyl, benzofuranyl, pyridazinyl, isoindolyl.
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 valency permits. The heterocyclic ring may be a single ring or a multiple ring system, such as a bicyclic ring, in which two or more rings are present in the form of a parallel ring, a bridged ring, or a spiro ring, in which at least one ring contains one or more heteroatoms.
Medicament or pharmaceutical composition
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.
The term "tautomer" refers to a functional group isomer produced by the rapid movement of an atom in a compound at two positions, the difference between the tautomers being the migration of protons and double bonds at the corresponding positions, specific examples of which include, but are not limited to, enol-and keto-type tautomers.
The term "enantiomer" refers to two stereoisomers that are mirror images of each other and that do not coincide, one of which is left-handed and the other of which is right-handed, and the term "diastereomer" refers to two stereoisomers that are not mirror images of each other and that possess two or more chiral centers.
The term "racemate" refers to a mixture in which chiral molecules having optical activity, when mixed in equal proportions with their enantiomers, cancel each other out due to their opposite optical effects; the term "mesogen" refers to a compound that possesses two or more chiral centers within the molecule, but that does not exhibit optical activity as a whole due to the presence of other factors, such as symmetry planes, etc. The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and acidic groups such as basic or organic salts of 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 from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers.
For oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be in the form of a non-toxic, pharmaceutically acceptable adjuvant such as a binder (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 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, sweetening agents, natural and synthetic gums (e.g., acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. For oral administration in liquid form, the pharmaceutical component may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous carriers (e.g., almond oil, oil esters, ethanol, or fractionated vegetable oils), preserving agents (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid), and the like. Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.
Tablets containing the active compound may be coated by methods well known in the art. The compositions of the present disclosure comprising as active compound a compound of formula I may also be incorporated into beads, microspheres or microcapsules, for example constructed from polyglycolic acid/lactic acid (PGLA). Liquid formulations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may be suitably formulated so as to provide controlled or delayed release of the active compound.
The medicaments or pharmaceutical compositions of the present disclosure may be delivered parenterally, i.e. by intravenous (i.v.), intraventricular (i.c.v), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.), or intradermal (i.d.), by direct injection, e.g. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampules or multi-dose containers with added preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, in the form of excipients (vehicles), and may contain formulatory agents such as anti-settling agents, stabilisers and/or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g. sterile pyrogen-free water) prior to use.
The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
Dosage forms for topical application of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compounds may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.
In addition to the active compounds of the present disclosure, the ointments, pastes, creams and gels may contain 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.
Ophthalmic formulations, ophthalmic ointments, powders, solutions (e.g., eye drops), and the like are also considered to be within the scope of this disclosure.
Examples of suitable aqueous and non-aqueous carriers that may be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by the use of a coating material, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents (e.g., sugars, sodium chloride, and the like) in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption (e.g., aluminum monostearate and gelatin).
The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated. The term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of the disease state being treated or otherwise provide the desired pharmacological and/or physiological effect. The precise dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), disease or disorder, and the treatment being administered. The effect of an effective amount may be relative to a control. These controls are known in the art and discussed herein, and may be, for example, the condition of the subject prior to or without administration of the drug or combination of drugs, or in the case of a combination of drugs, the combined effect may be compared to the effect of administration of only one drug.
The term "pharmaceutical composition" means a composition comprising a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature sensitive materials, temperature adjusting agents, adhesives, stabilizers, suspending agents, and the like.
In light of the foregoing disclosure, many other modifications, substitutions, or alterations are also possible in the form of modifications, substitutions, or alterations without departing from the spirit and scope of this disclosure.
Examples II
The materials and equipment used in the embodiments of the present disclosure are all known products and are obtained by purchasing commercially available products.
Example 1: preparation of Compounds 1, 2:
Figure SMS_35
intermediate 1b: preparation of 7-bromo-1, 2-dihydro-4H-benzo [ d ] [1,3] oxazin-4-one:
raw material 1a (2.16 g,10 mmol) was dissolved in 20mL anhydrous tetrahydrofuran, Then triphosgene (1.04 g,3.50 mmol) solution of tetrahydrofuran was slowly dropped thereinto at 0 deg.C, the reaction was stirred for 4 hours at normal temperature, ice water was added to the system, followed by suction filtration, and the filter cake was washed with dichloromethane to obtain intermediate 1b. The yield was 80%, 1 H NMR(400MHz，DMSO-d6)δ9.68(s，1H)，7.96(d.J＝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] + .
intermediate 1c: preparation of 7-bromo-1-methyl-2H-benzo [ d ] [1,3] oxazine-2, 4- (1H) -dione:
intermediate 1b (1.60 g,6.70 mmol) was added to 20mL of anhydrous DMF, then sodium hydride (0.30 g,8.00 mmol) was slowly added at 0deg.C, after stirring the reaction system at low temperature for 20 min, 500. Mu.L of methyl iodide was added, followed by stirring the reaction at room temperature for 2h, followed by quenching the excess sodium hydride with methanol, and column chromatography (petroleum ether/ethyl acetate=1:1) was concentrated to give the target intermediate 1c. The yield was 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] + .
