WO2024109799A1 - Pyrimidine derivative and application thereof in medicine - Google Patents

Pyrimidine derivative and application thereof in medicine Download PDF

Info

Publication number
WO2024109799A1
WO2024109799A1 PCT/CN2023/133209 CN2023133209W WO2024109799A1 WO 2024109799 A1 WO2024109799 A1 WO 2024109799A1 CN 2023133209 W CN2023133209 W CN 2023133209W WO 2024109799 A1 WO2024109799 A1 WO 2024109799A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
carbocycle
membered
optionally substituted
ring
Prior art date
Application number
PCT/CN2023/133209
Other languages
French (fr)
Chinese (zh)
Inventor
张晨
何平
宁文涛
廖鹏飞
宣兆利
高世东
唐平明
余彦
李瑶
严庞科
Original Assignee
西藏海思科制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 西藏海思科制药有限公司 filed Critical 西藏海思科制药有限公司
Publication of WO2024109799A1 publication Critical patent/WO2024109799A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to FGFR2 activity or expression.
  • Biliary tract cancer is a rare, heterogeneous disease that includes a variety of aggressive malignancies arising in the biliary tree.
  • BTC includes intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA).
  • iCCA intrahepatic cholangiocarcinoma
  • eCCA extrahepatic cholangiocarcinoma
  • FGFR fibroblast growth factor receptor
  • FGFR2 also known as CD332
  • CD332 is a protein encoded by a gene located on chromosome 10.
  • the FGFR family includes four receptor subtypes, namely FGFR1, FGFR3 and FGFR4, and up to 22 fibroblast growth factor ligands (FGFs). They are part of the tyrosine kinase signaling pathway (FGFs/FGFRs signaling pathway) responsible for cell proliferation and differentiation, and are responsible for regulating the basic developmental pathways of multiple organ systems. They play an important role in many physiological and pathological processes, including regulating angiogenesis, tissue homeostasis, wound repair, and tumor transformation by regulating cell proliferation, differentiation, survival, migration and metabolism.
  • FGFs/FGFRs signaling pathway tyrosine kinase signaling pathway
  • Fusions, amplifications, and mutations are oncogenic drivers that occur in a variety of tumor types.
  • pan-FGFR inhibitors validates the driver status in fusion-positive intrahepatic cholangiocarcinoma (ICC)
  • ICC fusion-positive intrahepatic cholangiocarcinoma
  • FGFR1-mediated toxicity hyperphosphatemia, tissue mineralization
  • targeted resistance mutations limit the efficacy of pan-FGFR inhibitors.
  • selective inhibitors can reduce toxicity and overcome acquired resistance to pan-FGFR inhibitors. Therefore, it is necessary to develop a compound that can inhibit with high selectivity for the treatment of related diseases caused by fusions, amplifications, and mutations.
  • the purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which are applied as FGFR2 inhibitors.
  • the compounds of the present invention can effectively inhibit FGFR2 and can be used to treat diseases such as tumors.
  • the compound of the present invention has good selectivity and inhibitory activity against FGFR2 kinase, has good inhibitory activity against tumor cells, and shows excellent oral exposure and good bioavailability, good safety, and lower CYP inhibition and hERG inhibition in pharmacokinetic tests.
  • the present invention provides a compound of general formula (I) or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • the compound represented by general formula (I) is selected from general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V), The compound represented by formula (VI), general formula (VII) or general formula (VIII),
  • the compound represented by general formula (I) is selected from general formula (I-a)
  • W is selected from N or CH, a1 is selected from 0 or 1;
  • the compound represented by general formula (I) is selected from general formula (I-b)
  • W is selected from N or CH, q1 is selected from 0, 1, 2, 3 or 4; in some embodiments, Selected from W is selected from N or CH, preferably
  • ring A, ring B, and ring C are each independently selected from phenyl, benzoC4-6 carbocycle, 5- to 6-membered heteroaryl, or 8-10-membered cycloheteroaryl, and the ring A is optionally substituted with 1 to 4 Ra , the ring B is optionally substituted with 1 to 4 Rb , and the ring C is optionally substituted with 1 to 4 Rc ;
  • ring B is selected from phenyl, naphthalene, benzoC 4-6 carbon ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;
  • Ring B is selected from
  • Ring B1 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b ;
  • Ring B1 is selected from Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
  • Ring B1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
  • Ring B1 is selected from Q 3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B 1 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
  • Ring B1 is selected from Q 3 Selected
  • B 2 is selected from C 4-6 carbocycle
  • B 3 is selected from C 4-6 carbocycle
  • Q3 is selected from Ring B1 is selected from C4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
  • Q3 is selected from Ring B1 is selected from phenyl, benzo C4-6 carbocycle, benzo 4 to 6-membered heterocycle, 5 to 6-membered heteroaryl, 8 to 10-membered heteroaryl, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
  • Q3 is selected from Ring B 1 is selected from phenyl or pyridinyl, said ring B 1 is optionally substituted by 1 to 4 R b , said Q 3 is optionally substituted by 1 to 4 R k ; in some embodiments, Q 3 is selected from Ring B 1 is selected from
  • ring A and ring B are each independently selected from phenyl, pyridine, pyrimidine, and ring A is optionally substituted by 1 to 4 Ra , and ring B is optionally substituted by 1 to 4 Rb ;
  • ring C is selected from pyrrole, pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine; in some embodiments, ring A is selected from W is selected from N or CH;
  • Ring A is preferred In some embodiments, Selected from
  • Ring B is selected from or Ring B1; In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Selected from
  • Ring C is selected from
  • Ring C is selected from
  • F1 or F2 is selected from N or CH;
  • Q is selected from a bond, -O-, -N(R q3 )-, -C( ⁇ O)N(R q3 )-, -N(R q3 )C( ⁇ O), -C( ⁇ O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • Q is selected from -O-, -N(R q3 )-, -C( ⁇ O)N(R q3 )-, -N(R q3 )C( ⁇ O), -C( ⁇ O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • Q is selected from -O-, -NH-, -N(CH 3 )-, -C( ⁇ O)NH-, -NHC( ⁇ O), -C( ⁇ O)-;
  • Q is selected from Q 1 ;
  • m is selected from 0 or 1;
  • R q1 , R q2 , and R q3 are each independently selected from H, C 1-6 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
  • R q1 , R q2 , and R q3 are each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
  • R q1 , R q2 , and R q3 are each independently selected from H, methyl, and ethyl;
  • D is selected from a bond, -NR n1 -, The D is optionally substituted by 1 to 6 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
  • D is selected from -NR n1 -, The D is optionally substituted by 1 to 4 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
  • D is selected from -NR n1 -
  • Q is selected from
  • D is selected from -NH-, -N( Rn1 )-, or one of the following groups optionally substituted by 1 to 4 R d :
  • the right side is directly connected to R 1 ;
  • -D- in Formula (VI) is selected from
  • D is selected from -NH-;
  • D 1 is selected from a 4- to 14-membered nitrogen-containing heterocyclic group
  • D1 is selected from 4 to 7 membered nitrogen-containing heteromonocycloalkyl, 4 to 7 membered nitrogen-containing heteromonocycloalkenyl, 5 to 14 membered nitrogen-containing heterospirocycloalkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;
  • D1 is selected from
  • D 2 is selected from C 3-14 carbocyclyl, 4 to 14 membered heterocyclyl;
  • D2 is selected from phenyl, benzo C4-7 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl, C3-7 monocycloalkyl, C3-7 monocycloalkenyl, C5-14 spirocycloalkyl, C5-14 cycloalkyl, C5-14 bridged cycloalkyl, 4 to 7 membered nitrogen-containing heteromonocyclyl, 5 to 14 membered nitrogen-containing heterospirocyclyl, 5 to 14 membered nitrogen-containing heterocyclocyclyl, 5 to 14 membered nitrogen-containing heterobridged cyclyl;
  • D2 is selected from Phenyl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;
  • D3 is selected from C7-14 carbocyclyl
  • D 3 is selected from benzo C 4-7 carbocyclyl, C 7-14 spirocycloalkyl, C 7-14 cycloalkyl, C 7-14 bridged cycloalkyl;
  • D3 is selected from
  • D3 is selected from one of the following groups optionally substituted with 1 to 4 Rd :
  • n1, n3, n5 are each independently selected from 0, 1 or 2;
  • n2 and n4 are each independently selected from 0 or 1;
  • n6 is selected from 0, 1, 2 or 3; In some embodiments, R n1 is selected from H, C 1-4 alkyl;
  • R n1 is selected from H, methyl, ethyl
  • Ra , Rb , and Rd are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2 , NH( CH3 ), N( CH3 ) 2 , CF3 , methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • each Ra is independently selected from deuterium, F, Cl, Br, cyano, CF3 , methyl;
  • each R b is independently selected from deuterium, F, Cl, Br, cyano, CF 3 , methyl;
  • each R d is independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, Propyl, isopropyl, methoxy, ethoxy;
  • R c1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl, or heterocycloalkyl being optionally substituted with 1 to 4 R k ;
  • R c1 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 R k ;
  • R c1 is selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 4 R k ;
  • R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 R k ;
  • R c1 is selected from CD 3 , CF 3 , methyl, ethyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
  • R c1 is selected from CD 3 , CF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
  • R c4 is selected from H, NH 2 , halogen, CN, OH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k ; in some embodiments, R c4 is selected from H, NH 2 , F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH
  • R c4 is selected from H, NH 2 , halogen, CN, C 1-4 alkyl, C 2-4 alkynyl, or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted with 1 to 4 R k ;
  • R c4 is selected from H, NH 2 , F, CN, methyl,
  • R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1-4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
  • R c5 is selected from -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
  • R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the Alkylene, carbocyclyl, heterocyclyl, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
  • R c5 is selected from
  • R c6 when R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, heteroaryl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 3 R k ;
  • R c6 when R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , wherein the alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
  • R c6 when R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
  • R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl
  • R c5 is selected from since
  • R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1 - 4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy,
  • R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, and the CH 2 , ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
  • R c5 is selected from
  • R c7 is selected from H or R c2 ;
  • R c5a is selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,
  • p1 or p2 is selected from 0, 1, 2, or 3; In some embodiments, p1 or p2 is selected from 0, 1, or 2;
  • R 1 is selected from halogen, CN,
  • R 1 is selected from CN
  • R is selected from
  • -DR 1 is selected from
  • R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, and 3-7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle, or heterocycle is optionally substituted with 1 to 4 R k ;
  • R is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k ;
  • R 1b and R 1c , R 1a and R 1b are directly connected to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • R n1 and R d are directly connected to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, which is optionally substituted by 1 to 4 R k ;
  • Rk is selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl , C2-4 alkenyl , C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, C3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy;
  • Rk is selected from deuterium, F, Cl, Br, I, CN, OH, NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 , N (CH2CH3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy , ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl,
  • Ring A, Ring B, and Ring C are each independently selected from phenyl, benzoC 4-6 carbocycle, 5- to 6-membered heteroaryl, or 8-10-membered cycloheteroaryl, wherein Ring A is optionally substituted by 1 to 4 Ra , Ring B is optionally substituted by 1 to 4 Rb , and Ring C is optionally substituted by 1 to 4 Rc ;
  • Q is selected from the key, -O-, -N(R q3 )-, -C( ⁇ O)N(R q3 )-, -N(R q3 )C( ⁇ O), -C( ⁇ O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • n is selected from 0 or 1;
  • R q1 , R q2 , and R q3 are each independently selected from H, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k ;
  • D is selected from a bond, -NR n1 -, The D is optionally substituted by 1 to 6 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
  • D1 is selected from 4 to 14-membered nitrogen-containing heterocyclic groups
  • D2 is selected from C3-14 carbocyclyl, 4 to 14 membered heterocyclyl;
  • D3 is selected from C7-14 carbocyclic group
  • R n1 is selected from H, C 1-4 alkyl
  • R1 is selected from halogen, CN,
  • R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, -C( ⁇ O)R, -C( ⁇ O)OR, -C( ⁇ O)N(R) 2 , C( ⁇ O)N(R)OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
  • R is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
  • R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • R n1 and R d are directly linked to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from the compounds represented by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII) and general formula (VIII),
  • Ring B is selected from phenyl, naphthalene, benzoC 4-6 carbon ring, benzo 4-6 membered heterocyclic ring, 5-6 membered heteroaryl, 8-10 membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;
  • Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said Q 3 is optionally substituted by 1 to 4 R k ;
  • Ring B 1 is selected from Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
  • B2 is selected from C4-6 carbocyclic ring
  • B3 is selected from C4-6 carbocyclic ring
  • Ring B1 is selected from C4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
  • Ring C is selected from
  • F1 or F2 is selected from N or CH;
  • Q is selected from -O-, -N(R q3 )-, -C( ⁇ O)N(R q3 )-, -N(R q3 )C( ⁇ O), -C( ⁇ O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • D is selected from -NR n1 -, The D is optionally substituted by 1 to 4 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
  • D1 is selected from 4 to 7 membered nitrogen-containing heteromonocyclic alkyl, 4 to 7 membered nitrogen-containing heteromonocyclic alkenyl, 5 to 14 membered nitrogen-containing heterospirocyclic alkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;
  • D2 is selected from phenyl, benzo C4-7 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl, C3-7 monocycloalkyl, C3-7 monocycloalkenyl, C5-14 spirocycloalkyl , C5-14 cycloalkyl, C5-14 bridged cycloalkyl, 4 to 7 membered nitrogen-containing heteromonocyclic group, 5 to 14 membered nitrogen-containing heterospirocyclic group, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged ring group;
  • D3 is selected from benzo C4-7 carbocyclyl, C7-14 spirocycloalkyl, C7-14 cycloalkyl, C7-14 bridged cycloalkyl;
  • R c1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl or 4 to 7 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
  • R c4 is selected from H, NH 2 , halogen, CN, OH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
  • R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1-4 alkyl, -NH-C 3-7 carbocycle , -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
  • R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl
  • R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , and the alkyl, heteroaryl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 3 R k ;
  • R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1 - 4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloal
  • R c7 is selected from H or R c2 ;
  • p1 or p2 is selected from 0, 1, 2 or 3;
  • R q1 , R q2 , and R q3 are each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
  • R c4 is selected from H, NH 2 , halogen, CN, C 1-4 alkyl, C 2-4 alkynyl or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted with 1 to 4 R k ;
  • R c5 is selected from -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
  • R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl
  • R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , wherein the alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
  • R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
  • R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • Rk is selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O - 3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, C3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy;
  • D 1 is selected from
  • D 2 is selected from Phenyl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;
  • D 3 is selected from
  • Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said Q3 is optionally substituted by 1 to 4 R k ;
  • Ring B 1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
  • B2 is selected from C4-6 carbocyclic ring
  • B3 is selected from C4-6 carbocyclic ring
  • Ring B1 is selected from phenyl, benzo C4-6 carbocycle, benzo 4 to 6-membered heterocycle, 5 to 6-membered heteroaryl, 8 to 10-membered heteroaryl, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
  • n1, n3, n5 are each independently selected from 0, 1 or 2;
  • n2 and n4 are each independently selected from 0 or 1;
  • n6 is 0, 1, 2 or 3;
  • R q1 , R q2 , and R q3 are each independently selected from H, methyl, and ethyl;
  • R n1 is selected from H, methyl, ethyl
  • Ra , Rb , and Rd are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2 , NH( CH3 ), N( CH3 ) 2 , CF3 , methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 R k ;
  • R c4 is selected from H, NH 2 , F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally substituted by 1 to 4 R k ;
  • Ring B is selected from
  • R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the alkylene, carbocyclyl, heterocyclyl, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
  • R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl
  • R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a
  • the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl
  • the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
  • R c5a is selected from CN or one of the following optionally substituted groups: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C ( ⁇ O)-cyclopropyl, —C( ⁇ O)-cyclobutyl, —C( ⁇ O)-cyclopentyl, —C( ⁇ O)-cycl
  • R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, and the CH 2 , ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
  • R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with 1 to 4 R k ;
  • R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • R n1 and R d are directly linked to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
  • R k is selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl,
  • D is selected from -NH-, -N( Rn1 )-, or one of the following groups optionally substituted by 1 to 4 R d :
  • the right side is directly connected to R 1 ;
  • D3 is selected from one of the following groups optionally substituted by 1 to 4 Rd :
  • R1 is selected from CN
  • p1 or p2 is selected from 0, 1 or 2;
  • Ra is independently selected from deuterium, F, Cl, Br, cyano, CF3 , and methyl;
  • R b is each independently selected from deuterium, F, Cl, Br, cyano, CF 3 , methyl;
  • R d is each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;
  • R c1 is selected from CD 3 , CF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
  • R c2 is selected from deuterium, F, Cl, Br, OH, CN, NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C( ⁇ O)NH-methyl, -C( ⁇ O)NH-ethyl, -C( ⁇
  • R c4 is selected from H, NH 2 , F, CN, methyl,
  • R c5 is selected from
  • R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl
  • R c5 is selected from
  • R c5a is selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,
  • R c5 is selected from
  • Q 3 is selected from phenyl, pyridyl or pyrimidinyl, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
  • Ring B 1 is selected from Q 3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B 1 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
  • Ring B 1 is selected from phenyl or pyridyl, said ring B 1 is optionally substituted by 1 to 4 R b , said Q 3 is optionally substituted by 1 to 4 R k ;
  • Ring B 1 is selected from Q 3 Selected
  • Ring B 1 is selected from
  • D is selected from -NH-;
  • the present invention relates to the compounds shown below or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from one of the structures shown in Table E-1.
