WO2019242587A1 - Inhibiteur hautement sélectif de fgfr i, son procédé de préparation et son utilisation - Google Patents

Inhibiteur hautement sélectif de fgfr i, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2019242587A1
WO2019242587A1 PCT/CN2019/091573 CN2019091573W WO2019242587A1 WO 2019242587 A1 WO2019242587 A1 WO 2019242587A1 CN 2019091573 W CN2019091573 W CN 2019091573W WO 2019242587 A1 WO2019242587 A1 WO 2019242587A1
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alkyl
deuterium
group
substituted
halogen
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PCT/CN2019/091573
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English (en)
Chinese (zh)
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邓海兵
应海燕
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN201980020073.8A priority Critical patent/CN111936493B/zh
Publication of WO2019242587A1 publication Critical patent/WO2019242587A1/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
    • A61K31/435—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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and particularly relates to a highly selective FGFRi inhibitor and a preparation method and application thereof.
  • Fibroblast growth factor receptor is a tyrosine kinase receptor that binds to fibroblast growth factor ligands.
  • four FGFR receptors have been found to be able to bind ligands and are closely related in a variety of physiological processes including tissue differentiation, angiogenesis, wound healing, and metabolic regulation.
  • the receptor undergoes dimerization and phosphorylation, stimulates the activation of protein kinase activity, and recruits many intracellular proteins to bind.
  • These protein interactions can help activate a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are important signaling pathways for cell growth, proliferation, and survival.
  • Abnormal activation of this signaling pathway can lead to tumor growth, progression, and resistance to traditional cancer therapies.
  • changes in genes that can cause ligand-independent receptor activation, including gene amplification, chromosomal translocation, and somatic mutations have been described.
  • large-scale DNA sequencing of thousands of tumor samples has revealed that the components in the FGFR signaling pathway are high-frequency mutation genes in human cancers.
  • somatic mutations of FGFR1 have been found in gliomas and lung cancers.
  • FGFR2 mutations are more common in gastric and endometrial cancers
  • FGFR3 mutations are found in bladder cancer and multiple myeloma.
  • FGFG4 mutations It is found in primary rhabdomyosarcoma.
  • FGF / FGFR-related tumor types include but are not limited to cancer (such as bladder cancer, breast cancer, cervical spine cancer, colon cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer)
  • cancer such as bladder cancer, breast cancer, cervical spine cancer, colon cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer
  • Malignant hematological diseases such as multiple myeloma, chronic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, myeloproliferative tumors and Fahrenheit macroglobulinemia
  • other tumors such as glioblastoma, melanoma, and rhabdomyosarcoma.
  • FGFR activation has also been found to be associated with bone and chondrocyte lesions, such as hypochondral hypoplasi
  • FGFR inhibitors Although some FGFR inhibitors have entered the clinical and preclinical R & D process, they usually have insufficient selectivity, and have inhibitory effects on other kinases such as c-kit, PDGFRa, which brings the concern that certain treatment windows are not large enough. . Therefore, the development of inhibitors targeted at FGFR selectivity would be of great significance in the clinical treatment of diseases with increased FGF or FGFR activity.
  • the object of the present invention is to provide an FGFR 2 and / or FGFR 3 inhibitor.
  • the first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:
  • X is selected from C (R 7 ) or N;
  • R 1 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, or -NR 8 R 9.
  • R 8 and R 9 are each independently selected from deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 10 , -C 0-8 -C (O) R 12 , -C 0-8 -C (O) NR 13 R 14 or -NR 13 R 14 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 member
  • Each R 10 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkoxy 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Or -NR 13 R 14 , the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl , C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 13 R 14 substituted by a substituent;
  • Each R 11 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, or 5- 10-membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 ring Alkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl Group, 5-10 membered heteroaryloxy group or -NR 13 R 14 substituent;
  • Each R 12 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 13 R 14 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryl
  • R 13, R 14 are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C 1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium , Halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1
  • R 13 and R 14 and the directly connected nitrogen atom together form a 4- to 10-membered heterocyclic group or a 4- to 10-membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, and hydroxyl group.
  • C 1-10 alkyl C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5 -10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • Each r is independently 0, 1, or 2.
