WO2020052349A1 - Fgfr抑制剂、其制备方法和应用 - Google Patents

Fgfr抑制剂、其制备方法和应用 Download PDF

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Publication number
WO2020052349A1
WO2020052349A1 PCT/CN2019/097361 CN2019097361W WO2020052349A1 WO 2020052349 A1 WO2020052349 A1 WO 2020052349A1 CN 2019097361 W CN2019097361 W CN 2019097361W WO 2020052349 A1 WO2020052349 A1 WO 2020052349A1
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Prior art keywords
alkyl
deuterium
substituted
group
membered
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PCT/CN2019/097361
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English (en)
French (fr)
Inventor
邓海兵
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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Application filed by 上海和誉生物医药科技有限公司 filed Critical 上海和誉生物医药科技有限公司
Priority to JP2020570836A priority Critical patent/JP7152794B2/ja
Priority to CA3103335A priority patent/CA3103335C/en
Priority to EP19861022.2A priority patent/EP3792261A4/en
Priority to RU2020143515A priority patent/RU2771526C1/ru
Priority to AU2019338992A priority patent/AU2019338992B2/en
Priority to MX2020013757A priority patent/MX2020013757A/es
Priority to US17/253,113 priority patent/US20210261544A1/en
Priority to BR112020026353-2A priority patent/BR112020026353A2/pt
Priority to KR1020217000669A priority patent/KR102531596B1/ko
Priority to CN201980032825.2A priority patent/CN112119064B/zh
Publication of WO2020052349A1 publication Critical patent/WO2020052349A1/zh

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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
    • A61K31/437—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
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    • 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • 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
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
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    • 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
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • 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
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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 an FGFR inhibitor, 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 of 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 are 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 hypo
  • FGFR inhibitors Although some FGFR inhibitors have entered the clinical and preclinical research and development 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 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 CH or N;
  • R 2 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 5 and R 6 are each independently 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 aforementioned groups are 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- to 10-membered heteroaryloxy or -NR 13 R 14
  • R 7 is selected from 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 heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group 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, C 3-10 cycloalkane , 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 substituents
  • 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 heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group Or -NR 13 R 14 , the above-mentioned groups are 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 heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy or -NR 13 R
  • 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 With a 5-10 membered heteroaryloxy 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 heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 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
  • R 13 and R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, 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-mentioned 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,
  • 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 selected from the group consisting 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.
  • R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, allyl, and C. 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, Aminocarbonyl or dimethylaminocarbonyl; the aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic With phenyl, phenyl, methoxy, ethoxy, hydroxy, amino, isopropylamino, dimethylamino or
  • each 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, cyano, and nitro. , Azide, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl, oxetanyl, azetidinyl, aziridinyl, phenyl, diazazole , Triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxy Methyl, amino, dimethylamino or acetylamino; the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyan
  • R 2 is selected from a C 5-8 aryl group or a 5-8 membered heteroaryl group.
  • R 2 is selected from a phenyl group or a 5- to 6-membered heteroaryl group, and the 5- 6-membered heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl or thiazolyl, as described above
  • the group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -S (O) r R 10 , -OR 11 , -C (O) OR 11 , -NR 13 R 14 , -C (O) NR 13 R 14 or -N (R 13 )
  • the compound of the formula (I) in the compound of the formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has the structure of the following formula (II):
  • X is selected from CH or N;
  • R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, methanesulfonyl, or aminosulfonyl; the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, methoxy, ethoxy, hydroxyl, amino, isopropyl With amino, dimethylamino or diethylamino substituents;
  • R 2 is selected from phenyl or 5- to 6-membered heteroaryl, said 5- to 6-membered heteroaryl is selected from pyridyl, pyrazolyl, imidazolyl or thiazolyl, the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -NR 13 R 14 or -C (O) NR 13 R 14 is substituted by a substituent, and the above-mentioned group is optionally further further selected from one or more selected from deuterium, halogen, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl , Halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero
  • Each R 3 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, Hydroxy, methoxy, ethoxy, or isopropoxy, the above groups are optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, trifluoromethyl, difluoromethyl Substituted with a substituent such as methyl, trideuteryl, dimethyl, cyclopropyl, oxetanyl, methoxy, ethoxy, hydroxy or carboxy;
  • Each R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, oxetanyl, azacyclopentyl, azacyclo Hexyl, hydroxy, methoxy, ethoxy, or isopropoxy; the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, methyl Substituted with oxy, ethoxy or hydroxy substituents;
  • R 10 , R 13 , R 14 and r are as described for the compound of formula (I).
  • each of R 10 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from hydrogen, deuterium, hydroxyl, and C 1-4 alkane. Radical, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroepoxy Group, C 5-8 aryl group, C 5-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group or -NR 13 R 14 , the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, halogen, hydroxy, carbonyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl , 3-8 membered heterocyclic
  • R 13, R 14 are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C 1-4 alkanoyl, the above groups are optionally further selected from one or more of deuterium , Halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4
  • R 13 and R 14 and the directly connected nitrogen atom together form a 4- to 8-membered heterocyclic group or a 4- to 8-membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more selected from deuterium, halogen, and hydroxyl , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, C 5-8 aryl, C 5-8 aryloxy, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-4 alkanoyl substituents;
  • Each r is independently 0, 1, or 2.
  • 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 a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • X 1 and X 2 are each independently selected from chlorine or bromine; X, R 1 , R 2 , R 3 , and R 4 are as described in the compound of formula (I).
  • 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 provides the use 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 myeloproliferative diseases, bone or chondrocyte disorders, and hypophosphatemia.
  • the myeloproliferative disease is selected from the group consisting of erythrocytosis, primary thrombocythemia, or primary myelofibrosis; and the skeletal or chondrocyte disorders are selected from the group consisting of dysplasia, cartilage dysplasia, and dwarfism.
  • hypophosphatemia is selected from the group consisting of X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.
  • the 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 selective FGFR inhibitor to treat and abnormally express and mutate FGFR receptors. Or diseases related to abnormal expression and activity of corresponding ligands.
