WO2019242587A1 - Highly selective fgfr i inhibitor, preparation method therefor and use thereof - Google Patents
Highly selective fgfr i inhibitor, preparation method therefor and use thereof Download PDFInfo
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- 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
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- RBMGRPGKIVMZRZ-UHFFFAOYSA-N CN(C)c1nc(-c(c(F)c(cc2OC)OC)c2F)cc2c1nc(N1CCC1)nc2 Chemical compound CN(C)c1nc(-c(c(F)c(cc2OC)OC)c2F)cc2c1nc(N1CCC1)nc2 RBMGRPGKIVMZRZ-UHFFFAOYSA-N 0.000 description 1
- HIPDCAHWDOIZLR-UHFFFAOYSA-N COc(cc(c(F)c1-c2cc3cnc(C(C4)C=NN4C(CC4)CN4S(C)(=O)=O)nc3c(N3CCOCC3)n2)OC)c1F Chemical compound COc(cc(c(F)c1-c2cc3cnc(C(C4)C=NN4C(CC4)CN4S(C)(=O)=O)nc3c(N3CCOCC3)n2)OC)c1F HIPDCAHWDOIZLR-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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.
Abstract
Provided are a highly selective FGFR i inhibitor having the structure of formula (I), a preparation method therefor and the use thereof, wherein the definition of each substituent is as described in the description and claims. The compound can be widely used in the preparation of drugs for treating tumors, cancers, myeloproliferative diseases, bone cell disorders or chondrocyte disorders, and hypophosphatemia, and is expected to be developed into a new generation of FGFR i inhibitor drugs.
Description
本发明属于药物合成领域，具体涉及一种高选择性FGFR i抑制剂及其制备方法和应用。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.
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。Fibroblast growth factor receptor (FGFR) is a tyrosine kinase receptor that binds to fibroblast growth factor ligands. At present, 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. When the ligand binds, 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.
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。Abnormal activation of this signaling pathway, such as overexpression of FGF ligands or activation mutations through FGFR, can lead to tumor growth, progression, and resistance to traditional cancer therapies. In human tumors, changes in genes that can cause ligand-independent receptor activation, including gene amplification, chromosomal translocation, and somatic mutations, have been described. And 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. For example, somatic mutations of FGFR1 have been found in gliomas and lung cancers. FGFR2 mutations are more common in gastric and endometrial cancers, while FGFR3 mutations are found in bladder cancer and multiple myeloma. FGFG4 mutations It is found in primary rhabdomyosarcoma.
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。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) 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) and other tumors (Such as glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in tumors, FGFR activation has also been found to be associated with bone and chondrocyte lesions, such as hypochondral hypoplasia and premature closure of cranial sutures.
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。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.
发明内容Summary of the Invention
本发明目的是提供一种FGFR 2和/或FGFR 3抑制剂。The object of the present invention is to provide an FGFR 2 and / or FGFR 3 inhibitor.
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：The first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:
其中，X选自C(R
7)或N；
Wherein X is selected from C (R 7 ) or N;
R
1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；
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. The above-mentioned groups are optionally further substituted by one or Multiple selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 5-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S ( O) r R 10, -C 0- 8 -OR 11, -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or- C 0-8 -N (R 13 ) -C (O) R 12 is substituted with a substituent, and the above-mentioned groups are optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, and 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 membered heteroaryl, = O, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 ,- C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;
R
2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、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；
R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0 -8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 , 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, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O , -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 The group is optionally further further selected from one or more of deuterium, halogen, cyano, nitro Azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkyl substituted with halo, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl Alkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;
R
3、R
4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、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元杂芳基或5-10元杂芳氧基，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
1-10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 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azide, 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 heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, 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 membered heteroaryl, = O, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C ( O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 substituted with a substituent;
R
5、R
6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 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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, -C 0-8 -S (O) r R 10, -C 0- 8 - OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 , the above-mentioned group is 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or- C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;
R
7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 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0 -8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 , 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, C 1-10 alkyl substituted with halo, deuterium substituted C 1- 10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S ( O) r R 10, -C 0- 8 -OR 11, -C 0-8 -C ( O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 substituted with a substituent;
R
8、R
9各自独立地选自氘、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、-C
0-8-S(O)
rR
10、-C
0-8-C(O)R
12、-C
0-8-C(O)NR
13R
14或-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元杂环基或4-10元杂芳基，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；
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 membered heteroaryl, = O, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O ) OR 11 , -C 0- 8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N ( R 13 ) -C (O) R 12 is substituted by a substituent, or R 8 and R 9 together with a directly connected nitrogen atom form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, The group is optionally further selected from one or more of the above-mentioned groups , Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, a halo substituted C 1-10 alkyl, C 1-10 alkoxy substituted with deuterium , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;
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；
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;
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；
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;
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；
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 heteroaryloxy or -NR 13 R 14 substituents;
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；
Each 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 1-10 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 heterocyclooxy, C 5-10 aryl, C 5-10 aromatic Substituted by oxo, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
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；
Alternatively, 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;
每个r各自独立地为0、1或2。Each r is independently 0, 1, or 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X选自C(R
7)或N；R
7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。
As a preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, X is selected from C (R 7 ) or N; R 7 is selected from hydrogen, deuterium, halogen, Cyano, nitro, azide, 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, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0- 4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 )- C (O) R 12 , the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5- 8-membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 substituted with R 10 , R 11 , R 12 , R 13 , R 14. r is as described for the compound of formula (I).
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X选自C(R
7)或N；R
7选自选自氢、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、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、氨基羰基、二甲氨基羰基或乙酰氨基；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。
As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, 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 further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl Substituted with a substituent of ethyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
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X选自C(R
7)或N；R
7选自氢、氘、氟、氯、氰基、硝基、叠氮基、甲基、乙基、异丙基、烯丙基、乙炔基、环丙基、环丙甲基、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、甲氧基、乙氧基、异丙氧基、甲氧乙基、乙氧乙基、羟甲基、羟乙基、氰甲基、三氟甲基、三氘甲基、二氟甲基、二氘甲基、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、氨基甲基、氨基羰基、二甲氨基羰基或乙酰氨基。
As a further preferred embodiment, 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, dideutermethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy , Acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetylamino.
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
5、R
6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。
As a preferred embodiment, 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. , Azide, 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, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 , said group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne Group, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl , = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 substituted with R 10 , R 11 , R 12 , R 13 , R 14. r is as described for the compound of formula (I).
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
5、R
6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、氨基羰基、二甲氨基羰基或乙酰氨基；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。
As a further preferred embodiment, 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.
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
3、R
4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、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元杂芳基或5-8元杂芳氧基，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、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。
As a preferred embodiment, 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. is further selected from substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, a halogen substituted C 1 to -4 alkyl, deuterium substituted C 1-4 alkyl, C 3- 8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0 -4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 substituted with R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
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
3、R
4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C
1-4烷基、C
1-4烷氧基、烯丙基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、苯基、二氮唑或三氮唑；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。
As a further preferred embodiment, 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. , Nitro, azide, C 1-4 alkyl, C 1-4 alkoxy, allyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic ring Group, 3-6 membered heterocyclic oxy, phenyl, diazole or triazole; the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, Cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino are substituted.
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
3-10环烷基、3-10元杂环基、C
5-10芳基、5-10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。
As a preferred embodiment, 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. 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heterocyclic Aryl, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0- 4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 , any of the above groups Is further selected from one or more of deuterium, halogen, cyano, nitro, azide, 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, = 0, -C 0-4 -S (O) r R 10 , -C 0-4- OR 11 、 -C 0-4 -C (O) OR 11 、 -C 0-4 -C (O) R 12 、 -C 0- 4 -OC (O) R 12 、 -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13) -C (O) R 12 substituent Substituent, the aforementioned groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl Base, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O ) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 Instead, R 10 , R 11 , R 12 , R 13 , R 14 , r are as described for the compound of formula (I).
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选自氢、氘、卤素、C
1-4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、-C
0-4-O-R
11、-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、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或-C
0-4-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、C
1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代，R
11、R
12、R
13、R
14、r如式(I)化合物所述。
As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, and C 3- 10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-4 -OR 11 , -C 0-4 -NR 13 R 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 13 R 14 or- C 0-4 -N (R 13 ) -C (O) R 12 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 ring Alkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0- 4 -C (O) OR 11 or -C 0-4 -NR 13 R 14 is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl Substituted by the substituents, R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
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C
3-8环烷基、3-8元杂环基、C
5-8芳基、5-8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
1-4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
1-10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
0-4-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
8、R
9、R
10、R
11、R
12、R
13、R
14、r如式(I)化合物所述。
As a preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R 1 is selected from a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, and C. 5-8 aryl, 5-8 membered heteroaryl or -NR 8 R 9 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, 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 , = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 The above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, a halogen substituted C 1- 10 alkyl group, deuterium-substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl Base, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0- 4- N (R 13 ) -C (O) R 12 is substituted by a substituent, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , r are as described in the compound of formula (I) .
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的所述式(I)化合物具有如下式(Ⅱa)结构：As a further preferred embodiment, 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):
其中，among them,
环A选自3-8元杂环基、C
5-8芳基或5-8元杂芳基；
Ring A is selected from 3-8 membered heterocyclyl, C 5-8 aryl or 5-8 membered heteroaryl;
R
2选自氢、氘、卤素、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、-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、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、-S(O)
rR
10、-O-R
11、-C(O)OR
11或-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、C
1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代；
R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -NR 13 R 14 , the aforementioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, = O, -S (O) r R 10 , -OR 11 , -C (O) OR 11 or -NR 13 R 14 Optionally further by one or more selected from the group consisting of deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, = 0, hydroxyl With methoxy, ethoxy, isopropoxy or carboxyl substituents;
R
3、R
4各自独立地选自氢、氘、卤素、羟基、氰基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基或3-6元杂环氧基，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、羟基或氨基的取代基所取代；
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、R
6各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、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、羟基或氨基的取代基所取代；
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
15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、＝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 15 is selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 8 cycloalkyl, , 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 Or -C 0-4 -N (R 13 ) -C (O) R 12 is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, Nitrogen, 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 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 substituents;
m为0、1、2或3；m is 0, 1, 2 or 3;
R
10、R
11、R
12、R
13、R
14、r如式(I)化合物所述。
R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
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环A选自4-8元含1或2个氮杂原子的杂环基、苯基或5-6元含1、2或3个氮杂原子的杂芳基，优选的，所述5-6元含氮杂芳基选自吡啶基、嘧啶基、哒嗪基、吡嗪基、1,3,5-三嗪基、吡咯基、吡唑基、咪唑基或三氮唑基；As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 4-8 membered heterocyclic group containing 1 or 2 nitrogen heteroatoms. , 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;
R
15选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
3-6环烷基、3-6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、C
1-4烷基、卤取代C
1-10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、-S(O)
rR
10、-O-R
11、-C(O)OR
11、-C(O)R
12、-O-C(O)R
12、-NR
13R
14或-C(O)NR
13R
14的取代基所取代；
R 15 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 Heteroaryl, = O, -S (O) r R 10 , -OR 11 , -C (O) OR 11 , -C (O) R 12 , -OC (O) R 12 or -C (O) NR 13 R 14 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -S (O) r R 10 ,- OR 11 , -C (O) OR 11 , -C (O) R 12 , -OC (O) R 12 , -NR 13 R 14 or -C (O) NR 13 R 14
m为0、1或2；m is 0, 1 or 2;
R
10、R
11、R
12、R
13、R
14、r如式(I)化合物所述。
R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
作为更进一步优选的方案，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，所述式(I)化合物具有如下式(Ⅲa
1)结构、式(Ⅲa
2)结构或式(Ⅲa
3)结构：
As a further preferred embodiment, 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:
其中，among them,
每个R
2各自独立地选自苯基、5-6元含1或2个氮杂原子杂芳基或-NR
13R
14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、环丙基或羟基的取代基所取代；
Each R 2 is independently selected from a phenyl group, a 5- to 6-membered heteroaryl group containing 1 or 2 nitrogen heteroatoms, or -NR 13 R 14 , and the aforementioned group is optionally further selected from one or more of deuterium and halogen , Cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxyl, methoxy, ethoxy, carboxyl, amino, dimethylamino or di An ethylamino substituent, and the above-mentioned groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, methyl, cyclopropyl, or hydroxyl;
R
5、R
6各自独立地选自氢、氘、卤素、甲基、异丙基、环丙基、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、氟或环丙基取代基所取代；
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各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、3-6元杂环基、羟基、甲氧基、乙氧基、羧基、甲基胺酰基、乙基胺酰基或环丙基胺酰基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、氰基、甲基、环丙基、环丁基、环己基、吗啉基、哌嗪基、甲磺酰基、羟基、甲氧基、羧基或乙酰基的取代基所取代；
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、R
14各自独立地选自氢、氘、C
1-4烷基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C
1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C
1-4烷酰基的取代基所取代，或者，
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和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C
1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、C
3-6环烷基、C
3-6环烷氧基、吗啉基、哌嗪基、氨基、二甲基氨基、二乙基氨基或C
1-4烷酰基的取代基所取代；
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;
所述杂环基各自独立地任选包含1或2个选自氮原子或氧原子的杂原子。The heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
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的所述式(I)化合物具有如下式(Ⅱb)结构：As a further preferred embodiment, 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):
其中，among them,
R
2选自氢、氘、卤素、C
1-4烷基、C
3-8环烷基、3-8元杂环基、C
5-8芳基、5-8元杂芳基或-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、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、-S(O)
rR
10、-O-R
11、-C(O)OR
11或-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、C
1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代；
R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, or -NR 13 R 14 , the aforementioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, = O, -S (O) r R 10 , -OR 11 , -C (O) OR 11 or -NR 13 R 14 Optionally further by one or more selected from the group consisting of deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, = 0, hydroxyl With methoxy, ethoxy, isopropoxy or carboxyl substituents;
R
3、R
4各自独立地选自氢、氘、卤素、羟基、氰基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基或3-6元杂环氧基，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、羟基或氨基的取代基所取代；
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、R
6各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、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、羟基或氨基的取代基所取代；
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
8、R
9各自独立地选自氘、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、-C
0-4-S(O)
rR
10或-C
0-4-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，或者，R
8、R
9和其直接相连的氮原子一起形成4-10元杂环基或4-10元杂芳基，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
1-4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 8 and R 9 are each independently selected from deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 10 or -C 0-4 -C (O) R 12 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, Azide, 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, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0 -4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O ) Is substituted by a substituent of R 12 , or R 8 and R 9 and a nitrogen atom directly connected thereto form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above group is optionally further substituted by one or A plurality of groups selected from the above are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl = O, -C 0-4 -S (O ) r R 10, -C 0-4 -OR 11, -C 0-4 -C (O) OR 11, -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 ;
R
10、R
11、R
12、R
13、R
14、r如式(I)化合物所述。
R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
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
8、R
9各自独立地选自氘、C
1-4烷基、C
3-6环烷基或3-6元杂环基，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
3-8环烷基、3-8元杂环基、C
5-8芳基、5-8元杂芳基、＝O、-O-R
11、-C(O)R
12、-O-C(O)R
12或-NR
13R
14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4-8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、C
1-4烷基、＝O、-S(O)
rR
10、-O-R
11或-C(O)R
12的取代基所取代；
As a still further preferred embodiment, R 8 and R 9 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof are each independently selected from the group consisting of deuterium, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -OR 11 , -C (O) R 12 , -OC (O) R 12 or -NR 13 R 14 is substituted by a substituent, or R 8 , R 9 and a 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 the above-mentioned groups. Further substituted with one or more substituents selected from the group consisting of deuterium, halogen, C 1-4 alkyl, = O, -S (O) r R 10 , -OR 11 or -C (O) R 12 ;
R
10、R
11、R
12、R
13、R
14、r如式(I)化合物所述。
R 10 , R 11 , R 12 , R 13 , R 14 and r are as described for the compound of formula (I).
