WO2022042666A1 - Inhibiteur sélectif de kinase rock2 - Google Patents

Inhibiteur sélectif de kinase rock2 Download PDF

Info

Publication number
WO2022042666A1
WO2022042666A1 PCT/CN2021/114868 CN2021114868W WO2022042666A1 WO 2022042666 A1 WO2022042666 A1 WO 2022042666A1 CN 2021114868 W CN2021114868 W CN 2021114868W WO 2022042666 A1 WO2022042666 A1 WO 2022042666A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methyl
amino
mmol
ethoxy
Prior art date
Application number
PCT/CN2021/114868
Other languages
English (en)
Chinese (zh)
Inventor
杨欣
郑鹛
诸葛定娟
孔祥文
朱明睿
崔荣
殷建明
吕裕斌
Original Assignee
杭州邦顺制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州邦顺制药有限公司 filed Critical 杭州邦顺制药有限公司
Publication of WO2022042666A1 publication Critical patent/WO2022042666A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • 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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/10—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 linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, in particular to a selective ROCK2 kinase inhibitor, its pharmaceutical composition, a preparation method and its use in preparing a medicine for preventing and/or treating indications related to ROCK2 signaling pathway.
  • Rho-related protein kinase is a serine/threonine protein kinase, and it is currently the most detailed Rho downstream target effector molecule.
  • ROCK includes two isoforms, ROCK1 and ROCK2. The amino acid sequence identity of these two isoforms is 65%, and the kinase domain has a high similarity of 92%.
  • ROCK1 is highly expressed in the lung, liver, spleen, kidney and testis.
  • ROCK2 levels are higher in the brain and heart.
  • the body mainly activates the ROCK1/2 signaling pathway through the combination of Rho and GTP, phosphorylates the downstream substrates of ROCK1/2 (such as MLC, GFAP, LIMK, etc.), remodels the cytoskeleton, induces actin filament stabilization and actin-myosus
  • ROCK1/2 such as MLC, GFAP, LIMK, etc.
  • the protein contracts, combines actin reticulum and myosin fibers, and modulates microtubule dynamics.
  • ROCK1/2 signaling is closely related to diabetic nephropathy, eye disease, tumor, fibrosis, nerve damage and other diseases, and has important development value.
  • ROCK1/2 inhibitors mainly for the treatment of ocular diseases, for improving and preventing cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemia symptoms, glaucoma, ocular hypertension, etc. .
  • ROCK2 inhibitors there is no selective ROCK2 inhibitor on the market.
  • Potential for autoimmune disease Therefore, the development of selective ROCK2 inhibitors may provide new treatment options for autoimmune and fibrotic diseases.
  • ROCK2 inhibitors have low activity, low inhibition rate and low selectivity for ROCK2.
  • compound 82 drug research and development code KD-025
  • patent CN101208094 has an IC50 of 105nM for ROCK2.
  • Patent WO2012040499 discloses compound 201, and records that its inhibition rate of ROCK2 at 500 nM is 0.67. And the toxic side effects are greater. Therefore, ROCK2 inhibitors with high activity, high inhibition rate, high selectivity and low toxicity and side effects are required.
  • the purpose of the present invention is to provide a new ROCK2 inhibitor, which has excellent inhibitory activity and good selectivity to ROCK2, and also has excellent properties such as excellent pharmacokinetic properties and high safety, which is ideal selective ROCK2 inhibitor.
  • the present invention adopts the following technical solutions:
  • the present invention first provides a compound having the structure shown in general formula (I):
  • Ring B is absent or a five- to six-membered unsaturated ring containing 0 to 3 N atoms;
  • L 1 is selected from -O(CR a R b ) n , C 1-6 alkylene or C 1-6 alkenylene;
  • L 2 is selected from C 1-6 alkylene or -NR d ;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; In the absence of B, R is attached to ring A;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl ;
  • alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R 4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n are each independently selected from an integer of 0-3.
  • L 2 is selected from C 1-6 alkylene or -NH-, preferably -CH 2 -, -CH 2 CH 2 - or -NH-;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, 1H-pyrazole or cyclohexylpyridine, preferably indazole or phenyl-1H-pyrazole;
  • R is selected from H, halogen, hydroxy, cyano, methyl, hydroxymethyl, trifluoromethyl, ethyl, isopropyl, methoxy, isopropoxy, cyclopropyl, cyclopentyl, cyclopropyl Hexyl or C 3-8 heterocycloalkyl, preferably H, fluorine, chlorine, methyl, trifluoromethyl, ethyl, isopropyl, methoxy, isopropoxy or cyclopropyl, when ring B is not When present, R is attached to ring A;
