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WO2021232367A1 - Dérivé de 3-vinyle indazole, son procédé de préparation et son utilisation - Google Patents

Dérivé de 3-vinyle indazole, son procédé de préparation et son utilisation Download PDF

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WO2021232367A1
WO2021232367A1 PCT/CN2020/091613 CN2020091613W WO2021232367A1 WO 2021232367 A1 WO2021232367 A1 WO 2021232367A1 CN 2020091613 W CN2020091613 W CN 2020091613W WO 2021232367 A1 WO2021232367 A1 WO 2021232367A1
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substituted
alkyl
unsubstituted
group
compound
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PCT/CN2020/091613
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Chinese (zh)
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叶庭洪
魏于全
姚于勤
余洛汀
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四川大学
上海医药集团股份有限公司
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Priority to PCT/CN2020/091613 priority Critical patent/WO2021232367A1/fr
Publication of WO2021232367A1 publication Critical patent/WO2021232367A1/fr

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    • 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
    • A61K31/44—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
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C07D401/06—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 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
    • C07D403/06—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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to a 3-vinylindazole derivative, a preparation method and application thereof, and belongs to the field of chemical medicine.
  • the main methods of treating cancer are: traditional therapies such as surgery, radiotherapy, chemotherapy, as well as targeted therapies, including immunotherapies such as PD1/PD-L1, CAR-T therapy, small molecule targeted drugs, monoclonal antibodies, and antibody conjugates Drugs, etc.
  • traditional therapies such as surgery, radiotherapy, chemotherapy, as well as targeted therapies, including immunotherapies such as PD1/PD-L1, CAR-T therapy, small molecule targeted drugs, monoclonal antibodies, and antibody conjugates Drugs, etc.
  • Traditional cancer treatment methods have limited effects, prone to recurrence, metastasis, or toxic side effects, and have a greater impact on the quality of life of patients.
  • Molecular targeted drugs have certain specificity, and small-molecule targeted drugs have always been an important treatment for diseases including cancer.
  • Receptor tyrosine kinases are receptor proteins located on the cell membrane that can transmit extracellular signals into the cell. Most RTKs with carcinogenic effects have low activity or expression levels in normal tissues, but they are over-activated or up-regulated in cancer cells. Receptor tyrosine kinases play an important regulatory role in tumor angiogenesis, tumor cell survival, proliferation, differentiation, and migration.
  • Fibroblast growth factor receptors are receptor tyrosine kinases located on the cell membrane, which can be activated by dimerization and autophosphorylation after binding to the ligand FGF, thereby activating PI3K- AKT, RAS-RAF-MAPK, JAK-STAT and PLC ⁇ four signal pathways.
  • FGFR plays an important role in normal physiological processes such as embryonic development, tissue repair, and maintenance of homeostasis.
  • the abnormality of FGF/FGFR is closely related to cancer and bone diseases.
  • FGFR amplification, mutation and chromosomal translocation make the FGF/FGFR signaling pathway abnormal, and promote tumor occurrence, development, metastasis and drug resistance.
  • FGFR signaling pathway plays a certain regulatory role, affecting the progress and prognosis of cancer.
  • Over-activation and over-expression of FGFR activate downstream signal pathways or autocrine-paracrine signals to produce bypass compensatory effects and make tumors resistant to radiotherapy, chemotherapy, targeted therapy and other therapies. Therefore, targeting FGFR is one of the important strategies for the treatment of cancer.
  • FGFR has also been reported in recent years to prove that it is closely related to pulmonary fibrosis.
  • IPF the proliferation of fibroblasts and the increase of matrix deposition can lead to lung injury and deterioration of lung function.
  • High levels of FGF2 were found in the alveolar lavage fluid and tissues of patients with acute lung injury and pulmonary fibrosis.
  • Mast cells expressing FGF2 accumulate in the extracellular matrix deposition area of IPF and the area where smooth muscle cells/myofibroblast-like cells proliferate.