  • X is selected from C (R 7 ) or N;
  • X is selected from C (R 7 ) or N; R 7 is selected from hydrogen and deuterium. , Halogen, cyano, nitro, azide, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl, oxetanyl, azetyl, azacyclo Hexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropyloxy, methoxycarbonyl, ethoxycarbonyl, acetyl, Acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetylamino; the above groups are optionally
  • X in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from C (R 7 ) or N;
  • R 7 is selected from hydrogen, deuterium, Fluorine, chlorine, cyano, nitro, azide, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azetidine Methyl, azacyclohexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxyethyl, ethyl Oxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideutermethyl, difluoromethyl,
  • each of R 5 and R 6 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, and nitro.
  • R 5 and R 6 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen, deuterium, halogen, cyano, and nitrate.
  • Base azide, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl, oxetanyl, azetyl, azacyclohexyl, phenyl, diazo Azole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetyl Oxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetylamino; the aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, Cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino are substituted.
  • each of R 3 and R 4 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, Nitro, azide, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 Heterocyclic group, 3-8 membered heterocyclic oxy group, C 5-8 aryl group, C 5-8 aryloxy group, 5-8 membered heteroaryl group or 5-8 membered heteroaryloxy group.
  • R 3 and R 4 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen, deuterium, halogen, hydroxyl, and cyano.
  • R 2 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, and C.
  • R 1 is selected from a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, and C.
  • the compound of formula (I) in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has the structure of formula (IIa):
  • Ring A is selected from 3-8 membered heterocyclyl, C 5-8 aryl or 5-8 membered heteroaryl;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkane Oxygen, 3-6 membered heterocyclyl or 3-6 membered heterocyclyl, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl Substituted with a substituent of phenyl, methoxy, ethoxy, hydroxy or amino;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxyl, methoxy, ethoxy, or isopropoxy, and The group is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxyl or amino;
  • n 0, 1, 2 or 3;
  • R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
  • Phenyl or a 5-6 membered heteroaryl group containing 1, 2 or 3 nitrogen heteroatoms preferably, the 5-6 membered nitrogen-containing heteroaryl group is selected from pyridyl, pyrimidinyl, pyridazinyl, pyridine Azinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl;
  • n 0, 1 or 2;
  • R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the structure of formula (IIIa 1 ), formula ( IIIa 2 ) structure or formula (IIIa 3 ) structure:
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, methyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, or isopropoxy, and the above-mentioned groups are optionally further Or more than one selected from deuterium, fluorine or cyclopropyl substituents;
  • R 15a , R 15b , R 15c , R 15d , R 15e , R 15f are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 member Heterocyclyl, hydroxy, methoxy, ethoxy, carboxyl, methylaminoacyl, ethylaminoacyl or cyclopropylaminoacyl are substituted by the substituents, and the above groups are optionally further selected by one or more From deuterium, fluorine, chlorine, cyano, methyl, cyclopropyl, cyclobutyl, cyclohexyl, morpholinyl, piperazinyl, methanesulfonyl, hydroxy, methoxy, carboxyl, or acetyl substituents Replace
  • R 13 and R 14 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclic group, and the above-mentioned groups are optionally further selected from one or more Deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, difluoromethyl, trifluoromethyl, dideuteryl methyl, trideuteryl methyl, methoxy, ethoxy, isopropoxy, cyclopropyl , A 3-8 membered heterocyclyl, a phenyl, a diazole, a triazole, an amino, a dimethylamino, a diethylamino, or a C 1-4 alkanoyl substituent, or,
  • R 13 , R 14 and the directly connected nitrogen atom together form a 4-8 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, Difluoromethyl, trifluoromethyl, dideutermethyl, trideutermethyl, methoxy, ethoxy, isopropoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, Morpholinyl, piperazinyl, amino, dimethylamino, diethylamino or C 1-4 alkanoyl substituents;
  • the heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
  • the compound of formula (I) in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has the structure of formula (IIb):
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkane Oxygen, 3-6 membered heterocyclyl or 3-6 membered heterocyclyl, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl Substituted with a substituent of phenyl, methoxy, ethoxy, hydroxy or amino;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxyl, methoxy, ethoxy, or isopropoxy, and The group is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxyl or amino;
  • R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
  • R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
  • the compound of the formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, the compound of the formula (I) has a structure of the following formula (IIIb):
  • R 2 is selected from phenyl, a 5- to 6-membered heteroaryl group containing 1 or 2 nitrogen heteroatoms, or -NR 13 R 14.