  • n are each independently selected from an integer of 0 to 3.
  • the present invention also provides a compound having the structure represented by the general formula (I'):
  • Ring B does not exist or is a five- to six-membered unsaturated ring containing 0 to 3 N atoms;
  • L 1 is selected from -O(CR a R b ) n , C 1-6 alkylene or C 1-6 alkenylene;
  • L 2 is selected from C 1-6 alkylene or -NR d ;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; In the absence of B, R is attached to ring A;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl ;
  • alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R 4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n are each independently selected from an integer of 0-3.
  • Ring B is absent or a five- to six-membered unsaturated ring containing 0 to 3 N atoms;
  • L 1 is selected from C 1-6 alkylene or C 1-6 alkenylene
  • R 1 is selected from
  • L 2 is selected from C 1-6 alkylene or -NR d ;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, when ring In the absence of B, R is attached to ring A;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl ;
  • alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R 4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n are each independently selected from an integer of 0-3.
  • the present invention also provides a compound having the structure represented by the general formula (I-1):
  • L 1 is selected from -O(CR a R b ) n , C 1-6 alkylene or C 1-6 alkenylene;
  • L 2 is selected from C 1-6 alkylene or -NR d ;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; In the absence of B, R is attached to ring A;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl ;
  • alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R 4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n are each independently selected from an integer of 0-3.
  • the present invention also provides a compound having the structure represented by the general formula (I-2):
  • L 2 is selected from C 1-6 alkylene or -NR d ;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the Alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted with 0-3 R4, when ring B is absent, R3 is attached to ring A ;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl ;
  • alkyl, alkylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n is selected from an integer of 0-3.
  • the present invention also provides compounds with the structures represented by the general formulas (I-3) and (I-3'):
  • L 1 is selected from -O(CR a R b ) n , C 1-6 alkylene or C 1-6 alkenylene;
  • L 2 is selected from C 1-6 alkylene or -NR d ;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; In the absence of B, R is attached to ring A;
  • R a , R b , R c , R d are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl ;
  • alkyl, alkylene, alkenylene, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R 4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n are each independently selected from an integer of 0-3.
  • the compound has the structure represented by the general formula (I-4),
  • Ring B does not exist or is a parallel five- to six-membered aromatic ring containing 0 to 3 N atoms;
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • R 2 is selected from indazole, phenyl-1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine;
  • R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, when ring In the absence of B, R is linked to a pyrimidine;
  • alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with 0-3 R4 ;
  • R 4 is selected from H, halogen, cyano, hydroxyl, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • n is selected from an integer of 0-3.
  • the compounds also have the following characteristics:
  • Ring B does not exist or is a benzene ring
  • R a and R b are independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy radical, cyclopropoxy, cyclobutoxy, and optionally substituted with 0-2 F atoms;
  • R 2 is selected from indazole, phenyl-1H-pyrazole
  • R 3 is selected from H, halogen, hydroxyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, and when ring B is absent, R 3 is linked to a pyrimidine;
  • n is selected from an integer of 0-3.
  • the compound has the structure represented by the general formula (I-5):
  • R a is selected from H
  • R b is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutyl oxy, and optionally substituted with 0-2 F atoms;
  • R 2 is selected from indazole, phenyl-1H-pyrazole; preferably indazole.