  • an FGFR inhibitor having the structure of formula (I), its preparation method and application, and the definition of each substituent is as described in the specification and claims.
  • 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 FGFR inhibitor drugs. Based on this, the present invention has been completed.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group.
  • C 1-8 alkyl refers to a linear alkyl group containing 1 to 8 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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 Butylbutyl, 2-ethylbutyl
  • 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 none of the rings have 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 a pair of adjacent carbon atoms with other rings in the system, where one or more rings (preferably 1 or 2) may contain one Or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated pi 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 may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated ⁇ -electron system.
  • Spiro heterocyclyl is divided into monospiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the 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 or 2) rings may contain 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 from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon.
  • 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 one ring A completely conjugated ⁇ -electron system in which one or more ring atoms (preferably 1, 2, 3, or 4) 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. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings.
  • the 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 carbon atom pairs) group, a polycyclic ring having a conjugated ⁇ -electron system (i.e., a 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 1 to 4 heteroatoms including heteroatoms of nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thiophene Group, 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- 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched Alkenyl. This includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • an alkenyl group 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 2-8 alkynyl refers to a straight or branched chain containing 2 to 8 carbons.
  • Alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • Alkoxy refers to -O- (alkyl), where alkyl is as defined above, for example, “C 1-8 alkoxy” refers to an alkyloxy group containing 1-8 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • an 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 left 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 -NR 13 R 14 means that the nitrogen atom in -NR 13 R 14 is connected 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 1-8 alkyl refers to a 1-8 carbon alkyl group optionally substituted by a hydrogen on an alkyl group with a fluorine, chlorine, bromine, or iodine atom, including, but not limited to, difluoromethyl, di Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl is optionally a 1-8 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.
  • THF means tetrahydrofuran.
  • PE means petroleum ether.
  • EA / EtOAc means ethyl acetate.
  • DCM means dichloromethane.
  • DIPEA means N, N-diisopropylethylamine.
  • LAH / LiAlH 4 refers to lithium aluminum hydride.
  • MnO 2 refers to manganese dioxide .
  • K 2 CO 3 refers to potassium carbonate.
  • K 3 PO 4 refers to potassium phosphate.
  • Cs 2 CO 3 refers to cesium carbonate.
  • Na 2 CO 3 refers to sodium carbonate.
  • NaHCO 3 means sodium hydrogen carbonate.
  • SO 2 Cl 2 refers to sulfoxide.
  • NBS N-bromosuccinimide.
  • I-PrMgCl means isopropylmagnesium chloride.
  • Select-F refers to 1-chloromethyl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt.
  • an heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more (preferably 1, 2, 3, or 4) hydrogen atoms in a group are substituted with each other independently by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, 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 / 500 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Is tetramethylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was measured 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 1 Synthesis of ethyl 6-chloro-4- (ethylamino) nicotinate
  • Step 3 Synthesis of 6-chloro-4- (ethylamino) nicotaldehyde
  • Step 4 Synthesis of 7-chloro-3- (3,5-dimethoxyphenyl) -1-ethyl-1,6-diazanaphthalene-2 (1H) -one
  • reaction liquid was reacted at 100 ° C for 17 hours.
  • the reaction solution was filtered with suction, and the filtrate was separated by reversed-phase column chromatography.
  • Step 1 Synthesis of 7-chloro-1-ethyl-2-carbonyl-1,2-dihydro-1,6-diazanaphthalene-3-carboxylic acid
  • Step 3 Synthesis of 3-bromo-1-ethyl-7- (1-methyl-1H-pyrazol-4-yl) -1,6-diazanaphthalene-2 (1H) -one
  • reaction solution was reacted at room temperature for 2 hours, quenched with a saturated ammonium chloride solution, and extracted with ethyl acetate.
  • reaction solution was reacted at 60 ° C for 16 hours.
  • the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • Caliper Assay is used to determine the inhibitory activity of compounds on FGFR1, FGFR2, and FGFR3.
  • the specific experimental process is as follows:
  • the kinase reaction of 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.
  • the IC 50 value was determined by analyzing the percentage inhibition at different compound concentrations through non-linear regression.
  • the enzymatic activities of the compounds in 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 cell lines 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), RT112 bladder cancer cells (with FGFR3-TACC3 fusion gene)
  • the specific experimental process is as follows:
  • the compounds of the present invention have a strong inhibitory effect on FGFR kinase activity, especially a very strong inhibitory effect on FGFR2 and / or FGFR3 kinase activity. It is expected to be developed into a new generation of FGFR inhibitors to meet the needs of clinical applications.