作为更进一步优选的方案，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，所述式(I)化合物具有如下式(Ⅲb)结构：As a further preferred embodiment, 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):
其中，among them,
R
2选自苯基、5-6元含1或2个氮杂原子杂芳基或-NR
13R
14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、环丙基或羟基的取代基所取代；
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 above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, C Substitution of 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxyl, methoxy, ethoxy, carboxyl, amino, dimethylamino, or diethylamino 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、R
6各自独立地选自氢、氘、卤素、甲基、异丙基、环丙基、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、氟或环丙基取代基所取代；
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各自独立地选自氘、C
1-4烷基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C
1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、＝O、氨基、二甲基氨基、二乙基氨基或C
1-4烷酰基的取代基所取代，或者，
R 8 and R 9 are each independently selected from 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, trideuteryl, methoxy, ethoxy, isopropyloxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, diazole, triazole, = 0, amino, dimethylamino, diethylamino or a C 1-4 alkanoyl substituent, or,
R
8、R
9和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C
1-4烷基、甲氧基、乙氧基、异丙氧基或C
1-4烷酰基的取代基所取代；
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、R
14各自独立地选自氢、氘、C
1-4烷基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C
1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C
1-4烷酰基的取代基所取代，或者，
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和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C
1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、C
3-6环烷基、C
3-6环烷氧基、吗啉基、哌嗪基、氨基、二甲基氨基、二乙基氨基或C
1-4烷酰基的取代基所取代；
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;
所述杂环基各自独立地任选包含1或2个选自氮原子或氧原子的杂原子。The heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
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：As a most preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
本发明第二方面提供前述式(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：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:
或者，or,
或者，or,
或者，or,
其中，X、R
1、R
2、R
3、R
4、R
5、R
6如式(I)化合物所述。
Among them, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as described in the compound of formula (I).
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。A third aspect of the present invention provides 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.
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。According to 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.
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。As a preferred solution, 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.
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。According to a fifth aspect of the present invention, 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. Applications.
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。As a preferred solution, 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. Disease, lethal teratosis (TD), Apel's syndrome, Krusson's syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin pattern syndrome, Pfeiffer syndrome or cranial muscle atrophy syndrome; The 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.
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；优选的，其用作选择性的FGFR 2和/或FGFR 3抑制剂来治疗和FGFR2或FGFR3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。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.
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)结构一种高选择性FGFRi抑制剂及其制备方法和应用，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FGFRi抑制剂药物。在此基础上，完成了本发明。After extensive and intensive research, the inventors of the present application have for the first time developed a highly selective FGFRi inhibitor with the structure of formula (I) and its preparation method and application. The definitions of the substituents are as described in the specification and claims. Described. 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.
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。Detailed description: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C
1-10烷基”指包括1至10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。
"Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group. For example, "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-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5- Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-bis Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched chains thereof Isomers, etc.
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。
The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, and cyanide. Radical, nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0- 8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent.
“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：
"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, "C 3-10 cycloalkyl" refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, of which:
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。Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
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：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 π-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:
“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："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 π-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:
“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："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 π-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:
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。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.
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。
A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 ,- C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0- 8 -OC (O) R 12 , -C 0 -8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted.
“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。
"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. For example, "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclyl" refers to a cyclic group containing 3 to 10 ring atoms.
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。Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
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：
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 π-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:
“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、2、3或4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或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：
"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 π 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:
“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(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、四环或多环桥杂环基，桥杂环基包括但不限于：
"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 π-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:
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：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:
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。
The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 ,- C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0- 8 -OC (O) R 12 , -C 0 -8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted.
“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：
"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:
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。
The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0- 8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8- NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 .
“杂芳基”指包含一个或多个(优选1、2、3或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："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:
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。
Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 ,- C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0- 8 -OC (O) R 12 , -C 0 -8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted.
“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-
10链烯基指含有2-10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。
"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.
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。
Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0- 8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8- NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 .
“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
2-10链炔基指含有2-10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。
"Alkynyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, C 2-10 alkynyl refers to a straight or branched chain containing 2 to 10 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
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。
The alkynyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0- 8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8- NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 .
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C
1-10烷氧基”指含1-10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。
"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.
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。
The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium and halogen. , Cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkane , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0- 8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent.
“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。
"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.
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。
The cycloalkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen , Cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkane , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent.
“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。
"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. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0- 8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8- NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 .
“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。
"C 5-10 aryloxy" refers to -O- (unsubstituted C 5-10 aryl), wherein C 5-10 aryl is as defined above, and C 5-10 aryloxy may be optional Substituted or unsubstituted, when substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, Nitrogen, 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 cycloalkane Group, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted.
“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。
"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. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0- 8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8- NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 .
“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 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-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 -S (O) r R 10 " means that the sulfur atom in -S (O) r R 10 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1- The definition of 8- alkyl is as described above.
“-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 -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-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) OR 11 " means that the carbonyl group in -C (O) OR 11 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl group The definition is as described above.
“-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 -C (O) R 12 " means that the carbonyl group in -C (O) R 12 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl group The definition is as described above.
“-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 -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
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 -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.
“-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 -C (= NR 13 ) R 12 " means that the carbonyl group in -C (= NR 13 ) R 12 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond and C 1 The definition of -8 alkyl is as described above.
“-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 -N (R 13 ) -C (= NR 14 ) R 12 " means that the carbonyl group in -N (R 13 ) -C (= NR 14 ) R 12 is attached to a C 0-8 alkyl group Where C 0 alkyl refers to a bond, and C 1-8 alkyl is as defined above.
“-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 -C (O) NR 13 R 14 " means that the carbonyl group in -C (O) NR 13 R 14 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1 The definition of -8 alkyl is as described above.
“-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。
"-C 0-8 -N (R 14 ) -C (O) R 13 " means that the nitrogen atom in -N (R 14 ) -C (O) R 13 is attached to a C 0-8 alkyl group, where C 0 alkyl means a bond, and C 1-8 alkyl is as defined above.
“卤取代C
1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10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。
"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.
“卤取代C
1-10烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10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。
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.
“卤素”指氟、氯、溴或碘。“MeOH”是指甲醇。“DMF”是指N，N-二甲基甲酰胺。“DCE”是指1,2-二氯乙烷。“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。“LiOH”是指氢氧化锂。“NaOH”是指氢氧化钠。“NaNO
2”是指亚硝酸钠。“CuI”是指碘化亚铜。“Na
2SO
4”是指硫酸钠。“HOAc”是指醋酸。“NH
4OAc”是指醋酸铵。“Et
3N”是指三乙胺。“NH
4Cl”是指氯化铵。“TFA”是指三氟乙酸。“m-CPBA”是指间氯过氧苯甲酸。“Pd(PPh
3)
4”是指四(三苯基膦)钯。“Pd(PPh
3)
2Cl
2“”是指”双三苯基磷二氯化钯。
"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.
“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。"Optional" or "optionally" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "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 .
“取代的”指基团中的一个或多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。"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. 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.
“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。"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.
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。The following describes the present invention in further detail and completeness with reference to the examples, but it is by no means limited to the present invention, and the present invention is not limited to the content of the examples.
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)。
The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts (δ) 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).
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)。Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 6120 mass spectrometer. For HPLC measurement, 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.
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。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.
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。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.
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(℃)。Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius (° C).
一、中间体的制备First, the preparation of intermediates
1、8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备1. Preparation of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
第一步：2,4-二氟-3-碘-1,5-二甲氧基苯的合成Step 1: Synthesis of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene
将化合物2,6-二氟-3,5-二甲氧基苯胺(27.0g，143mmol)加入6.0M盐酸溶液(240mL)中，冰水浴冷却下缓慢滴加NaNO
2水溶液(10.35g，150mmol，30mL水)。25分钟滴加完，继续反应15分钟，产生桔红色悬浊液，将其加入KI水溶液(94.9g，570mmol，150mL水)。升至室温，搅拌反应30分钟，析出固体。过滤，水洗，得粗产品。将粗产品加入MeOH(60mL)，室温搅拌30分钟。过滤，干燥得2,4-二氟-3-碘-1,5-二甲氧基苯(29.3g，收率：68％)。
Compound 2,6-difluoro-3,5-dimethoxyaniline (27.0 g, 143 mmol) was added to a 6.0 M hydrochloric acid solution (240 mL), and an aqueous NaNO 2 solution (10.35 g, 150 mmol, 30 mL of water). After 25 minutes of dropwise addition, the reaction was continued for 15 minutes to produce an orange-red suspension, which was added to an aqueous KI solution (94.9 g, 570 mmol, 150 mL of water). The temperature was raised to room temperature, and the reaction was stirred for 30 minutes to precipitate a solid. Filter and wash with water to obtain the crude product. The crude product was added to MeOH (60 mL) and stirred at room temperature for 30 minutes. Filtration and drying gave 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (29.3 g, yield: 68%).
1H NMR(400MHz,DMSO-d
6)δ6.69(t,J＝8.0Hz,1H),3.88(s,6H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 6.69 (t, J = 8.0 Hz, 1 H), 3.88 (s, 6 H).
第二步：(2,6-二氟-3,5-二甲氧基苯乙炔)基三甲基硅烷的合成Step 2: Synthesis of (2,6-difluoro-3,5-dimethoxyphenylethynyl) trimethylsilane
2,4-二氟-3-碘-1,5-二甲氧基苯(25.8g，86.0mmol)、三甲基硅基乙炔(36.5mL，258mmol)CuI(817mg，4.3mmol)以及三乙胺(35.8mL，258mmol)加入DMF(250mL)。抽换气，氮气保护，然后加入Pd(PPh
3)
2Cl
2(3.15g，4.3mmol)。加热50度，反应2小时。反应完全，加入饱和NH
4Cl水溶液淬灭，再入二氯甲烷萃取3次。合并有机相，Na
2SO
4干燥。过滤，浓缩，得粗产品(27.0g)，直接用于下步反应。
2,4-difluoro-3-iodo-1,5-dimethoxybenzene (25.8 g, 86.0 mmol), trimethylsilylacetylene (36.5 mL, 258 mmol) CuI (817 mg, 4.3 mmol), and triethyl Amine (35.8 mL, 258 mmol) was added to DMF (250 mL). Pump down, protect with nitrogen, and then add Pd (PPh 3 ) 2 Cl 2 (3.15 g, 4.3 mmol). It was heated at 50 degrees and reacted for 2 hours. The reaction was completed, quenched by the addition of saturated aqueous NH 4 Cl solution, and extracted 3 times with dichloromethane. The organic phases were combined, Na 2 SO 4 dried. Filtration and concentration gave the crude product (27.0 g), which was used directly in the next reaction.