  • the group is optionally substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, methyl, cyclopropyl, or hydroxyl;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, methyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, or isopropoxy, and the above-mentioned groups are optionally further Or more than one selected from deuterium, fluorine or cyclopropyl substituents;
  • R 8 , R 9 and the directly connected nitrogen atom together form a 4-8 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, Substituted with methoxy, ethoxy, isopropoxy or C 1-4 alkanoyl substituents;
  • R 13 and R 14 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclic group, and the above-mentioned groups are optionally further selected from one or more Deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, difluoromethyl, trifluoromethyl, dideuteryl methyl, trideuteryl methyl, methoxy, ethoxy, isopropoxy, cyclopropyl , A 3-8 membered heterocyclyl, a phenyl, a diazole, a triazole, an amino, a dimethylamino, a diethylamino, or a C 1-4 alkanoyl substituent, or,
  • R 13 , R 14 and the directly connected nitrogen atom together form a 4-8 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, Difluoromethyl, trifluoromethyl, dideutermethyl, trideutermethyl, methoxy, ethoxy, isopropoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, Morpholinyl, piperazinyl, amino, dimethylamino, diethylamino or C 1-4 alkanoyl substituents;
  • the heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • a second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a fourth aspect of the present invention there is provided an application of the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors or cancers.
  • the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, and esophageal cancer.
  • Gallbladder cancer pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin Gold lymphoma, Fahrenheit macroglobulinemia, hair-like lymphoma, cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
  • the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is provided for preparing a medicine for treating a myeloproliferative disease, bone or chondrocyte disorder, and hypophosphatemia.
  • the myeloproliferative disease is selected from the group consisting of erythrocytosis, primary thrombocytosis, or primary myelofibrosis; and the skeletal or chondrocyte disorders are selected from the group consisting of dysplasia, chondrogenesis, and dwarfism.
  • hypophosphatemia is selected from the group consisting of X-linked hypophosphatemia rickets, autosomal recessive hypophosphatemia rickets, autosomal dominant hypophosphatemia rickets, or tumor-induced ovarian softening.
  • a sixth aspect of the present invention provides the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, which is used as a FGFR inhibitor to treat and abnormally express FGFR receptors, mutations or corresponding Diseases associated with abnormal expression of ligand and abnormal activity; preferably, it is used as a selective FGFR 2 and / or FGFR 3 inhibitor to treat abnormal expression of FGFR2 or FGFR3 receptor, mutation or abnormal expression of corresponding ligand and abnormal activity Related diseases.
  • the compounds of the present invention can be widely used in the preparation of drugs for treating tumors, cancers, myeloproliferative diseases, bone or chondrocyte disorders, and hypophosphatemia, and are expected to be developed into a new generation of FGFRi inhibitor drugs. Based on this, the present invention has been completed.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group.
  • C 1-10 alkyl refers to a linear alkyl group containing 1 to 10 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylp
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • C 3-10 cycloalkyl refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, of which:
  • Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.
  • “Spirocycloalkyl” refers to polycyclic groups that share one carbon atom (called a spiro atom) between single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has A completely conjugated ⁇ -electron system.
  • Spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings.
  • Spirocycloalkyl includes but is not limited to:
  • fused cycloalkyl refers to a full-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings.
  • the fused cycloalkyl includes, but is not limited to:
  • Bridged cycloalkyl refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of them The ring has a completely conjugated ⁇ -electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings.
  • the bridged cycloalkyl includes but is not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl and the like.
  • a cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O) A heteroatom of r (where r is an integer of 0, 1, 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • r is an integer of 0, 1, 2
  • Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen and oxygen Or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system.
  • Spiro heterocyclyl is classified into monospiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between rings.
  • Spiro heterocyclyl includes, but is not limited to:
  • “Fused heterocyclyl” refers to a polycyclic heterocyclic group where each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more (preferably 1, 2, 3, or 4) rings may Contains one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated ⁇ electron system, in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected
  • a heteroatom of nitrogen, oxygen, or S (O) r where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl according to the number of constituent rings.
  • the fused heterocyclyl includes but is not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring A completely conjugated ⁇ -electron system in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, 1, 2) Heteroatom, the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl refers to a full-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group, a polycyclic ring having a conjugated pi-electron system (i.e., its ring with adjacent pairs of carbon atoms ) Group, for example, "C 5-10 aryl” refers to a full-carbon aryl group containing 5-10 carbons, and “5-10-membered aryl” refers to a full-carbon aryl group containing 5-10 carbons, including but Not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms including nitrogen, oxygen, and S (O) r (where r is the integer 0 , 1, 2) heteroatoms, for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms Family systems, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Heteroaryl may be optionally substituted or unsubstituted.