  • the compound has the structure represented by the general formula (I-6):
  • R a is selected from H
  • R b is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutyl oxy, and optionally substituted with 0-2 F atoms;
  • R 2 is selected from indazole, phenyl-1H-pyrazole
  • R3 is selected from H, halogen, methyl, ethyl, trifluoromethyl; preferably H, halogen, methyl, ethyl.
  • the new compounds provided by the present invention include but are not limited to the following compounds:
  • the above-mentioned compounds can be prepared by the following methods.
  • compound (I-41) is reacted with R 2 NH 2 to obtain compound (I-42), wherein X can be halogen; ring B is present or absent, and R 3 is selected from H, halogen, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, when ring B is absent, R 3 is attached to ring A.
  • R2 may be selected from indazole, phenyl - 1H-pyrazole, phenylpyridine, quinoline, isoquinoline, 3-thiazolylpyridine, pyridine, 1H-pyrazole or cyclohexylpyridine.
  • R 2 is a phenyl-1H-pyrazole group
  • the (trimethylsilyl)ethoxymethyl group is usually modified on the phenyl-1H-pyrazole (SEM) as a protecting group, which can be further removed in the subsequent reaction process.
  • Compound (I-42) is further reacted with the shown E)-(3-(3- Re -3-oxoprop-1-en-1-yl)phenyl)boronic acid compound to obtain compound (I-43) .
  • R e is a branched simple alkyl group, which can be methyl, ethyl, isopropyl and the like.
  • Compound (I-43) is reacted with an acid or a base to remove the group Re to obtain compound (I-44).
  • This step reaction can be operated together with the previous step reaction, or the group Re can be removed at the same time as the previous step reaction.
  • amino groups in order to reduce the active hydrogen on the amino group to participate in side reactions, the amino group can be protected, such as tert-butoxycarbonyl and the like.
  • the compound (I-4) obtained in the above steps is in the form of a crude product, which is usually further purified by preparative column chromatography, wherein the eluent environment used in preparative column chromatography will vary depending on the compound. Differences such as formic acid, trifluoroacetic acid or other common acids.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable excipient and/or diluent thereof.
  • Another aspect of the present invention provides the use of the compounds and pharmaceutical compositions of the present invention in the manufacture of a medicament for the treatment and/or prevention of ROCK2-related disorders.
  • the ROCK2-related disorder is selected from pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis or nonalcoholic steatohepatitis.
  • the compound provided by the invention has novel structure, strong activity, good selectivity, excellent pharmacokinetic properties, high safety and other excellent properties. Most of the compounds provided in this application have less toxic and side effects, and have better inhibitory effects on inflammatory factors, and are ideal selective ROCK2 kinase inhibitors.
  • the raw materials or reagents used in the present invention can be prepared by conventional methods or commercially available.
  • Step 2 Ethyl 3-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl)phenyl)acrylate (1b)
  • Methyl 2-isocyanatobenzoate 2a (1.65 g, 9.3 mmol) was dissolved in tetrahydrofuran (35 mL), 3-benzyloxyaniline (1.85 g, 9.3 mmol) and 4-dimethylaminopyridine ( 4.5 g, 37.2 mmol). The reaction solution was stirred at room temperature overnight. 1,8-Diazabicycloundec-7-ene (2 g, 13.1 mmol) was added and heated to 80°C and stirred for 1 hour.
  • Methyl 1H-indazole-5-carboxylate (3.0 mg, 17.0 mmol) was dissolved in N,N-dimethylformamide (30 mL), NaH (1.3 g, 20.5 mmol) was added at 0 °C, and the reaction solution was The reaction was stirred at 0°C for 15 minutes.
  • Potassium carbonate (739 mg, 5.4 mmol) was added to 5-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 2d (800 mg, 2.7 mmol) and 3-(3-(benzyloxy)phenyl)quinazoline-2,4(1H,3H)-dione 2b (1.2 g, 2.97 mmol) in dimethylformamide (10 mL) , heated to 50 °C under nitrogen and stirred overnight.
  • the sixth step 2-(3-(2,4-dioxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5- (yl)methyl)-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide (2f)
  • Potassium carbonate 25 mg, 0.178 mmol was added to a solution of the above crude (46 mg, 0.089 mmol) and 2-bromo-N-isopropylacetamide (15 mg, 0.107 mmol) in dimethylformamide (4 mL) at The tube was heated to 100°C and stirred overnight. The liquid quality monitored the formation of the target product.
