WO2023093787A1 - Composé de benzodiazépine et son application en tant qu'inhibiteur de la rho kinase - Google Patents

Composé de benzodiazépine et son application en tant qu'inhibiteur de la rho kinase Download PDF

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WO2023093787A1
WO2023093787A1 PCT/CN2022/133916 CN2022133916W WO2023093787A1 WO 2023093787 A1 WO2023093787 A1 WO 2023093787A1 CN 2022133916 W CN2022133916 W CN 2022133916W WO 2023093787 A1 WO2023093787 A1 WO 2023093787A1
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alkyl
hydroxyl
compound
pharmaceutically acceptable
membered
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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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成都奥睿药业有限公司
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the disclosure relates to the field of medicine, in particular to a benzodiazepine with Rho kinase inhibitory effect Compounds and methods for their preparation.
  • Rho kinase Rho kinase
  • ROCK Rho kinase
  • Rho protein kinase is one of the earliest discovered downstream targets of Rho protein. It is a kind of serine/threonine protein kinase with a relative molecular mass of 160kDa, including two subtypes, ROCKI and ROCKII. It plays an important role in a series of cell life activities such as mitotic adhesion, cytoskeleton adjustment, muscle cell contraction, and tumor cell infiltration. According to literature reports, ROCK kinase has been associated with various diseases, including hypertension, pulmonary hypertension, cardiovascular disease, inflammation, autoimmune disease, lung disease and ophthalmic disease, etc.
  • the existing drugs for glaucoma mainly focus on promoting the outflow of aqueous humor to achieve the effect of lowering intraocular pressure, but there are still some cases of glaucoma with normal intraocular pressure clinically, and the clinical interpretation of glaucoma is that different reasons cause progressive retinal nerve damage. Loss of ganglion cells, progressive depression of the optic disc, and visual field damage. These all suggest that the development of glaucoma drugs can not only reduce intraocular pressure, but more importantly, protect the optic nerve. Netarsudil is currently the only pan-ROCK inhibitor approved by the FDA.
  • ROCK II inhibitors can reduce intraocular pressure by regulating the actin cytoskeleton, extracellular matrix and Schemms duct endothelial cells in the trabecular meshwork, and at the same time, can effectively reduce the toxic and side effects of the drug.
  • ROCK II has a unique function in the development of blood vessels and nervous system, mainly distributed in muscle tissue and brain, while the expression of ROCK I is widely distributed, including liver, kidney, spleen, testis, Thymus and blood cells etc.
  • ROCKII selective inhibitors for a single subtype
  • a single subtype selective small molecule inhibitor as a probe can also discover different The special functions of subtypes in the process of disease development.
  • two ROCK II selective inhibitors have entered clinical trials and are progressing smoothly. Therefore, from the perspective of target druggability and drug safety, further development of highly selective ROCK II inhibitors has a good prospect.
  • the purpose of this disclosure is to provide the synthesis of a novel compound and its application in ROCK kinase inhibitor drugs.
  • the compound as a ROCKII selective kinase inhibitor, has high activity, good selectivity and low toxic and side effects. advantage.
  • the present disclosure provides compounds represented by the following formula (I) or their tautomers, enantiomers, diastereomers, enantiomers and diastereoisomers Mixtures, racemates, mesoforms, mixtures of racemates and mesoforms, pharmaceutically acceptable hydrates, salts or solvates,
  • n is selected from 1 or 2;
  • X1 is selected from CH or N;
  • R 1 can be the same or different;
  • R 1 is selected from hydrogen, amino, or C 1-3 alkyl, the amino is optionally substituted by C 1-6 alkyl or C 3-8 cycloalkylalkyl ;
  • A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O and S, or a 9-12 membered bicyclic heteroaryl group containing 1-3 atoms selected from N, O and S Aryl;
  • R 2 is selected from C 1-6 alkyl, 5-7 membered aryl, said C 1-6 alkyl, 5-7 membered aryl is optionally substituted by one or more halogen, amino or hydroxyl;
  • 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 and R 7 are independently selected from single bond, hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-8 cycloalkyl alkyl, containing 1-2 selected from N, O Or a 5-7-membered heterocycloalkyl group of atoms of S, the C 1-6 alkyl, C 3-7 cycloalkyl, C 4-8 cycloalkylalkyl, containing 1-2 selected from N, The 5-7 membered heterocycloalkyl group of O or S atoms is optionally substituted by one or two R 8 or -(CH 2 ) p -OC(O)R 9 ;
  • R 4 is selected from hydrogen, halogen, -B(OH) 2 , or dioxaborolyl, and the dioxaborolyl is substituted by one to more C 1-6 alkyl groups;
  • R 5 is selected from hydrogen or C 1-3 alkyl.