  • FGF2 plays an important role in the formation of fibrosis, and it directly participates in the cell proliferation and fibrosis after bleomycin-induced lung injury in mice.
  • the increase in angiogenesis in IPF may be mediated by FGF2/FGFR2 in the FGFR signaling pathway.
  • FGF1/FGFR is abundantly expressed in the pathogenesis of IPF patients, suggesting that abnormal FGF1/FGFR signals in IPF patients can promote the migration of fibroblasts and increase the MAPK signal to cause the occurrence of pulmonary fibrosis.
  • TGF- ⁇ 1 induces the expression of ⁇ -SMA in fibroblasts to up-regulate and release FGF2, and FGFR2c can inhibit the proliferation of fibroblasts in pulmonary fibrosis mice through ERK1/2 and Smad3 pathways.
  • FGFR plays an important role in liver fibrosis. Therefore, targeting FGFR may also be a new strategy for the treatment of pulmonary fibrosis and liver fibrosis.
  • the purpose of the present invention is to provide 3-vinylindazole derivatives and preparation methods and uses thereof.
  • the present invention provides the compound represented by formula I, its optical isomer, the compound or its optical isomer pharmaceutically acceptable salt:
  • ring A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted six-membered and five-membered aryl;
  • R 1 , R 2 , and R 3 are independently selected from H, halogen, substituted or unsubstituted alkyl;
  • Ring B is selected from substituted or unsubstituted 5- to 8-membered aryl groups.
  • ring A when ring A is a substituted phenyl group, it contains at least one substituent selected from the group consisting of halogen, unsubstituted alkyl, halogen-substituted alkyl, unsubstituted alkoxy, halogen-substituted alkoxy Group, hydroxyl.
  • the substituted phenyl group contains at least one substituent selected from the group consisting of halogen, unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, unsubstituted C1-C6 alkoxy, C1-C6 alkoxy and hydroxy substituted with halogen.
  • the substituted phenyl group contains at least one substituent selected from the group consisting of halogen, unsubstituted C1-C2 alkyl, halogen-substituted C1-C2 alkyl, unsubstituted C1-C2 alkoxy, C1-C2 alkoxy and hydroxy substituted with halogen.
  • the substituted phenyl group contains at least one substituent selected from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, and hydroxyl.
  • substituted phenyl group is selected from:
  • the substituted phenyl group contains at least one substituent selected from the group consisting of fluorine, chlorine, and methoxy.
  • substituted phenyl group is selected from:
  • ring A is a substituted or unsubstituted six-membered five-membered aryl group
  • the six-membered aryl group contains 0 to 2 heteroatoms.
  • the six-membered aryl group is phenyl.
  • the five-membered aryl group contains at least one heteroatom nitrogen.
  • the five-membered aryl group is selected from substituted or unsubstituted imidazolyl, oxazolyl or pyrrolyl.
  • the five-membered aryl group is selected from Wherein, R 4 to R 9 are independently selected from H, substituted or unsubstituted alkyl.
  • R 4 to R 9 are independently selected from H, unsubstituted C1-C6 alkyl or halogen-substituted C1-C6 alkyl.
  • R 4 to R 9 are independently selected from H, methyl or ethyl.
  • R 5 is selected from H, methyl or ethyl, and R 4 , R 6 , R 7 , R 8 , and R 9 are all H.
  • the six- and five-membered aryl group is selected from:
  • R 1 , R 2 , and R 3 are independently selected from H, halogen, unsubstituted C1-C6 alkyl or halogen-substituted C1-C6 alkyl.
  • R 1 , R 2 , and R 3 are independently selected from H, halogen or unsubstituted C1-C3 alkyl.
  • R 1 , R 2 , R 3 are independently selected from H, fluorine, chlorine or methyl.
  • R 2 is selected from H, fluorine, chlorine or methyl, and R 1 and R 3 are both H.