  • Step 7 2-(3-(1-((1H-indazol-5-yl)methyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl )phenoxy)-N-isopropylacetamide (7)
  • Triphenylphosphorus (516 mg, 1.97 mmol) was added to (4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl ) methanol 3a (500 mg, 1.64 mmol) in dichloromethane (8 mL) was stirred under nitrogen for 1 hour. Carbon tetrabromide (986 mg, 1.97 mmol) was added to the system, followed by stirring at room temperature overnight.
  • Step 5 2-(3-(1-(4-(1H-pyrazol-4-yl)benzyl)-2,4-dioxo-1,2-dihydroquinazoline-3(4H) -yl)phenoxy)-N-isopropylacetamide (8)
  • the target product 2-(3-(1-(4-(1H-pyrazol-4-yl)benzyl)-2 was obtained after preparation and purification by Prep-HPLC ,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenoxy)-N-isopropylacetamide 8 (41.8 mg, yield: 55%, white solid).
  • the first step 2-chloro-nitrogen-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazol-4-yl)phenyl)quinoline oxazolin-4-amine
  • 2,4-Dichloroquinazoline 500 mg, 2.53 mmol
  • 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1hydro-pyrazol-4-yl ) aniline 731 mg, 2.53 mmol
  • potassium acetate 743 mg, 7.59 mmol
  • Water (10 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (10 mL ⁇ 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure.
  • the fourth step (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylic acid
  • Step 5 (E)-3-(3-(4-((4-(1 Hydro-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-nitrogen- Isopropylacrylamide (22)
  • N-(2-Chloro-5-methylpyrimidin-4-yl)-1H-indazol-5-amine (1 g, 3.8 mmol), di-tert-butyl dicarbonate (3.3 g, 18.4 mmol) and triethyl
  • the amine 1.5 g, 15.4 mmol was dissolved in dichloromethane (10 mL), 4-dimethylaminopyridine was added, and the reaction system was stirred at room temperature overnight.
  • the fifth step (E)-3-(3-(4-(((1H-indazol-5-yl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid
  • the first step nitrogen-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1hydro-indazol-5-amine
  • 2,4-Dichloro-5-(trifluoromethyl)pyrimidine 500 mg, 2.31 mmol was dissolved in N,N-dimethylformamide (5 mL), and 1-hydro-indone was added at minus 40°C Azol-5-amine (308 mg, 2.31 mmol) and triethylamine (0.9 mL, 6.93 mmol), the reaction system was stirred at minus 40° C. for 2 hours. Water (20 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (20 mL ⁇ 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure.
  • Step 2 (E) Ethyl 3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)phenyl)acrylate ester
  • the third step (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)phenyl)acrylic acid
  • isopropylamine in the 4th step is changed to cyclopropylamine, obtains ((E)-3-(3-(4-(((1 hydrogen-indazol-5-yl)amino)quinoline oxazolin-2-yl)phenyl)-nitro-cyclopropylacrylamide (6.7 mg, yellow solid), yield: 18%.
  • Step 2 (E)-3-(3-(4-(((1H-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)acrylic acid
  • N-(2-Chloropyrimidin-4-yl)-1hydro-indazol-5-amine 80 mg, 0.33 mmol
  • E)-(3-(3-methoxy-3-oxoprop-1 -en-1-yl)phenyl)boronic acid 74 mg, 0.36 mmol
  • potassium carbonate 180 mg, 0.94 mmol
  • dioxane/H 2 O 6 mL, 5:2
  • Pd(dppf) was added under nitrogen Cl 2 (12 mg, 0.02 mmol), the reaction system was stirred at 100° C.
  • the third step (E)-3-(3-(4-(((1hydro-indazol-5-yl)amino)pyrimidin-2-yl)phenyl)-N-isopropylacrylamide
  • the first step 2-chloro-5-(trifluoromethyl)-N-(4-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)phenyl)pyrimidin-4-amine
  • Step 2 (E)-Ethyl 3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)) Methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylate
  • the third step (E)-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl) )-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid
  • the fourth step (E)-N-isopropyl-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)) Ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylamide
  • the fifth step (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl)-N-isopropylacrylamide
  • the first step (E)-N-cyclopropyl-3-(3-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)acrylamide
  • Step 2 (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-2-yl)phenyl)-N-ring Propyl acrylamide
  • the first step 2-chloro-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)pyrimidine
  • the third step (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylic acid
  • the first step 2-chloro-5-methyl-N-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl) phenyl)pyrimidin-4-amine
  • the fifth step (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)acrylic acid