  • R is selected from hydrogen, amino, or methyl, optionally substituted by C 3-8 cycloalkylalkyl;
  • R is hydrogen or amino, optionally substituted by cyclopropylmethyl
  • A is selected from a 5-7 membered monocyclic heteroaryl group containing 1-2 atoms selected from N, O, and S, or a heteroaryl group containing 1-3 atoms selected from N, O, and S 9-12 membered bicyclic heteroaryl;
  • A is selected from a 5-7-membered monocyclic heteroaryl group containing 1-2 N atoms, or a 9-12-membered bicyclic heteroaryl group containing 1-2 N atoms;
  • A is selected from pyridyl, pyrazolyl, benzopyrazolyl, or pyrrolopyridyl;
  • A is selected from pyridyl, pyrazolyl or benzopyrazolyl;
  • A is selected from
  • A is selected from
  • R is selected from C 1-6 alkyl, 5-7 membered aryl, and said C 1-6 alkyl, 5-7 membered aryl is optionally replaced by one or more halogens, Amino or hydroxyl substituted;
  • R is selected from C 1-3 alkyl, or phenyl, and said C 1-3 alkyl, phenyl is optionally substituted by one to three hydroxyl, amino or fluorine;
  • R2 is selected from methyl , ethyl, isopropyl, trifluoromethyl, -CH2OH , -CH2CH2OH , or phenyl;
  • R2 is selected from methyl, ethyl, isopropyl, -CH2OH or phenyl.
  • R 3 is hydrogen, C 1-6 alkoxy, C 1-6 carboxy, hydroxyl, halogen, -C(O)NR 6 R 7 or -OC(O)-R 11 ;
  • R 3 is hydrogen, C 1-3 alkoxy, C 1-3 carboxy, hydroxyl, halogen, -C(O)NR 6 R 7 or -OC(O)-R 11 ;
  • R 3 is hydrogen, methoxy, -C(O)OH, hydroxyl, fluorine, -C(O)NR 6 R 7 or -OC(O)-R 11 ;
  • R 6 and R 7 are independently selected from single bond, hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-8 cycloalkyl alkyl, containing 1-2 selected from N, O Or a 5-7-membered heterocycloalkyl group of atoms of S, the C 1-6 alkyl, C 3-7 cycloalkyl, C 4-8 cycloalkylalkyl, containing 1-2 selected from N, The 5-7 membered heterocycloalkyl group of O or S atoms is optionally substituted by one or two R 8 or -(CH 2 ) p -OC(O)R 9 ;
  • R 6 and R 7 are each independently selected from a single bond, hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-8 cycloalkylalkyl, 5 -7-membered heterocycloalkyl, said C 1-3 alkyl, C 4-8 cycloalkylalkyl, 5-7-membered heterocycloalkyl containing 1 N atom is optionally replaced by one or two Replaced by R 8 or -(CH 2 ) p -OC(O)R 9 ;
  • R is selected from hydrogen
  • R is selected from single bond, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-8 cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1 N atom , the C 1-3 alkyl, C 4-8 cycloalkylalkyl, 5-7 membered heterocycloalkyl containing 1 N atom is optionally replaced by one or two R 8 or -(CH 2 ) p -OC (O) R 9 replaced;
  • R is selected from a single bond, methyl, ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclobutyl, cyclobutanylmethyl, cyclopropanylmethyl or cyclohexyl Alkylmethyl, the methyl, ethyl, propyl, isopropyl, neopentyl, cyclobutanylmethyl, cyclopropanylmethyl or cyclohexylmethyl optionally replaced by one or two R 8 or -(CH 2 ) p -OC(O)R 9 are substituted;
  • R 6 , R 7 form a 3-7 membered ring together with their attached nitrogen atoms, and the 3-7 membered ring is optionally replaced by 1 to 3 halogen, cyano, hydroxyl or -(CH 2 ) p -OC (O)R 9 replaced;
  • R 6 , R 7 form a 4-5 membered ring together with their attached nitrogen atoms, and the 4-5 membered ring is optionally replaced by 1 to 2 fluorine, cyano, hydroxyl or -(CH 2 ) p -OC(O)R 9 replaced;