  • the present invention relates to a pharmaceutical composition, comprising any of the above compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and pharmaceutically acceptable carriers.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” described in the present application refers to the administration of a sufficient amount of the compound disclosed herein, which will alleviate one or more symptoms of the disease or condition (e.g., FGFR2 abnormal related diseases such as cancer) to some extent.
  • the result is to reduce and/or alleviate the signs, symptoms or causes of the disease, or any other desired changes in the biological system.
  • an "effective amount” for therapeutic use is the amount of the compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500m
  • the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to FGFR2 activity or expression (such as cancer).
  • a method for treating a disease in a mammal comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg/day, wherein the daily dose may be a single dose or divided doses.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day , 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day.
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
  • the present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for preparing drugs for treating diseases related to FGFR2 activity or expression, preferably, the disease is selected from tumors.
  • the present invention relates to the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease associated with FGFR2 activity or expression, preferably, the disease is selected from tumors.
  • the amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in the present invention are optionally replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C, and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O, and 18 O, sulfur isotopes include 32 S, 33 S, 34 S, and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C, and 14 C
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing in this article have the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S.
  • the N and S selectively substituted in the ring of the heterocycloalkyl can be oxidized to various oxidation states.
  • the heterocycloalkyl can be connected to a heteroatom or a carbon atom, the heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl can be connected to a bridge ring or a spiro ring.
  • Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • the heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to a substituted or unsubstituted straight chain and branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
  • Alkynyl refers to a substituted or unsubstituted straight or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain.
  • alkynyl radicals include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl,
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S.
  • the N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group may be connected to a heteroatom or a carbon atom, may be connected to an aromatic ring or a non-aromatic ring, may be connected to a bridged ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofur
  • Non-limiting examples include:
  • Spirocycle or “spirocyclyl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a “heterocyclyl” or “heterocycle” that is a monocyclic ring system.
  • Heterocyclic ring refers to a “cyclic ring” containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring with the parent The ring connected together is a heteroaryl ring, non-limiting examples of which include The heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.
  • Consing 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.
  • 0 to X substituents are substituted means substituted by 0, 1, 2, 3 .... X substituents, X is selected from any integer between 1 and 10.
  • 0 to 4 substituents are substituted means substituted by 0, 1, 2, 3 or 4 substituents.
  • 0 to 5 substituents are substituted means substituted by 0, 1, 2, 3, 4 or 5 substituents.
  • the heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from H or F.
  • X-Y membered rings (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) include X+1, X+2, X+3, X+4...Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence.
  • any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • alkyl optionally substituted by F means that the alkyl group may be but not necessarily be substituted by F, and includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Preparation specification refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to technicians in the field, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
  • THF Tetrahydrofuran
  • DMF N,N-dimethylformamide
  • DIPEA N,N-diisopropylethylamine
  • HATU CAS 148893-10-1
  • TCFH CAS 94790-35-9
  • 3a (0.5 g, 6 mmol) was dissolved in 5 mL DMF, and triethylamine (1.7 mL, 12 mmol) and (2.07 mL, 9 mmol) were added. The mixture was then reacted at room temperature for 3 h, and 50 mL of ethyl acetate was added for dilution. The mixture was washed with water (20 mL ⁇ 3) and 20 mL of saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain 3b (0.77 g, yield: 71%).
  • 3b (0.4 g, 2.2 mmol) was dissolved in 10 mL DMF, and bromomethylcyclopropane (0.32 mL, 3.3 mmol), potassium carbonate (912 mg, 6.6 mmol) and potassium iodide (365 mg, 2.2 mmol) were added in sequence under nitrogen protection, and the mixture was reacted at 80°C overnight. 50 mL of ethyl acetate was added to dilute the mixture, and the mixture was washed with water (20 mL ⁇ 3) and 20 mL of saturated brine, respectively. The organic phase was dried and concentrated, and the residue was separated and purified by column chromatography to obtain 3c (0.21 g, yield: 40%).
  • 3c (0.21 g, 0.88 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The system was then reacted at room temperature for 1 h and concentrated under reduced pressure. The residue was directly purified by reverse phase to obtain 3d (98 mg, yield: 80%).
  • the intermediate 3e (0.7 g, 3.07 mmol) was dissolved in 8 mL of 1,4-dioxane, and 3e-1 (884 mg, 3.07 mmol) and DIPEA (1.1 mL, 6.14 mmol) were added.
  • the reaction was carried out at 80 ° C for 1 h. 30 mL of ethyl acetate was added to the reaction, and the mixture was washed three times with water (20 mL ⁇ 3) and once with 20 mL of a saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain 3f (1.2 g, yield: 98%).
  • intermediate 3f (0.25 g, 0.64 mmol) was dissolved in 15 mL 1,4-dioxane and 1.5 mL water, and 1d (254 mg, 0.77 mmol), Pd(dppf)Cl 2 (47 mg, 0.064 mmol) and potassium carbonate (354 mg, 2.56 mmol) were added.
  • the system was then heated to 100 °C for 1 h. 20 mL of ethyl acetate was added to the reaction, and the mixture was washed with water (20 mL ⁇ 3) and 20 mL of a saturated NaCl aqueous solution once. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain 3g (198 mg, yield: 58%).
  • reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (50mL ⁇ 3), washed once with 200mL of saturated NaCl aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain 6A (97mg, yield 44.87%).
  • 15a (5.0 g, 21.12 mmol) was dissolved in 50 mL of dichloromethane at 0°C, triethylamine (4.28 g, 42.27 mmol) was added, and acryloyl chloride (1.91 g, 21.12 mmol) was added dropwise.
  • the reaction was allowed to react at room temperature for 1 h. 50 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 15b (3.0 g, yield: 48.80%).
  • 16a (0.9 g, 3.72 mmol), 2-chloro-4-methylpyrimidine (0.96 g, 7.43 mmol), potassium carbonate (1.54 g, 11.14 mmol) were dissolved in 20 mL DMF and reacted at 80 °C for 10 h. The mixture was diluted with water, extracted with ethyl acetate (20 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 16b (0.6 g, 48.41%).
  • 16b (0.6 g, 1.80 mmol), bipyralidin (0.91 g, 3.60 mmol), Pd(dppf)Cl 2 (0.15 g, 0.18 mmol), potassium acetate (0.53 g, 5.4 mmol) were dissolved in 20 mL 1,4-dioxane, replaced with nitrogen, and reacted at 100°C for 3 h.
  • the mixture was diluted with water, extracted with ethyl acetate (50 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16c (0.55 g, 80.36%).
  • 16c (0.56 g, 1.47 mmol), 4C-1 (0.60 g, 2.21 mmol), Pd(dppf)Cl 2 (0.12 g, 0.15 mmol), and cesium carbonate (0.61 g, 4.41 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water and reacted at 100°C for 3 h.
  • the mixture was diluted with water, extracted with ethyl acetate (20 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16d (0.3 g, 50.97%).
  • 16d (0.3 g, 0.75 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (0.17 mg, 1.50 mmol) and NIS (CAS 516-12-1) (0.34 g, 1.50 mmol) were added at 0°C, stirred at room temperature for 2 h, quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16e (0.24 g, 60.80%).
  • 19E (230 mg, 0.56 mmol) was dissolved in 6 mL of ethanol and 2 mL of water, and lithium hydroxide monohydrate (24 mg, 5.63 mmol) was added. The mixture was stirred at room temperature for 3 h, and concentrated under reduced pressure. The residue was separated and purified by reverse phase column chromatography and freeze-dried to obtain 19F (100 mg, yield: 45.05%).
  • 21b (5 g, 21.99 mmol) was dissolved in 20 mL DMF, and intermediate 21c (6.53 g, 32.98 mmol) and potassium carbonate (6.08 g, 43.98 mmol) were added in sequence, and the mixture was reacted at 80°C for 16 h. After cooling to room temperature, 40 mL of water was added, and ethyl acetate (40 mL ⁇ 2) was added for extraction. The ethyl acetate layers were combined, and the ethyl acetate layers were washed with water (50 mL ⁇ 2) and 50 mL of saturated NaCl aqueous solution in sequence.
  • 21d (3.6 g, 12.10 mmol) was dissolved in 30 mL of tetrahydrofuran, and tetrabutylammonium fluoride (4.75 g, 18.17 mmol) was added, and the mixture was reacted at room temperature for 16 h.
  • 24b (0.5 g, 1.70 mmol) was dissolved in 8 mL of acetonitrile, and DIPEA (0.66 g, 5.10 mmol) and phosphorus oxychloride (1.31 g, 8.55 mmol) were added in sequence, and the mixture was reacted at 85°C for 2 h under a nitrogen atmosphere.
  • 24e (0.048 g, 0.093 mmol) was dissolved in a mixed solvent of 2 mL ethanol and 0.2 mL water, and lithium hydroxide (0.039 g, 0.93 mmol) was added. The reaction was allowed to react at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, the pH was adjusted to 4 with 1N HCl, and the mixture was extracted twice with dichloromethane (5 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 24f (0.014 g, yield: 33.33%).
  • reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate (50 mL ⁇ 3), washed once with 200 mL of saturated NaCl aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography to obtain 25B (210 mg, yield 29.38%).
  • 28E (200.0 mg, 0.38 mmol) was dissolved in DCM (3 mL), and a hydrochloric acid-1,4-dioxane solution (2 mL) was added. The mixture was reacted at room temperature for 1 h, and triethylamine was added to adjust the pH to about 7-8. The solvent was removed to obtain a solid crude product of 28F (0.1 g).
  • 31B (470 mg, 0.89 mmol), 6B (160 mg, 1.16 mmol), Pd 2 (dba) 3 (81 mg, 0.089 mmol), S-phos (73 mg, 0.18 mmol) and cesium carbonate (580 mg, 1.78 mmol) were added to the sealed tube, dissolved in 1,4-dioxane (10 mL), replaced with nitrogen for protection, and reacted at 110° C. for 2 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 31C (211 mg, yield: 37.39%).
  • 31C (200 mg, 0.31 mmol) was dissolved in tetrahydrofuran (4 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at 70°C for 6 h. The mixture was concentrated under reduced pressure to obtain 31D (170 mg, crude product).