  • R 2 is selected from H or methyl, and both R 1 and R 3 are H.
  • ring B is selected from substituted or unsubstituted 5- to 6-membered aryl groups.
  • the aryl group contains 0 to 2 heteroatoms.
  • the heteroatom is nitrogen.
  • the aryl group is selected from phenyl, pyridyl, pyrimidinyl or pyrazolyl.
  • substituent selected from the group consisting of halogen, unsubstituted alkyl, halogen-substituted alkyl, unsubstituted
  • substituent selected from the group consisting
  • R 10 is selected from Substituted C1-C6 alkyl or halogen-substit
  • R 10 is an unsubstituted C1-C6 alkyl group.
  • R 10 is a methyl group.
  • n is 0 or 1.
  • R 11 and R 12 are independently selected from unsubstituted C1-C6 alkyl groups, or R 11 and R 12 are connected to form a substituted or unsubstituted morpholinyl or piperazinyl group.
  • R 11 and R 12 are both methyl groups.
  • the substituted morpholinyl and piperazinyl groups contain at least one substituent selected from the following group: substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxycarbonyl, benzyloxycarbonyl, fluorenyloxy Carbonyl.
  • the substituted morpholinyl and piperazinyl groups contain at least one substituent selected from the group consisting of methyl and tert-butoxycarbonyl.
  • R 11 and R 12 are connected to form Wherein, R 13 and R 15 are independently selected from H or methyl, and R 14 is selected from H, methyl or tert-butoxycarbonyl.
  • ring B is a substituted 6-membered aryl group, it is selected from:
  • ring B is an unsubstituted 6-membered aryl group, it is selected from
  • ring B is a substituted pyrazolyl group, and contains at least one substituent selected from the group consisting of unsubstituted alkyl, halogen-substituted alkyl, and hydroxy-substituted alkyl.
  • the substituted pyrazolyl group contains at least one substituent selected from the group consisting of unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, and hydroxy-substituted C1-C6 alkyl.
  • the substituted pyrazolyl contains only one substituent, and the substituent is a C1-C6 alkyl substituted with a hydroxy group.
  • the substituted pyrazolyl contains only one substituent, and the substituent is Further preferably, ring B is
  • ring B is selected from:
  • the compound is selected from:
  • the present invention provides a method for preparing the compound, its optical isomer, the compound or its optical isomer pharmaceutically acceptable salt, which comprises the following steps:
  • Y is halogen
  • R 16 and R 17 are independently selected from H, substituted or unsubstituted alkyl, or R 16 and R 17 are connected to form an alicyclic ring;
  • the nitrite is R 18 is selected from substituted or unsubstituted alkyl, and R 21 is selected from substituted or unsubstituted alkyl;
  • R 19 and R 20 are independently selected from H, substituted or unsubstituted alkyl, or R 19 and R 20 are connected to form an alicyclic ring.
  • Y is bromine
  • R 16 and R 17 are independently selected from H or an unsubstituted C1-C6 alkyl group, or R 16 and R 17 are connected to form a 5-membered alicyclic ring.
  • compound 2 is
  • R 18 is an unsubstituted C1-C6 alkyl group.
  • R 18 is isopentyl.
  • R 21 is an unsubstituted C1-C6 alkyl group.
  • R 21 is a methyl group.
  • R 19 and R 20 are independently selected from H or an unsubstituted C1-C6 alkyl group, or R 19 and R 20 are connected to form a 5-membered alicyclic ring.