1H NMR(400MHz,CDCl
3)δ6.61(t,J＝8.0Hz,1H),3.86(s,6H),0.28(s,9H)。
1 H NMR (400 MHz, CDCl 3 ) δ 6.61 (t, J = 8.0 Hz, 1 H), 3.86 (s, 6H), 0.28 (s, 9H).
第三步：3-乙炔基-2,4-二氟-1,5-二甲氧基苯的合成Step 3: Synthesis of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene
(2,6-二氟-3,5-二甲氧基苯乙炔)基三甲基硅烷(27.0g，粗品)加入THF/MeOH(200/200mL)，再加入NaOH水溶液(8.6mL，8.6mmol，1.0N)。室温搅拌15分钟。反应完全，加入饱和NH
4Cl水溶液淬灭，二氯甲烷萃取3次。合并有机相，无水Na
2SO
4干燥。过滤，浓缩，粗品加入MeOH(50mL)打浆，室温搅拌30分钟。过滤，得到3-乙炔基-2,4-二氟-1,5-二甲氧基苯(15.0g，2步收率：88％)。
(2,6-difluoro-3,5-dimethoxyphenylethynyl) trimethylsilane (27.0 g, crude) was added to THF / MeOH (200/200 mL), and then an aqueous NaOH solution (8.6 mL, 8.6 mmol) was added. , 1.0N). Stir at room temperature for 15 minutes. The reaction was complete, quenched by the addition of saturated aqueous NH 4 Cl, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous Na 2 SO 4. Filtration and concentration, the crude product was slurried with MeOH (50 mL) and stirred at room temperature for 30 minutes. Filtration gave 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (15.0 g, 2-step yield: 88%).
1H NMR(400MHz,CDCl
3)δ6.66(t,J＝8.0Hz,1H),3.88(s,6H),3.52(s,1H)。
1 H NMR (400 MHz, CDCl 3 ) δ 6.66 (t, J = 8.0 Hz, 1H), 3.88 (s, 6H), 3.52 (s, 1H).
第四步：5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯的合成Step 4: Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester
3-乙炔基-2,4-二氟-1,5-二甲氧基苯(10.0g，50.5mmol)和5-溴-2-甲硫基-嘧啶-4-羧酸甲酯(13.0g，49.5mmol)溶于DMF(100mL)，再加入CuI(479mg，2.52mmol)、Pd(PPh
3)
4(2.91g，2.52mmol)以及Et
3N(35.0mL，252.5mmol)，氮气保护。加热100度，反应1.5小时。反应完全，冷却至室温，加入饱和NH
4Cl水溶液淬灭，二氯甲烷萃取3次。合并有机相，无水Na
2SO
4干燥，过滤，浓缩。粗品经硅胶柱层析(PE:EA:DCM＝10:2:1)分离得到5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(15.4g，收率：82％)。
3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (10.0 g, 50.5 mmol) and 5-bromo-2-methylthio-pyrimidine-4-carboxylic acid methyl ester (13.0 g , 49.5 mmol) was dissolved in DMF (100 mL), and CuI (479 mg, 2.52 mmol), Pd (PPh 3 ) 4 (2.91 g, 2.52 mmol), and Et 3 N (35.0 mL, 252.5 mmol) were added, and protected by nitrogen. It was heated at 100 degrees and reacted for 1.5 hours. The reaction was complete, cooled to room temperature, quenched by the addition of saturated aqueous NH 4 Cl solution, and extracted 3 times with dichloromethane. The combined organic phases were dried over anhydrous Na 2 SO 4, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE: EA: DCM = 10: 2: 1) to obtain 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methyl Thio) pyrimidine-4-carboxylic acid methyl ester (15.4 g, yield: 82%).
1H NMR(400MHz,CDCl
3)δ8.82(s,1H),6.69(t,J＝8.0Hz,1H),4.03(s,3H),3.90(s,6H),2.63(s,3H)。
1 H NMR (400MHz, CDCl 3 ) δ8.82 (s, 1H), 6.69 (t, J = 8.0Hz, 1H), 4.03 (s, 3H), 3.90 (s, 6H), 2.63 (s, 3H) .
第五步：5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸的合成Step 5: Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(30.0g，78.9mmol)溶于THF(300mL)，再加入LiOH/H
2O(236.8mL，236.8mmol，1M)。室温搅拌反应2小时。反应完全，浓缩除去THF，再用稀盐酸酸化至pH约为3，析出固体。过滤，水洗，干燥得5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(28.5g，收率：99％)。
5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester (30.0 g, 78.9 mmol) was dissolved in THF (300 mL), and then added LiOH / H 2 O (236.8 mL, 236.8 mmol, 1M). The reaction was stirred at room temperature for 2 hours. The reaction was complete. The THF was removed by concentration, and then acidified with dilute hydrochloric acid to a pH of about 3, and a solid was precipitated. Filtration, washing with water and drying gave 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (28.5 g, yield : 99%).
1H NMR(400MHz,DMSO-d
6)δ8.98(s,1H),7.15(t,J＝8.0Hz,1H),3.90(s,6H),2.59(s,3H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 3.90 (s, 6H), 2.59 (s, 3H).
第六步：6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮的合成Step 6: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one Synthesis
5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(2.5g，6.83mmol)溶于DCE(50mL)，再加入TFA(0.5mL)和乙酸铜(68mg，0.34mmol)。加热回流，反应过夜。反应完全，浓缩，再加入MeOH(50mL)打浆，室温搅拌30分钟。过滤，固体再用MeOH(10mL)洗涤，干燥得6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(2.0g，收率：80％)。5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (2.5 g, 6.83 mmol) was dissolved in DCE (50 mL ), TFA (0.5 mL) and copper acetate (68 mg, 0.34 mmol) were added. Heat to reflux and react overnight. The reaction was complete, concentrated, and MeOH (50 mL) was added to beat and stirred at room temperature for 30 minutes. Filtered, washed the solid with MeOH (10 mL), and dried to give 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3, 4-d] pyrimidin-8-one (2.0 g, yield: 80%).
1H NMR(400MHz,DMSO-d
6)δ9.23(s,1H),7.22(t,J＝8.4Hz,1H),7.17(s,1H),3.93(s,6H),2.63(s,3H)。
1 H NMR (400MHz, DMSO-d 6 ) δ 9.23 (s, 1H), 7.22 (t, J = 8.4Hz, 1H), 7.17 (s, 1H), 3.93 (s, 6H), 2.63 (s, 3H).
第七步：6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 7: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one synthesis
6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(4.5g，12.3mmol)溶于HOAc(45mL)，中加入NH
4OAc(9.4g，123mmol)，反应液120℃搅拌过夜。室温冷却，加入适量水(30mL)，搅拌，抽滤，滤饼用水(20mL)洗涤，干燥得6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(4.22g，收率：94％)。
6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one (4.5g, 12.3 mmol) was dissolved in HOAc (45 mL), NH 4 OAc (9.4 g, 123 mmol) was added, and the reaction solution was stirred at 120 ° C. overnight. Cool at room temperature, add an appropriate amount of water (30mL), stir, suction filter, wash the filter cake with water (20mL), and dry to obtain 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (formaldehyde) Thio) pyrido [3,4-d] pyrimidin-8 (7H) -one (4.22 g, yield: 94%).
1H NMR(400MHz,DMSO-d
6)δ12.28(s,1H),9.24(s,1H),7.17(t,J＝8.4Hz,1H),6.76(s,1H),3.92(s,6H),2.63(s,3H)。
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.28 (s, 1H), 9.24 (s, 1H), 7.17 (t, J = 8.4 Hz, 1H), 6.76 (s, 1H), 3.92 (s, 6H), 2.63 (s, 3H).
第八步：8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成Step 8: Synthesis of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(1g,2.74mmol)溶于DCE(80mL)，加热至90度，然后加入苯膦酰二氯(3.0mL，21.92mmol)，加热搅拌16小时，冷却，在冰浴下调节pH至中性，DCM提取，硅胶柱层析(DCM/EtOAc＝0-10％)分离得到8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(930mg，产率88％)。6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one (1g, 2.74mmol ) Dissolved in DCE (80mL), heated to 90 degrees, then added phenylphosphonodichloride (3.0mL, 21.92mmol), heated and stirred for 16 hours, cooled, adjusted to neutral pH in an ice bath, DCM extraction, silica gel column Chromatography (DCM / EtOAc = 0-10%) gave 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3 , 4-d] pyrimidine (930 mg, 88% yield).
1H NMR(400MHz,CDCl
3)δ9.25(s,1H),7.78(t,J＝1.2Hz,1H),6.75(t,J＝8.0Hz,1H),3.93(s,6H),2.77(s,3H)。MS m/z(ESI):384[M+H]
+。
1 H NMR (400MHz, CDCl 3 ) δ9.25 (s, 1H), 7.78 (t, J = 1.2Hz, 1H), 6.75 (t, J = 8.0Hz, 1H), 3.93 (s, 6H), 2.77 (s, 3H). MS m / z (ESI): 384 [M + H] + .
2、8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的制备2. Preparation of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidine
8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(930mg，2.42mmol)溶于DCM(50mL)，加入m-CPBA(1.23g，6.05mmol)，室温下搅拌2小时。反应完全，加入硫代硫酸钠淬灭，DCM提取，硅胶柱层析(DCM/EtOAc＝0-35％)分离得到8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(800mg，产率79％)。8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (930mg, 2.42mmol) was dissolved DCM (50 mL), m-CPBA (1.23 g, 6.05 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was completed, quenched by adding sodium thiosulfate, extracted with DCM, and separated by silica gel column chromatography (DCM / EtOAc = 0-35%) to obtain 8-chloro-6- (2,6-difluoro-3,5-dimethyl Oxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidine (800 mg, yield 79%).
1H NMR(400MHz,CDCl
3)δ9.76(s,1H),8.03(t,J＝1.2Hz,1H),6.80(t,J＝8.0Hz,1H),3.95(s,6H),3.58(s,3H)。MS m/z(ESI):416[M+H]
+。
1 H NMR (400MHz, CDCl 3 ) δ 9.76 (s, 1H), 8.03 (t, J = 1.2 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H), 3.95 (s, 6H), 3.58 (s, 3H). MS m / z (ESI): 416 [M + H] + .
3、8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备3. Preparation of 8-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
第一步：5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯的合成Step 1: Synthesis of methyl 5-((3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
5-溴-2-(甲硫基)嘧啶-4-羧酸甲酯(2631mg，10.0mmol)，1-乙炔基-3,5-二甲氧基苯(1622mg，10.0mmol)溶于干燥THF(50mL)，抽换气，氮气保护。再依次加入Et
3N(2.8mL，20.0mmol)，Pd(PPh
3)
2Cl
2(702mg，1.0mmol)，PPh
3(525mg，2.0mmol)以及CuI(190 mg，1.0mmol)。加热至90℃，搅拌反应过夜。反应完全，冷却至室温，加入饱和NaHCO
3水溶液(100mL)，EtOAc(100mL)萃取2次。饱和食盐水洗涤，无水Na
2SO
4干燥。过滤，浓缩，硅胶柱层析(PE:EA4:1)分离得到5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(2.5g，收率：73％)。MS m/z(ESI):345.2[M+H]
+。
5-Bromo-2- (methylthio) pyrimidine-4-carboxylic acid methyl ester (2631mg, 10.0mmol), 1-ethynyl-3,5-dimethoxybenzene (1622mg, 10.0mmol) was dissolved in dry THF (50 mL), vented and protected with nitrogen. Et 3 N (2.8 mL, 20.0 mmol), Pd (PPh 3 ) 2 Cl 2 (702 mg, 1.0 mmol), PPh 3 (525 mg, 2.0 mmol), and CuI (190 mg, 1.0 mmol) were added in this order. Heat to 90 ° C and stir the reaction overnight. Completion of the reaction, was cooled to room temperature, saturated aqueous NaHCO 3 (100mL), EtOAc (100mL) and extracted twice. It was washed with saturated brine and dried over anhydrous Na 2 SO 4 . Filtration, concentration and silica gel column chromatography (PE: EA4: 1) gave 5-((3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester. (2.5 g, yield: 73%). MS m / z (ESI): 345.2 [M + H] + .