  • 34B (560 mg, 2.21 mmol), 4C (1.44 g, 3.98 mmol), Pd(dppf)Cl2 (140 mg, 0.22 mmol), and potassium carbonate (610 mg, 4.42 mmol) were dissolved in 10 mL of 1,4-dioxane and 3 mL of water, and the atmosphere was replaced with nitrogen for protection, and the reaction was carried out at 100 °C for 2 h. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (20 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34C (0.9 g, 99.70%).
  • 34C (1.04 g, 2.55 mmol) was dissolved in 40 mL of dichloromethane. Trifluoroacetic acid (0.38 mL, 5.1 mmol) and NIS (1.15 g, 5.1 mmol) were added at 0°C. The mixture was stirred at room temperature for 2 h, diluted with water, quenched with saturated sodium bicarbonate, extracted with dichloromethane (20 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34D (0.67 g, 49.17%).
  • 35A (1.2 g, 5.45 mmol) was dissolved in 25 mL of dichloromethane, triethylamine (1.13 mL, 8.15 mmol) was added at 0°C, nitrogen was replaced for protection, acryloyl chloride (0.54 g, 6.0 mmol) was slowly added dropwise, and the reaction was continued for 1 h under ice bath. Water was added for dilution, and dichloromethane was extracted (40 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 35B (1 g, 95.58%).
  • 34D 120 mg, 0.22 mmol
  • 35B 76 mg, 0.4 mmol
  • Pd(dppf)Cl 2 18 mg, 0.022 mmol
  • potassium carbonate 61 mg, 0.44 mmol
  • the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (10 mL ⁇ 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and then by reverse phase column chromatography, and lyophilized to obtain 35 (38 mg, 31.14%).
  • 35A (1.3 g, 5.89 mmol) and 2-fluoroacrylic acid (0.8 g, 8.88 mmol) were dissolved in 25 mL of dichloromethane, followed by the addition of HATU (3.36 g, 8.83 mmol) and DIPEA (1.52 g, 11.78 mmol), and the mixture was replaced with nitrogen for protection, and reacted at room temperature for 16 h.
  • the mixture was diluted with water, extracted with dichloromethane (40 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 36A (0.8 g, 64.69%).
  • 35A (1 g, 4.56 mmol) was dissolved in 25 mL of dichloromethane, triethylamine (1.14 mL, 8.21 mmol) was added at 0°C, nitrogen was replaced for protection, methacryloyl chloride (0.51 g, 4.83 mmol) was slowly added dropwise, and the reaction was continued for 1 h under ice bath. Water was added for dilution, dichloromethane was extracted (40 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 39A (0.45 g, 47.90%).
  • the test compound was diluted with DMSO to 2.5 ⁇ the detection concentration. 4 ⁇ L of the compound was transferred to a 384 reaction plate (784075, Greiner) using an electric pipette.
  • the kinase reaction buffer (5 ⁇ Buffer, 5 mM MgCl 2 , 1 mM DTT, 1% Tween 20), prepare FGFR1 kinase solution (working concentration: 0.3nM), transfer 2 ⁇ L of kinase solution to 384 reaction plate. Centrifuge at 1000rpm for 1 minute and incubate at 25°C for 10 minutes.
  • kinase solution (working concentration: 0.6 nM) was prepared using kinase reaction buffer (5X Buffer, 5 mM Mgcl2, 1 mM DTT) and 2.5 ⁇ L of kinase solution was transferred to the 384-well plate. Centrifuge at 1000 rpm for 1 minute. 1 minute, incubate at 25°C for 10 minutes.
  • the compounds of the present invention such as the example compounds, specifically compounds 1 to 46, have good FGFR2 kinase inhibitory activity and have good selectivity for FGFR2 kinase compared to FGFR1.
  • SNU16 cells (ATCC, CRL-5974) were cultured in a CO2 incubator at 37°C for 48h using DMEM complete medium (+10% FBS). The cells were trypsinized and counted, and then the density was adjusted to 4.44 ⁇ 104 /mL. 90 ⁇ L (4000) of cells were inoculated into each well of a transparent 96-well plate at the bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 ⁇ L of the diluted compound (starting at a final concentration of 1 ⁇ M, 3-fold dilution, 11 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO.
  • the compounds of the present invention especially the compounds of the examples, specifically compounds 1 to 46, have good inhibitory activity on the proliferation of SNU16 cells.
  • KATO III cells (ATCC, HTB-103) were cultured in a CO2 incubator at 37°C for 48 h using IMDM complete medium (+10% FBS). The cells were trypsinized and counted, and then the density was adjusted to 1.67 ⁇ 104 /mL. 90 ⁇ L (1500) of cells were inoculated into each well of a 96-well plate with a transparent bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 ⁇ L of the diluted compound (starting at a final concentration of 1 ⁇ M, 3-fold dilution, 10 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO.
  • the cells were placed in a CO2 incubator at 37°C for 96 h. After the incubation, the cells were removed.
  • the kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 ⁇ L CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on an oscillator for 15 minutes (the whole process must be protected from light), and the Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well. Calculate the inhibition rate of the compound.
  • the vertical axis of the data is the percentage of inhibition rate
  • the horizontal axis is the logarithm of the sample concentration (Log 10 ).
  • Example compounds 1 to 46 have good inhibitory activity against KATO III cell proliferation, as shown in Table 3.
  • Li7 cells (Mingzhou Bio, MZ-0519) were cultured in RPMI-1640 complete medium (+10% FBS) in a CO 2 incubator at 37°C for 48 h. The cells were trypsinized and counted, and then the density was adjusted to 1.67 ⁇ 10 4 cells/mL. 90 ⁇ L (3000 cells) of cells were inoculated into each well. ) to a transparent 96-well plate at the bottom, and transfer to a CO2 incubator and culture overnight at 37°C. After the cells were incubated overnight, 10 ⁇ L of the diluted compound (starting at a final concentration of 10 ⁇ M, 3-fold dilution, 10 concentrations) was added to each well using a spray gun.
  • the test compound was a serum-free medium containing DMSO. After mixing evenly, the plate was placed in a CO2 incubator at 37°C for 96 hours. After the incubation, the cells were taken out.
  • the kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 ⁇ L CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on an oscillator for 15 minutes (the whole process must be protected from light), and the Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well. Calculate the inhibition rate of the compound.
  • the vertical axis of the data is the percentage of inhibition rate
  • the horizontal axis is the logarithm of the sample concentration (Log 10 ).
  • Example compounds 1 to compound 46 have selective inhibitory effects on SUN-16 cells and KATO III cells.
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • CYP human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (with midazolam as substrate).
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • Example Compounds 1 to 46 have no significant inhibitory effect on any subtype of CYP enzymes.
  • mice Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, 6 BALB/c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline physiological saline
  • 0.5% MC 0.5% aqueous solution of methylcellulose
  • Example Compounds 1 to 46 have good pharmacokinetic properties. Specifically, Compound 15 has good oral absorption performance and lower clearance rate in mice.
  • the control compound 1 is a control compound 1
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, 6 SD rats/compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • Example compounds 1 to 46 have good pharmacokinetic properties.
  • compound 5 has better oral absorption performance and/or lower clearance rate in rats.
  • mice Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • Test method On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 0.5% MC: (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose aqueous solution.
  • Example Compounds 1 to 46 have good oral absorption properties in beagle dogs.
  • Test animals male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
  • Test method On the test day, 4-6 monkeys/compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 0.5% MC (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% methylcellulose aqueous solution.
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline physiological saline
  • 0.5% MC 0.5% methylcellulose aqueous solution.
  • 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube.
  • the blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.
  • the blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h.
  • all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
  • Example Compounds 1 to 46 have good oral absorption properties in monkeys.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller.
  • the tip resistance after perfusion of the electrode liquid was about 2-5M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz.
  • the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s.
  • This voltage stimulus was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • Example Compounds 1 to 46 have no significant hERG inhibitory activity.
  • the first day after grouping was recorded as D1.
  • the compound was initially administered twice a day.
  • the concomitant PK was measured 0.5, 1, 4, 7, and 24 h after administration on D1, and the second administration was performed 6 h after the first administration.
  • the animal body weight was recorded and the administration record was filled in on Days 1, 2, 3, 4, and 5.
  • On D5 blood phosphorus was measured 4 h after the first administration of the day, and concomitant PK was measured 0.5, 1, 4, 7, and 24 h after administration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, a preparation method therefor, and an application in the preparation of a medicament for treating diseases related to FGFR2 activity or expression.

Description

一种嘧啶衍生物及其在医药上的应用A pyrimidine derivative and its application in medicine 技术领域Technical Field
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗FGFR2活性或表达量相关疾病的药物中的应用。The present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to FGFR2 activity or expression.
背景技术Background technique
胆道癌(BTC)是一种罕见的异质性疾病，包括胆道树中出现的各种侵袭性恶性肿瘤。BTC包括肝内胆管癌(iCCA)、肝外胆管癌(eCCA)。患者的5年总生存率一直保持在2％以下，成纤维细胞生长因子受体(FGFR)在大约15-20％的肝内胆管癌中被异常激活。Biliary tract cancer (BTC) is a rare, heterogeneous disease that includes a variety of aggressive malignancies arising in the biliary tree. BTC includes intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). The 5-year overall survival rate of patients has remained below 2%, and fibroblast growth factor receptor (FGFR) is abnormally activated in approximately 15-20% of intrahepatic cholangiocarcinoma.
FGFR2又称CD332，由位于10号染色体上的基因编码的蛋白。FGFR家族包括4种受体亚型，分别为FGFR1、FGFR3和FGFR4，以及多达22个成纤维细胞生长因子配体(FGFs)，它们是负责细胞增殖和分化的酪氨酸激酶信号通路(FGFs/FGFRs信号通路)的一部分，负责调节多个器官系统的基本发育途径，并在许多生理和病理过程中发挥重要作用，包括调节血管生成、组织稳态、伤口修复，通过调节细胞的增殖、分化、存活、迁移和代谢进行肿瘤转化。在多种实体瘤中发现了突变，以尿路上皮癌与肝内胆管癌最为常见，其中肝内胆管癌(ICC)中的融合突变占总基因突变的9％。此外，通过可变剪接编码着具有不同表达域和配体特异性的b和c。FGFR2, also known as CD332, is a protein encoded by a gene located on chromosome 10. The FGFR family includes four receptor subtypes, namely FGFR1, FGFR3 and FGFR4, and up to 22 fibroblast growth factor ligands (FGFs). They are part of the tyrosine kinase signaling pathway (FGFs/FGFRs signaling pathway) responsible for cell proliferation and differentiation, and are responsible for regulating the basic developmental pathways of multiple organ systems. They play an important role in many physiological and pathological processes, including regulating angiogenesis, tissue homeostasis, wound repair, and tumor transformation by regulating cell proliferation, differentiation, survival, migration and metabolism. Mutations have been found in a variety of solid tumors, with urothelial carcinoma and intrahepatic cholangiocarcinoma being the most common, among which fusion mutations in intrahepatic cholangiocarcinoma (ICC) account for 9% of total gene mutations. In addition, b and c with different expression domains and ligand specificity are encoded through alternative splicing.
融合、扩增和突变是多种肿瘤类型中发生的致癌驱动因素。尽管泛FGFR抑制剂观察到的临床疗效验证了融合阳性肝内胆管癌(ICC)中的驱动状态，但是FGFR1介导的毒性(高磷血症、组织矿化)和靶向耐药突变的出现限制了泛FGFR抑制剂的疗效。然而，选择性抑制剂可以降低毒性并且克服泛FGFR抑制剂获得性耐药。因此，有必要开发一种能够高选择性抑制的化合物，用于治疗融合、扩增和突变引起的相关疾病。Fusions, amplifications, and mutations are oncogenic drivers that occur in a variety of tumor types. Although the clinical efficacy observed with pan-FGFR inhibitors validates the driver status in fusion-positive intrahepatic cholangiocarcinoma (ICC), the emergence of FGFR1-mediated toxicity (hyperphosphatemia, tissue mineralization) and targeted resistance mutations limit the efficacy of pan-FGFR inhibitors. However, selective inhibitors can reduce toxicity and overcome acquired resistance to pan-FGFR inhibitors. Therefore, it is necessary to develop a compound that can inhibit with high selectivity for the treatment of related diseases caused by fusions, amplifications, and mutations.
发明内容Summary of the invention
本发明的目的就是提供一类杂环类化合物或其药学上可接受的盐，将其应用于FGFR2抑制剂。本发明中的化合物能有效抑制FGFR2并可用于治疗肿瘤等疾病。The purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which are applied as FGFR2 inhibitors. The compounds of the present invention can effectively inhibit FGFR2 and can be used to treat diseases such as tumors.
本发明化合物对FGFR2激酶具有良好的选择性和抑制活性，对肿瘤细胞具有较好的抑制活性，且在药代动力学测试中表现出优异的口服暴露量和较好的生物利用度，较好的安全性，较低的CYP抑制和hERG抑制。The compound of the present invention has good selectivity and inhibitory activity against FGFR2 kinase, has good inhibitory activity against tumor cells, and shows excellent oral exposure and good bioavailability, good safety, and lower CYP inhibition and hERG inhibition in pharmacokinetic tests.