  • Alkenyl refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of an alkyl group, e.g., C 2- 10 alkenyl group refers to a straight chain containing 2-10 carbon atoms or branched Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkenyl may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • C 2-10 alkynyl refers to a straight or branched chain containing 2 to 10 carbons.
  • Alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • the alkynyl may be substituted or unsubstituted.
  • Alkoxy refers to -O- (alkyl), where alkyl is as defined above, for example, “C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • Cycloalkoxy refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is as defined above, for example, "C 3-10 cycloalkoxy” refers to a group containing 3 to 10 carbons. Cycloalkyloxy includes, but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted.
  • 3-10 membered heterocyclic oxy refers to -O- (unsubstituted 3-10 membered heterocyclyl), wherein the definition of 3-10 membered heterocyclyl is as described above, and 3-10 membered heterocyclyl It may be optionally substituted or unsubstituted.
  • 5-10 membered heteroaryloxy refers to -O- (unsubstituted 5-10 membered heteroaryl), wherein the definition of 5-10 membered heteroaryl is as described above, and 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted.
  • C 1-8 alkanoyl refers to the monovalent atomic group remaining after the C 1-8 alkyl acid has been removed from the hydroxyl group, and is usually also expressed as "C 0-7 -C (O)-", for example, “C 1 -C (O)-"means acetyl;” C 2 -C (O)-"means propionyl;” C 3 -C (O)-"means butyryl or isobutyryl.
  • -C 0-8 -OR 11 means that the oxygen atom in -OR 11 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and the definition of C 1-8 alkyl group is as described above.
  • -C 0-8 -OC (O) R 12 refers to a -OC (O) R 12 is an oxygen atom attached to C 0-8 alkyl, wherein C 0 alkyl means a bond, C 1- 8 alkyl
  • the definition of base is as described above.
  • -C 0-8 -NR 13 R 14 means that the nitrogen atom in -NR 13 R 14 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and the definition of C 1-8 alkyl group is as above As described.
  • Halo-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group optionally substituted with hydrogen on the alkyl by fluorine, chlorine, bromine, or iodine atoms, including, but not limited to, difluoromethyl, di Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • the hydrogen on the "halo-substituted C 1-10 alkoxy" alkyl is optionally a 1-10 carbon alkoxy group substituted with a fluorine, chlorine, bromine, or iodine atom. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • MeOH means methanol.
  • DMF means N, N-dimethylformamide.
  • DCE refers to 1,2-dichloroethane.
  • THF means tetrahydrofuran.
  • PE means petroleum ether.
  • EA / EtOAc means ethyl acetate.
  • DCM means dichloromethane.
  • LiOH means lithium hydroxide.
  • NaOH means sodium hydroxide.
  • NaNO 2 refers to sodium nitrite.
  • CuI means cuprous iodide.
  • Na 2 SO 4 refers to sodium sulfate.
  • HOAc means acetic acid.
  • NH 4 OAc means ammonium acetate.
  • Et 3 N refers to triethylamine.
  • NH 4 Cl means ammonium chloride.
  • TFA means trifluoroacetic acid.
  • M-CPBA refers to m-chloroperoxybenzoic acid.
  • Pd (PPh 3 ) 4 means tetrakis (triphenylphosphine) palladium.
  • Pd (PPh 3 ) 2 Cl 2 "means” bistriphenylphosphonium palladium dichloride.
  • heterocyclic group optionally substituted with alkyl group means that the alkyl group may but need not exist, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group are substituted independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom (such as an olefin) having an unsaturated bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). The internal standard was four. Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 6120 mass spectrometer.
  • an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column) were used.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
  • Step 4 Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester
  • Step 5 Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
  • Step 7 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one synthesis
  • Step 8 Synthesis of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
  • Step 1 Synthesis of methyl 5-((3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
  • Step 2 Synthesis of 5-((3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
  • Step 3 Synthesis of 6- (3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one
  • Step 4 Synthesis of 6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one
  • Step 5 Synthesis of 8-chloro-6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
  • Step 6 Synthesis of 8-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
  • Step 1 Synthesis of 2- (5-bromopyridin-2-yl) -2-methylpropionitrile
  • Step 3 Synthesis of (6- (2-cyanopropane-2-yl) pyridin-3-yl) boronic acid
  • the third step the synthesis of (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid
  • the second step the synthesis of (6- (methylcarbamoyl) pyridin-3-yl) boronic acid
  • Examples 2 to 4 are prepared by referring to the synthetic method of Example 1:
  • Second step 6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethyl-2- (methanesulfonyl) pyrido [3,4-d] pyrimidine -8-amine synthesis
  • Examples 45 to 50 are prepared by referring to the synthetic method of Example 44:
  • Step 1 Synthesis of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d] pyrimidine
  • Examples 52 to 54 were prepared by referring to the synthetic method of Example 51:
  • Examples 56-60 were prepared by referring to the synthetic method of Example 55:
  • Caliper Assay is used to determine the compound's inhibitory activity on FGFR1 and FGFR2.