第二步：5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸的合成Step 2: Synthesis of 5-((3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(600mg，1.742mmol)溶于甲醇(15mL)，加入一水合氢氧化锂(366mg，8.711mmol)的水溶液(5mL)。室温搅拌过夜，反应完全。减压蒸发除去有机溶剂，水相中加入EtOAc(30mL)，用1N盐酸溶液调节pH值到3～4。有机相分离后用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得到5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸，直接用于下一步反应。MS m/z(ESI):331.2[M+H]
+。
5-((3,5-Dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester (600 mg, 1.742 mmol) was dissolved in methanol (15 mL), and hydrogen monohydrate was added Aqueous solution (5 mL) of lithium oxide (366 mg, 8.711 mmol). After stirring at room temperature overnight, the reaction was complete. The organic solvent was removed by evaporation under reduced pressure, EtOAc (30 mL) was added to the aqueous phase, and the pH was adjusted to 3 to 4 with a 1N hydrochloric acid solution. The organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave 5-((3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid, which was directly used in the next reaction. MS m / z (ESI): 331.2 [M + H] + .
第三步：6-(3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮的合成Step 3: Synthesis of 6- (3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one
5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(584mg,1.768mmol)加入丙酮(25mL)，再向此悬浊液中加入AgNO
3(180mg,1.059mmol)。室温搅拌反应4小时，并有绿色固体析出。过滤得到6-(3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(600mg,粗品)。MS m/z(ESI):331.2[M+H]
+。
5-((3,5-Dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (584 mg, 1.768 mmol) was added to acetone (25 mL), and this suspension was added AgNO 3 (180 mg, 1.059 mmol) was added. The reaction was stirred at room temperature for 4 hours, and a green solid precipitated. Filtration gave 6- (3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one (600 mg, crude). MS m / z (ESI): 331.2 [M + H] + .
第四步：6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 4: Synthesis of 6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one
6-(3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(600mg，粗品)加入冰醋酸(50mL)，再加入醋酸铵(2.1g，27.243mmol)。加热至115℃反应16小时。反应完全，冷却至室温，缓慢倒入饱和碳酸氢钠水溶液。EtOAc(100mL)萃取。有机相分液后用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析(洗脱剂:CH
2Cl
2/MeOH 0～6％)分离得到6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(298mg，两步收率：50％)。MS m/z (ESI):330.2[M+H]
+。
6- (3,5-Dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one (600 mg, crude) was added to glacial acetic acid (50 mL) Then, add ammonium acetate (2.1 g, 27.243 mmol). The reaction was heated to 115 ° C for 16 hours. The reaction was complete, cooled to room temperature, and slowly poured into a saturated aqueous sodium hydrogen carbonate solution. EtOAc (100 mL) was extracted. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated after column chromatography (eluent: CH 2 Cl 2 / MeOH 0 to 6%) to obtain 6- (3,5-dimethoxy). Phenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one (298 mg, two-step yield: 50%). MS m / z (ESI): 330.2 [M + H] + .
第五步：8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成Step 5: Synthesis of 8-chloro-6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(200mg，0.61mmol)和N,N-二异丙基乙胺(780mg，6.1mmol)加入乙腈(10mL)，再加入POCl
3(4mL)。加热至90℃，搅拌反应过夜。减压蒸发，除去溶剂。加入EtOAc(10mL)稀释，用饱和碳酸氢钠溶液洗涤。有机相分离后用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩后柱层析(洗脱剂：PE/EtOAc＝0～40％)分离得到8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(60mg，收率：28％)。MS m/z(ESI):348.2[M+H]
+。
6- (3,5-Dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one (200 mg, 0.61 mmol) and N, N-di Isopropylethylamine (780 mg, 6.1 mmol) was added to acetonitrile (10 mL), and then POCl 3 (4 mL) was added. Heat to 90 ° C and stir the reaction overnight. Evaporate under reduced pressure and remove the solvent. EtOAc (10 mL) was added to dilute and washed with saturated sodium bicarbonate solution. The organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, 8-chloro-6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido was isolated by column chromatography (eluent: PE / EtOAc = 0 to 40%). [3,4-d] pyrimidine (60 mg, yield: 28%). MS m / z (ESI): 348.2 [M + H] + .
第六步：8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成Step 6: Synthesis of 8-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
化合物8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(920mg,2.65mmol)溶于二氯甲烷(32mL)，氮气换气三次，反应液冷却至-40℃。滴加SO
2Cl
2(0.64mL，8.0mmol)的二氯甲烷(4mL)溶液，维持40℃低温反应2.5小时。加入饱和NaHCO
3水溶液(50mL)淬灭，室温搅拌1小时，分液，水相二氯甲烷萃取(50mL),合并有机相，饱和食盐水洗涤两次，无水硫酸钠干燥，抽滤，滤液浓缩得到8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(1.02g，收率：98％)。MS(ESI):m/z 416.2及418.2[M+1]
+。
Compound 8-chloro-6- (3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (920 mg, 2.65 mmol) was dissolved in dichloromethane (32 mL) , Nitrogen was exchanged three times, and the reaction solution was cooled to -40 ° C. A solution of SO 2 Cl 2 (0.64 mL, 8.0 mmol) in dichloromethane (4 mL) was added dropwise, and the reaction was carried out at a low temperature of 40 ° C. for 2.5 hours. Saturated aqueous NaHCO 3 (50mL) was quenched stirred at room temperature for 1 hour and separated, the aqueous phase was extracted with dichloromethane (50mL), the combined organic phases were washed with brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated to give 8-chloro-6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (1.02 g, yield : 98%). MS (ESI): m / z 416.2 and 418.2 [M + 1] + .
4、(6-(2-氰基丙烷-2-基)吡啶-3-基)硼酸的制备4. Preparation of (6- (2-cyanopropane-2-yl) pyridin-3-yl) boronic acid
第一步：2-(5-溴吡啶-2-基)-2-甲基丙腈的合成Step 1: Synthesis of 2- (5-bromopyridin-2-yl) -2-methylpropionitrile
在2-(5-溴吡啶-2-基)乙酰腈(300mg,1.523mmol),叔丁醇钾(427mg,3.808mmol)和18-冠醚-6(60mg,0.228mmol)的四氢呋喃(8mL)溶液中，滴加碘甲烷(1.7g,12.184mmol)。滴加完后的混悬液继续搅拌18个小时。反应液用乙酸乙酯稀释后，用饱和食盐水洗两次。有机相用无水硫酸钠干燥，过滤，浓缩，柱层析(PE/EtOAc＝0～30％)分离得到2-(5-溴吡啶-2-基)-2-甲基丙腈(230mg,收率：67％)。MS m/z(ESI):225.2，227.2[M+H]
+。
Tetrahydrofuran (8 mL) in 2- (5-bromopyridin-2-yl) acetonitrile (300 mg, 1.523 mmol), potassium tert-butoxide (427 mg, 3.808 mmol), and 18-crown ether-6 (60 mg, 0.228 mmol) To the solution, methyl iodide (1.7 g, 12.184 mmol) was added dropwise. After the addition was complete, the suspension was stirred for 18 hours. The reaction solution was diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE / EtOAc = 0-30%) to give 2- (5-bromopyridin-2-yl) -2-methylpropionitrile (230mg, Yield: 67%). MS m / z (ESI): 225.2, 227.2 [M + H] + .
第二步：2-甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)丙腈的合成Second step: 2-methyl-2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyridin-2-yl) propane Synthesis of nitrile
在2-(5-溴吡啶-2-基)-2-甲基丙腈(230mg,1.022mmol)，双联嚬哪醇硼酸酯(520mg,2.044mmol)和醋酸钾(300mg,3.057mmol)的二氧六环(5.5mL)中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(66mg,0.081mmol)。反应液用氮气置换，然后加热到80℃搅拌20个小时。浓缩后，柱层析(PE：EtOAc＝0～40％)分离得到2-甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)丙腈(170mg粗品)。MS m/z(ESI):273.4[M+H]
+。
In 2- (5-bromopyridin-2-yl) -2-methylpropionitrile (230mg, 1.022mmol), dibinalol borate (520mg, 2.044mmol) and potassium acetate (300mg, 3.057mmol) To dioxane (5.5 mL), [1,1'-bis (diphenylphosphine) ferrocene] palladium dichloromethane complex (66 mg, 0.081 mmol) was added. The reaction solution was replaced with nitrogen, and then heated to 80 ° C and stirred for 20 hours. After concentration, column chromatography (PE: EtOAc = 0 to 40%) was used to separate 2-methyl-2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxane). Pentyl-2-yl) pyridin-2-yl) propionitrile (170 mg crude). MS m / z (ESI): 273.4 [M + H] + .
第三步：(6-(2-氰基丙烷-2-基)吡啶-3-基)硼酸的合成Step 3: Synthesis of (6- (2-cyanopropane-2-yl) pyridin-3-yl) boronic acid
在2-甲基-2-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)丙腈(170mg粗品)的甲醇(2mL)中加入2N盐酸(2mL)。该溶液在室温下搅拌18个小时。浓缩后加入水(10mL)。过滤并水洗得到(6-(2-氰基丙烷-2-基)吡啶-3-基)硼酸(80mg,两步收率：41％)。MS m/z(ESI):191.2[M+H]
+。
In 2-methyl-2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyridin-2-yl) propionitrile (170mg Crude) methanol (2 mL) was added 2N hydrochloric acid (2 mL). The solution was stirred at room temperature for 18 hours. After concentration, water (10 mL) was added. Filtration and washing with water gave (6- (2-cyanopropane-2-yl) pyridin-3-yl) boronic acid (80 mg, two-step yield: 41%). MS m / z (ESI): 191.2 [M + H] + .
5、(1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-1H-吡唑-4-基)硼酸的制备5. Preparation of (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid
第一步、叔-丁基3-((甲磺酰)氧代)吡咯烷-1-羧酸酯的合成First step, synthesis of tert-butyl 3-((methanesulfonyl) oxo) pyrrolidine-1-carboxylic acid ester
叔-丁基3-羟基吡咯烷-1-羧酸酯(1.0g,5.35mmol)和N,N-二异丙基乙胺溶于二氯甲烷(20mL)，反应液冷却至0℃，在0度下滴加甲基磺酰氯(736mg，6.42mmol)。反应液在室温反应2小时，加入二氯甲烷(100mL)稀释，分别用饱和碳酸氢钠(50mL)和氯化铵溶液(50mL)洗涤，并用无水硫酸钠干燥。过滤，旋蒸浓缩得叔-丁基3-((甲磺酰)氧代)吡咯烷-1-羧酸酯(1.40g，收率：99％)。MS m/z(ESI):206.2[M-Bu+H]
+。
Tert-Butyl 3-hydroxypyrrolidine-1-carboxylic acid ester (1.0 g, 5.35 mmol) and N, N-diisopropylethylamine were dissolved in dichloromethane (20 mL), and the reaction solution was cooled to 0 ° C. Methanesulfonyl chloride (736 mg, 6.42 mmol) was added dropwise at 0 degrees. The reaction solution was reacted at room temperature for 2 hours, diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate (50 mL) and ammonium chloride solution (50 mL), and dried over anhydrous sodium sulfate. It was filtered and concentrated by rotary evaporation to obtain tert-butyl 3-((methanesulfonyl) oxo) pyrrolidine-1-carboxylic acid ester (1.40 g, yield: 99%). MS m / z (ESI): 206.2 [M-Bu + H] + .
第二步、叔-丁基3-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-基)吡咯烷-1-羧酸酯的合成Second step, tert-butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1H-pyrazole-1- Of phenyl) pyrrolidine-1-carboxylate
在叔-丁基3-((甲磺酰)氧代)吡咯烷-1-羧酸酯(1.40g，5.28mmol)和4-吡唑硼酸频哪醇酯(683mg，3.52mmol)的乙腈(10mL)溶液中，加入碳酸铯(1.72g，5.28mmol)。反应 液在100℃反应17个小时。冷却，加水(100mL)稀释，乙酸乙酯(60mL*2)萃取，饱和食盐水洗涤(50mL)，并用无水硫酸钠干燥。过滤，滤液浓缩，柱层析(DCM:EtOAc＝0-30％)分离得到叔-丁基3-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-基)吡咯烷-1-羧酸酯(700mg，收率：55％)。MS m/z(ESI):308.4[M-Bu+H]
+。
In tert-butyl 3-((methanesulfonyl) oxo) pyrrolidine-1-carboxylic acid ester (1.40 g, 5.28 mmol) and 4-pyrazoleboronic acid pinacol ester (683 mg, 3.52 mmol) in acetonitrile ( 10 mL) solution, cesium carbonate (1.72 g, 5.28 mmol) was added. The reaction solution was reacted at 100 ° C for 17 hours. It was cooled, diluted with water (100 mL), extracted with ethyl acetate (60 mL * 2), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and column chromatography (DCM: EtOAc = 0-30%) gave t-butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxane) Borapent-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester (700 mg, yield: 55%). MS m / z (ESI): 308.4 [M-Bu + H] + .