  • R 6 , R 7 together with the nitrogen atom to which they are attached form an azetidine optionally replaced by 1 to 2 fluorine, cyano, hydroxyl or -(CH 2 ) p -OC(O)R 9 replaced;
  • R 8 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, halogen, hydroxyl, C 1-6 carboxyl, containing 1-2 selected from N, O or S Atomic 4-7 membered heterocycloalkyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, containing 1-2 selected from N, O or S
  • the 4-7 membered heterocycloalkyl group of atoms is optionally substituted by one or more hydroxyl, halogen, C 1-6 alkyl, or nitro groups;
  • R is selected from C 1-3 alkyl, C 1-3 alkoxy, C 3-7 cycloalkyl, fluorine, hydroxyl, C 1-3 carboxyl, containing 1-2 selected from N or O
  • a 4-7 membered heterocycloalkyl group of atoms wherein, the C 1-3 alkyl, C 1-3 alkoxy, C 3-7 cycloalkyl, containing 1-2 selected from N, O Atomic 4-7 membered heterocycloalkyl is optionally substituted by one to three hydroxyl, halogen, C 1-3 alkyl, nitro;
  • R is selected from methyl, methoxy, fluorine, hydroxyl, carboxyl, piperidinyl, cyclopropyl, cyclobutyl, isopropyl, cyclohexyl, morpholinyl, azetidinyl, Tetrahydropyranyl, wherein, the methyl, piperidyl, cyclopropyl, cyclobutyl, isopropyl, cyclohexyl, morpholinyl, azetidinyl, tetrahydropyranyl optional substituted by one or two fluorine, methyl, hydroxyl, or nitro groups;
  • p is selected from 0, 1 or 2;
  • R is selected from 5-7 membered aryl, 5-7 membered monocyclic heteroaryl containing 1 N atom, 5-7 membered heterocycloalkyl containing 1 N atom, C 1-6 alkyl Or C 3-7 cycloalkyl, wherein, the 5-7 membered aryl group, the 5-7 membered monocyclic heteroaryl group containing 1 N atom, the 5-7 membered heterocyclic ring containing 1 N atom Alkyl or C 1-6 alkyl is optionally substituted by one or more R 10 ;
  • R 9 is 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 replaced by Replaced by one or more R 10 ;
  • R 9 is selected from phenyl, C 1-3 alkyl or C 3-7 cycloalkyl, wherein, the phenyl, C 1-3 alkyl are optionally substituted by one or two R 10 ;
  • R is selected from phenyl, cyclopropyl, cyclobutyl, tert-butyl or n-propyl, wherein, said phenyl, cyclopropyl, cyclobutanyl, tert-butyl or n- Propyl is optionally substituted by one or two R 10 ;
  • Each R 10 is the same or different from each other and is selected from hydroxyl, nitro, C 1-3 alkyl, halogen or -ONO 2 ;
  • R 10 is selected from C 1-3 alkyl, halogen, -ONO 2 ;
  • R 10 is selected from fluorine, chlorine, cyano, methyl
  • R9 is selected from
  • R9 is selected from
  • R 11 is selected from 5-7 membered aryl groups, and the 5-7 membered aryl groups are optionally substituted by one or more halogen, hydroxyl, nitro or amino groups;
  • R 11 is selected from phenyl optionally substituted by one or two halogen, hydroxyl, nitro or amino;
  • R 11 is
  • R is selected from hydrogen, methoxy, fluorine, hydroxyl, -C(O)OH,
  • R is selected from hydrogen, methoxy, fluorine, hydroxyl,
  • R 4 is selected from hydrogen, halogen, -B(OH) 2 , or dioxaborolyl, and the dioxaborolyl is substituted by one to more C 1-6 alkyl groups;
  • R 4 is selected from hydrogen, fluorine, bromine, -B(OH) 2 , or
  • R 4 is fluorine, bromine
  • R 5 is selected from hydrogen, or C 1-3 alkyl
  • R is selected from hydrogen, or methyl
  • R 5 is hydrogen
  • R 1 , R 2 , R 3 , R 4 and n are as defined above.