Intermediate 1d: (S) -8-bromo-1, 3-dimethyl-3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_36
-preparation of 2, 5-diketones:
triethylamine (2.4 mL,17.6 mmol) was added to a DME and water mixture of intermediate 1c (1.5 g,5.86 mmol) and L-alanine (0.57 g,6.45 mmol), the reaction was stirred at 60℃for 2h, concentrated under reduced pressure, 10mL of acetic acid was added, then heated under reflux for 4h, acetic acid was further removed under reduced pressure, extraction was performed with dichloromethane and water, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the filtrate after celite filtration was subjected to column chromatography (dichloromethane/methanol=20:1) to give intermediate 1d. The yield was 40%. MS (ESI), positive ion) m/z:283.12 285.30 [ M+H ] ] + .
Intermediate 1e: (S) -8-bromo-4- (3-methoxybenzyl) -1, 3-dimethyl-3,4-dihydro-1H-benzo [ e ]][1，4]Diaza-type
Figure SMS_37
-preparation of 2, 5-diketones:
intermediate 1d (88 mg,0.22 mmol) was dissolved in tetrahydrofuran, the reaction system was then cooled to 0deg.C, sodium hydride (8 mg,0.32 mmol) was added, stirred for 10min, 3-methoxybromobenzyl (80 mg,0.4 mmol) was added dropwise, the reaction was allowed to proceed to room temperature for 1h, TLC monitored for completion of the reaction, excess sodium hydride was quenched with saturated ammonium chloride, ethyl acetate was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to column chromatography (petroleum ether/ethyl acetate=2:1) to give white solid as intermediate 1e. The yield was 80%. MS (ESI), positive ion) m/z:403.20 405.25 [ M+H ] +.
Compound 1: (S) -4- (3-methoxybenzyl) -1, 3-dimethyl-8- (pyridin-4-yl) -3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_38
-preparation of 2, 5-diketones:
intermediate 1e (48 mg,0.12 mmol), 4-pyridineboronic acid (18 mg,0.15 mmol), K 2 CO 3 (50 mg,0.36 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (8 mg,0.01 mmo;) was placed in a double-necked flask, and a 1, 4-dioxane/water (V/v=5/1) mixture was added thereto, followed by a reaction at 85℃for 5 hours under the protection of argon. After TLC monitoring the reaction completion, the reaction solution was cooled and filtered through celite, and the filtrate was concentrated under reduced pressure by column chromatography (petroleum ether/ethyl acetate=1:5) to separate a white solid, compound 1. The yield was 80%. 1 H NMR(400MHz，DMSO-d 6 )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] + .
Compound 2: (S) -4- (3-methoxybenzyl) -1, 3-dimethyl-8- (2-aminopyridin-4-yl) -3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_39
-preparation of 2, 5-diketones:
compound 2 was synthesized in analogy to compound 1, starting from intermediate 1e and 2-amino 4-pyridineboronic acid in 60% yield.
1 H NMR(400MHz，DMSO-d 6 )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] + .
Example 2: preparation of Compounds 3, 4:
Figure SMS_40
intermediate 3a: (R) -8-bromo-1, 3-dimethyl-3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_41
-preparation of 2, 5-diketones:
intermediate 3a was prepared in a similar manner to 1D starting from intermediate 1c and D-alanine in 40% yield. MS (ESI), positive ion) m/z:283.16 285.32 [ M+H ] +.
Intermediate 3b: (R) -8-bromo-4- (3-methoxybenzyl) -1, 3-dimethyl-3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_42
-preparation of 2, 5-diketones:
intermediate 3b was prepared in a similar manner to 1e, starting from intermediate 3a, in 80% yield. MS (ESI), positive ion) m/z:403.23 405.36 [ M+H ] +.