本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
The present invention provides a compound of general formula (I) or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
在一些实施方案中，通式(I)所示的化合物选自通式(II)、通式(III)、通式(IV)、通式(V)、通 式(VI)、通式(VII)、通式(VIII)所示的化合物，
In some embodiments, the compound represented by general formula (I) is selected from general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V), The compound represented by formula (VI), general formula (VII) or general formula (VIII),
在一些实施方案中，通式(I)所示的化合物选自通式(I-a)In some embodiments, the compound represented by general formula (I) is selected from general formula (I-a)
W选自N或CH，a1选自0或1； W is selected from N or CH, a1 is selected from 0 or 1;
在一些实施方案中，通式(I)所示的化合物选自通式(I-b)In some embodiments, the compound represented by general formula (I) is selected from general formula (I-b)
W选自N或CH，q1选自0、1、2、3或4；在一些实施方案中，选自 W选自N或CH，优选 W is selected from N or CH, q1 is selected from 0, 1, 2, 3 or 4; in some embodiments, Selected from W is selected from N or CH, preferably
在一些实施方案中，环A、环B、环C各自独立的选自苯基、苯并C4-6碳环、5至6元杂芳基或8-10元并环杂芳基，所述环A任选被1至4个Ra取代，所述环B任选被1至4个Rb取代，所述环C任选被1至4个Rc取代；In some embodiments, ring A, ring B, and ring C are each independently selected from phenyl, benzoC4-6 carbocycle, 5- to 6-membered heteroaryl, or 8-10-membered cycloheteroaryl, and the ring A is optionally substituted with 1 to 4 Ra , the ring B is optionally substituted with 1 to 4 Rb , and the ring C is optionally substituted with 1 to 4 Rc ;
在一些实施方案中，环B选自苯基、萘环、苯并C4-6碳环、苯并4至6元杂环、5至6元杂芳基、8至10元并环杂芳基，所述环B任选被1至4个Rb取代；In some embodiments, ring B is selected from phenyl, naphthalene, benzoC 4-6 carbon ring, benzo 4 to 6 membered heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;
在一些实施方案中，环B选自 In some embodiments, Ring B is selected from
在一些实施方案中，环B1选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代；In some embodiments, Ring B1 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b ;
在一些实施方案中，环B1选自Q3选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；In some embodiments, Ring B1 is selected from Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
在一些实施方案中，环B1选自Q3选自C6-10芳基、5至10元杂芳基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；In some embodiments, Ring B1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
在一些实施方案中，环B1选自Q3选自苯基、吡啶基或嘧啶基，所述环B1任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述Q3任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代；In some embodiments, Ring B1 is selected from Q 3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B 1 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
在一些实施方案中，环B1选自 Q3选自 In some embodiments, Ring B1 is selected from Q 3 Selected
在一些实施方案中，B2选自C4-6碳环，B3选自C4-6碳环；In some embodiments, B 2 is selected from C 4-6 carbocycle, B 3 is selected from C 4-6 carbocycle;
在一些实施方案中，Q3选自环B1选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代； In some embodiments, Q3 is selected from Ring B1 is selected from C4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
在一些实施方案中，Q3选自环B1选自苯基、苯并C4-6碳环、苯并4至6元杂环，5至6元杂芳基、8至10元杂芳基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；In some embodiments, Q3 is selected from Ring B1 is selected from phenyl, benzo C4-6 carbocycle, benzo 4 to 6-membered heterocycle, 5 to 6-membered heteroaryl, 8 to 10-membered heteroaryl, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
在一些实施方案中，Q3选自环B1选自苯基或吡啶基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；在一些实施方案中，Q3选自 环B1选自 In some embodiments, Q3 is selected from Ring B 1 is selected from phenyl or pyridinyl, said ring B 1 is optionally substituted by 1 to 4 R b , said Q 3 is optionally substituted by 1 to 4 R k ; in some embodiments, Q 3 is selected from Ring B 1 is selected from
在一些实施方案中，环A、环B各自独立的选自苯基、吡啶、嘧啶，所述环A任选被1至4个Ra取代，所述环B任选被1至4个Rb取代；在一些实施方案中，环C选自吡咯、嘧啶、7H-吡咯[2,3-d]嘧啶；在一些实施方案中，环A选自W选自N或CH；In some embodiments, ring A and ring B are each independently selected from phenyl, pyridine, pyrimidine, and ring A is optionally substituted by 1 to 4 Ra , and ring B is optionally substituted by 1 to 4 Rb ; in some embodiments, ring C is selected from pyrrole, pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine; in some embodiments, ring A is selected from W is selected from N or CH;
环A优选在一些实施方案中，选自 Ring A is preferred In some embodiments, Selected from
在一些实施方案中，环B选自或环B1；在一些实施方案中，环B选自 在一些实施方案中，环B选自在一些实施方案中，选自 In some embodiments, Ring B is selected from or Ring B1; In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Selected from
在一些实施方案中，环C选自 In some embodiments, Ring C is selected from
在一些实施方案中，环C选自 In some embodiments, Ring C is selected from
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，F1或F2选自N或CH；In some embodiments, F1 or F2 is selected from N or CH;
在一些实施方案中，Q选自键、-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、C4-10碳环、4至10元杂环，所述的碳环或杂环任选被1至4个Rk取代；In some embodiments, Q is selected from a bond, -O-, -N(R q3 )-, -C(═O)N(R q3 )-, -N(R q3 )C(═O), -C(═O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Q选自-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、C4-10碳环、4至10元杂环，所述的碳环或杂环任选被1至4个Rk取代；In some embodiments, Q is selected from -O-, -N(R q3 )-, -C(═O)N(R q3 )-, -N(R q3 )C(═O), -C(═O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Q选自苯基、萘基、苯并C4-6碳环、苯并4至6元杂环、-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-，所述的苯基、萘基、苯并C4-6碳环、苯并4至6元杂环任选被1至4个Rk取代；In some embodiments, Q is selected from Phenyl, naphthyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, -O-, -N(R q3 )-, -C(＝O)N(R q3 )-, -N(R q3 )C(＝O), -C(＝O)-, wherein the phenyl, naphthyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Q选自 -O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-，所述 任选被1至4个Rk取代；In some embodiments, Q is selected from -O-, -NH-, -N(CH 3 )-, -C(=O)NH-, -NHC(=O), -C(=O)-, the Optionally substituted with 1 to 4 R k ;
在一些实施方案中，Q选自 -O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-；In some embodiments, Q is selected from -O-, -NH-, -N(CH 3 )-, -C(═O)NH-, -NHC(═O), -C(═O)-;
在一些实施方案中，Q选自Q1；In some embodiments, Q is selected from Q 1 ;
在一些实施方案中，Q1选自-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、 In some embodiments, Q1 is selected from -O-, -N( Rq3 )-, -C(=O)N( Rq3 )-, -N( Rq3 )C(=O), -C(=O)-,
在一些实施方案中，Q1选自-O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-、 In some embodiments, Q 1 is selected from -O-, -NH-, -N(CH 3 )-, -C(=O)NH-, -NHC(=O), -C(=O)-,
在一些实施方案中，m选自0或1；In some embodiments, m is selected from 0 or 1;
在一些实施方案中，Rq1、Rq2、Rq3各自独立的选自H、C1-6烷基，所述的烷基任选被1至4个Rk取代；In some embodiments, R q1 , R q2 , and R q3 are each independently selected from H, C 1-6 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rq1、Rq2、Rq3各自独立的选自H、C1-4烷基，所述的烷基任选被1至4个Rk取代；In some embodiments, R q1 , R q2 , and R q3 are each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rq1、Rq2、Rq3各自独立的选自H、甲基、乙基； In some embodiments, R q1 , R q2 , and R q3 are each independently selected from H, methyl, and ethyl;
在一些实施方案中，D选自键、-NRn1-、所述D任选被1至6个Rd取代，D1或D2右侧与R1直接连接；In some embodiments, D is selected from a bond, -NR n1 -, The D is optionally substituted by 1 to 6 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
Q与D不能同时为键；Q and D cannot be bonds at the same time;
在一些实施方案中，D选自-NRn1-、所述D任选被1至4个Rd取代，D1或D2右侧与R1直接连接；In some embodiments, D is selected from -NR n1 -, The D is optionally substituted by 1 to 4 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
在一些实施方案中，D选自-NRn1-，Q选自 In some embodiments, D is selected from -NR n1 -, Q is selected from
在一些实施方案中，D选自-NH-、-N(Rn1)-、或者任选被1至4个Rd取代的如下基团之一： 右侧与R1直接连接；In some embodiments, D is selected from -NH-, -N( Rn1 )-, or one of the following groups optionally substituted by 1 to 4 R d : The right side is directly connected to R 1 ;
Q与D的连接键不能形成N-N、N-O；The bond between Q and D cannot form N-N or N-O;
在一些实施方案中，通式(VI)中-D-选自 In some embodiments, -D- in Formula (VI) is selected from
在一些实施方案中，通式(VII)中D选自-NH-；In some embodiments, in Formula (VII), D is selected from -NH-;
在一些实施方案中，D1选自4至14元含氮杂环基；In some embodiments, D 1 is selected from a 4- to 14-membered nitrogen-containing heterocyclic group;
在一些实施方案中，D1选自4至7元含氮杂单环烷基、4至7元含氮杂单环烯基、5至14元含氮杂螺环烷基、5至14元含氮杂并环烷基、5至14元含氮杂桥环烷基；In some embodiments, D1 is selected from 4 to 7 membered nitrogen-containing heteromonocycloalkyl, 4 to 7 membered nitrogen-containing heteromonocycloalkenyl, 5 to 14 membered nitrogen-containing heterospirocycloalkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;
在一些实施方案中，D1选自 In some embodiments, D1 is selected from
在一些实施方案中，D2选自C3-14碳环基、4至14元杂环基；In some embodiments, D 2 is selected from C 3-14 carbocyclyl, 4 to 14 membered heterocyclyl;
在一些实施方案中，D2选自苯基、苯并C4-7碳环基、苯并4至7元杂环基、5至6元杂芳基、C3-7单环烷基、C3-7单环烯基、C5-14螺环烷基、C5-14并环烷基、C5-14桥环烷基、4至7元含氮杂单环基、5至14元含氮杂螺环基、5至14元含氮杂并环基、5至14元含氮杂桥环基；In some embodiments, D2 is selected from phenyl, benzo C4-7 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl, C3-7 monocycloalkyl, C3-7 monocycloalkenyl, C5-14 spirocycloalkyl, C5-14 cycloalkyl, C5-14 bridged cycloalkyl, 4 to 7 membered nitrogen-containing heteromonocyclyl, 5 to 14 membered nitrogen-containing heterospirocyclyl, 5 to 14 membered nitrogen-containing heterocyclocyclyl, 5 to 14 membered nitrogen-containing heterobridged cyclyl;
在一些实施方案中，D2选自 苯基、苯并C4-6碳环基、苯并4至6元杂环基、5至6元杂芳基；In some embodiments, D2 is selected from Phenyl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;
在一些实施方案中，D3选自C7-14碳环基；In some embodiments, D3 is selected from C7-14 carbocyclyl;
在一些实施方案中，D3选自苯并C4-7碳环基、C7-14螺环烷基、C7-14并环烷基、C7-14桥环烷基； In some embodiments, D 3 is selected from benzo C 4-7 carbocyclyl, C 7-14 spirocycloalkyl, C 7-14 cycloalkyl, C 7-14 bridged cycloalkyl;
在一些实施方案中，D3选自 In some embodiments, D3 is selected from
在一些实施方案中，D3选自任选被1至4个Rd取代的如下基团之一： In some embodiments, D3 is selected from one of the following groups optionally substituted with 1 to 4 Rd :
在一些实施方案中，n1、n3、n5各自独立的选自0、1或2；In some embodiments, n1, n3, n5 are each independently selected from 0, 1 or 2;
在一些实施方案中，n2、n4各自独立的选自0或1；In some embodiments, n2 and n4 are each independently selected from 0 or 1;
在一些实施方案中，n6自0、1、2或3；在一些实施方案中，Rn1选自H、C1-4烷基；In some embodiments, n6 is selected from 0, 1, 2 or 3; In some embodiments, R n1 is selected from H, C 1-4 alkyl;
在一些实施方案中，Rn1选自H、甲基、乙基；In some embodiments, R n1 is selected from H, methyl, ethyl;
在一些实施方案中，Ra、Rb、Rc、Rd各自独立的选自H、氘、卤素、CN、OH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、-OC1-6烷基、-SC1-6烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-NH-5至6元杂芳基-C1-4烷基、-NH-3至7元杂环-C3-6碳环、-NH-3至7元杂环-4至6元杂环、-C1-4亚烷基-C3-6碳环、-C1-4亚烷基-3至7元杂环、-C(＝O)NH2、-C(＝O)NH-C1-6烷基、-C(＝O)NH-C3-6碳环、-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6碳环、C3-6碳环、3至7元杂环，所述烷基、亚烷基、烯基、炔基、杂芳基、碳环或杂环任选被1至4个Rk取代；In some embodiments, Ra , Rb , Rc , and Rd are each independently selected from H, deuterium, halogen, CN, OH, NH2 , NHC1-6 alkyl, N( C1-6 alkyl) 2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OC1-6 alkyl, -SC1-6 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -NH-5 to 6 membered heteroaryl- C1-4 alkyl, -NH-3 to 7 membered heterocycle- C3-6 carbocycle, -NH-3 to 7 membered heterocycle-4 to 6 membered heterocycle, -C1-4 alkylene- C3-6 carbocycle, -C1-4 alkylene-3 to 7 membered heterocycle, -C(=O) NH2 , -C(=O)NH-C R k is substituted with 1 to 4 R k ;
在一些实施方案中，Ra、Rb、Rd各自独立的选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-C(＝O)NH-C1-6烷基、-C(＝O)NH-C3-6碳环、C3-6碳环、3至7元杂环，所述烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；In some embodiments, Ra , Rb , and Rd are each independently selected from deuterium, halogen, CN, OH , NH2, NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH -3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, -C(=O)NH- C1-6 alkyl, -C(=O)NH- C3-6 carbocycle, C3-6 carbocycle, 3 to 7 membered heterocycle, and the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 Rk ;
在一些实施方案中，Ra、Rb、Rd各自独立的选自氘、F、Cl、Br、I、氰基、OH、NH2、NH(CH3)、N(CH3)2、CF3、甲基、乙基、丙基、异丙基、丁基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基；In some embodiments, Ra , Rb , and Rd are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2 , NH( CH3 ), N( CH3 ) 2 , CF3 , methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
在一些实施方案中，Ra各自独立的选自氘、F、Cl、Br、氰基、CF3、甲基；In some embodiments, each Ra is independently selected from deuterium, F, Cl, Br, cyano, CF3 , methyl;
在一些实施方案中，Rb各自独立的选自氘、F、Cl、Br、氰基、CF3、甲基；In some embodiments, each R b is independently selected from deuterium, F, Cl, Br, cyano, CF 3 , methyl;