  • a pharmaceutical composition comprising the above compound or its tautomers, enantiomers, diastereomers, enantiomers and diastereoisomers
  • the mesoform, the mixture of the racemate and the mesoform, the pharmaceutically acceptable hydrate, the pharmaceutically acceptable salt or solvate and the pharmaceutical composition are used in the preparation for preventing and/or treating abnormal Rho Drug use for disorders associated with kinase activity.
  • the above compound or its tautomers, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, racemates Application of the meso body, the mixture of the raceme body and the meso body, the pharmaceutically acceptable hydrate, the pharmaceutically acceptable salt or solvate and the pharmaceutical composition in the preparation of the Rho kinase inhibitor.
  • a method of inhibiting Rho kinase in a patient in need thereof comprising administering to the patient the above compound or a tautomer, enantiomer, diastereoisomer thereof isomers, mixtures of enantiomers and diastereomers, racemates, mesoforms, mixtures of racemates and mesoforms, pharmaceutically acceptable hydrates, pharmaceutically Acceptable salts, solvates or pharmaceutical compositions thereof.
  • a method of inhibiting Rho kinase in a biological sample which comprises subjecting the biological sample to the above-mentioned compound or its tautomer, enantiomer, diastereoisomer isomers, mixtures of enantiomers and diastereomers, racemates, mesoforms, mixtures of racemates and mesoforms, pharmaceutically acceptable hydrates, pharmaceutically acceptable Accepted salts, solvates or pharmaceutical compositions thereof.
  • a method for treating a Rho kinase-mediated disorder in a patient in need thereof comprising administering to the patient the above compound or its tautomer, enantiomer isomers, diastereomers, mixtures of enantiomers and diastereomers, racemates, mesoforms, mixtures of racemates and mesoforms, pharmaceutically acceptable Hydrates, pharmaceutically acceptable salts, solvates, or pharmaceutical compositions thereof;
  • Rho kinase-mediated disorders include, but are not limited to: cardiovascular and cerebrovascular disorders, smooth muscle-related disorders, fibrotic diseases, inflammatory diseases, neurological disorders, oncological disorders, elevated intraocular pressure disorders, diabetes, organ Transplantation, infection and autoimmune disorders.
  • Compounds of the present disclosure may be asymmetric, eg, possess one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents. Racemates, diastereomers, enantiomers are included within the scope of the present disclosure.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms
  • C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.
  • substituted or “substituted” means that any one or more hydrogen atoms on a specified atom or group are replaced by a substituent, as long as the valence of the specified atom or group is normal and the substituted compound is stable of.
  • the type and number of substituents can be arbitrary on a chemically achievable basis.
  • any variable eg Rn
  • Rn a variable that occurs more than once in the composition or structure of a compound
  • its definition is independent at each occurrence.
  • a group is substituted with one to three R
  • said group may optionally be substituted with up to three R, with independent options for each occurrence of R.
  • combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms.
  • C 1-6 alkyl includes C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It can be divalent, eg methylene, ethylene.
  • 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, tert-butoxy , sec-butoxy, n-pentoxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n- Nonyloxy, n-decyloxy, etc., but not limited thereto.
  • cycloalkylalkyl refers to a cycloalkyl substituent attached through an alkyl chain.
  • examples of cycloalkylalkyl substituents include cyclohexylethyl where the cyclohexane is attached through an ethane linker.
  • Other examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylethyl, cycloheptylethyl, cyclohexylmethyl.
  • examples of the halogen group may include fluorine, chlorine, bromine or iodine.
  • cycloalkyl refers to a monocyclic saturated hydrocarbon system free of heteroatoms and double bonds.
  • C 3-8 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system by removing one hydrogen from a single carbon atom of the parent aromatic ring system. atoms are obtained. It includes bicyclic radicals 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.
  • heterocycloalkyl refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms.
  • Specific examples of the heterocyclic group include piperidinyl or tetrahydropyrrolyl, but are not limited thereto.
  • heteroaryl refers to a monovalent aryl group containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group can be a single ring or a polycyclic ring system, such as a bicyclic , wherein two or more rings exist in the form of parallel rings, bridged rings or spiro rings, wherein at least one ring contains one or more heteroatoms.
  • heteroaryl examples include pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, Imidazopyridyl, benzofuryl, pyridazinyl, isoindolyl, but not limited thereto.