Compound 3: (R) -4- (3-methoxybenzyl) -1, 3-dimethyl-8- (pyridin-4-yl) -3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_43
-preparation of 2, 5-diketones:
the preparation method of the compound 3 is similar to that of the compound 1, and the compound is prepared by taking the intermediate 3b and 4-pyridine boric acid as raw materials, and the yield is 75%.
1 H NMR(400MHz，DMSO-d 6 )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] + 。
Intermediate 3c: (R) -4- (3-hydroxybenzyl) -1, 3-dimethyl-8- (pyridin-4-yl) -3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_44
-preparation of 2, 5-diketones:
compound 3 (80 mg,0.21 mmol) was dissolved in dichloromethane (2 mL), and boron tribromide (48 μL,0.5 mmol) was added to the solution in an ice-water bath and reacted at room temperature for 1 hour. TLC monitoring reaction completion, adding saturated sodium bicarbonate to the reaction solution, quenching, extracting with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating the filtrate by column chromatography (petroleum ether/ethyl acetate=1:10) to obtain white solid, namely intermediate 3c, with a yield of 30%. MS (ESI), positive ion) m/z:388.23.[ M+H ]] + .
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]Diaza-type
Figure SMS_45
-4-yl) phenyl 2, 4-dimethylbenzoic acid methyl ester->
Intermediate 3c (38 mg,0.1 mmol) was dissolved in acetonitrile (1 mL), 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 monitoring reaction is complete, methanol is added to terminate the reaction, then decompression concentration is directly carried out, and compound 4 is obtained through silica gel column chromatography purification.
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] + .
Compounds 5-6 were prepared in a similar manner to compound 3, as shown in Table 1 below.
Table 1: process for preparing compounds 5-6
Figure SMS_46
Example 3: preparation of compounds 7, 8:
Figure SMS_47
intermediate 7a: (R) -8-bromo-4- ((6-fluoro-2-pyridinyl) methyl) -1, 3-dimethyl-3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_48
-preparation of 2, 5-diketones:
intermediate 7a was synthesized in a similar manner to intermediate 3b, starting from intermediate 3a and 2-bromomethyl-6-fluoropyridine in 90% yield. MS (ESI), positive ion) m/z:392.25 394.28 [ M+H ] +.
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]Diaza-type
Figure SMS_49
-preparation of 2, 5-diketones:
Figure SMS_50
the synthesis of the compound 7 is similar to the compound 3, and the compound is obtained by taking the intermediate 7a and 2-amino 4-pyridine boric acid as raw materials to react, and the yield is 70%.
1 H NMR(400MHz，DMSO-d 6 )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)，6.90-6.85(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]+.
Intermediate 7b: (R) -8-bromo-4- ((6-hydroxy-2-pyridinyl) methyl) -1, 3-dimethyl-3, 4-dihydro-1H-benzo [ e][1，4]Diaza-type
Figure SMS_51
-preparation of 2, 5-diketones:
Figure SMS_52
intermediate 7a (60 mg,0.15 mmol) was dissolved in tetrahydrofuran (3 mL), then aqueous hydrochloric acid (2 mL,4 mol/L) was added, the reaction was carried out at 50℃for 5 hours, after the completion of the reaction, sodium bicarbonate was added to adjust the pH to neutral, ethyl acetate was used for extraction, the organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and intermediate 7b was obtained after chromatography on a silica gel column in 20% yield. MS (ESI), positive ion) m/z:390.23 392.24 [ M+H ] +.
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]Diaza-type
Figure SMS_53
-preparation of 2, 5-diketones:
Figure SMS_54
the synthesis of the compound 8 is similar to the compound 1, and the compound is obtained by taking the intermediate 7b and 2-amino-4-pyridine boric acid as raw materials to react, and the yield is 70%.
1 H NMR(400MHz，DMSO-d 6 )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]+.
Example 4: preparation of compounds 9, 10, 11:
Figure SMS_55
intermediate 9a: (R) -3- ((8-bromo-1, 3-dimethyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_56
-4-yl) methylene) benzoic acid methyl ester preparation:
Figure SMS_57
intermediate 9a was synthesized in a similar manner to intermediate 3b, starting from intermediate 3a and methyl 3-bromomethylbenzoate in 85% yield. MS (ESI), positive ion) m/z:431.18 433.21 [ M+H ] +.
Intermediate 9b: (R) -3- ((8- (pyridin-4-yl) -1, 3-dimethyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e ]][1，4]Diaza-type
Figure SMS_58
-4-yl) methylene) benzoic acid methyl ester preparation:
Figure SMS_59
intermediate 9b was synthesized in a similar manner to compound 3, starting from intermediate 9a and 4-pyridineboronic acid in 75% yield. MS (ESI), positive ion) m/z: [ M+H ] + ].