Abstract

一种具有式(I)结构的化合物和其制备方法，及其作为FGFR抑制剂，在***、癌症、骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症中的用途。

Description

FGFR抑制剂、其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种FGFR抑制剂、其制备方法和应用。
技术背景
成纤维细胞生长因子受体(FGFR)是和成纤维细胞生长因子配体相结合的酪氨酸激酶受体。目前已经有4种FGFR受体被发现能够结合配体，并在包括组织分化，血管生成，伤口愈合，和代谢调节的多种生理性的过程中密切相关。当配体结合时，受体会发生二聚化和磷酸化，刺激蛋白激酶活性活化，并招募许多细胞内蛋白相结合。这些蛋白相互作用能帮助一系列胞内信号传导通路的活化，包括Ras-MAPK,AKT-PI3K,以及磷酸酯酶C这些对细胞生长，增殖以及生存非常重要的信号通路。
该信号通路的异常激活，比如FGF配体的过表达或者通过FGFR的活化突变会带来肿瘤生长，进展以及对于传统癌症疗法的抗性。在人类肿瘤中，能带来不依赖于配体的受体激活的基因上的变化，包括基因扩增，染色体转位以及体突变等等已经有被描述。而大批量对于上千肿瘤样品的DNA测序已经揭示FGFR信号通路中的组成成分是人类癌症中高频率突变的基因。比如FGFR1的体细胞突变已经在神经胶质瘤和肺癌中被发现，FGFR2的突变多见于胃癌和子宫内膜癌，而FGFR3的突变在膀胱癌以及多发性骨髓瘤中被发现，FGFG4的突变则在原发性的横纹肌肉瘤中被发现。
FGF/FGFR相关的肿瘤类型包括但不局限于癌症(比如膀胱癌，乳腺癌，颈椎癌，结肠癌，子宫内膜癌，胃癌，头颈癌，肾癌，肝癌，肺癌，卵巢癌，***癌)；恶性血液疾病(比如多发性骨髓瘤，慢性淋巴性淋巴瘤，成人T细胞白血病，急性骨髓性白血病，非何杰金氏淋巴瘤，骨髓增殖性肿瘤和华氏巨球蛋白血症)以及其他肿瘤(比如胶质母细胞瘤，黑色素瘤以及横纹肌肉瘤)。除了在肿瘤中的作用之外，FGFR的活化还被发现和骨骼和软骨细胞病变相关，比如软骨发育不全和颅缝早闭。
虽然已经有一些FGFR抑制剂进入到了临床及临床前的研发过程中,但通常会有选择性不够好，对于c-kit,PDGFRa等其他激酶也有抑制作用，从而带来一定治疗窗口不够大的担忧。因此，研发靶向于FGFR选择性的抑制剂在临床上治疗具有升高的FGF或者FGFR活性的疾病时会非常有意义。
发明内容
本发明目的是提供一种FGFR抑制剂。
本发明第一方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐：
Figure PCTCN2019097361-appb-000001
其中，X选自CH或N；
R 1选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-S(O)R 5、-S(O) 2R 6或-C(O)R 7，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3- 10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0- 8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
R 2选自C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基或-NR 8R 9，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0- 8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
每个R 3各自独立地选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1- 10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、 -C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
每个R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 10、-C 0- 8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0- 8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
R 5、R 6各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5- 10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
R 7选自C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
R 8、R 9各自独立地选自氘、羟基、C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-S(O) rR 10、-C(O)R 12或-C(O)NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0- 8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0- 8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代，或者，R 8、R 9和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
每个R 10选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷 基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
每个R 11选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
每个R 12选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
每个R 13、R 14各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代，
或者，R 13、R 14和其直接相连的氮原子一起形成4-10元杂环基或4-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代；
每个r各自独立地为0、1或2。
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-S(O)R 5、-S(O) 2R 6或-C(O)R 7，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 5、R 6、R 7、R 10、R 11、R 12、R 13、R 14、r如式(I)化合物所述。
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、C 1-4烷基、烯丙基、C 3-6环烷基、3-6元杂环基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧羰基、乙氧羰基、乙酰基、氨基羰基或二甲氨基羰基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、C 3-6环烷基、 3-6元杂环基、苯基、甲氧基、乙氧基、羟基、氨基、异丙基氨基、二甲基氨基或二乙基氨基的取代基所取代。
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中每个R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如式(I)化合物所述。
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中每个R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、烯丙基、乙炔基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基或乙酰氨基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中每个R 3各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0- 4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如式(I)化合物所述。
作为优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自C 5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、 -C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如式(I)化合物所述。
作为进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自苯基或5-6元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-6芳基、5-6元杂芳基、＝O、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(O)NR 13R 14或-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1- 4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-6元杂芳基、＝O、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(O)NR 13R 14或-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如式(I)化合物所述。
作为更进一步优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自苯基或5-6元杂芳基，所述5-6元杂芳基选自吡啶基、嘧啶基、哒嗪基、吡嗪基、1,3,5-三嗪基、吡咯基、吡唑基、咪唑基、三氮唑基或噻唑基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-8元杂环基、-S(O) rR 10、-O-R 11、-C(O)OR 11、-NR 13R 14、-C(O)NR 13R 14或-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3- 8环烷基、3-8元杂环基、＝O、-S(O) rR 10、-O-R 11或-NR 13R 14的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如式(I)化合物所述。
作为更进一步优选的方案，在所述式(I)化合物、其立体异构体、前药或其药学上可接受盐中所述式(I)化合物具有如下式(Ⅱ)结构：
Figure PCTCN2019097361-appb-000002
其中，X选自CH或N；
R 1选自氢、氘、C 1-4烷基、C 3-6环烷基、3-6元杂环基、甲磺酰基或氨基磺酰基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、C 3-6环烷基、3-6元杂环基、苯基、甲氧基、乙氧基、羟基、氨基、异丙基氨基、二甲基氨基或二乙基氨基的取代基所取代；
R 2选自苯基或5-6元杂芳基，所述5-6元杂芳基选自吡啶基、吡唑基、咪唑基或噻唑基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、羟基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-8元杂环基、-NR 13R 14或-C(O)NR 13R 14的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、羟基、C 1-4烷氧基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、-S(O) rR 10或-NR 13R 14的取代基所取代；
每个R 3各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、羟基、甲氧基、乙氧基或异丙氧基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、氧杂环丁基、甲氧基、乙氧基、羟基或羧基的取代基所取代；
每个R 4各自独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、羟基、甲氧基、乙氧基或异丙氧基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、甲氧基、乙氧基或羟基的取代基所取代；
R 10、R 13、R 14、r如式(I)化合物所述。
作为更进一步优选的方案，在所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中每个R 10选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 13R 14的取代基所取代；
每个R 13、R 14各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2- 4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-4烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-4烷酰基的取代基所取代，