  • Step 6 (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-methylpyrimidin-2-yl)phenyl)- N-Cyclopropylacrylamide
  • the first step (E)-N-cyclopropyl-3-(3-(5-(trifluoromethyl)-4-((4-(1-((2-(trimethylsilyl)) Ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)phenyl)acrylamide
  • Step 2 (E)-3-(3-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Phenyl)-N-cyclopropylacrylamide
  • ROCK1 kinase activity was detected by Mobility shift assay with KD-025 as positive control.
  • the ROCK1 kinase used was purchased from Carna, the ROCK2 kinase was purchased from signalchem, and the substrate LIMKtide was purchased from GL.
  • the 10 mM test compound prepared with DMSO was diluted to a concentration of 10 ⁇ M, followed by 3-fold gradient dilution to obtain a total of 10 test compound solutions of different concentrations, which were tested in duplicate.
  • Positive and negative control wells were added with 250 nL DMSO.
  • Use 1 ⁇ Kinase buffer to prepare 2.5 times the final concentration of kinase solution.
  • the reaction was initiated by adding 15 ⁇ L of a mixed solution of ATP and LIMKtide at 5/3 times the final concentration. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, incubate at room temperature for a corresponding time after shaking and mixing, add 30 ⁇ L of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake and mix. Conversion rates were read with the Caliper EZ Reader II.
  • Inhibition % (positive control conversion read-sample conversion read)/(positive control conversion read-negative control conversion read) x 100%.
  • concentration concentration as the X-axis
  • percentage inhibition rate as the Y-axis
  • IC50 values of each compound are shown in Table 1 below.
  • Patent CN101208094 discloses the compound KD-025, and records that its IC50 for ROCK2 is 105nM.
  • this application also tested the ROCK2 inhibitory activity of CN101208094 compound 80 and CN105101996 compound 164 head-to-head.
  • the IC50s of ROCK2 and ROCK1 of CN101208094 compound 80 were both >250 nM.
  • CN105101996 Compound 164 has ROCK2 IC50>250nM and ROCK1 IC50 of 50-250nM.
  • Most of the compounds in this application have better IC50 for ROCK2 than compound KD-025 and the above-mentioned patented compounds, and the IC50 of compounds 21, 23, 27, 33, 37, 38, and 42 have obvious advantages.
  • Patent WO2012040499 discloses compound 201, and records that its inhibition rate of ROCK2 at 500 nM is 0.67.
  • the required concentration is much less than 500 nM, especially compounds 21, 23, 27, 33, 37, 38, 39, 42, and 44 have obvious advantages.
  • the CD-1 mice were administered continuously for 14 days, and each compound was set up in 3 dose groups (100mpk, 300mpk, 600mpk), and the death and toxicity of the mice were observed after daily administration for 14 days.
  • dose groups 100mpk, 300mpk, 600mpk
  • the mice were all 6-8 weeks old and weighing 18-22 grams.
  • Toxicity observation indicators mainly include: vital signs, breathing, nutritional status, mental status, behavioral activities, muscles, reflexes, eye, nose, oral cavity, gastrointestinal tract reactions, abdominal status, urine, coat, skin and mucous membranes, perineal status, etc. .
  • mice showed no abnormal reaction; 300mpk mice observed erection in 1 mouse, other mice had no abnormality; 600mpk mice had 1 death, and the rest of the mice observed lack of energy , arched back, bristles.
  • mice at 100mpk and 300mpk showed no abnormal reaction; some mice at 600mpk had piloerection, and other mice had no abnormality.
  • PBMC human peripheral blood mononuclear cells
  • CD4+ T cells were adjusted to a concentration of 2 ⁇ 10 6 /mL.
  • CD4+ T cells 50 ⁇ L/well
  • anti-human CD3/CD28 beads cells 50 ⁇ L/well
  • the inhibitory activity of compounds 21, 23 and 27 on IL-17 was significantly higher than that of KD-025 in a dose-dependent manner.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de kinase ROCK2 tel que représenté par la formule générale (I) et son utilisation dans la préparation d'un médicament pour la prévention et/ou le traitement de troubles liés à ROCK2. Le composé est un inhibiteur sélectif de la kinase ROCK2 hautement efficace et peut être utilisé pour traiter et/ou prévenir des maladies telles que la fibrose pulmonaire, la fibrose hépatique, la fibrose rénale, la fibrose cardiaque ou la stéatohépatite non alcoolique.
PCT/CN2021/114868 2020-08-28 2021-08-27 Inhibiteur sélectif de kinase rock2 WO2022042666A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202010891846.4 2020-08-28
CN202010891846 2020-08-28
CN202011392113 2020-12-02
CN202011392113.2 2020-12-02
CN202110079361.X 2021-01-20
CN202110079361 2021-01-20