Intermediate 9c: (R) -3- ((8- (2-aminopyralid)Pyridin-4-yl) -1, 3-dimethyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e ][1，4]Diaza-type
Figure SMS_60
-4-yl) methylene) benzoic acid preparation:
Figure SMS_61
intermediate 9b (500 mg,1.16 mmol) was dissolved in methanol/water (5 mL, V/V, 4/1), sodium hydroxide (120 mg,3.0 mmol) was added, the reaction was completed at room temperature, TLC was monitored, diluted hydrochloric acid was added to adjust pH to neutrality, and concentrated under reduced pressure, and purification by silica gel column chromatography gave intermediate 9c in 90% yield. MS (ESI), positive ion) m/z: [ M+H ] + ].
Compound 9: (R) -3- ((8- (pyridin-4-yl) -1, 3-dimethyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e ]][1，4]Diaza-type
Figure SMS_62
-4-yl) methylene) -N- ((3-hydroxycyclobutyl) methyl) benzamide preparation:
Figure SMS_63
intermediate 9c (50 mg,0.12 mmol) was dissolved in N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (46. Mu.L, 0.3 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (91 mg,0.24 mmol) were added thereto, and after stirring at room temperature for 10 minutes, 3- (aminomethyl) cyclobutanol (24 mg,0.24 mmol) was added thereto and reacted at room temperature for 2 hours. TLC showed complete reaction of the starting material and purification of the reaction solution directly over reverse phase silica gel C-18 gave compound 9 in 60% yield.
1 H NMR(400MHz，Methanol-d 4 )δ8.82(s，2H)，8.19(d，J＝5.6Hz，2H)，8.06(d，J＝8.6Hz，1H)，7.90-7.84(m，2H)，7.75-7.68(m，2H)，7.49-7.40(m，2H)，5.05-4.87(m，2H)，4.57-4.48(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]+.
Compound 10: (R) -3- ((8- (pyridin-4-yl) -1, 3-dimethyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e ] ][1，4]Diaza-type
Figure SMS_64
-4-yl) methylene) benzamide) methyl) cyclobutyl 2, 4-dimethylbenzoic acid methyl ester preparation:
Figure SMS_65
compound 9 (50 mg,0.12 mmol) was dissolved in N, N-dimethylformamide (1 mL), and N, N-diisopropylethylamine (46. Mu.L, 0.3 mmol), 2, 4-dimethylbenzoyl chloride (40 mg,0.24 mmol) and 4-dimethylaminopyridine (3 mg,0.02 mmol) were added and reacted at room temperature for 2 hours. TLC showed complete reaction of the starting material and purification of the reaction solution directly over reverse phase silica gel C-18 gave compound 10 in 60% yield.
1 H 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]+.
Compound 11: (R) -3- ((8- (pyridin-4-yl) -1, 3-dimethyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e ]][1，4]Diaza-type
Figure SMS_66
-4-yl) methylene) benzamide) methylene) cyclobutyl 3, 3-difluorocyclobutanoate preparation:
Figure SMS_67
after dissolving compound 9 (50 mg,0.12 mmol) in N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (46. Mu.L, 0.3 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (91 mg,0.24 mmol) were added, and 3, 3-difluorocyclobutanecarboxylic acid (36 mg,0.24 mmol) were reacted at room temperature for 2 hours. TLC showed complete reaction of the starting material and purification of the reaction solution directly over reverse phase silica gel C-18 gave compound 11 in 60% yield.
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]+.
The compounds in the following table were prepared in analogy to compounds 9-11.
Table 2: examples 12-52, 94-111 preparation method
Figure SMS_68
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Figure SMS_69
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Figure SMS_70
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Figure SMS_71
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Figure SMS_72
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Figure SMS_73
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Figure SMS_74
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Figure SMS_75
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Figure SMS_76
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Figure SMS_77
Example 5: preparation of Compound 53:
Figure SMS_78
intermediate 53a was synthesized in a similar manner to intermediate 3a, starting from intermediate 1c and D-serine in a yield of 30%. MS (ESI), positive ion) m/z:299.23 301.30[ M+H ] +.