或者，R 13、R 14和其直接相连的氮原子一起形成4-8元杂环基或4-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-4烷酰基的取代基所取代；
每个r各自独立地为0、1或2。
作为最优选的方案，所述式(I)化合物、其立体异构体、前药或其药学上可接受盐包括但不限于如下化合物：
Figure PCTCN2019097361-appb-000003
Figure PCTCN2019097361-appb-000004
Figure PCTCN2019097361-appb-000005
Figure PCTCN2019097361-appb-000006
本发明第二方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：
Figure PCTCN2019097361-appb-000007
或者，
Figure PCTCN2019097361-appb-000008
其中，X 1、X 2各自独立的选自氯或溴；X、R 1、R 2、R 3、R 4如式(I)化合物所述。
本发明第三方面提供一种药物组合物，其包括前述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
本发明第四方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备***或癌症药物中的应用。
作为优选的方案，所述的肿瘤或癌症选自膀胱癌、乳腺癌、***、大肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、食管癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性髓细胞白血病、霍奇金淋巴瘤或非霍奇金淋巴瘤、华氏巨球蛋白血症、毛发样淋巴瘤、细胞淋巴瘤、伯基特淋巴瘤、胶质母细胞瘤、黑色素瘤或横纹肌肉瘤。
本发明第五方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备治疗骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症药物中的应用。
作为优选的方案，所述的骨髓增生性疾病选自红细胞增多症、原发性血小板增多症或原发性骨髓纤维化；所述的骨骼或软骨细胞紊乱选自发育不良、软骨发育不良、侏儒症、致死性畸胎(TD)、阿佩尔氏综合症、克鲁松氏综合症、Jackson-Weiss综合症、Beare-Stevenson皮肤回纹综合症、Pfeiffer综合症或颅肌萎缩综合症；所述的低磷血症选自X-连锁低磷性佝偻病、常染色体隐性低磷性佝偻病、常染色体显性低磷性佝偻病或肿瘤诱发的卵巢软化症。
本发明第六方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，其用作选择性的FGFR抑制剂来治疗和FGFR受体异常表达，突变或相应配体异常表达及活性异常相关的疾病。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种具有式(I)结构一种FGFR抑制剂、其制备方法和应用，各取代基的定义如说明书和权利要求书所述。本发明系列化合物可广泛应用于制备***、癌症、骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症的药物，有望开发成新一代FGFR抑制剂药物。在此基础上，完成了本发明。
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C 1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、 3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，例如，“C 3-10环烷基”指包括3至10个碳原子的环烷基，分为单环环烷基、多环环烷基，其中：
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基包括但不限于：
Figure PCTCN2019097361-appb-000009
“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环(优选1或2个)可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于：
Figure PCTCN2019097361-appb-000010
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于：
Figure PCTCN2019097361-appb-000011
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0- 8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。例如，“5-10元杂环基”指包含5至10个环原子的环基，“3-10元杂环基”指包含3至10个环原子的环基。
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于：
Figure PCTCN2019097361-appb-000012
“稠杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个(优选1或2个)环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于：
Figure PCTCN2019097361-appb-000013
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子(优选1、2、3或4个)选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于：
Figure PCTCN2019097361-appb-000014
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：
Figure PCTCN2019097361-appb-000015
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0- 8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子 体系的多环(即其带有相邻对碳原子的环)基团，例如，“C 5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于：
Figure PCTCN2019097361-appb-000016
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，例如，5-8元杂芳基指含有5-8个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于：
Figure PCTCN2019097361-appb-000017
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0- 8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，例如，C 2- 8链烯基指含有2-8个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、 1-，2-或3-丁烯基等。
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如，C 2-8链炔基指含有2-8个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C 1-8烷氧基”指含1-8个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5- 10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“环烷氧基”指和-O-(未取代的环烷基)，其中环烷基的定义如上所述，例如，“C 3-10环烷氧基”指含3-10个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。
环烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5- 10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“3-10元杂环氧基”指和-O-(未取代的3-10元杂环基)，其中3-10元杂环基的定义如上所述，3-10元杂环氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、 C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“C 5-10芳氧基”指和-O-(未取代的C 5-10芳基)，其中C 5-10芳基的定义如上所述，C 5-10芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“5-10元杂芳氧基”指和-O-(未取代的5-10元杂芳基)，其中5-10元杂芳基的定义如上所述，5-10元杂芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代。
“C 1-8烷酰基”指C 1-8烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-7-C(O)-”，例如，“C 1-C(O)-”是指乙酰基；“C 2-C(O)-”是指丙酰基；“C 3-C(O)-”是指丁酰基或异丁酰基。
“-C 0-8-S(O) rR 10”指-S(O) rR 10中的硫原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-O-R 11”指-O-R 11中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(O)OR 11”指-C(O)OR 11中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(O)R 12”指-C(O)R 12中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-O-C(O)R 12”指-O-C(O)R 12中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-NR 13R 14”指-NR 13R 14中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(＝NR 13)R 12”指-C(＝NR 13)R 12中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-N(R 13)-C(＝NR 14)R 12”指-N(R 13)-C(＝NR 14)R 12中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(O)NR 13R 14”指-C(O)NR 13R 14中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-N(R 14)-C(O)R 13”指-N(R 14)-C(O)R 13中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“卤取代C 1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“卤取代C 1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“卤素”指氟、氯、溴或碘。“MeOH”是指甲醇。“DMF”是指N，N-二甲基甲酰胺。“THF”是指四氢呋喃。“PE”是指石油醚。“EA/EtOAc”是指乙酸乙酯。“DCM”是指二氯甲烷。“DIPEA”是指N,N-二异丙基乙胺。“LAH/LiAlH 4”是指氢化铝锂。“MnO 2”是指二氧化锰 。“K 2CO 3”是指碳酸钾。“K 3PO 4”是指磷酸钾。“Cs 2CO 3”是指碳酸铯。“Na 2CO 3”是指碳酸钠。“NaHCO 3”是指碳酸氢钠。“SO 2Cl 2”是指氯化亚砜。“NBS”是指N-溴代丁二酰亚胺。“i-PrMgCl”是指异丙基氯化镁。“select-F”是指1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个(优选1、2、3或4个)氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400/500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟 台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。
一、 中间体的制备
1、7-氯-3-(3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000018
第一步：乙基6-氯-4-(乙胺基)尼古丁酸酯的合成
Figure PCTCN2019097361-appb-000019
在乙基4,6-二氯尼古丁酸酯(5.00g，22.7mmol)的乙腈溶液(70mL)中，加入N,N-二异丙基乙胺(8.78g，27.3mmol)和乙胺(1.76g，27.3mmol，70％水溶液)。该反应液置于封管内，在70℃反应18小时。冷却，加入乙酸乙酯稀释(200mL)，饱和食盐水溶液(150mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩得到乙基6-氯-4-(乙胺基)尼古丁酸酯(5.20g，收率：100％)。MS m/z(ESI):229.2[M+H] +.