  • compound 3 is
  • preparation method meets at least one of the following:
  • the palladium catalyst in step a is palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride,
  • Step a Adding a base to the reaction system, the base being one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, and cesium carbonate;
  • step a the molar ratio of compound 1: compound 2: base: palladium catalyst is 1: (1.1 ⁇ 1.5): (2.0 ⁇ 3.0): (0.003 ⁇ 0.010);
  • the reaction solvent in step a is one or more of dioxane, water, toluene, DMF, n-butanol, isopropanol, and sec-butanol;
  • the reaction solvent in step a is a mixed solvent of 1,4-dioxane:water volume ratio (4-8):1;
  • step a The reaction temperature in step a is 90-110°C;
  • step a The reaction time of step a is 5-10h;
  • Step a is reacted under N 2 protection
  • Step b Dissolve Intermediate I in the reaction solvent, add alkali and acid anhydride and stir thoroughly, and add nitrite for reaction to obtain Intermediate II;
  • the base in step b is potassium acetate
  • step b the molar ratio of intermediate I: base: acid anhydride: nitrite is 1: (1.1 ⁇ 1.5): (1.8 ⁇ 2.5): (3 ⁇ 5);
  • the reaction solvent in step b is toluene
  • Step b adding nitrite and refluxing reaction for 4-8h;
  • Step c reacts under acidic conditions
  • step c hydrochloric acid is added to the reaction system
  • step c 6N HCl is added to the reaction system;
  • the reaction solvent in step c is an alcohol solvent
  • the reaction solvent in step c is methanol
  • step d the intermediate III is dissolved in the reaction solvent, a base is added, and I 2 is dissolved in the reaction solvent and added dropwise to the reaction solution to obtain the intermediate IV through the reaction;
  • the alkali is one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide;
  • step d the molar ratio of Intermediate III: I 2 : Base is 1: (1.5-2.0): 2.0;
  • step d is DMF
  • step d The reaction temperature in step d is 25 to 80°C;
  • step d The reaction time of step d is 2-10h;
  • the palladium catalyst in step e is palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene] One or more of palladium dichloride dichloromethane complex and tris(dibenzylidene indeneacetone) dipalladium;
  • Step e adding a base to the reaction system, the base being one or more of DIEA, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, and cesium carbonate;
  • step e the molar ratio of intermediate IV: compound 3: base: palladium catalyst is 1: (1.1 ⁇ 1.5): (2.0 ⁇ 3.0): (0.003 ⁇ 0.010);
  • the reaction solvent in step e is one or more of dioxane, water, toluene, DMF, n-butanol, isopropanol, and sec-butanol;
  • the reaction solvent in step e is a mixed solvent of 1,4-dioxane:water volume ratio (4-8):1;
  • step e The reaction temperature in step e is 90-110°C;
  • step e The reaction time of step e is 5-10h;
  • Step e is reacted under N 2 protection.
  • the present invention provides the use of the compound, its optical isomer, the compound or its optical isomer pharmaceutically acceptable salt in the preparation of FGFR kinase inhibitor drugs.
  • the drug is an FGFR1, FGFR2 and/or FGFR3 kinase inhibitor.
  • the present invention provides the use of the compound, its optical isomer, the compound or its optical isomer pharmaceutically acceptable salt in the preparation of a medicine for treating and/or preventing cancer.
  • the cancer is breast cancer, lung cancer, gastric cancer, kidney cancer, colorectal cancer, liver cancer, melanoma, bladder cancer, urothelial cancer and/or cholangiocarcinoma.
  • the lung cancer is non-small cell lung cancer.
  • the present invention provides the use of the compound, its optical isomer, the compound or its optical isomer pharmaceutically acceptable salt in the preparation of a medicine for treating and/or preventing organ fibrosis.
  • the organ fibrosis is pulmonary fibrosis or liver fibrosis.
  • the present invention provides a pharmaceutical composition, which uses the compound, its optical isomer, the compound or its pharmaceutically acceptable salt as the active ingredient, and pharmaceutically acceptable excipients or auxiliary materials are added.
  • the compounds and derivatives provided by the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • alkyl is a linear or branched saturated hydrocarbon group.
  • Examples of C 1 -C 6 alkyl groups include but are not limited to methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ) , Tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), new Pentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-pentyl (C 5 ) and n-hexyl (C 6 ).