Intermediate 53b: (R) -3- ((8-bromo-3- (hydroxymethyl) -1-methyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_79
-4-yl) methylene) benzoic acid methyl ester:
Figure SMS_80
intermediate 53a (95 mg,0.24 mmol) was dissolved in N, N-dimethylformamide, then the reaction system was cooled to 0 ℃, cesium carbonate (117 mg,0.36 mmol), 3-bromomethylbenzoate (82 mg,0.36 mmol) was added, the reaction was allowed to proceed to room temperature for 5h, tlc monitored the reaction was complete, ethyl acetate was extracted, the organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to column chromatography (petroleum ether/ethyl acetate=2:1) to give a white solid as intermediate 53b. The yield was 60%. MS (ESI), positive ion) m/z:447.23 449.25[ M+H ] +.
Intermediate 53c: (R) -3- ((8- (4-aminopyridyl) -3- (hydroxymethyl) -1-methyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_81
-4-yl) methylene) benzoic acid methyl ester:
Figure SMS_82
Intermediate 53c was synthesized in a similar manner to compound 3, starting from intermediate 53b and 4-amino-2-pyridineboronic acid in 70% yield. MS (ESI), positive ion) m/z:461.22[ M+H ] +.
Intermediate 53d: (R) -3- ((8- (4-aminopyridyl) -3- (hydroxymethyl) -1-methyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_83
-4-yl) methylene) benzoic acid:
Figure SMS_84
intermediate 53d was synthesized in a similar manner to compound 8, starting from intermediate 21c in 80% yield. MS (ESI), positive ion) m/z:447.31[ M+H ] +.
Compound 53: (R) -3- ((8- (4-aminopyridyl) -3- (hydroxymethyl) -1-methyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_85
-4-yl) methylene) -N- ((1-methyl-4-piperidinyl) methyl) benzamide:
Figure SMS_86
compound 53 was synthesized in analogy to compound 9, starting from intermediate 53d and was reacted with (1-methyl-4-piperidin-) methylamine in 60% yield.
1 H NMR(400MHz，DMSO-d 6 )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]+.
Compounds 54-59 in the following table were prepared in a similar manner to compound 53.
Table 3: process for the preparation of compounds 54-59
Figure SMS_87
Figure SMS_88
Example 6: preparation of Compound 60
Figure SMS_89
Intermediate 60a: (R) -3- ((8- (4-chloropyridinyl) -3-methyl-1-methyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_90
-4-yl) methylene) benzoic acid methyl ester:
Figure SMS_91
intermediate 60a was synthesized in a similar manner to 9b, starting from intermediate 9a and 2-chloro-4-pyridineboronic acid in 88% yield. MS (ESI), positive ion) m/z:464.22[ M+H ] +.
Intermediate 60b: (R) -3-Mono ((8- (2- ((cyclopropylmethyl) amino-4-pyridinyl) -3-methyl-1-methyl-2, 5-dione-1, 2,3, 5-tetrahydro-4H-benzo [ e)][1，4]Diaza-type
Figure SMS_92
-4-yl) methylene) benzoic acid methyl ester:
Figure SMS_93
intermediate 60a (93 mg,0.2 mmol) was dissolved in anhydrous toluene (3 mL), 4, 5-bis (diphenylphosphine) -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 reacted at 100deg.C under nitrogen for 12 hours. After completion of the TLC monitoring, the reaction solution was directly concentrated under reduced pressure and then subjected to silica gel column chromatography (petroleum ether/ethyl acetate=0:1) to give a white solid as intermediate 60b. MS (ESI), positive ion) m/z:499.33[ M+H ] +.
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]Diaza-type
Figure SMS_94
-4-yl) methylene) benzoic acid: />
Figure SMS_95
Intermediate 60c was synthesized in a similar manner to intermediate 9c, starting from intermediate 60b in 80% yield. MS (ESI), positive ion) m/z:485.31[ M+H ] +.
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]Diaza-type
Figure SMS_96
-4-yl) methylene) benzamide) methyl) -3-hydroxyazetidine-1-carboxylic acid ester:
Figure SMS_97
intermediate 60d was synthesized in analogy to compound 9, starting from intermediate 60c and tert-butyl 3- (aminomethyl) -3-hydroxyazetidine-1-carboxylate in 75% yield. MS (ESI), positive ion) m/z:669.50[ M+H ] +.
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]Diaza-type
Figure SMS_98
-4-yl) methylene) -N- ((3-hydroxyazetidin-3-yl) methyl) benzamide.