  • 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.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • the heterocyclic ring can be a monocyclic or polycyclic ring system, such as a bicyclic ring, in which two or more rings exist in the form of fused rings, bridged rings or spiro rings, and at least one of the rings contains one or more heteroatoms.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without, commensurate with a reasonable benefit/risk ratio, undue toxicity, irritation, allergic response or other problems or complications of those compounds, materials, compositions and/or dosage forms.
  • 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 lies in the migration of the proton and the double bond at the corresponding position, Specific examples thereof include, but are not limited to, enol and keto tautomers.
  • enantiomer refers to two stereoisomers that are mirror images of each other and cannot be superimposed, one of which is left-handed and the other is right-handed, and the term “diastereoisomer” refers to two Stereoisomers that are not mirror images of each other and possess two or more chiral centers.
  • racemate refers to a mixture in which an optically active chiral molecule and its enantiomers are mixed in equal proportions, because of their opposite optical effects and cancel each other out; the term “meso” refers to A compound that has two or more chiral centers, but due to other factors, such as symmetry planes, the molecule as a whole does not show optical activity.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and basic or organic salts of acidic groups such as carboxylic acids.
  • Pharmaceutically acceptable salts include, for example, conventional non-toxic or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids.
  • Such conventional nontoxic salts include, for example, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; 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, water Cylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • a drug or pharmaceutical composition of the present disclosure may be formulated orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. apply.
  • the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized cornstarch, polyvinylpyrrolidone, or hypromellose based cellulose); fillers (for example, lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (such as , magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (for example, potato starch or hydroxy sodium starch acetate); or wetting agents (for example, sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth, or algina
  • binders e.
  • the pharmaceutical composition can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), anti-settling agent (e.g., sorbitol syrup, cellulose-derived or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia), non-aqueous carriers (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils), preservatives (e.g., p- methyl hydroxybenzoate or p-hydroxybenzoate propyl or sorbic acid) and other combinations.
  • Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.
  • compositions of the present disclosure comprising a compound of formula I as the active compound may also be incorporated into beads, microspheres or microcapsules, for example constructed of polyglycolic/lactic acid (PGLA).
  • PGLA polyglycolic/lactic acid
  • Liquid preparations 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 suitably be formulated so as to provide controlled or delayed release of the active compound.
  • a drug or pharmaceutical composition of the present disclosure may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.) Or intradermal (i.d.) administration, by direct injection, via eg bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with added preservatives.
  • compositions may take such forms as excipients, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as anti-settling, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use.
  • a medicament or pharmaceutical composition of the present disclosure may also be formulated for rectal administration, eg, as a suppository or retention enema (eg, containing conventional suppository bases such as cocoa butter or other glycerides).
  • a suppository or retention enema eg, containing conventional suppository bases such as cocoa butter or other glycerides.
  • Dosage forms for topical administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants which may be required.
  • Such ointments, pastes, creams and gels may contain, in addition to the active compounds of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose-derived substances, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose-derived substances, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • Ophthalmic formulations e.g., ophthalmic ointments, powders, solutions (eg, eye drops), and the like are also considered within the scope of the present disclosure.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil, ) and injectable organic esters (such as ethyl oleate).
  • polyols such as glycerol, propylene glycol, polyethylene glycol, etc.
  • suitable mixtures thereof such as vegetable oils (such as olive oil, ) and injectable organic esters (such as ethyl oleate).
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents 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 (eg, sugars, sodium chloride, and the like) in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form is brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents 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 is
  • treating includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.
  • effective amount or “therapeutically effective amount” refers to a dose sufficient to treat, suppress or alleviate one or more symptoms of the disease state being treated or otherwise provide a desired pharmacological and/or physiological effect.
  • the precise dosage will vary depending on factors such as subject dependent variables (eg, age, immune system health, etc.), the disease or disease, and the treatment being administered.
  • the effect of an effective amount can 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 drug combination, or in the case of drug combinations, the combined effects may be Compared to the effect of administering only one drug.
  • composition means a composition comprising the compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one selected from the following pharmaceutically acceptable ingredients depending on the mode of administration and the nature of the dosage form, Including but not limited to: carrier, diluent, adjuvant, excipient, preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, flavoring agent, antibacterial agent , antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.
  • the raw materials and equipment used in the specific embodiments of the present disclosure are all known products obtained by purchasing commercially available products.