  • alkoxy refers to the group -OR, where R is alkyl as defined above.
  • Examples of C 1 ⁇ C 6 alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy Group, n-hexyloxy and 1,2-dimethylbutoxy.
  • aryl refers to a group of a 4n+2 aromatic ring system containing or not containing heteroatoms in the aromatic ring system, wherein the heteroatoms are selected from nitrogen, oxygen and/or sulfur.
  • alicyclic refers to a saturated or partially unsaturated cyclic hydrocarbon group.
  • alkoxycarbonyl refers to the group ROC (O) -, wherein R is alkyl as defined above, preferably R is a C 1 ⁇ C 6 alkyl (i.e., C1 ⁇ C6 of the present invention, the alkoxycarbonyl group) .
  • R is alkyl as defined above, preferably R is a C 1 ⁇ C 6 alkyl (i.e., C1 ⁇ C6 of the present invention, the alkoxycarbonyl group) .
  • Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl.
  • pharmaceutically acceptable means that a certain carrier, carrier, diluent, excipient, and/or the formed salt is usually chemically or physically compatible with other ingredients constituting a certain pharmaceutical dosage form, and physiologically Compatible with the receptor.
  • pharmaceutically acceptable salt refers to the acid and/or basic salt formed by the compound of the present invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (internal salts), and also includes quaternary ammonium salts, For example, alkyl ammonium salts.
  • zwitterionic salts internal salts
  • quaternary ammonium salts For example, alkyl ammonium salts.
  • These salts can be obtained directly in the final isolation and purification of the compound. It can also be obtained by appropriately mixing the above-mentioned compound with a certain amount of acid or base (e.g., equivalent).
  • These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • the pharmaceutically acceptable excipients in the present invention refer to substances contained in the dosage form in addition to the active ingredients.
  • the pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of the component will not change the dominant position of the above-mentioned pharmaceutical composition in the course of disease treatment, but only exerts auxiliary functions. These auxiliary functions only It is the utilization of the known activity of the ingredient, and it is a commonly used adjuvant therapy in the medical field. If the aforementioned auxiliary components are used in combination with the pharmaceutical composition of the present invention, they should still fall within the protection scope of the present invention.
  • the present invention provides a class of 3-vinylindazole derivatives with novel structures.
  • Biological experiments have proved that the compound provided by the present invention has a significant inhibitory effect on the activity of FGFR kinase, and can effectively inhibit breast cancer, lung cancer, gastric cancer, kidney cancer, colorectal cancer, liver cancer, melanoma, bladder cancer, urothelial cancer and
  • the proliferation of a variety of cancer cells such as cholangiocarcinoma has a broad-spectrum anti-cancer effect; in addition, it also shows a significant inhibitory effect on the proliferation of fibroblasts.
  • the cloth is comparable, the anti-fibrosis effect is significant, and it also has a good inhibitory effect on hepatic stellate cells.
  • the invention provides new options for the development and application of anti-cancer and anti-fibrosis drugs.
  • Figure 1 is a drug-time curve diagram of compound 4-20 of the present invention in biological experiments
  • Figure 2 is a graph of HE and Masson staining of lung tissue 14 days after administration in an animal experiment
  • Figure 3 shows the HE and Masson staining of lung tissue 28 days after administration in an animal experiment.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products.
  • the main biological experiment instruments and equipment are as follows. Ultra-clean workbench BHC-1000IIA/B3: Sujing Antai Biotechnology Company; Constant temperature water bath PolyScience 9505: PolyScience Company; Sterilizer MLS-3780: SANYO Company; Oven: Binder Company; Ultra-pure water meter Milli-Q Integral 10 :Millipore company; microplate reader Multiscan MK3, cell incubator, low-speed centrifuge Sorvall ST1: Thermofisher company; Centrifuge 5415C ultracentrifuge: Germany Eppendorf company; NUAIRE NU-425-600E biological safety cabinet: American Nuaire company; BCD-215YD Type ordinary refrigerator: China Haier company; SANYO (-80°C) ultra-low temperature refrigerator: Japan Sanyo Electric Group; Rocker 51702 shaker: American Cole Parmer company; 96-well cell culture plate: Costa Corning company; ordinary optical microscope: Olympus company; Liquid gun: Thermo Company; PH meter
  • the cell line used in the experiment was purchased from ATCC, USA.