在一些实施方案中，Rd各自独立的选自氘、F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、 丙基、异丙基、甲氧基、乙氧基；In some embodiments, each R d is independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, Propyl, isopropyl, methoxy, ethoxy;
在一些实施方案中，Rc1选自H、C1-4烷基、C3-6环烷基或4至7元杂环烷基，所述烷基、环烷基或杂环烷基任选被1至4个Rk取代；In some embodiments, R c1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl, or heterocycloalkyl being optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc1选自H、C1-4烷基或C3-6环烷基，所述烷基或环烷基任选被1至4个Rk取代；In some embodiments, R c1 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc1选自H、甲基、乙基、环丙基、环丁基、环戊基或环己基，所述甲基、乙基、环丙基、环丁基、环戊基或环己基任选被1至4个Rk取代；In some embodiments, R c1 is selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc1选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个Rk取代；In some embodiments, R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc1选自CD3、CF3、甲基、乙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、 In some embodiments, R c1 is selected from CD 3 , CF 3 , methyl, ethyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
在一些实施方案中，Rc1选自CD3、CF3、甲基、乙基、丙基、异丙基、环丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、 In some embodiments, R c1 is selected from CD 3 , CF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
在一些实施方案中，Rc2各自独立的选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-C(＝O)NH-C1-4烷基、-C(＝O)NH-C3-6碳环、-NHC(＝O)-C1-4烷基、-NHC(＝O)-C3-6碳环、C3-6碳环、3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；In some embodiments, R c2 is each independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -C(＝O)NH-C 1-4 alkyl, -C(＝O)NH-C 3-6 carbocycle, -NHC(＝O)-C 1-4 alkyl, -NHC(＝O)-C 3-6 carbocycle, C 3-6 carbocyclic ring, 3-7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Rc2各自独立的选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、-O-环丙基、-NH-环丙基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-C(＝O)NH-甲基、-C(＝O)NH-乙基、-C(＝O)NH-环丙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、吡唑、咪唑、噁唑、噻唑，所述的甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、吡唑、咪唑、噁唑、噻唑任选被1至4个Rk取代； In some embodiments, each R c2 is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole, the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole are optionally substituted by 1 to 4 R k replaces;
在一些实施方案中，Rc2选自氘、F、Cl、Br、OH、CN、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑、-C(＝O)NH-甲基、-C(＝O)NH-乙基、-C(＝O)NH-环丙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基，所述的甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基、吡唑、咪唑、噁唑、噻唑、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基的取代基所取代；In some embodiments, R c2 is selected from deuterium, F, Cl, Br, OH, CN, NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)NH- )-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, wherein the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazole, imidazole, oxazole, thiazole, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 , N ( CH2CH3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
在一些实施方案中，Rc3各自独立的选自H、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；In some embodiments, R c3 is each independently selected from H, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle, 3 to 7 membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc3各自独立的选自H、NH2、-C(＝O)NH2、甲基、乙基、环丙基、环丁基、环戊基；In some embodiments, R c3 is each independently selected from H, NH 2 , -C(=O)NH 2 , methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl;
在一些实施方案中，Rc3各自独立的选自H、NH2或-C(＝O)NH2；In some embodiments, each R c3 is independently selected from H, NH 2 or -C(=O)NH 2 ;
在一些实施方案中，Rc4选自H、NH2、卤素、CN、OH、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；在一些实施方案中，Rc4选自H、NH2、F、Cl、Br、I、CN、甲基、乙基、乙炔基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑，所述的甲基、乙基、乙炔基、吡唑、咪唑、噁唑、噻唑任选被1至4个Rk取代；In some embodiments, R c4 is selected from H, NH 2 , halogen, CN, OH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k ; in some embodiments, R c4 is selected from H, NH 2 , F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Rc4选自H、NH2、卤素、CN、C1-4烷基、C2-4炔基或-NH-5至6元杂芳环，所述的烷基、炔基或杂芳环任选被1至4个Rk取代；In some embodiments, R c4 is selected from H, NH 2 , halogen, CN, C 1-4 alkyl, C 2-4 alkynyl, or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc4选自H、NH2、F、CN、甲基、 In some embodiments, R c4 is selected from H, NH 2 , F, CN, methyl,
在一些实施方案中，Rc5选自H、氘、卤素、CN、羟基、NH2、-NHC1-4烷基、-NH-C3-7碳环、-NH-3至7元杂环、C1-4烷基、C1-4烷氧基、C3-6环烷基、-NH-5至6元杂芳基-C1-3亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述烷基、亚烷基、烷氧基、环烷基、碳环基、杂环基、杂芳基任选地被1至4个Rk取代；In some embodiments, R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1-4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc5选自-NH-C3-6碳环、-NH-3至6元杂环、-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述烷基、亚烷基、烷氧基、环烷基、碳环基、杂环基、杂芳基任选地被1至4个Rk取代；In some embodiments, R c5 is selected from -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc5选自-NH-C3-6碳环、-NH-吡唑、-NH-吡咯、-NH-咪唑、-NH-三氮唑、-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述的5至6元杂芳基选自吡唑基、吡咯基、咪唑基或三氮唑基，所述 亚烷基、碳环基、杂环基、杂芳基、吡唑基、吡咯基、咪唑基或三氮唑基任选地被1至4个Rk取代；In some embodiments, R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the Alkylene, carbocyclyl, heterocyclyl, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc5选自 In some embodiments, R c5 is selected from
在一些实施方案中，Rc6选自H、卤素、OH、NH2、C1-4烷基、CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环或3至7元杂环，所述烷基、亚烷基、烯基、炔基、碳环、杂环、任选地被1至4个Rk取代；In some embodiments, R c6 is selected from H, halogen, OH, NH 2 , C 1-4 alkyl, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle or 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle, heterocycle, is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc6选自H、卤素、OH、NH2、C1-4烷基、CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-4至6元杂环、-O-C3-6碳环、-O-4至6元杂环、C3-6碳环或4至7元杂环烷环，所述烷基、亚烷基、烯基、炔基、碳环、杂环、杂环烷环任选地被1至4个Rk取代；In some embodiments, R c6 is selected from H, halogen, OH, NH 2 , C 1-4 alkyl, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-4 to 6 membered heterocycle, -OC 3-6 carbocycle, -O-4 to 6 membered heterocycle, C 3-6 carbocycle or 4 to 7 membered heterocycloalkane ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle, heterocycle, heterocycloalkane ring is optionally substituted with 1 to 4 R k ;
在一些实施方案中，Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基、乙基、CN、乙炔基、-CH2-乙炔基、丙炔基、甲氧基、乙氧基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基，所述甲基、乙基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、环丁基或环戊基任选地被1至4个Rk取代；In some embodiments, R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl, ethyl, CN, ethynyl, -CH 2 -ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, said methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl being optionally substituted with 1 to 4 R k ;
在一些实施方案中，当Rc6选自H、卤素、OH、NH2或C1-4烷基时，Rc5选自-NH-5至6元杂芳基-C1-3亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述的烷基、杂芳基、亚烷基、碳环基或杂环基任选被1至3个Rk取代；In some embodiments, when R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, heteroaryl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 3 R k ;
在一些实施方案中，当Rc6选自H、卤素、OH、NH2或C1-4烷基时，Rc5选自-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6环烷基-Rc5a、-NH-5至6元杂芳基-4至6元杂环烷基-Rc5a，所述的烷基、杂芳基、亚烷基、环烷基或杂环烷基任选被1至3个Rk取代；In some embodiments, when R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , wherein the alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
在一些实施方案中，当Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基或乙基时，Rc5选自-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6环烷基-Rc5a、-NH-5至6元杂芳基-4至6元杂环烷基-Rc5a，所述的5至6元杂芳基选自吡唑基、吡咯基、咪唑基或三氮唑基，所述的杂芳基、亚烷基、环烷基或杂环烷基任选被1至3个Rk取代；In some embodiments, when R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
在一些实施方案中，当Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基或乙基时，Rc5选 自 In some embodiments, when R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from since
在一些实施方案中，当Rc6选自CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环或3至7元杂环时，Rc5选自H、氘、卤素、CN、羟基、NH2、-NHC1-4烷基、-NH-C3-7碳环、-NH-3至7元杂环、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述烷基、亚烷基、烯基、炔基、烷氧基、环烷基、碳环、杂环任选地被1至4个Rk取代；In some embodiments, when R c6 is selected from CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle or 3 to 7 membered heterocycle, R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1 - 4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocycle, heterocycle are optionally substituted with 1 to 4 R k ;
在一些实施方案中，当Rc6选自CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-4至6元杂环、-O-C3-6碳环、-O-4至6元杂环、C3-6环烷基或4至7元杂环烷环时，Rc5选自-NH-C3-6碳环、-NH-5至6元杂芳环，所述烷基、亚烷基、烯基、炔基、烷氧基、碳环、杂环、环烷基或杂环烷基任选地被1至4个Rk取代；In some embodiments, when R c6 is selected from CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-4 to 6 membered heterocycle, -OC 3-6 carbocycle, -O-4 to 6 membered heterocycle, C 3-6 cycloalkyl or 4 to 7 membered heterocycloalkyl ring, R c5 is selected from -NH-C 3-6 carbocycle, -NH-5 to 6 membered heteroaryl ring, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, carbocycle, heterocycle, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，当Rc6选自CN、乙炔基、-CH2-乙炔基、丙炔基、甲氧基、乙氧基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基时，Rc5选自-NH-C3-6碳环、-NH-吡唑、-NH-吡咯、-NH-咪唑、-NH-三氮唑，所述的CH2、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、吡唑基、吡咯基、咪唑基或三氮唑基任选地被1至4个Rk取代；In some embodiments, when R c6 is selected from CN, ethynyl, -CH 2 -ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, and the CH 2 , ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
在一些实施方案中，当Rc6选自CN、乙炔基、-CH2-乙炔基、丙炔基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基时，Rc5选自 In some embodiments, when R c6 is selected from CN, ethynyl, -CH 2 -ethynyl, propynyl, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl, or cyclopentyl, R c5 is selected from
在一些实施方案中，Rc7选自H或Rc2；In some embodiments, R c7 is selected from H or R c2 ;
在一些实施方案中，Rc5a选自CN、-O-C1-3烷基、-S-C1-3烷基、C3-6碳环、-O-C3-6碳环、4至6元杂环、-O-4至6元杂环、-C(＝O)C3-6碳环、-C(＝O)-4至6元杂环，所述的烷基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In some embodiments, R c5a is selected from CN, -OC 1-3 alkyl, -SC 1-3 alkyl, C 3-6 carbocycle, -OC 3-6 carbocycle, 4 to 6 membered heterocycle, -O-4 to 6 membered heterocycle, -C(=O)C 3-6 carbocycle, -C(=O)-4 to 6 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
在一些实施方案中，Rc5a选自CN或任选取代的如下基团之一：-O-甲基、-O-乙基、-S-甲基、-S-乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-O-环丙基、-O-环丁基、-O-环戊基、-O-环己基、-O-氮杂环丁基、-O-氮杂环戊基、-O-氮杂环己基、-C(＝O)-环丙基、-C(＝O)-环丁基、-C(＝O)-环戊基、-C(＝O)-环己 基、-C(＝O)-氮杂环丁基、-C(＝O)-氮杂环戊基、-C(＝O)-氮杂环己基、-C(＝O)-氧杂环丁基、-C(＝O)-氧杂环戊基、-C(＝O)-氧杂环己基，当被取代时，被1至4个选自氘、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、甲氧基或乙氧基的取代基所取代；In some embodiments, R c5a is selected from CN or one of the following groups which are optionally substituted: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl. -C(=O)-azetidinyl, -C(=O)-aziridinyl, -C(=O)-azetidinyl, -C(=O)-azetidinyl, -C(=O)-azetidinyl, -C(=O)-oxadienyl, -C(=O)-oxadienyl, -C(=O)-oxadienyl, when substituted, are substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2 , methyl, ethyl, methoxy or ethoxy;
在一些实施方案中，Rc5a选自CN、-O-甲基、-O-乙基、-S-甲基、-S-乙基、环丙基、 In some embodiments, R c5a is selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,
在一些实施方案中，p1或p2选自0、1、2或3；在一些实施方案中，p1或p2选自0、1或2；In some embodiments, p1 or p2 is selected from 0, 1, 2, or 3; In some embodiments, p1 or p2 is selected from 0, 1, or 2;
在一些实施方案中，R1选自卤素、CN、 In some embodiments, R 1 is selected from halogen, CN,
在一些实施方案中，R1选自CN、 In some embodiments, R 1 is selected from CN,
在一些实施方案中，R1选自 In some embodiments, R is selected from
在一些实施方案中，-D-R1选自 In some embodiments, -DR 1 is selected from
在一些实施方案中，R1a、R1b、R1c、R1d各自独立的选自H、氘、卤素、CN、-C(＝O)R、-C(＝O)OR、-C(＝O)N(R)2、C(＝O)N(R)OR、C1-6烷基、C2-6烯基、C2-6炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；In some embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, -C(＝O)R, -C(＝O)OR, -C(＝O)N(R) 2 , C(＝O)N(R)OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle, or heterocycle is optionally substituted with 1 to 4 R k ;
在一些实施方案中，R1a、R1b、R1c、R1d各自独立的选自H、氘、卤素、CN、C1-4烷基、C2-4烯基、C2-4炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；In some embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, and 3-7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle, or heterocycle is optionally substituted with 1 to 4 R k ;
在一些实施方案中，R1e选自卤素或-OS(＝O)2R；In some embodiments, R 1e is selected from halogen or -OS(=O) 2 R;
在一些实施方案中，R1e选自卤素或-OS(＝O)2C1-4烷基，所述烷基任选被1至4个Rk取代；In some embodiments, R 1e is selected from halogen or -OS(=O) 2 C 1-4 alkyl, which is optionally substituted with 1 to 4 R k ;