第三步、(1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-1H-吡唑-4-基)硼酸的合成The third step, the synthesis of (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid
在叔-丁基3-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-基)吡咯烷-1-羧酸酯(700mg，1.93mmol的乙腈(30mL)和水(10mL)混合溶液中，加入高碘酸钠(2.06g，9.64mmol)和乙酸铵(1.51g，9.64mmol)。反应液室温反应17个小时，加入乙酸乙酯(100mL)稀释，无水硫酸钠干燥。过滤，滤液浓缩，反相柱层析[流动相:(乙腈:水＝0～30％)]分离得到(1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-1H-吡唑-4-基)硼酸(210mg，收率：39％)。MS m/z(ESI):226.2[M-Bu+H]
+。
Tert-Butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1H-pyrazol-1-yl) pyrrole To a mixed solution of alkane-1-carboxylic acid ester (700 mg, 1.93 mmol of acetonitrile (30 mL) and water (10 mL), sodium periodate (2.06 g, 9.64 mmol) and ammonium acetate (1.51 g, 9.64 mmol) were added. Reaction The solution was reacted at room temperature for 17 hours, diluted with ethyl acetate (100 mL), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and reversed-phase column chromatography [mobile phase: (acetonitrile: water = 0-30%)] was isolated and obtained 1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid (210 mg, yield: 39%). MS m / z (ESI): 226.2 [M-Bu + H] + .
中间体6～8参照中间体5的合成方法制备得到：Intermediates 6 to 8 are prepared by referring to the synthesis method of intermediate 5:
9、(6-(甲基氨基甲酰)吡啶-3-基)硼酸的制备9. Preparation of (6- (methylcarbamoyl) pyridin-3-yl) boronic acid
第一步、5-溴-N-甲基甲基吡啶酰胺的合成First step, synthesis of 5-bromo-N-methylmethylpyridinamide
在5-溴邻吡啶甲酸(1.0g,4.95mmol)和甲胺水溶液(576mg,7.43mmol)的N,N-二甲基甲酰胺(10mL)溶液中，加入N,N-二异丙基乙胺(3.19g,24.75mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.90g,9.9mmol)和1-羟基苯并***(1.34g,9.9mmol)。反应液在室温下搅拌18小时，加入乙酸乙酯(150mL)稀释,分别用饱和碳酸氢钠(50mL)和 氯化铵溶液(50mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩得到5-溴-N-甲基甲基吡啶酰胺(300mg，收率：28％)。MS m/z(ESI):215.2,217.2[M+H]
+。
To a solution of 5-bromo-o-picolinic acid (1.0 g, 4.95 mmol) and an aqueous solution of methylamine (576 mg, 7.43 mmol) in N, N-dimethylformamide (10 mL) was added N, N-diisopropylethyl Amine (3.19 g, 24.75 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.90 g, 9.9 mmol), and 1-hydroxybenzotriazole (1.34 g , 9.9 mmol). The reaction solution was stirred at room temperature for 18 hours, diluted with ethyl acetate (150 mL), washed with saturated sodium bicarbonate (50 mL) and ammonium chloride solution (50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 5-bromo-N-methylmethylpyridinamide (300 mg, yield: 28%). MS m / z (ESI): 215.2, 217.2 [M + H] + .
第二步、(6-(甲基氨基甲酰)吡啶-3-基)硼酸的合成The second step, the synthesis of (6- (methylcarbamoyl) pyridin-3-yl) boronic acid
在5-溴-N-甲基甲基吡啶酰胺(300mg,1.4mmol)和联硼酸频那醇酯(533mg,2.1mmol)的1,4-二氧六环(6mL)溶液中，加入乙酸钾(342mg,3.5mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(98mg,0.14mmol)。反应液在85℃下搅拌18小时。反应液过滤，1,4-二氧六环(5mL)洗涤滤饼，滤液浓缩，反相柱层析[流动相:(乙腈:水＝0～20％)]分离得到(6-(甲基氨基甲酰)吡啶-3-基)硼酸(170mg，收率：67％)。MS m/z(ESI):180.2[M+H]
+。
To a solution of 5-bromo-N-methylmethylpyridinamide (300 mg, 1.4 mmol) and pinacol diborate (533 mg, 2.1 mmol) in 1,4-dioxane (6 mL) was added potassium acetate. (342 mg, 3.5 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (98 mg, 0.14 mmol). The reaction solution was stirred at 85 ° C for 18 hours. The reaction solution was filtered, the filter cake was washed with 1,4-dioxane (5 mL), and the filtrate was concentrated. Reverse phase column chromatography [mobile phase: (acetonitrile: water = 0 to 20%)] was separated to obtain (6- (methyl Carbamoyl) pyridin-3-yl) boronic acid (170 mg, yield: 67%). MS m / z (ESI): 180.2 [M + H] + .
中间体11～12参照中间体10的合成方法制备得到：Intermediates 11 to 12 are prepared by referring to the synthesis method of intermediate 10:
二、实施例化合物的制备Preparation of Example Compounds
实施例1 6-(2,6-二氟-3,5-二甲氧苯基)-8-(2-氟苯基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶的制备Example 1 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (pyridin-3-yl) pyrido [3,4- d) Preparation of pyrimidine
第一步：6-(2,6-二氟-3,5-二甲氧苯基)-8-(2-氟苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成First step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (methylthio) pyrido [3,4-d ] Pyrimidine synthesis
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(60mg,0.156mmol)和2-氟苯硼酸(88mg,0.625mol)的二氧六环(4mL)溶液中，加入四(三苯基磷)钯(18mg,0.016mmol)和2N碳酸钠水溶液(0.3mL)。该反应液用氮气置换，然后加热到90℃搅拌18个小时。浓缩后直接柱层析(DCM：EtOAc＝0～15％)分离得到6-(2,6-二氟-3,5-二甲氧苯基)-8-(2-氟苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(63mg,收率：91％)。MS m/z(ESI): 444.4[M+H]
+。
Between 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (60 mg, 0.156 mmol) and To a solution of 2-fluorophenylboronic acid (88 mg, 0.625 mol) in dioxane (4 mL), tetrakis (triphenylphosphonium) palladium (18 mg, 0.016 mmol) and a 2N aqueous sodium carbonate solution (0.3 mL) were added. The reaction solution was replaced with nitrogen, and then heated to 90 ° C and stirred for 18 hours. After concentration, direct column chromatography (DCM: EtOAc = 0 to 15%) was used to isolate 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (2-fluorophenyl) -2. -(Methylthio) pyrido [3,4-d] pyrimidine (63 mg, yield: 91%). MS m / z (ESI): 444.4 [M + H] + .
第二步：6-(2,6-二氟-3,5-二甲氧苯基)-8-(2-氟苯基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶的合成Second step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (pyridin-3-yl) pyrido [3,4 -d] Synthesis of pyrimidine
在6-(2,6-二氟-3,5-二甲氧苯基)-8-(2-氟苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(30mg,0.068mmol),3-吡啶基硼酸(41.6mg,0.338mol),((噻吩-2-羰基)氧代)铜(32mg,0.170mmol)和醋酸锌(25mg,0.136mmol)的二氧六环(4mL)溶液中，加入四(三苯基磷)钯(7.8mg,0.007mmol)。该反应液用氮气置换，然后加热到120℃搅拌18个小时。二氯甲烷稀释后，用饱和氯化铵洗涤，有机相过滤掉不溶物后，浓缩并直接制备板(DCM：MeOH＝50:1)分离得到6-(2,6-二氟-3,5-二甲氧苯基)-8-(2-氟苯基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶(13.7mg,收率：42％)。MS m/z(ESI):475.4[M+H]
+。
In 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine ( 30 mg, 0.068 mmol), 3-pyridylboronic acid (41.6 mg, 0.338 mol), ((thiophene-2-carbonyl) oxo) copper (32 mg, 0.170 mmol) and zinc acetate (25 mg, 0.136 mmol) in dioxane To a ring (4 mL) solution, tetrakis (triphenylphosphine) palladium (7.8 mg, 0.007 mmol) was added. The reaction solution was replaced with nitrogen, and then heated to 120 ° C and stirred for 18 hours. After diluting with dichloromethane, washing with saturated ammonium chloride, filtering off the insolubles in the organic phase, concentrating and directly preparing a plate (DCM: MeOH = 50: 1) to separate 6- (2,6-difluoro-3,5 -Dimethoxyphenyl) -8- (2-fluorophenyl) -2- (pyridin-3-yl) pyrido [3,4-d] pyrimidine (13.7 mg, yield: 42%). MS m / z (ESI): 475.4 [M + H] + .
1H NMR(400MHz,CDCl
3)δ9.78(s,1H),9.67(s,1H),8.87(d,J＝7.9Hz,1H),8.80(s,1H),8.02(t,J＝1.2Hz,1H),7.81(td,J＝7.3,1.8Hz,1H),7.56(tdd,J＝7.3,5.1,1.8Hz,2H),7.36(td,J＝7.5,1.1Hz,1H),7.33–7.27(m,1H),6.77(t,J＝8.0Hz,1H),3.95(s,6H)。
1 H NMR (400MHz, CDCl 3 ) δ 9.78 (s, 1H), 9.67 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.80 (s, 1H), 8.02 (t, J = 1.2Hz, 1H), 7.81 (td, J = 7.3, 1.8Hz, 1H), 7.56 (tdd, J = 7.3, 5.1, 1.8Hz, 2H), 7.36 (td, J = 7.5, 1.1Hz, 1H), 7.33–7.27 (m, 1H), 6.77 (t, J = 8.0Hz, 1H), 3.95 (s, 6H).
实施例2～4参照实施例1的合成方法制备得到：Examples 2 to 4 are prepared by referring to the synthetic method of Example 1:
实施例5 4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-甲基-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉的制备Example 5 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4 -d] pyrimidin-8-yl) morpholine
第一步：4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)吗啉的合成First step: 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8-yl) Synthesis of morpholine
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(700mg，1.83mmol)的乙腈溶液(7mL)中，加入N,N-二异丙基乙胺(472mg，3.66mmol)和***啉(800mg，9.15mmol)。该反应液置于封管内，在90度反应18小时。冷却，加入乙酸乙酯稀释(100mL)稀释，饱和氯化铵溶液(50mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩，柱层析(EA:DCM＝0～20％)分离得到4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)吗啉(700mg，收率：88％)。MS m/z(ESI):435.4[M+H]
+。
8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (700mg, 1.83mmol) To an acetonitrile solution (7 mL), N, N-diisopropylethylamine (472 mg, 3.66 mmol) and morpholine (800 mg, 9.15 mmol) were added. The reaction solution was placed in a sealed tube and reacted at 90 degrees for 18 hours. Cool, dilute with ethyl acetate (100 mL), wash with saturated ammonium chloride solution (50 mL), and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and column chromatography (EA: DCM = 0 ~ 20%) was used to separate 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio). ) Pyrido [3,4-d] pyrimidin-8-yl) morpholine (700 mg, yield: 88%). MS m / z (ESI): 435.4 [M + H] + .
第二步：4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-甲基-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉的合成Second step: 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1-methyl-1H-pyrazol-4-yl) pyrido [3, Synthesis of 4-d] pyrimidin-8-yl) morpholine
在4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)吗啉(400mg，0.92mmol)和1-甲基-1H-吡唑-4-硼酸(348mg，2.76mmol)的四氢呋喃溶液(10mL)中，加入3-甲基水杨酸铜(I)(394mg，1.84mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(67mg,0.09mmol)和乙酸锌(338mg，1.84mmol)。反应液在120度反应18小时。冷却，加入乙酸乙酯稀释(100mL)稀释，饱和氯化铵溶液(50mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩，柱层析(EA:DCM＝0～100％)分离得到4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-甲基-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉(200mg，收率：46％)。MS m/z(ESI):469.4[M+H]
+。
In 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8-yl) morpholine ( 400 mg, 0.92 mmol) and 1-methyl-1H-pyrazole-4-boronic acid (348 mg, 2.76 mmol) in a tetrahydrofuran solution (10 mL), and copper 3-methylsalicylate (394 mg, 1.84 mmol) was added. ), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (67 mg, 0.09 mmol) and zinc acetate (338 mg, 1.84 mmol). The reaction solution was reacted at 120 degrees for 18 hours. Cool, dilute with ethyl acetate (100 mL), wash with saturated ammonium chloride solution (50 mL), and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and column chromatography (EA: DCM = 0 ~ 100%) was used to separate 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1-methyl -1H-pyrazol-4-yl) pyrido [3,4-d] pyrimidin-8-yl) morpholine (200 mg, yield: 46%). MS m / z (ESI): 469.4 [M + H] + .