第二步：(6-氯-4-(乙胺基)吡啶-3-基)甲醇的合成
Figure PCTCN2019097361-appb-000020
在冰浴冷却下，将乙基6-氯-4-(乙胺基)尼古丁酸酯(5.00g，22.7mmol)溶于四氢呋喃溶液(70mL)中，分批缓慢加入LiAlH 4(1.73g，44.48mmol)。反应液冰浴条件下反应1小时。十水合硫酸钠淬灭，室温搅拌1小时，抽滤，滤液浓缩旋干得到(6-氯-4-(乙胺基)吡啶-3-基)甲醇(4.20g，收率：99％)。MS m/z(ESI):187.2[M+H] +.
第三步：6-氯-4-(乙胺基)尼古丁醛的合成
Figure PCTCN2019097361-appb-000021
在(6-氯-4-(乙胺基)吡啶-3-基)甲醇(4.2g，22.5mmol)的二氯甲烷(50mL)和四氢呋喃(50mL)混合溶液中加入MnO 2(23.5g，270mmol)。反应液室温搅拌过夜。抽滤，乙酸乙酯洗涤，滤液浓缩旋干得到6-氯-4-(乙胺基)尼古丁醛(3.5g，收率：84％)。MS m/z(ESI):185.0[M+H] +.
第四步：7-氯-3-(3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮的合成
Figure PCTCN2019097361-appb-000022
在6-氯-4-(乙胺基)尼古丁醛(1.50g，8.12mmol)和乙基2-(3,5-二甲氧苯基)乙酸酯(1.82g，8.12mmol)的N,N-二甲基甲酰胺中(50mL)加入K 2CO 3(2.24g，16.24mmol)。该反应液在110℃反应17小时。反应液冷却至室温，倒入水中，抽滤，滤饼干燥得到7-氯-3-(3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(2.30g，收率：82％)。MS m/z(ESI):345.0[M+H] +.
中间体2～8参照中间体1的合成方法制备得到：
Figure PCTCN2019097361-appb-000023
Figure PCTCN2019097361-appb-000024
9、7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000025
7-氯-3-(3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(500mg，1.45mmol)的乙腈溶液(8mL)冷却至-30℃，在该温度条件下缓慢滴加SO 2Cl 2(640mg，3.62mmol)。反应液在-30℃反应30分钟。反应液用饱和碳酸氢钠淬灭，抽滤，滤饼洗涤，干燥得到7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(520mg，收率：87％)。MS m/z(ESI):413.2，415.2[M+H] +.
中间体10～16参照中间体9的合成方法制备得到：
Figure PCTCN2019097361-appb-000026
Figure PCTCN2019097361-appb-000027
17、7-氯-1-乙基-3-(2-氟-3,5-二甲氧苯基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000028
在-15℃下，往7-氯-3-(3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(300mg,0.870mmol)的乙腈溶液里一次性加入select-F(370mg，1.044mmol)。反应液缓慢升至室温，搅拌1小时。发现还有原料剩余，再降温至-15℃，补加select-F(300mg，0.847mmol)。缓慢升至室温，搅拌50分钟。反应液中加DCM稀释，用饱和NaHCO 3溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩，柱层析分离(PE:EtOAc＝0-17％)得7-氯-1-乙基-3-(2-氟-3,5-二甲氧苯基)-1,6-二氮杂萘-2(1H)-酮(223mg，纯度：76％)。取粗品(80mg)用制备板再分离(PE/EtOAc＝8:1)得到7-氯-1-乙基-3-(2-氟-3,5-二甲氧苯基)-1,6-二氮杂萘-2(1H)-酮(43mg)。MS m/z(ESI):363.2[M+H] +.
18、7-氯-3-(2-氯-3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000029
7-氯-3-(3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(200mg，0.58mmol)的乙腈溶液(5mL)冷却至-30℃，在该温度条件下缓慢滴加SO 2Cl 2(86mg，0.64mmol)。反应液在-30℃反应20分钟。反应液用饱和碳酸氢钠淬灭，乙酸乙酯萃取，浓缩，柱层析分离(EA/DCM＝0％-10％)得到7-氯-3-(2-氯-3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(165mg，收率：75％)。MS m/z(ESI):379.2，381.2[M+H] +.
19、4-(2-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-基)乙基)吗啉的制备
Figure PCTCN2019097361-appb-000030
在4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(1.0g，5.15mmol)和4-(2-溴乙基)***啉氢溴酸盐(1.40g，7.72mmol)的N,N-二甲基甲酰胺溶液(8mL)中加Cs 2CO 3
(3.35g，10.3mmol)。反应液在100℃反应17小时。反应液抽滤，滤液反相柱层析分离
(CH 3CN:H 2O＝0％-15％)得到4-(2-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-
基)乙基)吗啉(1.1g，收率:70％)。MS m/z(ESI):308.2[M+H] +.
20、3-溴-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000031
第一步：7-氯-1-乙基-2-羰基-1,2-二氢-1,6-二氮杂萘-3-羧酸的合成
Figure PCTCN2019097361-appb-000032
在6-氯-4-(乙胺基)尼古丁醛(700mg，3.79mmol)的乙醇溶液(7mL)中加入2,2-二甲基-1,3-二噁烷-4,6-二酮(546mg，3.79mmol)、哌啶(32mg，0.38mmol)和醋酸(68mg，1.14mmol)。反应液回流反应3小时。反应液冷却至室温，抽滤，乙醇洗涤滤饼，固体干燥得7-氯-1-乙基-2-羰基-1,2-二氢-1,6-二氮杂萘-3-羧酸(850mg，收率89％)。MS m/z(ESI):253.2[M+H] +.