在一些实施方案中，R选自H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；In some embodiments, R is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k ;
在一些实施方案中，R1e选自F、Cl、Br、I、-OS(＝O)2CH3、-OS(＝O)2CF3；In some embodiments, R 1e is selected from F, Cl, Br, I, -OS(=O) 2 CH 3 , -OS(=O) 2 CF 3 ;
在一些实施方案中，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；In some embodiments, R 1b and R 1c , R 1a and R 1b are directly connected to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Rn1与Rd直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；In some embodiments, R n1 and R d are directly connected to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, which is optionally substituted by 1 to 4 R k ;
在一些实施方案中，Rk选自氘、卤素、CN、OH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、-OC1-6烷基、-SC1-6烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C(＝O)-C3-6碳环、-C(＝O)-3至7元杂环、-C1-4亚烷基-C3-6碳环、-C1-4亚烷基-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；In some embodiments, Rk is selected from deuterium, halogen, CN, OH, NH2 , NHC1-6 alkyl, N( C1-6 alkyl) 2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OC1-6 alkyl, -SC1-6 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C(=O) -C3-6 carbocycle, -C(=O)-3 to 7 membered heterocycle, -C1-4 alkylene -C3-6 carbocycle , -C1-4 alkylene-3 to 7 membered heterocycle, C3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 members selected from deuterium, halogen, CN, OH, NH2 , C1-6 alkyl, C substituted by 1-6 alkoxy substituents;
在一些实施方案中，Rk选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；In some embodiments, Rk is selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl , C2-4 alkenyl , C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, C3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy;
在一些实施方案中，Rk选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、甲硫基、-O-环丙基、-NH-环丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取 代；In some embodiments, Rk is selected from deuterium, F, Cl, Br, I, CN, OH, NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 , N (CH2CH3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy , ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 1 to 4 substituents selected from halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy generation;
在一些实施方案中，通式(I-a)的定义与通式(VIII)或通式(VII)中定义相同；In some embodiments, Formula (Ia) Definition and general formula (VIII) Or general formula (VII) Same as defined in;
在一些实施方案中，通式(VIII)中 In some embodiments, the general formula (VIII) middle
作为本发明的第一种实施方案，下述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
As a first embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,
环A、环B、环C各自独立的选自苯基、苯并C4-6碳环、5至6元杂芳基或8-10元并环杂芳基，所述环A任选被1至4个Ra取代，所述环B任选被1至4个Rb取代，所述环C任选被1至4个Rc取代；Ring A, Ring B, and Ring C are each independently selected from phenyl, benzoC 4-6 carbocycle, 5- to 6-membered heteroaryl, or 8-10-membered cycloheteroaryl, wherein Ring A is optionally substituted by 1 to 4 Ra , Ring B is optionally substituted by 1 to 4 Rb , and Ring C is optionally substituted by 1 to 4 Rc ;
Q选自键、-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、C4-10碳环、4至10元杂环，所述的碳环或杂环任选被1至4个Rk取代；Q is selected from the key, -O-, -N(R q3 )-, -C(═O)N(R q3 )-, -N(R q3 )C(═O), -C(═O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
m选自0或1；m is selected from 0 or 1;
Rq1、Rq2、Rq3各自独立的选自H、C1-6烷基，所述的烷基任选被1至4个Rk取代；R q1 , R q2 , and R q3 are each independently selected from H, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k ;
D选自键、-NRn1-、所述D任选被1至6个Rd取代，D1或D2右侧与R1直接连接；D is selected from a bond, -NR n1 -, The D is optionally substituted by 1 to 6 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
Q与D不能同时为键；Q and D cannot be bonds at the same time;
Q与D的连接键不能形成N-N、N-O；The bond between Q and D cannot form N-N or N-O;
D1选自4至14元含氮杂环基； D1 is selected from 4 to 14-membered nitrogen-containing heterocyclic groups;
D2选自C3-14碳环基、4至14元杂环基； D2 is selected from C3-14 carbocyclyl, 4 to 14 membered heterocyclyl;
D3选自C7-14碳环基； D3 is selected from C7-14 carbocyclic group;
Rn1选自H、C1-4烷基；R n1 is selected from H, C 1-4 alkyl;
Ra、Rb、Rc、Rd各自独立的选自H、氘、卤素、CN、OH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、-OC1-6烷基、-SC1-6烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-NH-5至6元杂芳基-C1-4烷基、-NH-3至7元杂环-C3-6碳环、-NH-3至7元杂环-4至6元杂环、-C1-4亚烷基-C3-6碳环、-C1-4亚烷基-3至7元杂环、-C(＝O)NH2、-C(＝O)NH-C1-6烷基、-C(＝O)NH-C3-6碳环、-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6碳环、C3-6碳环、3至7元杂环，所述烷基、亚烷基、烯基、炔基、杂芳基、碳环或杂环任选被1至4个Rk取代； Ra , Rb , Rc , and Rd are each independently selected from H, deuterium, halogen, CN, OH , NH2, NHC1-6 alkyl, N( C1-6 alkyl) 2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OC1-6 alkyl, -SC1-6 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH -C3-6 carbocycle , -NH-3 to 7 membered heterocycle, -NH-5 to 6 membered heteroaryl- C1-4 alkyl, -NH-3 to 7 membered heterocycle- C3-6 carbocycle, -NH-3 to 7 membered heterocycle-4 to 6 membered heterocycle, -C1-4 alkylene- C3-6 carbocycle, -C1-4 alkylene-3 to 7 membered heterocycle, -C(=O) NH2 , -C(=O)NH-C R k is substituted with 1 to 4 R k ;
R1选自卤素、CN、 R1 is selected from halogen, CN,
R1a、R1b、R1c、R1d各自独立的选自H、氘、卤素、CN、-C(＝O)R、-C(＝O)OR、-C(＝O)N(R)2、C(＝O)N(R)OR、C1-6烷基、C2-6烯基、C2-6炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, -C(═O)R, -C(═O)OR, -C(═O)N(R) 2 , C(═O)N(R)OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
R1e选自卤素或-OS(＝O)2R；R 1e is selected from halogen or -OS(=O) 2 R;
R选自H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
作为选择，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
作为选择，Rn1与Rd直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R n1 and R d are directly linked to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
Rk选自氘、卤素、CN、OH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、-OC1-6烷基、-SC1-6烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C(＝O)-C3-6碳环、-C(＝O)-3至7元杂环、-C1-4亚烷基-C3-6碳环、-C1-4亚烷基-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代。R k is selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C(＝O)-C 3-6 carbocycle, -C(＝O)-3 to 7 membered heterocycle, -C 1-4 alkylene-C 3-6 carbocycle, -C 1-4 alkylene-3 to 7 membered heterocycle, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 members selected from deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C The moiety is substituted by 1-6 alkoxy substituents.
作为本发明的第二种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，通式(I)所示的化合物选自通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)、通式(VIII)所示的化合物，

As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I) is selected from the compounds represented by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII) and general formula (VIII),

环B选自苯基、萘环、苯并C4-6碳环、苯并4至6元杂环、5至6元杂芳基、8至10元并环杂芳基，所述环B任选被1至4个Rb取代；Ring B is selected from phenyl, naphthalene, benzoC 4-6 carbon ring, benzo 4-6 membered heterocyclic ring, 5-6 membered heteroaryl, 8-10 membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;
Q3选自C4-10碳环、4至10元杂环，所述Q3任选被1至4个Rk取代；Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said Q 3 is optionally substituted by 1 to 4 R k ;
环B1选自Q3选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Ring B 1 is selected from Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
B2选自C4-6碳环，B3选自C4-6碳环； B2 is selected from C4-6 carbocyclic ring, B3 is selected from C4-6 carbocyclic ring;
或者Q3选自环B1选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Or Q3 is selected from Ring B1 is selected from C4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
环C选自 Ring C is selected from
F1或F2选自N或CH； F1 or F2 is selected from N or CH;
Q选自-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、C4-10碳环、4至10元杂环，所述的碳环或杂环任选被1至4个Rk取代；Q is selected from -O-, -N(R q3 )-, -C(═O)N(R q3 )-, -N(R q3 )C(═O), -C(═O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
Q1选自-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、任选被1至4个Rk取代的 Q1 is selected from -O-, -N( Rq3 )-, -C(=O)N( Rq3 )-, -N( Rq3 )C(=O), -C(=O)-, optionally substituted with 1 to 4 Rk
D选自-NRn1-、所述D任选被1至4个Rd取代，D1或D2右侧与R1直接连接；D is selected from -NR n1 -, The D is optionally substituted by 1 to 4 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
D1选自4至7元含氮杂单环烷基、4至7元含氮杂单环烯基、5至14元含氮杂螺环烷基、5至14元含氮杂并环烷基、5至14元含氮杂桥环烷基； D1 is selected from 4 to 7 membered nitrogen-containing heteromonocyclic alkyl, 4 to 7 membered nitrogen-containing heteromonocyclic alkenyl, 5 to 14 membered nitrogen-containing heterospirocyclic alkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;
D2选自苯基、苯并C4-7碳环基、苯并4至7元杂环基、5至6元杂芳基、C3-7单环烷基、C3-7单环烯基、C5-14螺环烷基、C5-14并环烷基、C5-14桥环烷基、4至7元含氮杂单环基、5至14元含氮杂螺环基、5至14元含氮杂并环基、5至14元含氮杂桥环基； D2 is selected from phenyl, benzo C4-7 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl, C3-7 monocycloalkyl, C3-7 monocycloalkenyl, C5-14 spirocycloalkyl , C5-14 cycloalkyl, C5-14 bridged cycloalkyl, 4 to 7 membered nitrogen-containing heteromonocyclic group, 5 to 14 membered nitrogen-containing heterospirocyclic group, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged ring group;
D3选自苯并C4-7碳环基、C7-14螺环烷基、C7-14并环烷基、C7-14桥环烷基； D3 is selected from benzo C4-7 carbocyclyl, C7-14 spirocycloalkyl, C7-14 cycloalkyl, C7-14 bridged cycloalkyl;
Rc1选自H、C1-4烷基、C3-6环烷基或4至7元杂环烷基，所述烷基、环烷基或杂环烷基任选被1至4个Rk取代；R c1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl or 4 to 7 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
Rc2各自独立的选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-C(＝O)NH-C1-4烷基、-C(＝O)NH-C3-6碳环、-NHC(＝O)-C1-4烷基、-NHC(＝O)-C3-6碳环、C3-6碳环、3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R c2 is each independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -C(＝O)NH-C 1-4 alkyl, -C(＝O)NH-C 3-6 carbocycle, -NHC(＝O)-C 1-4 alkyl, -NHC(＝O)-C 3-6 carbocycle, C 3-6 carbocyclic ring, 3-7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
Rc3各自独立的选自H、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R c3 is each independently selected from H, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
Rc4选自H、NH2、卤素、CN、OH、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R c4 is selected from H, NH 2 , halogen, CN, OH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
Rc5选自H、氘、卤素、CN、羟基、NH2、-NHC1-4烷基、-NH-C3-7碳环、-NH-3至7元杂环、C1-4烷基、C1-4烷氧基、C3-6环烷基、-NH-5至6元杂芳基-C1-3亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述烷基、亚烷基、烷氧基、环烷基、碳环基、杂环基、杂芳基任选地被1至4个Rk取代；R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1-4 alkyl, -NH-C 3-7 carbocycle , -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -NH-5 to 6 membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6 membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6 membered heteroaryl-4 to 6 membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
Rc6选自H、卤素、OH、NH2、C1-4烷基、CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环或3至7元杂环，所述烷基、亚烷基、烯基、炔基、烷氧基、环烷基、碳环、杂环任选地被1至4个Rk取代；R c6 is selected from H, halogen, OH, NH 2 , C 1-4 alkyl, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle or 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocycle, heterocycle is optionally substituted with 1 to 4 R k ;
当Rc6选自H、卤素、OH、NH2或C1-4烷基时，Rc5选自-NH-5至6元杂芳基-C1-3亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述的烷基、杂芳基、亚烷基、碳环基或杂环基任选被1至3个Rk取代；When R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , and the alkyl, heteroaryl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 3 R k ;
Rc5a选自CN、-O-C1-3烷基、-S-C1-3烷基、C3-6碳环、-O-C3-6碳环、4至6元杂环、-O-4至6元杂环、-C(＝O)C3-6碳环、-C(＝O)-4至6元杂环，所述的烷基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R c5a is selected from CN, -OC 1-3 alkyl, -SC 1-3 alkyl, C 3-6 carbocycle, -OC 3-6 carbocycle, 4- to 6-membered heterocycle, -O-4- to 6-membered heterocycle, -C(=O)C 3-6 carbocycle, -C(=O)-4- to 6-membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
当Rc6选自CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环或3至7元杂环时，Rc5选自H、氘、卤素、CN、羟基、NH2、-NHC1-4烷基、-NH-C3-7碳环、-NH-3至7元杂环、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述烷基、亚烷基、烯基、炔基、烷氧基、环烷基、碳环、杂环、任选地被1至4个Rk取代； When R c6 is selected from CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle or 3 to 7 membered heterocycle, R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1 - 4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocycle, heterocycle, are optionally substituted with 1 to 4 R k ;
Rc7选自H或Rc2；R c7 is selected from H or R c2 ;
p1或p2选自0、1、2或3；p1 or p2 is selected from 0, 1, 2 or 3;
各个基团定义与第一种实施方案相同。The definitions of the various groups are the same as in the first embodiment.