1H NMR(400MHz,CDCl
3)δ9.16(s,1H),8.09(s,1H),8.03(s,1H),7.16(d,J＝1.3Hz,1H),6.62(t,J＝7.9Hz,1H),4.10(t,J＝4.7Hz,4H),3.92(s,3H),3.87(t,J＝4.7Hz,4H),3.84(s,6H)。
1 H NMR (400MHz, CDCl 3 ) δ 9.16 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.16 (d, J = 1.3 Hz, 1H), 6.62 (t, J = 7.9 Hz, 1H), 4.10 (t, J = 4.7 Hz, 4H), 3.92 (s, 3H), 3.87 (t, J = 4.7 Hz, 4H), 3.84 (s, 6H).
实施例6～43参照实施例5的合成方法制备得到：Examples 6 to 43 were prepared by referring to the synthetic method of Example 5:
实施例44 2-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基吡啶并[3,4-d]嘧啶-8-胺的制备Example 44 2- (Azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethylpyrido [3,4- d) Preparation of pyrimidine-8-amine
第一步：6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺的合成First step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethyl-2- (methylthio) pyrido [3,4-d] pyrimidine -8-amine synthesis
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(120mg,0.313mmol)的乙腈(5mL)中加入二甲胺的水溶液(0.5mL，40％)，该反应液置于密封罐中，加热到105℃搅拌16个小时。浓缩后，加乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩后直接得到6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺(109mg,收率：89％)。MS m/z(ESI):393.4[M+H]
+。
8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (120 mg, 0.313 mmol) A solution of dimethylamine in water (0.5 mL, 40%) was added to acetonitrile (5 mL). The reaction solution was placed in a sealed tank and heated to 105 ° C. and stirred for 16 hours. After concentration, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to directly obtain 6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N -Dimethyl-2- (methylthio) pyrido [3,4-d] pyrimidine-8-amine (109 mg, yield: 89%). MS m / z (ESI): 393.4 [M + H] + .
第二步：6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺的合成Second step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethyl-2- (methanesulfonyl) pyrido [3,4-d] pyrimidine -8-amine synthesis
8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(109mg，0.278mmol)溶于DCM(5mL)中，加入m-CPBA(144mg，0.833mmol)，室温下搅拌20个小时。加入硫代硫酸钠淬灭，DCM提取，硅胶柱层析(DCM/EtOAc＝0-15％)分离得到6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺(42mg，收率：35％)。MS m/z(ESI):425.4[M+H]
+。
8-Chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (109mg, 0.278mmol) was dissolved To DCM (5 mL), m-CPBA (144 mg, 0.833 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Quenched with sodium thiosulfate, extracted with DCM, and separated by silica gel column chromatography (DCM / EtOAc = 0-15%) to obtain 6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethyl-2- (methanesulfonyl) pyrido [3,4-d] pyrimidine-8-amine (42 mg, yield: 35%). MS m / z (ESI): 425.4 [M + H] + .
第三步：2-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基吡啶并[3,4-d]嘧啶-8-胺的合成Third step: 2- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethylpyrido [3,4 -d] Synthesis of pyrimidine-8-amine
6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺(20mg,0.047mmol),氮杂环丁烷盐酸盐(22mg,0.236mmol)和N,N-二异丙基乙胺(48mg,0.376mmol)的二氧六环(3mL)溶液在100℃下搅拌18个小时。浓缩后直接制备板(PE：EtOAc＝3:1)分离得到2-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-N,N-二甲基吡啶并[3,4-d]嘧啶-8-胺(15.6mg,收率：83％)。MS m/z(ESI):402.4[M+H]
+。
6- (2,6-difluoro-3,5-dimethoxyphenyl) -N, N-dimethyl-2- (methanesulfonyl) pyrido [3,4-d] pyrimidine-8-amine (20 mg, 0.047 mmol), a solution of azetidine hydrochloride (22 mg, 0.236 mmol) and N, N-diisopropylethylamine (48 mg, 0.376 mmol) in dioxane (3 mL) at 100 ° C Stir for 18 hours. After concentration, the plate was prepared directly (PE: EtOAc = 3: 1) and 2- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -N was isolated. , N-dimethylpyrido [3,4-d] pyrimidin-8-amine (15.6 mg, yield: 83%). MS m / z (ESI): 402.4 [M + H] + .
1H NMR(400MHz,CDCl
3)δ8.92(s,1H),7.03(s,1H),6.68(t,J＝7.9Hz,1H),4.27(t,J＝7.5Hz,4H),3.91(s,6H),3.46(s,6H),2.44(p,J＝7.5Hz,2H)。
1 H NMR (400MHz, CDCl 3 ) δ8.92 (s, 1H), 7.03 (s, 1H), 6.68 (t, J = 7.9Hz, 1H), 4.27 (t, J = 7.5Hz, 4H), 3.91 (s, 6H), 3.46 (s, 6H), 2.44 (p, J = 7.5 Hz, 2H).
实施例45～50参照实施例44的合成方法制备得到：Examples 45 to 50 are prepared by referring to the synthetic method of Example 44:
实施例51 6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基-3-甲基吖丁啶-1-基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶的制备Example 51 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -2- (pyridine -3-yl) pyrido [3,4-d] pyrimidine
第一步：8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶的合成Step 1: Synthesis of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d] pyrimidine
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(100mg,0.260mmol),3-吡啶硼酸(95.8mg,0.78mmol),3-甲基水杨酸铜(I)(111.6mg,0.52mmol)和醋酸锌(143.1mg,0.78mmol)的二氧六环(3.0mL)溶液中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(19.1mg,0.026mmol)。该反应液用氮气置换，然后加热到50℃搅拌24个小时。二氯甲烷稀释后，用饱和氯化铵洗涤，有机相过滤掉不溶物后，浓缩并直接制备板(DCM：MeOH＝50:1)分离得到8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶(38.0mg,收率：35％)。MS m/z(ESI):415.8[M+H]
+。
At 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (100 mg, 0.260 mmol), A solution of 3-pyridineboronic acid (95.8mg, 0.78mmol), copper (I) 3-methylsalicylate (111.6mg, 0.52mmol) and zinc acetate (143.1mg, 0.78mmol) in dioxane (3.0mL) To this, [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloride (19.1 mg, 0.026 mmol) was added. The reaction solution was replaced with nitrogen, and then heated to 50 ° C and stirred for 24 hours. After diluting with dichloromethane, washing with saturated ammonium chloride, filtering off the insolubles in the organic phase, concentrating and directly preparing a plate (DCM: MeOH = 50: 1) to obtain 8-chloro-6- (2,6-difluoro) -3,5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d] pyrimidine (38.0 mg, yield: 35%). MS m / z (ESI): 415.8 [M + H] + .
第二步：6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基-3-甲基吖丁啶-1-基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶的合成Second step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -2- ( Synthesis of pyridin-3-yl) pyrido [3,4-d] pyrimidine
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶(8.0mg,0.019mmol)，3-甲氧基-3-甲基环丁胺盐酸盐(10.45mg,0.076mmol)的乙腈(2.0ml)溶液中，加入二异丙基乙胺(12.2mg,0.095mmol)后，密封，加热至95℃搅拌16小时，浓缩并直 接制备板(DCM：MeOH＝50:1)分离得到6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基-3-甲基吖丁啶-1-基)-2-(吡啶-3-基)吡啶并[3,4-d]嘧啶(6.8mg,收率：73.5％)。MS m/z(ESI):480.5[M+H]
+。
8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d] pyrimidine (8.0 mg, 0.019 mmol), 3-methoxy-3-methylcyclobutylamine hydrochloride (10.45mg, 0.076mmol) in acetonitrile (2.0ml), and after adding diisopropylethylamine (12.2mg, 0.095mmol) , Sealed, heated to 95 ° C. and stirred for 16 hours, concentrated and directly prepared a plate (DCM: MeOH = 50: 1) to obtain 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -2- (pyridin-3-yl) pyrido [3,4-d] pyrimidine (6.8 mg, yield: 73.5%). MS m / z (ESI): 480.5 [M + H] + .
1H NMR(400MHz,CDCl
3)9.71(s,1H),9.32(s,1H),8.79-8.72(m,2H),7.495(dd,J＝8.0Hz,1H),7.07(s,1H),6.71(t,J＝8.0Hz,1H),4.78(m,4H),3.93(s,6H),3.36(s,3H),1.63(s,3H)。
1 H NMR (400MHz, CDCl 3 ) 9.71 (s, 1H), 9.32 (s, 1H), 8.79-8.72 (m, 2H), 7.495 (dd, J = 8.0Hz, 1H), 7.07 (s, 1H) , 6.71 (t, J = 8.0 Hz, 1H), 4.78 (m, 4H), 3.93 (s, 6H), 3.36 (s, 3H), 1.63 (s, 3H).
实施例52～54参照实施例51的合成方法制备得到：Examples 52 to 54 were prepared by referring to the synthetic method of Example 51:
实施例55 4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-(1-(甲磺酰)吡咯烷-3-基)-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉的制备Example 55 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1- (1- (methanesulfonyl) pyrrolidin-3-yl) -1H- Preparation of pyrazol-4-yl) pyrido [3,4-d] pyrimidin-8-yl) morpholine
第一步：叔-丁基3-(4-(6-(2,6-二氟-3,5-二甲氧苯基)-8-吗啉代吡啶并[3,4-d]嘧啶-2-基)-1H-吡唑-1-基)吡咯烷-1-羧酸酯的合成First step: tert-butyl 3- (4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -8-morpholinopyrido [3,4-d] pyrimidine Synthesis of 2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester
在4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)吗啉(30mg，0.07mmol)和(1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-1H-吡唑-4-基)硼酸(39mg，0.14mmol)的四氢呋喃溶液(2mL)中，加入3-甲基水杨酸铜(I)(30mg，0.14mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(5mg,0.007mmol)和乙酸锌(26mg，0.14mmol)。反应液在120℃反应18小时。冷却，加入乙酸乙酯稀释(60mL)稀释，饱和氯化铵溶液(20mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩，制备板(EA:DCM＝4：1)分离得到叔-丁基3-(4-(6-(2,6-二氟-3,5-二甲氧苯基)-8-吗啉代吡啶并[3,4-d]嘧啶-2-基)-1H-吡唑-1-基)吡咯烷-1-羧酸酯(25mg，收率：58％)。MS m/z(ESI):624.6[M+H]
+。
In 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8-yl) morpholine ( 30mg, 0.07mmol) and (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid (39mg, 0.14mmol) in tetrahydrofuran (2mL) In this, copper (I) 3-methylsalicylate (30 mg, 0.14 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (5 mg, 0.007 mmol), and Zinc acetate (26 mg, 0.14 mmol). The reaction solution was reacted at 120 ° C for 18 hours. Cooled, diluted with ethyl acetate (60 mL), washed with saturated ammonium chloride solution (20 mL), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, the preparation plate (EA: DCM = 4: 1) was separated to obtain tert-butyl 3- (4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -8 -Morpholinopyrido [3,4-d] pyrimidin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester (25 mg, yield: 58%). MS m / z (ESI): 624.6 [M + H] + .
1H NMR(400MHz,CDCl
3)δ9.29(s,1H),8.30(s,1H),8.21(s,1H),7.25(s,1H),6.74(t,J＝7.9Hz,1H),5.02–4.95(m,1H),4.29(t,J＝4.2Hz,4H),3.99(t,J＝4.6Hz,4H),3.94(s,6H),3.89–3.77(m,2H),3.71–3.60(m,2H),2.53–2.42(m,2H),1.49(s,9H).
1 H NMR (400MHz, CDCl 3 ) 9.29 (s, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.25 (s, 1H), 6.74 (t, J = 7.9Hz, 1H) , 5.02–4.95 (m, 1H), 4.29 (t, J = 4.2Hz, 4H), 3.99 (t, J = 4.6Hz, 4H), 3.94 (s, 6H), 3.89–3.77 (m, 2H), 3.71--3.60 (m, 2H), 2.53--2.42 (m, 2H), 1.49 (s, 9H).
第二步：4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-(吡咯烷-3-基)-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉的合成Second step: 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl ) Synthesis of pyrido [3,4-d] pyrimidin-8-yl) morpholine
在叔-丁基3-(4-(6-(2,6-二氟-3,5-二甲氧苯基)-8-吗啉代吡啶并[3,4-d]嘧啶-2-基)-1H-吡唑-1-基)吡咯烷-1-羧酸酯(23mg，0.037mmol)的二氯甲烷溶液(2mL)中，加入三氟乙酸(1mL)。反应液在室温反应1小时。反应液加入二氯甲烷稀释(30mL)稀释，饱和碳酸氢钠溶液(30mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩，制备板(二氯甲烷:甲醇＝10：1)分离得到4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-(吡咯烷-3-基)-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉(19mg，收率：98％)。MS m/z(ESI):524.6[M+H]
+。
In tert-butyl 3- (4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -8-morpholinopyrido [3,4-d] pyrimidine-2- Yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid ester (23 mg, 0.037 mmol) in a dichloromethane solution (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (30 mL), washed with a saturated sodium bicarbonate solution (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a plate (dichloromethane: methanol = 10: 1) to isolate 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1- ( Pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d] pyrimidin-8-yl) morpholine (19 mg, yield: 98%). MS m / z (ESI): 524.6 [M + H] + .