Figure SMS_99
Intermediate 60d (60 mg,0.1 mmol) was dissolved in methanol (1 mL), hydrogen chloride (0.1 mL,4mol/L of 1, 4-dioxane solution) was added and reacted at room temperature for 2 hours, after which TLC showed completion of the reaction, the reaction was concentrated under reduced pressure, and then subjected to silica gel column chromatography (dichloromethane/methanol=10:1) to give a white solid as compound 60. 1 H NMR(400MHz，Methanol-d 4 )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+.
Compounds 112-116 in the following table were prepared in a similar manner to compound 60.
Table 4: process for preparing compounds 112-116
Figure SMS_100
Figure SMS_101
Example 7: preparation of Compounds 61, 62
Figure SMS_102
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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]Diaza-type
Figure SMS_103
-4-yl) methylene) benzoyl) azetidinyl-3-carbonitrile:
Figure SMS_104
compound 61 was synthesized in a similar manner to compound 21, starting from intermediate 60b in 75% yield. 1 H NMR(400MHz，Methanol-d 4 )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)，3.48-3.43(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]+.
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]Diaza-type
Figure SMS_105
-4-yl) methylene) -N- ((3-hydroxycyclobutyl) methylene) benzamide:
Figure SMS_106
intermediate 62a was synthesized in a similar manner to compound 61, starting from intermediate 60b in 75% yield. MS (ESI), positive ion) m/z:568.45[ M+H ] +.
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]Diaza-type
Figure SMS_107
-4-yl) methylene) benzamide) methyl) cyclobutyl 3, 4-dichlorobenzoate:
Figure SMS_108
compound 62 was synthesized in a similar manner to compound 10, starting from intermediate 62a and 3, 4-dichlorobenzoyl chloride in 75% yield.
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，1H)，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]+.
Example 8: preparation of Compound 117
Figure SMS_109
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]Diaza-type
Figure SMS_110
Preparation of (4-yl) methylene) -5-fluorobenzamide) methyl) cyclobutyl ester
Figure SMS_111
Intermediate 117a was synthesized in a similar manner to compound 10, starting from 2-bromopropionyl chloride and compound 96 in 82% yield, MS (ESI, positive ion) m/z:637.37 639.36[ M+H ] +.
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]Diaza-type
Figure SMS_112
Preparation of (4-yl) methylene) -5-fluorobenzamide) methyl) cyclobutyl ester
Figure SMS_113
Intermediate 117a (100 mg,0.19 mmol) was dissolved in N, N-dimethylformamide (2 mL), followed by addition of potassium carbonate (52 mg,0.38 mmol), (R) -2-methyltetrahydrofyrrole (21 mg,0.25 mmol), and reaction at room temperature for 2 hours, purification over C-18 reverse-phase silica gel gave compound 117 in 52% yield. 1 H NMR(400MHz，DMSO-d 6 )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＝16.4Hz，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]+.
Test example 1: benzodiazepines
Figure SMS_114
In vitro kinase assay of ketone derivatives
In vitro excitationEnzyme assays were performed using the Kinase Profiler service provided by Eurofins Inc. The experimental procedure is briefly described as follows: the small molecule to be tested (0.001-10 mu M), the protein kinase to be tested, and the kit comprising the substrate, 10mM magnesium acetate and [ gamma- ] 33 P-ATP]By adding Mg/ATPmix to start the reaction, and after incubation for a period of time at room temperature, adding 3% phosphate solution to the buffer to stop the reaction. Subsequently, 10. Mu.L of the reaction mixture was quantitatively pipetted onto a P30 filter paper and washed 3 times with 75mM phosphate solution and once again with methanol, and the P30 filter paper was air-dried and then added to scintillation liquid for scintillation counting. Half inhibition concentration IC for inhibition activity of compound 50 To express, IC 50 Values were obtained from the inhibition fit corresponding to each concentration gradient and the results are shown in table 5 below. The results in the table are summarized, and the compounds of the present invention have good selective inhibitory activity against ROCKII kinase relative to ROCKI kinase.
Table 5: kinase inhibition data for each compound
Figure SMS_115
Note that: "/" indicates no test.