  • Various necessities for cell culture were purchased from Gibco BRL, including DMEM medium, RPMI 1640 medium, fetal bovine serum (FBS) and pancreatin.
  • Tetramethylazazole blue (MTT) and dimethyl sulfoxide (DMSO) were purchased from Sigma Company in the United States.
  • the compound was diluted with DMSO to 50 times the final highest inhibitor concentration required in the reaction. Transfer 100 ⁇ L of compound dilution to a 96-well plate. Add 100 ⁇ L of DMSO to the two blank wells of the same 96-well plate. This 96-well plate serves as the source plate. Transfer 10 ⁇ L of compound from the source plate to the 96-well plate as the intermediate plate. Add 90 ⁇ L of l1x kinase buffer to each well of the middle plate. Mix the compounds in the middle plate on a shaker for 10 minutes. Transfer 5 ⁇ L from each well of the 96-well middle plate to a 384-well plate, and set up secondary wells. Add kinase to 1x Kinase Alkaline Buffer.
  • the assay plate already contains 5 ⁇ L of compound 10% DMSO solution. Add 10 ⁇ L of l2.5x enzyme solution to each well of the 384-well assay plate. Incubate for 10 minutes at room temperature. Add 10 ⁇ L of 2.5x peptide solution to each well of the 384-well assay plate. After incubating at 28°C for a specific time, add 25 ⁇ L of stop buffer to stop the reaction. Collect data on Caliper and convert the data to IC 50 .
  • Passage is generally 1 time in 3 to 4 days; Passage of adherent growth cells: The cells adhere to the wall and grow to about 80% of the bottom of the bottle, remove the culture bottle from the incubator, aspirate the medium, and wash once with 0.25% pancreatin Then add 0.25% trypsin digestion solution for digestion. After observing the cell shrinkage and rounding, add complete medium to stop the digestion, and pipette to disperse and fall off the cells. Collect the cell suspension, centrifuge at 1500rpm/min for 3min, and pour the supernatant. , The cell pellet is resuspended in complete medium and pipetted evenly, and then divided into 3 to 5 bottles for culture. Generally, it is passaged once every 3 to 4 days.
  • Collect the cells in the logarithmic growth phase (4T1 mouse breast cancer cell line; MDA-MB-231 human breast cancer cell line; A549 human non-small cell lung cancer line; SUN-16 human poorly differentiated gastric cancer cell; NIH3T3 mouse adult Fibroblasts; human lung fibroblasts HPF (Catalog#3300)), seeded in a 96-well plate at a rate of 2.5 ⁇ 10 3 to 1 ⁇ 10 4 per well, in a cell incubator at 37°C and 5% CO 2 Incubate in medium overnight for 24 hours, dilute the drug to be tested with DMEM medium and add it to a 96-well plate. Each drug has 8 gradients, and each gradient contains 3 replicate wells.
  • the dosing group add 100 ⁇ L of the compound medium solution to each well according to the gradient (final concentrations are 1000, 333, 127, 42.3, 14.1, 4.7, 1.56, 0.53 nM), and each concentration has 3 replicate wells; negative control
  • 100 ⁇ L of blank medium containing 1 ⁇ DMSO was added to each well for a total of 6 multiple wells; in the blank control group, only 100 ⁇ L of medium was added to each well. Place the plate in a 37°C, 5% CO 2 cell culture incubator for 72 hours.
  • the invisible control group and the blank group add 20 ⁇ L of MTT solution (5mg/mL) to each well, continue to incubate for 2-4 hours.