作为本发明的第三种实施方案，上述通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)、通式(VIII)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a third embodiment of the present invention, the compounds represented by the above-mentioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,
Q选自苯基、萘基、苯并C4-6碳环、苯并4至6元杂环、-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-，所述的苯基、萘基、苯并C4-6碳环、苯并4至6元杂环任选被1至4个Rk取代；Q is selected from Phenyl, naphthyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, -O-, -N(R q3 )-, -C(＝O)N(R q3 )-, -N(R q3 )C(＝O), -C(＝O)-, wherein the phenyl, naphthyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring is optionally substituted by 1 to 4 R k ;
Rq1、Rq2、Rq3各自独立的选自H、C1-4烷基，所述的烷基任选被1至4个Rk取代；R q1 , R q2 , and R q3 are each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
Ra、Rb、Rd各自独立的选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-C(＝O)NH-C1-6烷基、-C(＝O)NH-C3-6碳环、C3-6碳环、3至7元杂环，所述烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代； Ra , Rb , and Rd are each independently selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl , C2-4 alkenyl, C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, -C(=O)NH- C1-6 alkyl, -C(=O)NH- C3-6 carbocycle, C3-6 carbocycle , 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 Rk ;
Rc3各自独立的选自H、NH2、-C(＝O)NH2、甲基、乙基、环丙基、环丁基、环戊基；R c3 is each independently selected from H, NH 2 , -C(=O)NH 2 , methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl;
Rc4选自H、NH2、卤素、CN、C1-4烷基、C2-4炔基或-NH-5至6元杂芳环，所述的烷基、炔基或杂芳环任选被1至4个Rk取代；R c4 is selected from H, NH 2 , halogen, CN, C 1-4 alkyl, C 2-4 alkynyl or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted with 1 to 4 R k ;
Rc5选自-NH-C3-6碳环、-NH-3至6元杂环、-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述烷基、亚烷基、烷氧基、环烷基、碳环基、杂环基、杂芳基任选地被1至4个Rk取代；R c5 is selected from -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
Rc6选自H、卤素、OH、NH2、C1-4烷基、CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-4至6元杂环、-O-C3-6碳环、-O-4至6元杂环、C3-6碳环或4至7元杂环烷环，所述烷基、亚烷基、烯基、炔基、烷氧基、环烷基、碳环、杂环、杂环烷环任选地被1至4个Rk取代；R c6 is selected from H, halogen, OH, NH 2 , C 1-4 alkyl, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-4 to 6 membered heterocycle, -OC 3-6 carbocycle, -O-4 to 6 membered heterocycle, C 3-6 carbocycle or 4 to 7 membered heterocycloalkyl ring, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocycle, heterocycle, heterocycloalkyl ring is optionally substituted with 1 to 4 R k ;
当Rc6选自H、卤素、OH、NH2或C1-4烷基时，Rc5选自-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6环烷基-Rc5a、-NH-5至6元杂芳基-4至6元杂环烷基-Rc5a，所述的烷基、杂芳基、亚烷基、环烷基或杂环烷基任选被1至3个Rk取代；When R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , wherein the alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
当Rc6选自CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-4至6元杂环、-O-C3-6碳环、-O-4至6元杂环、C3-6环烷基或4至7元杂环烷环时，Rc5选自-NH-C3-6碳环、-NH-5至6元杂芳环，所述烷基、亚烷基、烯基、炔基、烷氧基、碳环、杂环、环烷基或杂环烷基任选地被1至4个Rk取代；When R c6 is selected from CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-4 to 6-membered heterocycle, -OC 3-6 carbocycle, -O-4 to 6-membered heterocycle, C 3-6 cycloalkyl or 4 to 7-membered heterocycloalkyl ring, R c5 is selected from -NH-C 3-6 carbocycle, -NH-5 to 6-membered heteroaryl ring, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, carbocycle, heterocycle, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
R1a、R1b、R1c、R1d各自独立的选自H、氘、卤素、CN、C1-4烷基、C2-4烯基、C2-4炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
作为选择，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
R1e选自卤素或-OS(＝O)2C1-4烷基，所述烷基任选被1至4个Rk取代； R 1e is selected from halogen or -OS(=O) 2 C 1-4 alkyl, which is optionally substituted with 1 to 4 R k ;
Rk选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代； Rk is selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O - 3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, C3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy;
其余基团定义与本发明第二种实施方案相同。The remaining groups are defined the same as in the second embodiment of the present invention.
作为本发明的第四种实施方案，上述通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)、通式(VIII)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a fourth embodiment of the present invention, the compounds represented by the above-mentioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,
D1选自 D 1 is selected from
D2选自 苯基、苯并C4-6碳环基、苯并4至6元杂环基、5至6元杂芳基；D 2 is selected from Phenyl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;
D3选自 D 3 is selected from
Q3选自C6-10芳基、5至10元杂芳基，所述Q3任选被1至4个Rk取代；Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said Q3 is optionally substituted by 1 to 4 R k ;
环B1选自Q3选自C6-10芳基、5至10元杂芳基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Ring B 1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
B2选自C4-6碳环，B3选自C4-6碳环； B2 is selected from C4-6 carbocyclic ring, B3 is selected from C4-6 carbocyclic ring;
或者Q3选自环B1选自苯基、苯并C4-6碳环、苯并4至6元杂环，5至6元杂芳基、8至10元杂芳基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Or Q3 is selected from Ring B1 is selected from phenyl, benzo C4-6 carbocycle, benzo 4 to 6-membered heterocycle, 5 to 6-membered heteroaryl, 8 to 10-membered heteroaryl, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
n1、n3、n5各自独立的选自0、1或2；n1, n3, n5 are each independently selected from 0, 1 or 2;
n2、n4各自独立的选自0或1； n2 and n4 are each independently selected from 0 or 1;
n6自0、1、2或3；n6 is 0, 1, 2 or 3;
Rq1、Rq2、Rq3各自独立的选自H、甲基、乙基；R q1 , R q2 , and R q3 are each independently selected from H, methyl, and ethyl;
Rn1选自H、甲基、乙基；R n1 is selected from H, methyl, ethyl;
Ra、Rb、Rd各自独立的选自氘、F、Cl、Br、I、氰基、OH、NH2、NH(CH3)、N(CH3)2、CF3、甲基、乙基、丙基、异丙基、丁基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基； Ra , Rb , and Rd are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2 , NH( CH3 ), N( CH3 ) 2 , CF3 , methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
Rc1选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个Rk取代；R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 R k ;
Rc2各自独立的选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、-O-环丙基、-NH-环丙基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-C(＝O)NH-甲基、-C(＝O)NH-乙基、-C(＝O)NH-环丙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、吡唑、咪唑、噁唑、噻唑，所述的甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、吡唑、咪唑、噁唑、噻唑任选被1至4个Rk取代；R c2 is each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole, the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole are optionally substituted by 1 to 4 R k replaces;
Rc4选自H、NH2、F、Cl、Br、I、CN、甲基、乙基、乙炔基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑，所述的甲基、乙基、乙炔基、吡唑、咪唑、噁唑、噻唑任选被1至4个Rk取代；R c4 is selected from H, NH 2 , F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally substituted by 1 to 4 R k ;
环B选自 Ring B is selected from
Rc5选自-NH-C3-6碳环、-NH-吡唑、-NH-吡咯、-NH-咪唑、-NH-三氮唑、-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述的5至6元杂芳基选自吡唑基、吡咯基、咪唑基或三氮唑基，所述亚烷基、碳环基、杂环基、杂芳基、吡唑基、吡咯基、咪唑基或三氮唑基任选地被1至4个Rk取代；R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the alkylene, carbocyclyl, heterocyclyl, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基、乙基、CN、乙炔基、-CH2-乙炔基、丙炔基、甲氧基、乙氧基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基，所述甲基、乙基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、环丁基或环戊基任选地被1至4个Rk取代；R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl, ethyl, CN, ethynyl, -CH 2 -ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted with 1 to 4 R k ;
当Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基或乙基时，Rc5选自-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6环烷基-Rc5a、-NH-5至6元杂芳基-4至6元杂环烷基-Rc5a，所述的5至6元杂芳基选自吡唑基、吡咯基、咪唑基或三氮唑基，所述的杂芳基、亚烷基、环烷基或杂环烷基任选被1至3个Rk取代； When R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
Rc5a选自CN或任选取代的如下基团之一：-O-甲基、-O-乙基、-S-甲基、-S-乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-O-环丙基、-O-环丁基、-O-环戊基、-O-环己基、-O-氮杂环丁基、-O-氮杂环戊基、-O-氮杂环己基、-C(＝O)-环丙基、-C(＝O)-环丁基、-C(＝O)-环戊基、-C(＝O)-环己基、-C(＝O)-氮杂环丁基、-C(＝O)-氮杂环戊基、-C(＝O)-氮杂环己基、-C(＝O)-氧杂环丁基、-C(＝O)-氧杂环戊基、-C(＝O)-氧杂环己基，当被取代时，被1至4个选自氘、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、甲氧基或乙氧基的取代基所取代；R c5a is selected from CN or one of the following optionally substituted groups: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C (═O)-cyclopropyl, —C(═O)-cyclobutyl, —C(═O)-cyclopentyl, —C(═O)-cyclohexyl, —C(═O)-azetidinyl, —C(═O)-aziridine, —C(═O)-azetidinyl, —C(═O)-azetidinyl, —C(═O)-oxetanyl, —C(═O)-oxolanyl, —C(═O)-oxetanyl, when substituted, by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, methoxy or ethoxy;
当Rc6选自CN、乙炔基、-CH2-乙炔基、丙炔基、甲氧基、乙氧基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基时，Rc5选自-NH-C3-6碳环、-NH-吡唑、-NH-吡咯、-NH-咪唑、-NH-三氮唑，所述的CH2、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、吡唑基、吡咯基、咪唑基或三氮唑基任选地被1至4个Rk取代；When R c6 is selected from CN, ethynyl, -CH 2 -ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, and the CH 2 , ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
R1a、R1b、R1c、R1d各自独立的选自H、氘、F、Cl、Br、I、CN、甲基、乙基、乙烯基、乙炔基、环丙基、环丁基、环戊基或环己基，所述甲基、乙基、乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基任选被1至4个Rk取代；R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with 1 to 4 R k ;
作为选择，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
作为选择，Rn1与Rd直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R n1 and R d are directly linked to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
R1e选自F、Cl、Br、I、-OS(＝O)2CH3、-OS(＝O)2CF3；R 1e is selected from F, Cl, Br, I, -OS(=O) 2 CH 3 , -OS(=O) 2 CF 3 ;
Rk选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、甲硫基、-O-环丙基、-NH-环丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；R k is selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from halogen, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy;
其余基团定义与本发明第二种或者第三种实施方案相同。The remaining groups are defined the same as in the second or third embodiment of the present invention.
作为本发明的第五种实施方案，上述通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)、通式(VIII)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a fifth embodiment of the present invention, the compounds represented by the above-mentioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,
Q选自-O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-，所述任选被1至4个Rk取代；Q is selected from -O-, -NH-, -N(CH 3 )-, -C(=O)NH-, -NHC(=O), -C(=O)-, the Optionally substituted with 1 to 4 R k ;
Q1选自-O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-、 Q1 is selected from -O-, -NH-, -N( CH3 )-, -C(=O)NH-, -NHC(=O), -C(=O)-,
选自 Selected from
选自 Selected from
D选自-NH-、-N(Rn1)-、或者任选被1至4个Rd取代的如下基团之一： 右侧与R1直接连接；D is selected from -NH-, -N( Rn1 )-, or one of the following groups optionally substituted by 1 to 4 R d : The right side is directly connected to R 1 ;
D3选自任选被1至4个Rd取代的如下基团之一： D3 is selected from one of the following groups optionally substituted by 1 to 4 Rd :
R1选自CN、 R1 is selected from CN,
p1或p2选自0、1或2；p1 or p2 is selected from 0, 1 or 2;
其余基团定义与本发明第二、三或四种实施方案中任意一种相同。The remaining groups are defined the same as in any one of the second, third or fourth embodiments of the present invention.
作为本发明的第六种实施方案，前述通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a sixth embodiment of the present invention, the compounds represented by the aforementioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,
Ra各自独立的选自氘、F、Cl、Br、氰基、CF3、甲基；Ra is independently selected from deuterium, F, Cl, Br, cyano, CF3 , and methyl;
Rb各自独立的选自氘、F、Cl、Br、氰基、CF3、甲基；R b is each independently selected from deuterium, F, Cl, Br, cyano, CF 3 , methyl;
Rd各自独立的选自氘、F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基；R d is each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;
Rc1选自CD3、CF3、甲基、乙基、丙基、异丙基、环丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、 R c1 is selected from CD 3 , CF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
Rc2选自氘、F、Cl、Br、OH、CN、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑、-C(＝O)NH-甲基、-C(＝O)NH-乙基、-C(＝O)NH-环丙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基，所述的甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基、吡唑、咪唑、噁唑、噻唑、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基的取代基所取代；R c2 is selected from deuterium, F, Cl, Br, OH, CN, NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C(═O)NH-methyl, -C(═O)NH-ethyl, -C(═O)NH-cyclopropyl, -NHC(═O)NH- )-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, wherein the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazole, imidazole, oxazole, thiazole, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 , N ( CH2CH3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Rc4选自H、NH2、F、CN、甲基、 R c4 is selected from H, NH 2 , F, CN, methyl,
Rc5选自 R c5 is selected from
当Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基或乙基时，Rc5选自 When R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from
Rc5a选自CN、-O-甲基、-O-乙基、-S-甲基、-S-乙基、环丙基、 R c5a is selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,
当Rc6选自CN、乙炔基、-CH2-乙炔基、丙炔基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基时，Rc5选自 When R c6 is selected from CN, ethynyl, -CH 2 -ethynyl, propynyl, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, R c5 is selected from
Q3选自苯基、吡啶基或嘧啶基，所述Q3任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代；Q 3 is selected from phenyl, pyridyl or pyrimidinyl, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
环B1选自Q3选自苯基、吡啶基或嘧啶基，所述环B1任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述Q3任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ring B 1 is selected from Q 3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B 1 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
或者Q3选自环B1选自苯基或吡啶基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Or Q3 is selected from Ring B 1 is selected from phenyl or pyridyl, said ring B 1 is optionally substituted by 1 to 4 R b , said Q 3 is optionally substituted by 1 to 4 R k ;
其余基团定义与本发明第二、三、四或五种实施方案中任意一种相同。The remaining groups are defined the same as in any one of the second, third, fourth or fifth embodiments of the present invention.