Claims (10)

1. A compound represented by the formula (I) or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate thereof,
Figure FDA0003962015060000011
wherein n is selected from 1 or 2;
X 1 selected from CH or N;
n R 1 May be the same or different; r is R 1 Selected from hydrogen, amino or C 1-3 Alkyl, said amino optionally being C 1-6 Alkyl or C 3-8 Cycloalkyl alkyl substituted;
a is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O, S, or a 9-12 membered bicyclic heteroaryl group containing 1-3 atoms selected from N, O, S;
R 2 selected from C 1-6 Alkyl, 5-7 membered aryl, said C 1-6 Alkyl, 5-7 membered aryl optionally substituted with one or more halo, amino or hydroxy;
R 3 is hydrogen, C 1-6 Alkoxy, C 1-6 Carboxyl, hydroxyl, halogen, -C (O) NR 6 R 7 or-OC (O) -R 11 ；
R 6 、R 7 Are independently selected from 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, said 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 with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
R 4 selected from hydrogen, halogen, -B (OH) 2 Or a dioxaborolan group, said dioxaborolan group being substituted with one to more C' s 1-6 Alkyl substitution;
R 5 selected from hydrogen or C 1-3 An alkyl group.
2. The compound represented by the formula (I) according to claim 1, wherein R 1 Selected from hydrogen, amino, or methyl, the amino optionally being C 3-8 Cycloalkyl alkyl substituted;
preferably, R 1 Is hydrogen or amino optionally substituted with cyclopropylmethyl;
preferably, A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2N atoms or a 9-12 membered bicyclic heteroaryl group containing 1-2N atoms;
preferably, a is selected from pyridinyl, pyrazolyl, benzopyrazolyl or pyrrolopyridinyl;
preferably, a is selected from pyridinyl, pyrazolyl or benzopyrazolyl;
preferably, A is selected from
Figure FDA0003962015060000012
Preferably, the method comprises the steps of,
Figure FDA0003962015060000013
Selected from->
Figure FDA0003962015060000014
Figure FDA0003962015060000015
Preferably, R 2 Selected from C 1-3 Alkyl or phenyl, said C 1-3 Alkyl, phenyl optionally substituted with one to three hydroxy, amino or fluoro;
preferably, R 2 Selected from methyl, ethyl, isopropyl, trifluoromethyl, -CH 2 OH、-CH 2 CH 2 OH or phenyl.
3. The compound represented by the formula (I) according to claim 1 or 2, wherein R 3 Is hydrogen, C 1-3 Alkoxy, C 1-3 Carboxyl, hydroxyl, halogen, -C (O) NR 6 R 7 or-OC (O) -R 11 ；
Wherein R is 11 Selected from 5-7 membered aryl, said 5-7 membered aryl optionally substituted with one or more halogen, hydroxy, nitro or amino groups;
wherein R is 6 、R 7 Each independently selected from single bond, hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, said C 1-3 Alkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, optionally substituted with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
or R is 6 、R 7 Together with the nitrogen atom to which they are attached form a 3-7 membered ring, said 3-7 membered ring optionally being substituted with 1 to 3 halogen, cyano, hydroxy or- (CH) 2 ) p -OC(O)R 9 Substituted;
R 8 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, halogen, hydroxy, C 1-6 A carboxyl group, a 4-7 membered heterocycloalkyl group 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 with one or more hydroxy, halogen, C 1-6 Alkyl, or nitro;
R 9 selected from the group consisting of 5-7 membered aryl, 5-7 membered monocyclic heteroaryl containing 1N atom, 5-7 membered heterocycloalkyl containing 1N atom, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the 5-7 membered aryl, 5-7 membered monocyclic heteroaryl containing 1N atom, 5-7 membered heterocycloalkyl containing 1N atom or C 1-6 Alkyl is optionally substituted with one or more R 10 Substituted;
each R is 10 Identical to or different from each other, selected from hydroxy, nitro, cyano, C 1-3 Alkyl, halogen or-ONO 2 ；
Preferably, R 3 Is hydrogen, methoxy, -C (O) OH, hydroxy, fluoro, -C (O) NR 6 R 7 or-OC (O) -R 11 ；
Preferably, R 6 Selected from hydrogen;
preferably, R 7 Selected from single bonds, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, said C 1-3 Alkyl, C 4-8 Cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1N atom, optionally substituted with one or two R 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 7 Selected from single bond, methyl, ethyl, propyl,Isopropyl, isobutyl, neopentyl, cyclobutyl, cyclobutanylmethyl, cyclopropanylmethyl or cyclohexanylmethyl, said methyl, ethyl, propyl, isopropyl, neopentyl, cyclobutanylmethyl, cyclopropanylmethyl or cyclohexanylmethyl optionally being substituted by one or two R' s 8 Or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 6 、R 7 Together with the nitrogen atom to which they are attached form a 4-5 membered ring, said 4-5 membered ring optionally being substituted with 1 to 2 fluorine, cyano, hydroxy or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 6 、R 7 Together with the nitrogen atom to which they are attached, form an azetidine, optionally substituted with 1 to 2 fluorine, cyano, hydroxy or- (CH) 2 ) p -OC(O)R 9 Substituted;