  • the specific experimental process is as follows:
  • the kinase reaction performed in the present invention is performed in a 384-well plate, using a certain concentration of kinase (Carna) and a certain concentration of ATP and 1 ⁇ M peptide FAM-P22 (GL Biochem, Cat. No. 112393)) at 50 mM HEPES, pH 7.5, 0.0015% Brij-35 and basic kinase buffer incubation reaction at 28 ° C for a certain time; for FGFR1, the enzyme concentration is 0.25nM, ATP concentration is 382 ⁇ M, the reaction time is 20 minutes; , The enzyme concentration is 2.5nM, the ATP concentration is 1 ⁇ M, and the reaction time is 40 minutes;
  • stop solution 100mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50mM EDTA and 0.015% Brij35
  • Caliper microfluidic migration migration technology was used to separate phosphorylated and unphosphorylated peptides, and the analytes were transferred by a constant buffer flow through the chip, and the substrate peptide migration was monitored by its labeled fluorescent signal. The amount of phosphate peptide formed was used to calculate the kinase activity.
  • IC 50 values were determined by non-linear regression analysis of percent inhibition at different compound concentrations. The enzymatic activities of the compounds of the specific examples are shown in Table 1.
  • the present invention evaluates the inhibitory effect of the compound on the cell proliferation dependent on the FGFR signaling pathway through a survival experiment, and is measured using a CTG reagent (Promega, # G7573).
  • Select the cell line that can represent different tumor types such as H1581 lung cancer cells from Nanjing Kebai (with FGFR1 gene amplification) or Snu-16 gastric cancer cells (with FGFR2 gene amplification).
  • the specific experimental process is as follows:
  • the compounds of the present invention have a strong inhibitory effect on FGFR, especially FGFR1 and / or FGFR2 kinase activity.
  • the compounds of the present invention have very good selectivity for FGFR1, and are expected to be developed into a new generation of FGFR inhibitors, especially highly selective FGFR2 inhibitors, to meet the needs of clinical applications.

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Abstract

L'invention concerne un inhibiteur hautement sélectif de FGFR i ayant la structure de formule (I), son procédé de préparation et son utilisation, la définition de chaque substituant étant telle que décrite dans la description et les revendications. Le composé fourni par la présente invention peut être largement utilisé dans la préparation de médicaments pour le traitement de tumeurs, de cancers, de maladies myéloprolifératives, de troubles de cellules osseuses ou de troubles de chondrocytes, et d'hypophosphatémie, et est supposé être développé en une nouvelle génération de médicaments inhibiteurs de FGFR i.
PCT/CN2019/091573 2018-06-19 2019-06-17 Inhibiteur hautement sélectif de fgfr i, son procédé de préparation et son utilisation WO2019242587A1 (fr)

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WO2021145521A1 (fr) * 2020-01-15 2021-07-22 한국과학기술연구원 Dérivé de pyrido[3,4-d]pyrimidine et composition pharmaceutique thérapeutique le comprenant

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CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
WO2018113584A1 (fr) * 2016-12-19 2018-06-28 上海和誉生物医药科技有限公司 Inhibiteur de fgfr4, son procédé de préparation et son utilisation pharmaceutique
CN109745325A (zh) * 2017-11-08 2019-05-14 上海翰森生物医药科技有限公司 Fgfr4抑制剂、其制备方法和用途

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CN103261167A (zh) * 2010-12-17 2013-08-21 霍夫曼-拉罗奇有限公司 取代的6，6-稠合含氮杂环化合物及其用途
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
WO2018113584A1 (fr) * 2016-12-19 2018-06-28 上海和誉生物医药科技有限公司 Inhibiteur de fgfr4, son procédé de préparation et son utilisation pharmaceutique
CN109745325A (zh) * 2017-11-08 2019-05-14 上海翰森生物医药科技有限公司 Fgfr4抑制剂、其制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021145521A1 (fr) * 2020-01-15 2021-07-22 한국과학기술연구원 Dérivé de pyrido[3,4-d]pyrimidine et composition pharmaceutique thérapeutique le comprenant

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