  • the pharmacokinetic analysis of the compound 4-20 of the present invention is completed by the testing service provided by Medicipuya Pharmaceutical Technology (Shanghai) Co., Ltd. 8 SPF-grade male SD rats (6 experimental rats, and the rest as blank controls) used in this experiment were transferred from the experimental institution animal reserve (999M-017), Shanghai Xipuer-Bikai Experimental Animal Co., Ltd. The experiment was divided into two groups, each group of 3 mice, respectively: a single intravenous injection with a dose of 2 mg/kg, a dose of 0.4 mg/mL, a dose of 5 mL/kg, and a dose of 20 mg/kg. The drug concentration was 2 mg/mL and the administration volume was 10 mL/kg.
  • the animals in the oral administration group were fasted overnight for 10-14 hours before administration and 4 hours after administration. And set the blood sampling time points as follows: before administration, after administration 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, 10 times, after blood collection through the jugular vein, each sample is collected about 0.20 mL, heparin sodium is anticoagulated and placed on ice after collection.
  • Plasma sample processing place the blood sample on ice after collection, and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6800g, 6mins, 2-8°C). Plasma samples were stored in a refrigerator at -80°C before analysis.
  • mice Male C57BL/6 mice (7-9 weeks old, weighing 18-22 g) were purchased from Hua Fukang (Beijing, China). The mice are housed and maintained in the facility under SPF conditions. On the 0th day of the experiment, the mice were anesthetized with 10% chloral hydrate, and then a single intratracheal instillation of bleomycin sulfate dissolved in normal saline (2 mg/kg body weight) was given to the mice, and an equal volume was injected at the same time To the rats in the control group.
  • mice were randomly divided into groups on the second day, each with 10 mice, and the compound 4-20 (YTH-17; 30mg/kg, 60mg/kg) and 4-22 (YTH-18; 30mg/kg) of the present invention were orally administered orally every day 60mg/kg), the positive control is Nintedanib (BIBF1120) (30mg/Kg, the solvent is (5% DMSO + 40% PEG400 + 55% normal saline)) medicine and an equal volume of solvent as a control. After 14 or 28 days of administration, the mice were sacrificed.
  • mice were sacrificed on the 14th or 28th day of the experiment.
  • the lung tissue samples were placed in 4% (m/v) PBS-buffered paraformaldehyde solution. Three days later, part of the tissue was rinsed in water for 2 hours, then dehydrated with gradient ethanol and embedded in paraffin.
  • the tissues wrapped in paraffin were cut into serial sections (3 ⁇ m) and stained with hematoxylin and eosin or Masson trichrome to evaluate the histopathological changes and the degree of accumulated collagen fibers.
  • Table 2 lists the inhibition of FGFR1 kinase by some of the compounds synthesized in the present invention.
  • the letter A represents an IC 50 of 50 nM or less
  • the letter B represents an IC 50 of 50 nM to 100 nM
  • the letter C represents an IC 50 of 100 nM to 500 nM
  • the letter D represents an IC 50 of 500 nM or more.
  • Table 2 The IC 50 value of some compounds of the present invention for inhibiting FGFR1 kinase
  • Table 3 lists the inhibitory effects of some of the compounds synthesized in the present invention on various kinases.
  • the letter A represents an IC 50 of 50 nM or less
  • the letter B represents an IC 50 of 50 nM to 100 nM
  • the letter C represents an IC 50 of 100 nM to 500 nM
  • the letter D represents an IC 50 of 500 nM or more.
  • Table 3 The IC 50 values of some compounds of the present invention for inhibiting related kinases
  • Table 4 lists the inhibition of the proliferation of SNU16 cells by some of the compounds synthesized by the present invention under 72 hours of action.
  • the letter A represents an IC 50 of 50 nM or less
  • the letter B represents an IC 50 of 50 nM to 100 nM
  • the letter C represents an IC 50 of 100 nM to 500 nM
  • the letter D represents an IC 50 of 500 nM or more.