第二步：1-乙基-7-(1-甲基-1H-吡唑-4-基)-2-羰基-1,2-二氢-1,6-二氮杂萘-3-羧酸的合成
Figure PCTCN2019097361-appb-000033
在7-氯-1-乙基-2-羰基-1,2-二氢-1,6-二氮杂萘-3-羧酸(850mg，3.36mmol)和1-甲基-1H-吡唑-4-硼酸(848mg，6.73mmol)的1,4-二氧六环溶液(15mL)中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(246mg，0.34mmol)和Na 2CO 3(2N,5mL)。反应液95℃反应16小时。反应液冷却至室温，加入水，乙酸乙酯萃取，水相用2N盐酸溶液调pH为2～3，沉淀物抽滤，乙醇洗涤，干燥得到1-乙基-7-(1-甲基-1H-吡唑-4-基)-2-羰基-1,2-二氢-1,6-二氮杂萘-3-羧酸(950mg，收率:95％)。MS m/z(ESI):299.2[M+H] +.
第三步：3-溴-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的合成
Figure PCTCN2019097361-appb-000034
在1-乙基-7-(1-甲基-1H-吡唑-4-基)-2-羰基-1,2-二氢-1,6-二氮杂萘-3-羧酸(400mg，1.34mmol)的N,N-二甲基甲酰胺(18mL)和水(2mL)溶液中，加入N-溴代丁二酰亚胺(477mg，2.68mmol)和醋酸锂(273mg，2.68mmol)。反应液在110℃微波反应3小时。反应液冷却至室温，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，有机相旋蒸浓缩，柱层析分离(乙 酸乙酯/二氯甲烷＝0～20％)得3-溴-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮(150mg，收率：34％)。MS m/z(ESI):333.2,335.2[M+H] +.
中间体21～27参照中间体20的合成方法制备得到：
Figure PCTCN2019097361-appb-000035
28、2-(2,6-二氟-3,5-二甲氧苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环的制备
Figure PCTCN2019097361-appb-000036
在-10℃下，往2,4-二氟-3-碘-1,5-二甲氧基苯(1.00g，3.33mmol)的四氢呋喃溶液(15mL)中，缓慢加入异丙基氯化镁溶液(2.0mL，4.0mmol，2N四氢呋喃溶液)。反应液在-10℃反应10分钟，加入2-异丙氧基-4,4,5,5-四甲基-1,3,2-二噁硼戊环(805mg，4.33mmol)。反应液在室温反应2小时，饱和氯化铵溶液淬灭，乙酸乙酯萃取。有机相水洗，干燥，浓缩，柱层析分离(EA/DCM＝0～20％)得2-(2,6-二氟-3,5-二甲氧苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(800mg，收率：80％)。MS m/z(ESI):301.0[M+H] +.
二、实施例化合物的制备
实施例1 3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000037
在7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(50mg，0.12mmol)和1-甲基-1H-吡唑-4-硼酸(30mg，0.24mmol)的1,4-二氧六环溶液(2mL)中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg，0.012mmol)和Na 2CO 3(0.5mL，1.0mmol，2N)水溶液。反应液95℃反应16小时。反应液冷却至室温，加入水，乙酸乙酯萃取，有机相浓缩，制备板分离(EA/DCM＝1/2)得到3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮(35mg，收率：63％)MS m/z(ESI):459.4,461.4[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.25(s,1H),8.05(s,1H),7.64(s,1H),7.35(s,1H),6.65(s,1H),4.41(q,J＝7.1Hz,2H),4.01(s,3H),3.96(s,6H),1.43(t,J＝7.0Hz,3H).
实施例2～24参照实施例1的合成方法制备得到：
Figure PCTCN2019097361-appb-000038
Figure PCTCN2019097361-appb-000039
Figure PCTCN2019097361-appb-000040
Figure PCTCN2019097361-appb-000041
Figure PCTCN2019097361-appb-000042
Figure PCTCN2019097361-appb-000043
实施例25 3-(2,6-二氟-3,5-二甲氧苯基)-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000044
在3-溴-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮(50mg，0.15mmol)和2-(2,6-二氟-3,5-二甲氧苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(180mg，0.60mmol)的1,4-二氧 六环(5mL)和水(1mL)溶液中，加入氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(12mg，0.015mmol)和K 3PO 4(127mg,0.60mmol)。反应液60℃反应16小时。反应液冷却至室温，加入水，乙酸乙酯萃取，有机相浓缩，柱层析分离(乙酸乙酯/二氯甲烷＝0～50％)得到3-(2,6-二氟-3,5-二甲氧苯基)-1-乙基-7-(1-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮(38mg，收率:59％)。MS m/z(ESI):427.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.74(s,1H),8.04(d,J＝4.5Hz,2H),7.80(s,1H),7.31(s,1H),6.71(t,J＝8.0Hz,1H),4.39(q,J＝7.2Hz,2H),4.00(s,3H),3.91(s,6H),1.43(t,J＝7.1Hz,3H).
实施例26～41参照实施例25的合成方法制备得到：
Figure PCTCN2019097361-appb-000045
Figure PCTCN2019097361-appb-000046
Figure PCTCN2019097361-appb-000047
Figure PCTCN2019097361-appb-000048
实施例42 3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(3-甲基-1-(2-吗啉代乙基)-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2019097361-appb-000049
第一步：3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(3-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的合成
Figure PCTCN2019097361-appb-000050
在7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-1,6-二氮杂萘-2(1H)-酮(450mg，1.09mmol)和3-甲基吡唑-4-硼酸频那醇酯(340mg，1.63mmol)的1,4-二氧六环溶液(15mL)中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg，0.11mmol)和Na 2CO 3(3.0mL，6.0mmol,2N)水溶液。反应液90℃反应16小时。反应液冷却至室温，加入水，乙酸乙酯萃取，有机相浓缩，柱层析分离(MeOH/DCM＝0～5％)得到3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(3-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮(310mg，收率：62％)。
MS m/z(ESI):459.0,461.0[M+H] +.