1H NMR(400MHz,CDCl
3)δ9.18(s,1H),8.16(s,2H),7.25(s,1H),6.64(s,1H),5.03(s,1H),4.12(s,4H),3.88(br s,10H),3.64(s,2H),3.58(s,2H),2.51(s,1H),2.35(s,1H)。
1 H NMR (400MHz, CDCl 3 ) δ9.18 (s, 1H), 8.16 (s, 2H), 7.25 (s, 1H), 6.64 (s, 1H), 5.03 (s, 1H), 4.12 (s, 4H), 3.88 (br s, 10H), 3.64 (s, 2H), 3.58 (s, 2H), 2.51 (s, 1H), 2.35 (s, 1H).
第三步：4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-(1-(甲磺酰)吡咯烷-3-基)-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉的合成Third step: 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1- (1- (methanesulfonyl) pyrrolidin-3-yl) -1H -Pyrazol-4-yl) pyrido [3,4-d] pyrimidin-8-yl) morpholine
在4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-(吡咯烷-3-基)-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉(17mg，0.033mmol)和N,N-二异丙基乙胺(13mg,0.098mmol)的二氯甲烷溶液(2mL)中，三氟甲磺酰氯(8mg,0.065mmol)。反应液在室温反应1小时。反应液加入二氯甲烷稀释(30mL)稀释，饱和氯化铵溶液(20mL)洗涤，并用无水硫酸钠干燥。过滤，滤液浓缩，制备板(二氯甲烷:乙酸乙酯＝1：1)分离得到4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(1-(1-(甲磺酰)吡咯烷-3-基)-1H-吡唑-4-基)吡啶并[3,4-d]嘧啶-8-基)吗啉(11mg，收率：59％)。MS m/z(ESI):602.6[M+H]
+。
4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d] pyrimidin-8-yl) morpholine (17 mg, 0.033 mmol) and N, N-diisopropylethylamine (13 mg, 0.098 mmol) in dichloromethane solution (2 mL), trifluoro Methanesulfonyl chloride (8 mg, 0.065 mmol). The reaction solution was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (30 mL), washed with a saturated ammonium chloride solution (20 mL), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the plate was prepared (dichloromethane: ethyl acetate = 1: 1) to obtain 4- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (1 -(1- (methanesulfonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d] pyrimidin-8-yl) morpholine (11 mg, yield: 59 %). MS m / z (ESI): 602.6 [M + H] + .
1H NMR(400MHz,CDCl
3)δ9.26(s,1H),8.24(s,1H),8.21(s,1H),7.26–7.25(m,1H),6.72(t,J＝7.9Hz,1H),5.07–4.99(m,1H),4.23–4.13(m,4H),3.98–3.94(m,4H),3.94(s,6H),3.92–3.83(m,2H),3.71–3.63(m,2H),2.93(s,3H),2.57–2.49(m,2H)。
1 H NMR (400MHz, CDCl 3 ) 9.26 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.26–7.25 (m, 1H), 6.72 (t, J = 7.9Hz, 1H), 5.07--4.99 (m, 1H), 4.23--4.13 (m, 4H), 3.98--3.94 (m, 4H), 3.94 (s, 6H), 3.92--3.83 (m, 2H), 3.71--3.63 ( m, 2H), 2.93 (s, 3H), 2.57–2.49 (m, 2H).
实施例56-60参照实施例55的合成方法制备得到：Examples 56-60 were prepared by referring to the synthetic method of Example 55:
生物学测试评价Evaluation of biological tests
一、FGFR 1～2的体外生物化学激酶分析I. Analysis of FGFR 1-2 in vitro biochemical kinases
本发明采用Caliper Assay测定化合物对FGFR1,FGFR2抑制活性的特性。具体实验过程如下：In the present invention, Caliper Assay is used to determine the compound's inhibitory activity on FGFR1 and FGFR2. The specific experimental process is as follows:
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；1. 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 μM 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 382μM, the reaction time is 20 minutes; , The enzyme concentration is 2.5nM, the ATP concentration is 1μM, and the reaction time is 40 minutes;
2、添加停止溶液(100mM HEPES,pH7.5,0.2％Caliper涂布试剂，50mM EDTA及0.015％Brij35)终止反应；2. Add stop solution (100mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50mM EDTA and 0.015% Brij35) to stop the reaction;
3、将已终止激酶反应的孔板转移至Caliper读取数据；3. Transfer the wells that have stopped the kinase reaction to Caliper to read the data;
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。4. 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.
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。
5. 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.
表1酶学活性检测结果及其选择性Table 1 Enzymatic activity test results and selectivity
二、细胞增殖实验(Cell Titer Glo(CTG)实验)Cell proliferation experiment (Cell Titer Glo (CTG) experiment)
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)具体实验过程如下：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:
1、将90ul细胞接种到组织培养基处理的96孔板(Costar#3904)，在37℃5％二氧化碳培养箱中培养过夜，随后加入10μL包含10倍其终浓度的化合物稀释液的培养基。1. Inoculate 90ul cells into a tissue culture medium-treated 96-well plate (Costar # 3904), incubate overnight at 37 ° C in a 5% carbon dioxide incubator, and then add 10 μL of the medium containing 10 times its final concentration of the compound dilution.
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。2. Evaluate the dose-effect effect by serial dilution of the test compound, starting at 10 μM or lower.
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
3. After incubating the cells for 3 days at 37 ° C and 5% CO 2 , add 50 μL of CTG, and use Envision (Pelkin Elmer) to take readings to quantify the ATP levels of the cells. Add the ATP levels of the cells after different concentrations of inhibitors to the DMSO control. Compared to the group's cellular ATP levels, the compound's percent inhibition of cell proliferation / survival can be evaluated
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。
4, using compound concentration (IC 50) Graphpad Prism four parameter curve fit of measured results in half-maximal growth inhibition. The cell activity of the specific compound is shown in Table 2.
表2细胞活性检测结果及其选择性Table 2 Cell viability test results and selectivity
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尤其是FGFR1和/或FGFR2激酶活性具有很强的抑制作用。另外，从上述实验结果来看，本发明系列化合物对于FGFR1具有非常好的选择性，有望开发成新一代FGFR抑制剂，特别是高选择性FGFR2抑制剂，满足临床应用需求。From the enzymatic or cellular activity data of the compounds of the specific examples, the compounds of the present invention have a strong inhibitory effect on FGFR, especially FGFR1 and / or FGFR2 kinase activity. In addition, from the above experimental results, 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.
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。All documents mentioned in the present invention are incorporated by reference in this application, as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
Claims (19)
- 式(I)化合物、其立体异构体、前药或其药学上可接受盐：Compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof:
其中，among them,X选自C(R 7)或N； X is selected from C (R 7 ) or N;R 1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； 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. The above-mentioned groups are optionally further substituted by one or Multiple selected from deuterium, halogen, cyano, nitro, azide, 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, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or- C 0-8 -N (R 13 ) -C (O) R 12 is substituted with a substituent, and the above-mentioned groups are optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, and 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 membered heteroaryl, = O, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 ,- C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;R 2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、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； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0 - 8 -C (O) OR 11 , -C 0-8 -C (O) R 12, -C 0-8 -OC (O) R 12, -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 , 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, C 3- 10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O , -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 The group is optionally further further selected from one or more of deuterium, halogen, cyano, nitro Azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkyl substituted with halo, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl Alkyl, 3-10 membered heterocyclyl, C 5- 10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 、 -C 0-8 -C (O) OR 11 、 -C 0-8 -C (O) R 12 、 -C 0-8 -OC (O) R 12 、 -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、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元杂芳基或5-10元杂芳氧基，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 1-10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 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azide, 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 heterocyclyloxy, C 5- 10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, 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 group, a halogen substituted C 1- 10 alkyl group, deuterium-substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C ( O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 substituted with a substituent;R 5、R 6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 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S (O) r R 10 , -C 0-8- OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 , the above-mentioned group is 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 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or- C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;R 7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 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0 - 8 -C (O) OR 11 , -C 0-8 -C (O) R 12, -C 0-8 -OC (O) R 12, -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 , 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 membered heteroaryl, = O, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C ( O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 substituted with a substituent;R 8、R 9各自独立地选自氘、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、-C 0-8-S(O) rR 10、-C 0-8-C(O)R 12、-C 0-8-C(O)NR 13R 14或-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元杂环基或4-10元杂芳基，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； 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 membered heteroaryl, = O, -C 0-8 -S ( O) r R 10, -C 0-8 -OR 11, -C 0- 8 -C (O ) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N ( R 13 ) -C (O) R 12 is substituted by a substituent, or R 8 and R 9 together with a directly connected nitrogen atom form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, The group is optionally further selected from one or more of the above-mentioned groups , Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, a halo substituted C 1-10 alkyl, C 1-10 alkoxy substituted with deuterium , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 10 , -C 0-8 -OR 11 , -C 0- 8 -C (O) OR 11 , -C 0-8 -C (O) R 12 , -C 0-8 -OC (O) R 12 , -C 0-8 -NR 13 R 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 13 R 14 or -C 0-8 -N (R 13 ) -C (O) R 12 is substituted by a substituent;每个R 10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； Each R 10 is 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 ring Alkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryl Oxygen 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 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;每个R 11独立地选自氢、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； Each R 11 is independently 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- to 10-membered heteroaryl, the above 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 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered Substituted with heteroaryl, 5- to 10-membered heteroaryloxy or -NR 13 R 14 substituents;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； 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 heteroaryloxy or -NR 13 R 14 substituents;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； Each of 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 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 1-10 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 heterocyclooxy, C 5-10 aryl, C 5-10 aromatic Substituted by oxo, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;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； Alternatively, 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;每个r各自独立地为0、1或2。Each r is independently 0, 1, or 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，X选自C(R 7)或N；R 7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； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that X is selected from C (R 7 ) or N; R 7 is selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heteroaryl Cyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O ) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N ( R 13 ) -C (O) R 12 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aromatic Group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 ,- C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 is substituted by R 10 , R 11 , R 12 , R 13 , R 14 , r are as described in claim 1;优选的，R 7选自选自氢、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、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、氨基羰基、二甲氨基羰基或乙酰氨基；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； Preferably, R 7 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl, and oxo Butyl, azetidinyl, azacyclohexyl, 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 further substituted by one or more Substituted with a substituent selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino;更优选的，R 7选自氢、氘、氟、氯、氰基、硝基、叠氮基、甲基、乙基、异丙基、烯丙基、乙炔基、环丙基、环丙甲基、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、甲氧基、乙氧基、异丙氧基、甲氧乙基、乙氧乙基、羟甲基、羟乙基、氰甲基、三氟甲基、三氘甲基、二氟甲基、二氘甲基、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、氨基甲基、氨基羰基、二甲氨基羰基或乙酰氨基。 More preferably, R 7 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azide, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, and cyclopropylmethyl. Yl, oxetanyl, azetidinyl, azacyclohexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy , Isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideutermethyl, difluoromethyl, dideutermethyl, methoxy Carbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetylamino.
- 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 5、R 6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； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, and cyanide. Nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5 -8aryl , 5-8 membered heteroaryl, -C 0-4 -S (O) r R 10 , -C 0- 4 -OR 11 , -C 0-4 -C (O) OR 11 ,- C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 , the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, halogen-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 Heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4- C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 is substituted by R 10 , R 11 , R 12 , R 13 , R 14 , r are as described in claim 1;优选的，R 5、R 6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、氨基羰基、二甲氨 基羰基或乙酰氨基；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。 Preferably, R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl , Oxetanyl, azetidinyl, azacyclohexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy Group, isopropyloxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetylamino; the above groups are optional It is further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino.
- 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 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、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元杂芳基或5-8元杂芳氧基，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、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； The compound of formula (I), a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, and hydroxyl group. , cyano, nitro, azido, C 1-4 alkyl, C 1- 4 alkoxy group, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy , 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, or 5-8 membered heteroaryloxy, The aforementioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 , R 10 , R 11 , R 12 , R 13 , R 14 , r are as described in claim 1;优选的，R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-4烷基、C 1-4烷氧基、烯丙基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、苯基、二氮唑或三氮唑；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。 Preferably, R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C 1-4 alkyl, C 1-4 alkoxy, allyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclooxy, phenyl, diazole or triazole; the above groups are optional It is further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino.