  • Embodiment 1 the preparation of compound 1,2:
  • the raw material 1a (2.16g, 10mmol of 2-amino-4-bromobenzoic acid) was dissolved in 20mL of anhydrous tetrahydrofuran, and then a solution of triphosgene (1.04g, 3.50mmol) in tetrahydrofuran was slowly dropped into it at 0°C, The reaction was stirred at room temperature for 4 h, ice water was added to the system and filtered with suction, and the filter cake was washed with dichloromethane to obtain intermediate 1b.
  • Embodiment 2 the preparation of compound 3,4:
  • the preparation method of compound 3 is similar to that of 1, using intermediate 3b and 4-pyridineboronic acid as raw materials, and the yield is 75%.
  • Embodiment 3 the preparation of compound 7,8:
  • intermediate 7a is similar to that of intermediate 3b. It is obtained from the reaction of intermediate 3a and 2-bromomethyl-6-fluoropyridine as raw materials, and the yield is 90%. MS(ESI,positive ion)m/z:392.25,394.28.[M+H]+.
  • Embodiment 4 the preparation of compound 9,10,11:
  • intermediate 9a is similar to that of intermediate 3b, obtained by reacting intermediate 3a with methyl 3-bromomethylbenzoate as raw materials, and the yield is 85%.
  • Embodiment 5 the preparation of compound 53:
  • intermediate 53a The synthesis of intermediate 53a is similar to that of intermediate 3a, obtained from the reaction of intermediate 1c and D-serine, with a yield of 30%. MS (ESI, positive ion) m/z: 299.23, 301.30 [M+H]+.
  • Embodiment 6 the preparation of compound 60
  • intermediate 60c The synthesis of intermediate 60c is similar to that of intermediate 9c, obtained from intermediate 60b as a raw material, and the yield is 80%. MS(ESI,positive ion)m/z: 485.31[M+H]+.
  • intermediate 60d is similar to that of compound 9, obtained from the reaction of intermediate 60c and tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate as raw materials, with a yield of 75%.
  • Embodiment 7 the preparation of compound 61,62
  • Embodiment 8 the preparation of compound 117
  • intermediate 117a is similar to that of compound 10, prepared from 2-bromopropionyl chloride and compound 96, with a yield of 82%, MS (ESI, positive ion) m/z: 637.37, 639.36 [M+H]+ .
  • Test Example 1 Benzodiazepines In vitro kinase assay of ketone derivatives
  • the inhibitory activity of the compound is represented by the half inhibitory concentration IC 50 , and the IC 50 value is obtained by fitting the inhibition rate corresponding to each concentration gradient.
  • Table 5 The results are shown in Table 5 below. Based on the results in the table, relative to ROCK I kinase, the compound of the present invention has good selective inhibitory activity on ROCK II kinase.

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Abstract

L'invention concerne un composé de benzodiazépine ayant une structure représentée par la formule (I) et servant d'inhibiteur ROCK II kinase, et une application de celui-ci dans un médicament inhibiteur de la Rho kinase et son procédé de préparation.
PCT/CN2022/133916 2021-11-24 2022-11-24 Composé de benzodiazépine et son application en tant qu'inhibiteur de la rho kinase WO2023093787A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044753A2 (fr) * 2004-10-19 2006-04-27 Smithkline Beecham Corporation Composes chimiques
WO2010114894A1 (fr) * 2009-03-31 2010-10-07 Arqule, Inc. Composés hétérocycliques substitués
CN102753179A (zh) * 2009-11-17 2012-10-24 密执安大学评议会 具有治疗性能的1,4-苯并二氮杂*-2,5-二酮和相关化合物
CN102753544A (zh) * 2009-11-17 2012-10-24 密执安大学评议会 具有治疗性能的1，4-苯并二氮杂*-2，5-二酮和相关化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044753A2 (fr) * 2004-10-19 2006-04-27 Smithkline Beecham Corporation Composes chimiques
WO2010114894A1 (fr) * 2009-03-31 2010-10-07 Arqule, Inc. Composés hétérocycliques substitués
CN102753179A (zh) * 2009-11-17 2012-10-24 密执安大学评议会 具有治疗性能的1,4-苯并二氮杂*-2,5-二酮和相关化合物
CN102753544A (zh) * 2009-11-17 2012-10-24 密执安大学评议会 具有治疗性能的1，4-苯并二氮杂*-2，5-二酮和相关化合物

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