第二步：3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(3-甲基-1-(2-吗啉代乙基)-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮的合成
Figure PCTCN2019097361-appb-000051
在3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(3-甲基-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮(100mg，0.218mmol)和4-(2-溴乙基)***啉氢溴酸盐(119mg,0.435mmol)的DMF(5mL)溶液中，加入碳酸铯(355mg,1.09mmol)。反应液于90℃搅拌2小时。往反应液中加入饱和食盐水，过滤，柱层析分离(MeOH/DCM＝0～8％)得到粗品(80mg)。该粗品再用SFC分离得到 3-(2,6-二氯-3,5-二甲氧苯基)-1-乙基-7-(3-甲基-1-(2-吗啉代乙基)-1H-吡唑-4-基)-1,6-二氮杂萘-2(1H)-酮。MS m/z(ESI):572,574[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.03(s,1H),7.65(s,1H),7.33(s,1H),6.64(s,1H),4.39(q,J＝7.1Hz,2H),4.25(t,J＝6.7Hz,2H),3.96(s,6H),3.71(t,J＝4.6Hz,4H),2.87(t,J＝6.8Hz,2H),2.60(s,3H),2.52(t,J＝4.7Hz,4H),1.43(t,J＝7.1Hz,3H).
实施例43～52参照实施例42的合成方法制备得到：
Figure PCTCN2019097361-appb-000052
Figure PCTCN2019097361-appb-000053
Figure PCTCN2019097361-appb-000054
生物学测试评价
一、FGFR 1～3的体外生物化学激酶分析
本发明采用Caliper Assay测定化合物对FGFR1,FGFR2,FGFR3抑制活性的特性。具体实验过程如下：
1、本发明所进行的激酶反应在384孔板中进行，用一定浓度的激酶(Carna)和一定浓度的ATP以及1μM的肽FAM-P22(GL Biochem,Cat.No.112393))，在50mM HEPES,pH7.5,0.0015％Brij-35以及基础激酶缓冲液的反应体系中28℃下孵育反应一定时间；对于FGFR1，酶浓度为0.25nM,ATP浓度为382μM,反应时间为20分钟；对于FGFR2，酶浓度为2.5nM,ATP浓度为1μM,反应时间为40分钟；对于FGFR3，酶浓度为8nM,ATP浓度为4.7μM,反应时间为30分钟；
2、添加停止溶液(100mM HEPES,pH 7.5,0.2％Caliper涂布试剂，50mM EDTA及0.015％Brij35)终止反应；
3、将已终止激酶反应的孔板转移至Caliper读取数据；
4、使用Caliper微流体迁移偏移技术分离磷酸化与未磷酸化的肽，并通过恒定缓冲液流经芯片来转移分析物，且通过其标记的荧光信号监控底物肽的迁移，利用所形成的磷酸基肽的量计算激酶活性；
5、通过非线性回归分析不同化合物浓度下的抑制百分比来测定IC 50值，具体实施例化合物酶学活性见表1。
表1酶学活性检测结果
Figure PCTCN2019097361-appb-000055
Figure PCTCN2019097361-appb-000056
二、细胞增殖实验(Cell Titer Glo(CTG)实验)
本发明通过存活率的实验来评价化合物对依赖于FGFR信号通路的细胞增殖抑制作用，使用CTG试剂(Promega,#G7573)来测量。挑选了能代表不同肿瘤类型的细胞系，比如来自于南京科佰的H1581肺癌细胞(有FGFR1基因的扩增)或Snu-16胃癌细胞(有FGFR2基因的扩增),RT112膀胱癌细胞(有FGFR3-TACC3融合基因)具体实验过程如下：
1、将90μL细胞接种到组织培养基处理的96孔板(Costar#3904)，在37℃5％CO 2培养箱中培养过夜，随后加入10μL包含10倍其终浓度的化合物稀释液的培养基；
2、通过测试化合物系列稀释来评价剂量效应作用，从10μM或者更低浓度开始；
3、将细胞在37℃，5％CO 2下孵育3天后，加入50μL CTG，使用Envision(Pelkin Elmer)进行读数，来定量细胞ATP水平将不同浓度抑制剂作用后的细胞ATP水平和加入DMSO对照组的细胞ATP水平相比，可以评价化合物对于细胞增殖/存活的抑制百分比
4、使用Graphpad Prism中四参数曲线拟合来测定导致半数最大生长抑制的化合物浓度(IC 50)，具体实施例化合物细胞活性见表2。
表2细胞活性检测结果
Figure PCTCN2019097361-appb-000057
从具体实施例化合物酶学或细胞活性数据来看，本发明系列化合物对FGFR激酶活性具有很强的抑制作用，尤其是对FGFR2和/或FGFR3激酶活性具有非常强的抑制作用。有望开发成新一代FGFR抑制剂，满足临床应用需求。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 式(I)化合物、其立体异构体、前药或其药学上可接受盐：
    Figure PCTCN2019097361-appb-100001
    其中，X选自CH或N；
    R 1选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-S(O)R 5、-S(O) 2R 6或-C(O)R 7，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3- 10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0- 8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
    R 2选自C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基或-NR 8R 9，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0- 8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
    每个R 3各自独立地选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1- 10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、 -C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
    每个R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 10、-C 0- 8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0- 8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
    R 5、R 6各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5- 10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
    R 7选自C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
    R 8、R 9各自独立地选自氘、羟基、C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-S(O) rR 10、-C(O)R 12或-C(O)NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0- 8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0- 8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代，或者，R 8、R 9和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 10、-C 0-8-O-R 11、-C 0-8-C(O)OR 11、-C 0-8-C(O)R 12、-C 0-8-O-C(O)R 12、-C 0-8-NR 13R 14、-C 0-8-C(＝NR 13)R 12、-C 0-8-N(R 13)-C(＝NR 14)R 12、-C 0-8-C(O)NR 13R 14或-C 0-8-N(R 13)-C(O)R 12的取代基所取代；
    每个R 10选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷 基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
    每个R 11选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
    每个R 12选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 13R 14的取代基所取代；
    每个R 13、R 14各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代，
    或者，R 13、R 14和其直接相连的氮原子一起形成4-10元杂环基或4-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代；
    每个r各自独立地为0、1或2。
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，
    R 1选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-S(O)R 5、-S(O) 2R 6或-C(O)R 7，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 5、R 6、R 7、R 10、R 11、R 12、R 13、R 14、r如权利要求1所述；