preferably, R 8 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, fluoro, hydroxy, C 1-3 A carboxyl group, a 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N or O, wherein said 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 with one to three hydroxy, halogen, C 1-3 Alkyl, nitro substituted;
preferably, R 8 Selected from methyl, methoxy, fluoro, hydroxy, carboxy, piperidinyl, cyclopropyl, cyclobutyl, isopropyl, cyclohexyl, morpholinyl, azetidinyl, tetrahydropyranyl, wherein the methyl, piperidinyl, cyclopropyl, cyclobutyl, isopropyl, cyclohexyl, morpholinyl, azetidinyl, tetrahydropyranyl are optionally substituted with one or two fluoro, methyl, hydroxy, or nitro groups;
p is selected from 0, 1 or 2;
Preferably, R 9 Selected from phenyl, C 1-3 Alkyl or C 3-7 Cycloalkyl, wherein the phenyl, C 1-3 Alkyl is optionally substituted with one or two R 10 Substituted;
preferablyGround, R 9 Selected from phenyl, cyclopropanyl, cyclobutyl, t-butyl, or n-propyl, wherein the phenyl, cyclopropanyl, cyclobutyl, t-butyl, or n-propyl is optionally substituted with one or two R 10 Substituted;
preferably, R 10 Selected from C 1-3 Alkyl, halogen, cyano, -ONO 2 ；
Preferably, R 10 Selected from fluorine, chlorine, cyano, methyl; preferably, R 9 Selected from the group consisting of
Figure FDA0003962015060000021
Figure FDA0003962015060000022
Preferably, R 11 Selected from phenyl optionally substituted with one or two halogen, hydroxy, nitro or amino groups;
preferably, R 11 Is that
Figure FDA0003962015060000023
Preferably, R 3 Selected from the group consisting of hydrogen, methoxy, fluoro, hydroxy, -C (O) OH,
Figure FDA0003962015060000024
Figure FDA0003962015060000025
/>
Figure FDA0003962015060000031
/>
Figure FDA0003962015060000041
Figure FDA0003962015060000042
Preferably, R 4 Selected from hydrogen, fluorine, bromine, -B (OH) 2 Or->
Figure FDA0003962015060000043
Preferably, R 4 Fluorine and bromine;
preferably, R 5 Selected from hydrogen, or methyl;
preferably, R 5 Is hydrogen.
4. The compound represented by formula (I) according to claim 1, wherein the compound has a structure represented by formula (IIIA), (IIIB), (IIIC) or (IIID):
Figure FDA0003962015060000044
wherein R is 1 、R 2 、R 3 、R 4 The definition of n is defined as formula (I).
5. The compound represented by formula (I) according to claim 1, wherein the compound has a structure represented by formula (IV):
Figure FDA0003962015060000051
Wherein X is 1 、R 2 、R 3 、R 4 Is defined as in claim 1.
6. The compound represented by formula (I) according to claim 1, which is selected from the following compounds:
Figure FDA0003962015060000052
/>
Figure FDA0003962015060000061
/>
Figure FDA0003962015060000071
/>
Figure FDA0003962015060000081
/>
Figure FDA0003962015060000091
/>
Figure FDA0003962015060000101
/>
Figure FDA0003962015060000111
/>
Figure FDA0003962015060000121
/>
Figure FDA0003962015060000131
7. pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 6 or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate and pharmaceutically acceptable auxiliary.
8. Use of a compound according to any one of claims 1 to 6, or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition according to claim 7, for the preparation of a medicament for the prophylaxis and/or treatment of a condition associated with aberrant Rho kinase activity.
9. Use of a compound according to any one of claims 1 to 6, or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, pharmaceutically acceptable hydrate, pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition according to claim 7, for the preparation of a Rho kinase inhibitor.
10. A method of inhibiting Rho kinase in a biological sample, comprising contacting the biological sample with a compound according to any one of claims 1-6, or a tautomer, enantiomer, diastereomer, mixture of enantiomer and diastereomer, racemate, meso, mixture of racemate and meso, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable salt, solvate, or a pharmaceutical composition of claim 7.
CN202211486877.7A 2021-11-24 2022-11-24 Benzodiazepine compounds and their use as Rho kinase inhibitors Pending CN116178337A (en)

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