  • Table 4 The IC 50 value of some compounds of the present invention in inhibiting the proliferation of SUN16 cells
  • Table 5 The IC 50 value of some compounds of the present invention in inhibiting tumor cell proliferation
  • Table 6 lists the inhibition of the proliferation of NIH-3T3 cells and human lung fibroblasts of some compounds synthesized by the present invention after 72 hours of action.
  • Table 6 The IC 50 values of some compounds of the present invention in inhibiting the proliferation of NIH-3T3 cells and human lung fibroblasts
  • Figure 1 shows the blood concentration and time curve.
  • a single intravenous injection (1-A) or oral gavage (1-B) dose: 2mg/kg, 20mg/kg
  • SD rats three male rats in each group, respectively numbered : 101/102/103, 201/202/203
  • the study found that the average half-life after intravenous administration was 5.81h, and the average AUC(0-t) was 2771.74h*ng/mL.
  • the average half-life was 3.44h
  • the average AUC(0-t) was 20917.54h*ng/mL
  • the average oral bioavailability was calculated to be 75.47%.

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Abstract

La présente invention relève du domaine de la médecine chimique, et concerne un dérivé de 3-vinyle indazole, son procédé de préparation et son utilisation. La présente invention concerne un composé représenté par la formule I, un isomère optique de celui-ci, et un sel pharmaceutiquement acceptable du composé ou de son isomère optique. Des expériences biologiques montrent que le dérivé de 3-vinyle indazole fourni par la présente invention a un effet inhibiteur significatif sur l'activité de la kinase FGFR, peut inhiber de manière efficace la prolifération de multiples types de cellules cancéreuses dans le cancer du sein, le cancer du poumon, le cancer gastrique, le cancer du rein, le cancer colorectal, le cancer du foie, le mélanome, le cancer de la vessie, le carcinome urothélial, le cholangiocarcinome et analogues, et a un effet anticancéreux à large spectre; en outre, le dérivé de 3-vinyle indazole présente également un effet inhibiteur significatif sur la prolifération de fibroblastes, a un effet équivalent au médicament Nintedanib actuellement utilisé sur le plan clinique pour le traitement de la fibrose pulmonaire, et a un effet thérapeutique anti-fibrose significatif; de plus, le dérivé de 3-vinyle indazole présente également un bon effet inhibiteur sur les cellules stellaires hépatiques. La présente invention offre une nouvelle option pour le développement et l'utilisation de médicaments anticancéreux et anti-fibrose.
PCT/CN2020/091613 2020-05-21 2020-05-21 Dérivé de 3-vinyle indazole, son procédé de préparation et son utilisation WO2021232367A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1374950A (zh) * 1999-07-02 2002-10-16 阿古龙制药公司 抑制蛋白激酶的吲唑化合物和药物组合物及它们的应用
WO2018136010A1 (fr) * 2017-01-20 2018-07-26 Aslan Pharmaceuticals Pte Ltd Polythérapie
CN110452176A (zh) * 2018-05-07 2019-11-15 四川大学 吲唑类衍生物及其制备方法和用途
CN111205227A (zh) * 2018-11-22 2020-05-29 四川大学 3-乙烯基吲唑类衍生物及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1374950A (zh) * 1999-07-02 2002-10-16 阿古龙制药公司 抑制蛋白激酶的吲唑化合物和药物组合物及它们的应用
WO2018136010A1 (fr) * 2017-01-20 2018-07-26 Aslan Pharmaceuticals Pte Ltd Polythérapie
CN110452176A (zh) * 2018-05-07 2019-11-15 四川大学 吲唑类衍生物及其制备方法和用途
CN111205227A (zh) * 2018-11-22 2020-05-29 四川大学 3-乙烯基吲唑类衍生物及其制备方法和用途

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