    优选的，R 1选自氢、氘、C 1-4烷基、烯丙基、C 3-6环烷基、3-6元杂环基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧羰基、乙氧羰基、乙酰基、氨基羰基或二甲氨基羰基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、 乙基、C 3-6环烷基、3-6元杂环基、苯基、甲氧基、乙氧基、羟基、氨基、异丙基氨基、二甲基氨基或二乙基氨基的取代基所取代。
  3. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，每个R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 10、-C 0- 4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如权利要求1所述；
    优选的，每个R 4各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、烯丙基、乙炔基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基或乙酰氨基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。
  4. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，
    每个R 3各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如权利要求1所述。
  5. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，
    R 2选自C 5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、 C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 10、-C 0-4-O-R 11、-C 0-4-C(O)OR 11、-C 0-4-C(O)R 12、-C 0-4-O-C(O)R 12、-C 0-4-NR 13R 14、-C 0-4-C(＝NR 13)R 12、-C 0-4-N(R 13)-C(＝NR 14)R 12、-C 0-4-C(O)NR 13R 14或-C 0-4-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如权利要求1所述；
    优选的，R 2选自苯基或5-6元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-6芳基、5-6元杂芳基、＝O、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(O)NR 13R 14或-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-6元杂芳基、＝O、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14、-C(O)NR 13R 14或-N(R 13)-C(O)R 12的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如权利要求1所述。
  6. 根据权利要求5所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 2选自苯基或5-6元杂芳基，所述5-6元杂芳基选自吡啶基、嘧啶基、哒嗪基、吡嗪基、1,3,5-三嗪基、吡咯基、吡唑基、咪唑基、三氮唑基或噻唑基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-8元杂环基、-S(O) rR 10、-O-R 11、-C(O)OR 11、-NR 13R 14、-C(O)NR 13R 14或-N(R 13)-C(O)R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、＝O、-S(O) rR 10、-O-R 11或-NR 13R 14的取代基所取代，R 10、R 11、R 12、R 13、R 14、r如权利要求5所述。
  7. 根据权利要求1-6任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，所述式(I)化合物具有如下式(Ⅱ)结构：
    Figure PCTCN2019097361-appb-100002
    其中，X选自CH或N；
    R 1选自氢、氘、C 1-4烷基、C 3-6环烷基、3-6元杂环基、甲磺酰基或氨基磺酰基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、C 3-6环烷基、3-6元杂环基、苯基、甲氧基、乙氧基、羟基、氨基、异丙基氨基、二甲基氨基或二乙基氨基的取代基所取代；
    R 2选自苯基或5-6元杂芳基，所述5-6元杂芳基选自吡啶基、吡唑基、咪唑基或噻唑基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、羟基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-8元杂环基、-NR 13R 14或-C(O)NR 13R 14的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、羟基、C 1-4烷氧基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、-S(O) rR 10或-NR 13R 14的取代基所取代；
    每个R 3各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、羟基、甲氧基、乙氧基或异丙氧基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、氧杂环丁基、甲氧基、乙氧基、羟基或羧基的取代基所取代；
    每个R 4各自独立地选自氢、氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、羟基、甲氧基、乙氧基或异丙氧基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、甲氧基、乙氧基或羟基的取代基所取代；
    R 10、R 13、R 14、r如权利要求1所述。
  8. 根据权利要求7所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，
    每个R 10选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 13R 14的取代基所取代；
    每个R 13、R 14各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2- 4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-4烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-4烷酰基的取代基所取代，
    或者，R 13、R 14和其直接相连的氮原子一起形成4-8元杂环基或4-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-4烷酰基的取代基所取代；
    每个r各自独立地为0、1或2。
  9. 根据权利要求1-8任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2019097361-appb-100003
    Figure PCTCN2019097361-appb-100004
    Figure PCTCN2019097361-appb-100005
    Figure PCTCN2019097361-appb-100006
  10. 权利要求1-9任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：
    Figure PCTCN2019097361-appb-100007
    或者，
    Figure PCTCN2019097361-appb-100008
    其中，X 1、X 2各自独立的选自氯或溴；X、R 1、R 2、R 3、R 4如权利要求1所述。
  11. 一种药物组合物，其包括权利要求1-9任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
  12. 权利要求1-9任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备***或癌症药物中的应用；优选的，所述的肿瘤或癌症选自膀胱癌、乳腺癌、***、大肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、食管癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性髓细胞白血病、霍奇金淋巴瘤或非霍奇金淋巴瘤、华氏巨球蛋白血症、毛发样淋巴瘤、细胞淋巴瘤、伯基特淋巴瘤、胶质母细胞瘤、黑色素瘤或横纹肌肉瘤。
  13. 权利要求1-9任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备治疗骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症药物中的应用。
  14. 根据权利要求13所述的应用，其特征在于，所述的骨髓增生性疾病选自红细胞增多症、原发性血小板增多症或原发性骨髓纤维化；所述的骨骼或软骨细胞紊乱选自发育不良、软骨发育不良、侏儒症、致死性畸胎(TD)、阿佩尔氏综合症、克鲁松氏综合症、Jackson-Weiss综合症、Beare-Stevenson皮肤回纹综合症、Pfeiffer综合症或颅肌萎缩综合症；所述的低磷血症选自X-连锁低磷性佝偻病、常染色体隐性低磷性佝偻病、常染色体显性低磷性佝偻病或肿瘤诱发的卵巢软化症。
  15. 根据权利要求1-9任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其用作FGFR抑制剂来治疗和FGFR受体异常表达，突变或相应配体异常表达及活性异常相关的疾病。
PCT/CN2019/097361 2018-09-14 2019-07-23 Fgfr抑制剂、其制备方法和应用 WO2020052349A1 (zh)

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