Publications (1)

Publication Number Publication Date
WO2022042666A1 true WO2022042666A1 (fr) 2022-03-03

Family

ID=80352676

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/114868 WO2022042666A1 (fr) 2020-08-28 2021-08-27 Inhibiteur sélectif de kinase rock2

Country Status (2)

Country Link
CN (1) CN114105976B (fr)
WO (1) WO2022042666A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114573566B (zh) * 2021-03-04 2023-05-30 杭州邦顺制药有限公司 选择性rock2激酶抑制剂
CN116891460A (zh) * 2023-07-12 2023-10-17 浙江大学 一种吲唑类衍生物或其药用盐及应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005272321A (ja) * 2004-03-23 2005-10-06 Ono Pharmaceut Co Ltd 含窒素複素環化合物およびその医薬用途
CN101679303A (zh) * 2007-06-01 2010-03-24 默克专利有限公司 哒嗪酮衍生物
WO2010104851A1 (fr) * 2009-03-09 2010-09-16 Surface Logix, Inc. Inhibiteurs de la rho kinase
WO2015157556A1 (fr) * 2014-04-09 2015-10-15 Kadmon Corporation, Llc Traitement de la réaction du greffon contre l'hôte
CN105120869A (zh) * 2012-10-05 2015-12-02 卡德门企业有限公司 眼部病症的治疗
CN111825675A (zh) * 2019-04-15 2020-10-27 武汉朗来科技发展有限公司 Rock抑制剂及其制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CR9465A (es) * 2005-03-25 2008-06-19 Surface Logix Inc Compuestos mejorados farmacocineticamente
WO2012040499A2 (fr) * 2010-09-22 2012-03-29 Surface Logix, Inc. Inhibiteurs métaboliques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005272321A (ja) * 2004-03-23 2005-10-06 Ono Pharmaceut Co Ltd 含窒素複素環化合物およびその医薬用途
CN101679303A (zh) * 2007-06-01 2010-03-24 默克专利有限公司 哒嗪酮衍生物
WO2010104851A1 (fr) * 2009-03-09 2010-09-16 Surface Logix, Inc. Inhibiteurs de la rho kinase
CN105120869A (zh) * 2012-10-05 2015-12-02 卡德门企业有限公司 眼部病症的治疗
WO2015157556A1 (fr) * 2014-04-09 2015-10-15 Kadmon Corporation, Llc Traitement de la réaction du greffon contre l'hôte
CN111825675A (zh) * 2019-04-15 2020-10-27 武汉朗来科技发展有限公司 Rock抑制剂及其制备方法和用途

Also Published As

Publication number Publication date
CN114105976A (zh) 2022-03-01
CN114105976B (zh) 2024-04-26

Similar Documents

Publication Publication Date Title
JP6917988B2 (ja) 血漿カリクレイン阻害薬としてのヘテロアリールカルボキサミド誘導体
TWI591067B (zh) 吡唑并吡啶及吡唑并嘧啶
JP6855477B2 (ja) 血漿カリクレイン阻害薬としてのヘテロアリールカルボキサミド誘導体
TWI675028B (zh) 做為週期素依賴型激酶（ｃｄｋ）抑制劑之2-ｈ-吲唑衍生物及其醫療用途
JP2020143131A (ja) Ｅｇｆｒモジュレーターとしての置換２−アミノピリミジン誘導体
US9315487B2 (en) Tetrahydroquinoline derivatives useful as bromodomain inhibitors
JP5480936B2 (ja) Ｊａｋ経路の阻害のための組成物および方法
US7074799B2 (en) Substituted quinazolin-4-ylamine analogues
EP2498607B1 (fr) Inhibiteurs de kinases
US8283356B2 (en) 2,4- Di(hetero)-arylamino-pyrimidine derivatives as ZAP-70 and/or SYK inhibitors
TWI609866B (zh) 新穎吡唑衍生物
TW201619150A (zh) 用於調節ｅｇｆｒ突變型激酶活性的化合物及組成物
WO2015127872A1 (fr) Dérivés de 1,5-diamine phénylène 2,4-disubstitués et leurs applications, compositions pharmaceutiques et compositions pharmaceutiquement acceptables préparées à partir de ces dérivés
TW200843777A (en) Inhibitors of the hedgehog pathway
WO2022166974A1 (fr) Dérivé de pyridopyrimidinone, son procédé de préparation et son utilisation
TW200800900A (en) Novel pyridine derivatives and pyrimidine derivatives
MX2014008647A (es) Compuesto de pirazin-carboxamida.
TW201940166A (zh) 作為cdk4及cdk6抑制劑之2h-吲唑衍生物及其治療用途
WO2022042666A1 (fr) Inhibiteur sélectif de kinase rock2
JP2019507766A (ja) 線維症の治療のための新規化合物及びその医薬組成物
WO2018010514A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de fgfr
CN103038228A (zh) 作为前列腺素d2受体拮抗剂的取代的嘧啶类化合物
CN115702145A (zh) 用于治疗炎性疾病的取代的吡啶
CN113677680A (zh) Egfr抑制剂及其组合物和应用
TW202204351A (zh) 具有大環結構的化合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21860500

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21860500

Country of ref document: EP

Kind code of ref document: A1