- 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 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10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； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, and hydrogen. Nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5 -10 membered heteroaryl, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 , The aforementioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, 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, = 0, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0- 4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0- 4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 1 2 is substituted by a substituent, and the above-mentioned group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, a halogen substituted C 1- 4 alkyl group, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl group, 5 -8-membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0- 4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) Substituted by a substituent of R 12 , R 10 , R 11 , R 12 , R 13 , R 14 , r are as described in claim 1;优选的，R 2选自氢、氘、卤素、C 1-4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、-C 0-4-O-R 11、-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、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或-C 0-4-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、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代，R 11、R 12、R 13、R 14、r如权利要求1所述。 Preferably, R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl , -C 0-4 -OR 11 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 , the above-mentioned groups are optionally further substituted by one or Multiple selected from deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 or -C 0-4 -NR 13 R 14 The above groups are optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideuterylmethyl, dideuterylmethyl, and cyclo The propyl, = O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxyl substituents are substituted, and R 11 , R 12 , R 13 , R 14 , and r are as described in claim 1.
- 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C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8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 1-4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 1-10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 0-4-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 8、R 9、R 10、R 11、R 12、R 13、R 14、r如权利要求1所述。 The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R 1 is selected from C 3-8 cycloalkyl, 3-8 membered hetero A cyclic group, a C 5-8 aryl group, a 5-8 membered heteroaryl group, or -NR 8 R 9 , and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, and azido , 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 Heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4- C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 The above-mentioned groups are optionally further substituted with one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterated C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5- 10-membered heteroaryl, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 、 -C 0-4 -C (O) OR 11 、 -C 0-4 -C (O) R 12 、 -C 0-4 -OC (O) R 12 、 -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 is substituted by R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , r as Claim 1.
- 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，所述式(I)化合物具有如下式(Ⅱa)结构：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the structure of formula (IIa):
其中，环A选自3-8元杂环基、C 5-8芳基或5-8元杂芳基； Wherein ring A is selected from a 3-8 membered heterocyclic group, a C 5-8 aryl group or a 5-8 membered heteroaryl group;R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基或-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、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、-S(O) rR 10、-O-R 11、-C(O)OR 11或-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、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, or -NR 13 R 14 , the aforementioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, = O, -S (O) r R 10 , -OR 11 , -C (O) OR 11 or -NR 13 R 14 Optionally further by one or more selected from the group consisting of deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, = 0, hydroxyl With methoxy, ethoxy, isopropoxy or carboxyl substituents;R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基或3-6元杂环氧基，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、羟基或氨基的取代基所取代； 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、R 6各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、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、羟基或氨基的取代基所取代； 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 15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、＝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 15 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl , 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 Or -C 0-4 -N (R 13 ) -C (O) R 12 is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, Nitrogen, 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 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 substituents;m为0、1、2或3；m is 0, 1, 2 or 3;R 10、R 11、R 12、R 13、R 14、r如权利要求1所述。 R 10 , R 11 , R 12 , R 13 , R 14 , and r are as described in claim 1. - 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，环A选自4-8元含1或2个氮杂原子的杂环基、苯基或5-6元含1、2或3个氮杂原子的杂芳基，优选的，所述5-6元含氮杂芳基选自吡啶基、嘧啶基、哒嗪基、吡嗪基、1,3,5-三嗪基、吡咯基、吡唑基、咪唑基或三氮唑基；The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 7, wherein ring A is selected from the group consisting of 4 to 8 members containing 1 or 2 nitrogen heteroatoms. Heterocyclyl, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 nitrogen heteroatoms, preferably, the 5-6 membered nitrogen-containing heteroaryl is selected from pyridyl, pyrimidinyl, pyridazine Base, pyrazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl;R 15选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6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、C 1-4烷基、卤取代C 1-10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、-S(O) rR 10、-O-R 11、-C(O)OR 11、-C(O)R 12、-O-C(O)R 12、-NR 13R 14或-C(O)NR 13R 14的取代基所取代； R 15 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 Heteroaryl, = O, -S (O) r R 10 , -OR 11 , -C (O) OR 11 , -C (O) R 12 , -OC (O) R 12 or -C (O) NR 13 R 14 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -S (O) r R 10 ,- OR 11 , -C (O) OR 11 , -C (O) R 12 , -OC (O) R 12 , -NR 13 R 14 or -C (O) NR 13 R 14m为0、1或2；m is 0, 1 or 2;R 10、R 11、R 12、R 13、R 14、r如权利要求7所述。 R 10 , R 11 , R 12 , R 13 , R 14 , and r are as described in claim 7.
- 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，所述式(I)化合物具有如下式(Ⅲa 1)结构、式(Ⅲa 2)结构或式(Ⅲa 3)结构： The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that the compound of formula (I) has the structure of formula (IIIa 1 ), (IIIa 2 ) structure or formula (IIIa 3 ) structure:其中，
among them,每个R 2各自独立地选自苯基、5-6元含1或2个氮杂原子杂芳基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、环丙基或羟基的取代基所取代； Each R 2 is independently selected from a phenyl group, a 5- to 6-membered heteroaryl group containing 1 or 2 nitrogen heteroatoms, or -NR 13 R 14 , and the aforementioned group is optionally further selected from one or more of deuterium and halogen , Cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxyl, methoxy, ethoxy, carboxyl, amino, dimethylamino or di An ethylamino substituent, and the above-mentioned groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, methyl, cyclopropyl, or hydroxyl;R 5、R 6各自独立地选自氢、氘、卤素、甲基、异丙基、环丙基、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、氟或环丙基取代基所取代； 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各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、羟基、甲氧基、乙氧基、羧基、甲基胺酰基、乙基胺酰基或环丙基胺酰基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、氰基、甲基、环丙基、环丁基、环己基、吗啉基、哌嗪基、甲磺酰基、羟基、甲氧基、羧基或乙酰基的取代基所取代； 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 ReplaceR 13、R 14各自独立地选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代，或者， 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和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、C 3-6环烷基、C 3-6环烷氧基、吗啉基、哌嗪基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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;所述杂环基各自独立地任选包含1或2个选自氮原子或氧原子的杂原子。The heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom. - 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，所述式(I)化合物具有如下式(Ⅱb)结构：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the structure of formula (IIb):
其中，R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基或-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、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、-S(O) rR 10、-O-R 11、-C(O)OR 11或-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、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； Wherein R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, or -NR 13 R 14 , the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, = O, -S (O) r R 10 , -OR 11 , -C (O) OR 11 or -NR 13 R 14 The group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideutermethyl, dideutermethyl, cyclopropyl, = 0 With hydroxy, methoxy, ethoxy, isopropoxy or carboxyl substituents;R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基或3-6元杂环氧基；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、羟基或氨基的取代基所取代； 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、R 6各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、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、羟基或氨基的取代基所取代； 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; 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 8、R 9各自独立地选自氘、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、-C 0-4-S(O) rR 10或-C 0-4-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，或者，R 8、R 9和其直接相连的氮原子一起形成4-10元杂环基或4-10元杂芳基，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 1-4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 8 and R 9 are each independently selected from deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 10 or -C 0-4 -C (O) R 12 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, Azide, 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, = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0 -4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O ) Is substituted by a substituent of R 12 , or R 8 and R 9 and a nitrogen atom directly connected thereto form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above group is optionally further substituted by one or A plurality of groups selected from the above are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, 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 , = O, -C 0-4 -S (O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C (O) OR 11 , -C 0-4 -C (O) R 12 , -C 0-4 -OC (O) R 12 , -C 0-4 -NR 13 R 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 13 R 14 or -C 0-4 -N (R 13 ) -C (O) R 12 ReplaceR 10、R 11、R 12、R 13、R 14、r如权利要求1所述。 R 10 , R 11 , R 12 , R 13 , R 14 , and r are as described in claim 1. - 根据权利要求10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 8、R 9各自独立地选自氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，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 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-O-R 11、-C(O)R 12、-O-C(O)R 12或-NR 13R 14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4-8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、C 1-4烷基、＝O、-S(O) rR 10、-O-R 11或-C(O)R 12的取代基所取代； The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 10, wherein R 8 and R 9 are each independently selected from deuterium and C 1-4 alkane Group, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 ring Alkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -OR 11 , -C (O) R 12 , -OC (O) R 12 or- NR 13 R 14 is substituted by a substituent, or R 8 , R 9 and a directly connected nitrogen atom together form a 4- to 8-membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more of the above-mentioned groups Optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, C 1-4 alkyl, = 0, -S (O) r R 10 , -OR 11 or -C (O) R 12 ;R 10、R 11、R 12、R 13、R 14、r如权利要求10所述。 R 10 , R 11 , R 12 , R 13 , R 14 , and r are as described in claim 10.
- 根据权利要求10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(Ⅲb)结构：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 10, wherein the compound of formula (I) has a structure of the following formula (IIIb):
其中，among them,R 2选自苯基、5-6元含1或2个氮杂原子杂芳基或-NR 13R 14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、环丙基或羟基的取代基所取代； 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 above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, C Substitution of 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxyl, methoxy, ethoxy, carboxyl, amino, dimethylamino, or diethylamino 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、R 6各自独立地选自氢、氘、卤素、甲基、异丙基、环丙基、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、氟或环丙基取代基所取代； 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各自独立地选自氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、＝O、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代，或者， R 8 and R 9 are each independently selected from 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, trideuteryl, methoxy, ethoxy, isopropyloxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, diazole, triazole, = 0, amino, dimethylamino, diethylamino or a C 1-4 alkanoyl substituent, or,R 8、R 9和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、甲氧基、乙氧基、异丙氧基或C 1-4烷酰基的取代基所取代； 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、R 14各自独立地选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代，或者， 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和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、C 3-6环烷基、C 3-6环烷氧基、吗啉基、哌嗪基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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;所述杂环基各自独立地任选包含1或2个选自氮原子或氧原子的杂原子。The heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom. - 根据权利要求1-12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：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, characterized in that it is selected from the following compounds:
- 权利要求1-13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：The method for preparing a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, comprising the following steps:
或者，or,
或者，or,
或者，or,
其中，X、R 1、R 2、R 3、R 4、R 5、R 6如权利要求1所述。 Wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as described in claim 1. - 一种药物组合物，其包括权利要求1-13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。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-13, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- 权利要求1-13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。The use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 in the preparation of a medicament for treating tumors or cancers; preferably, the tumour or The 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, 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's lymphoma or non-Hodgkin's lymphoma, Fahrenheit macroglobulinemia , Hair-like lymphoma, cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
- 权利要求1-13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。The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the preparation of a medicament for the treatment of myeloproliferative diseases, bone or chondrocyte disorders, and hypophosphatemia Application.
- 根据权利要求17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。The use according to claim 17, wherein 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 Dysplasia, cartilage dysplasia, dwarfism, lethal teratosis (TD), Apel's syndrome, Krusson's syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin pattern syndrome, Pfeiffer syndrome Or cranial muscle atrophy syndrome; the 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.
- 根据权利要求1-13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；优选的，其用作选择性的FGFR 2和/或FGFR 3抑制剂来治疗和FGFR2或FGFR3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。The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, which is used as a FGFR inhibitor to treat and abnormally express FGFR receptors, mutate or Diseases associated with abnormal expression of the corresponding ligand and abnormal activity; preferably, it is used as a selective FGFR 2 and / or FGFR 3 inhibitor to treat abnormal expression, mutation or abnormal expression and activity of the corresponding ligand of FGFR2 or FGFR3 Abnormally related diseases.
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| WO2021145521A1 (en) * | 2020-01-15 | 2021-07-22 | 한국과학기술연구원 | Pyrido[3,4-d]pyrimidine derivative and therapeutic pharmaceutic composition comprising same |
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| CN103261167A (en) * | 2010-12-17 | 2013-08-21 | 霍夫曼-拉罗奇有限公司 | Substituted 6,6-used nitrogenous heterocyclic compounds and uses thereof |
| CN105307657A (en) * | 2013-03-15 | 2016-02-03 | 西建阿维拉米斯研究公司 | Heteroaryl compounds and uses thereof |
| WO2018113584A1 (en) * | 2016-12-19 | 2018-06-28 | 上海和誉生物医药科技有限公司 | Fgfr4 inhibitor, preparation method therefor and pharmaceutical use thereof |
| CN109745325A (en) * | 2017-11-08 | 2019-05-14 | 上海翰森生物医药科技有限公司 | FGFR4 inhibitor, preparation method and use |
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| CN103261167A (en) * | 2010-12-17 | 2013-08-21 | 霍夫曼-拉罗奇有限公司 | Substituted 6,6-used nitrogenous heterocyclic compounds and uses thereof |
| CN105307657A (en) * | 2013-03-15 | 2016-02-03 | 西建阿维拉米斯研究公司 | Heteroaryl compounds and uses thereof |
| WO2018113584A1 (en) * | 2016-12-19 | 2018-06-28 | 上海和誉生物医药科技有限公司 | Fgfr4 inhibitor, preparation method therefor and pharmaceutical use thereof |
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| WO2021145521A1 (en) * | 2020-01-15 | 2021-07-22 | 한국과학기술연구원 | Pyrido[3,4-d]pyrimidine derivative and therapeutic pharmaceutic composition comprising same |
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