作为本发明的第七种实施方案，前述通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)、通式(VIII)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a seventh embodiment of the present invention, the compounds represented by the aforementioned general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,
选自 Selected from
通式(VI)中-D-选自 In the general formula (VI), -D- is selected from
环B1选自Q3选自 Ring B 1 is selected from Q 3 Selected
或者Q3选自环B1选自 Or Q 3 is selected from Ring B 1 is selected from
通式(VII)中D选自-NH-；In the general formula (VII), D is selected from -NH-;
通式(VIII)中 General formula (VIII) middle
其余基团定义与本发明第二、三、四、五或六种实施方案中任意一种相同。The remaining groups are defined the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.
本发明涉及如下所示的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一。The present invention relates to the compounds shown below or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from one of the structures shown in Table E-1.
表E-1
























Table E-1
























本发明涉及一种药物组合物，包括任意上述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及要学上可接受的载体。The present invention relates to a pharmaceutical composition, comprising any of the above compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and pharmaceutically acceptable carriers.
本发明涉及一种药物组合物，包括治疗有效量的本发明上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
在一些实施方案中，本发明的药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如FGFR2异常相关疾病如癌症)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望的改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。"Effective amount" or "therapeutically effective amount" described in the present application refers to the administration of a sufficient amount of the compound disclosed herein, which will alleviate one or more symptoms of the disease or condition (e.g., FGFR2 abnormal related diseases such as cancer) to some extent. In some embodiments, the result is to reduce and/or alleviate the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg -200mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.
在一些实施方案中，该药物组合物包括但不限于1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、 250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选FGFR2活性或表达量相关疾病(如癌症)。A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to FGFR2 activity or expression (such as cancer).
一种用于治疗哺乳动物的疾病的方法，所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1000mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。A method for treating a disease in a mammal, comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg/day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day , 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
本发明涉及任意上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与FGFR2活性或表达量相关疾病的药物中的应用，优选地，所述疾病选自肿瘤。The present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for preparing drugs for treating diseases related to FGFR2 activity or expression, preferably, the disease is selected from tumors.
本发明涉及上述的药物组合物在用于制备治疗与FGFR2活性或表达量相关疾病的药物中的应用，优选地，所述疾病选自肿瘤。The present invention relates to the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease associated with FGFR2 activity or expression, preferably, the disease is selected from tumors.
本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。The amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮、F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in the present invention are optionally replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C, and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O, and 18 O, sulfur isotopes include 32 S, 33 S, 34 S, and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“卤素”是指F、Cl、Br或I。"Halogen" refers to F, Cl, Br or I.
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，为1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、 新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。"Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing in this article have the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。"Alkylene" refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S selectively substituted in the ring of the heterocycloalkyl can be oxidized to various oxidation states. The heterocycloalkyl can be connected to a heteroatom or a carbon atom, the heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl can be connected to a bridge ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。"Alkenyl" refers to a substituted or unsubstituted straight chain and branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl groups appearing in this article have the same definition as this definition. The alkenyl group can be monovalent, divalent, trivalent or tetravalent.
“炔基”是指取代的或者未取代的直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，包括但不限于在主链包括2至10个碳原子、2至6个碳原子、2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"Alkynyl" refers to a substituted or unsubstituted straight or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain. Examples of alkynyl radicals include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent.
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be connected to a heteroatom or a carbon atom, may be connected to an aromatic ring or a non-aromatic ring, may be connected to a bridged ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O)n的杂原子。非限制性实施例包括：
"Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O or S(=O) n . Non-limiting examples include:
。“螺环”或“螺环基”可以是一价、二价、三价或四价。"Spirocycle" or "spirocyclyl" may be monovalent, divalent, trivalent or tetravalent.
“并环”或“并环基”是指系统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基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： “并环”或“并环基”可以是一价、二价、三价或四价。"Cyclic" or "Cyclic radical" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the cyclic system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，桥环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括 立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O) n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。"Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。"Carbobridged ring", "bridged carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，。"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" that is a monocyclic ring system.
“杂并环”、“杂并环基”“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。"Heterocyclic ring", "heterocyclic group", "cyclic heterocyclic group" or "heterocyclic group" refers to a "cyclic ring" containing a heteroatom.
“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。"Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom.
“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。"Heterobridged ring", "heterobridged cyclic group", "bridged heterocyclic group" or "heterobridged cyclic group" refers to a "bridged ring" containing a heteroatom.
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结 构连接在一起的环为杂芳基环，非限制性实施例包含本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。"Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 selected heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring with the parent The ring connected together is a heteroaryl ring, non-limiting examples of which include The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基，Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spirocyclyl, cyclocyclyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -( CH2 ) m -C(=O)-R a , -O-( CH2 ) m -C(=O)-R a , -( CH2 ) m -C(=O)-NR b R c , -( CH2 ) mS (=O) nR a , -( CH2 ) m -alkenyl-R a , OR d , or -( CH2 ) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c , wherein R b and R c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an alternative, R b and R c can form a five- or six-membered cycloalkyl or heterocyclyl, Ra and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or cycloalkyl.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。“Containing 1 to 5 heteroatoms selected from O, S, and N” means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代，X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选被0至4个选自H或F的取代基所取代”是指杂桥环任选被0、1、2、3或4个选自H或F的取代基所取代。"0 to X substituents are substituted" means substituted by 0, 1, 2, 3 .... X substituents, X is selected from any integer between 1 and 10. For example, "0 to 4 substituents are substituted" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "0 to 5 substituents are substituted" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from H or F.
X-Y元的环(X选自小于Y大于等于3的整数，Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。X-Y membered rings (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) include X+1, X+2, X+3, X+4...Y membered rings. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings. For example, "4-7 membered heteromonocyclic rings" refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings, and "5-10 membered heterocyclic rings" refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings.
当某一个基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团连接。当该化学键的连接方式是不定位的，且可连接位点存在氢原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。例如表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，也包括了例如表示该哌啶基上的R基团可以位于C上，可以位于N上，至少包括了 When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
当所列举的连接基团没有指明其连接方向时，其连接方向包括了从左向右和从右向左的读取顺序的方向进行连接，例如A-L-B，L选自-M-W-时，包括了A-M-W-B和A-W-M-B。When the listed connecting groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环 境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes the event or circumstance. For example, "alkyl optionally substituted by F" means that the alkyl group may be but not necessarily be substituted by F, and includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。"Preparation specification" refers to the weight of the main drug contained in each vial, tablet or other unit preparation. "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、光学异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers and conformational isomers.
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。" IC50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm； The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 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；Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;
为了完成本发明的目的，根据本邻域技术人员已知的有机合成技术，从市售的化学品和/或化学文献中描述的化合物开始，制备本文所述反应中使用的化合物“商业上可用的化学品”是从标准的商业来源获得的，包括上海阿拉丁生化科技股份有限公司，上海麦克林生化科技有限公司，Sigma-Aldrich，阿法埃莎(中国)化学有限公司，梯希爱(上海)化成工业发展有限公司，安耐吉化学，上海泰坦科技股份有限公司，科龙化工，百灵威科技有限公司等。In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to technicians in the field, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
THF：四氢呋喃；DMF：N,N-二甲基甲酰胺；DIPEA：N,N-二异丙基乙胺；HATU：CAS148893-10-1；TCFH:CAS 94790-35-9THF: Tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1; TCFH: CAS 94790-35-9
实施例1：化合物1的制备
Example 1: Preparation of Compound 1
第一步：1j的合成Step 1: Synthesis of 1j
将1i(2g，6.48mmol)加入15mL甲醇中，加入15mL甲醇钠的甲醇溶液(30％)。80℃反应6h。将反应冷却至室温，减压浓缩，残余物用乙酸乙酯和石油醚的混合体系打浆，过滤后收集滤饼，为1j(1.7g，产率86.29％)。1i (2 g, 6.48 mmol) was added to 15 mL of methanol, and 15 mL of a methanol solution of sodium methoxide (30%) was added. The reaction was carried out at 80°C for 6 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was slurried with a mixture of ethyl acetate and petroleum ether, filtered, and the filter cake was collected to obtain 1j (1.7 g, yield 86.29%).
LCMS m/z(ESI):305.0[M+H]+ LCMS m/z(ESI):305.0[M+H] +
第二步：1k的合成Step 2: 1k synthesis
在封管中加入1j(400mg，1.32mmol)，1d(CAS:2549188-28-3)(565mg，1.71mmol)，Pd(dtbpf)Cl2(CAS：95408-45-0)(85mg，0.13mmol)、磷酸钾(560mg，2.64mmol)、10mL二氧六环和2mL水，90℃反应3h。冷却至室温，加水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，残余物经硅胶柱柱层析分离，得1k(290mg，产率57.76％)。1j (400 mg, 1.32 mmol), 1d (CAS: 2549188-28-3) (565 mg, 1.71 mmol), Pd (dtbpf) Cl 2 (CAS: 95408-45-0) (85 mg, 0.13 mmol), potassium phosphate (560 mg, 2.64 mmol), 10 mL of dioxane and 2 mL of water were added to a sealed tube and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 1k (290 mg, yield 57.76%).
LCMS m/z(ESI):381.2[M+H]+ LCMS m/z(ESI):381.2[M+H] +
第三步：1l的合成Step 3: Synthesis of 1l
将1k(230mg，0.60mmol)溶于6mL二氯甲烷中，加入三氟乙酸(0.14mL，1.80mmol)，0℃加入NIS(CAS:516-12-1)(203mg，0.90mmol)，反应1h。加硫代硫酸钠溶液淬灭反应，加水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，残余物经硅胶柱柱层析分离，得1l(240mg，产率78.95％)。1k (230 mg, 0.60 mmol) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (0.14 mL, 1.80 mmol) was added, and NIS (CAS: 516-12-1) (203 mg, 0.90 mmol) was added at 0°C, and the reaction was continued for 1 h. Sodium thiosulfate solution was added to quench the reaction, and the mixture was diluted with water and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 1l (240 mg, yield 78.95%).
LCMS m/z(ESI):507.1[M+H]+ LCMS m/z(ESI):507.1[M+H] +
第四步：化合物1的合成Step 4: Synthesis of Compound 1
在封管中加入1k(230mg，0.45mmol)，1f(157mg，0.54mmol)，Pd(dppf)Cl2·CH2Cl2(CAS:95464-05-4)(41mg，0.05mmol)、磷酸钾(191mg，0.90mmol)，6mL二氧六环和1mL水，90℃反应3h。冷却至室温，加水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，残余物经硅胶柱柱层析分离，得化合物1(50mg，产率20.58％)。 1k (230 mg, 0.45 mmol), 1f (157 mg, 0.54 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (CAS: 95464-05-4) (41 mg, 0.05 mmol), potassium phosphate (191 mg, 0.90 mmol), 6 mL of dioxane and 1 mL of water were added to the sealed tube, and the mixture was reacted at 90° C. for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 1 (50 mg, yield 20.58%).
LCMS m/z(ESI):540.3[M+H]+ LCMS m/z(ESI):540.3[M+H] +
实施例2:化合物2的制备
Example 2: Preparation of Compound 2
第一步：2a的合成Step 1: Synthesis of 2a
封管中加入1i(330mg，1.07mmol)，用5mL乙腈悬浮，加入11mL二甲胺的四氢呋喃溶液(2M)，90℃反应2h。冷却至室温，减压浓缩，残余物用乙酸乙酯和石油醚的混合体系打浆，过滤后收集滤饼得到2a(330mg，产率97.34％)。1i (330 mg, 1.07 mmol) was added to the sealed tube, suspended with 5 mL of acetonitrile, and 11 mL of dimethylamine tetrahydrofuran solution (2 M) was added, and the mixture was reacted at 90°C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was slurried with a mixture of ethyl acetate and petroleum ether, and the filter cake was collected after filtration to obtain 2a (330 mg, yield 97.34%).
LCMS m/z(ESI):318.0[M+H]+ LCMS m/z(ESI):318.0[M+H] +
第二步：2b的合成Step 2: Synthesis of 2b
在封管中加入2a(330mg，1.04mmol)，1d(447mg，1.35mmol)，Pd(dtbpf)Cl2(82mg，0.1mmol)、磷酸钾(441mg，2.08mmol)，5mL二氧六环和1mL水，90℃反应3h。冷却至室温，加水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，残余物经硅胶柱柱层析分离，得2b(202mg，产率49.39％)。2a (330 mg, 1.04 mmol), 1d (447 mg, 1.35 mmol), Pd(dtbpf)Cl2 (82 mg, 0.1 mmol), potassium phosphate (441 mg, 2.08 mmol), 5 mL of dioxane and 1 mL of water were added to a sealed tube and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 2b (202 mg, yield 49.39%).
LCMS m/z(ESI):394.2[M+H]+ LCMS m/z(ESI):394.2[M+H] +
第三步：2c的合成Step 3: Synthesis of 2c
将2b(188mg，0.48mmol)溶于6mL二氯甲烷，加入三氟乙酸(0.11mL，1.43mmol)，0℃加入NIS(162mg，0.72mmol)，反应1h。加硫代硫酸钠溶液淬灭反应，加水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，残余物经硅胶柱柱层析分离得2c(173mg，产率69.48％)。2b (188 mg, 0.48 mmol) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (0.11 mL, 1.43 mmol) was added, and NIS (162 mg, 0.72 mmol) was added at 0°C, and the reaction was allowed to proceed for 1 h. Sodium thiosulfate solution was added to quench the reaction, and the mixture was diluted with water and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain 2c (173 mg, yield 69.48%).
LCMS m/z(ESI):520.1[M+H]+ LCMS m/z(ESI):520.1[M+H] +
第四步：化合物2的合成Step 4: Synthesis of Compound 2
在封管中加入2c(170mg，0.33mmol)，1f(113mg，0.39mmol)，Pd(dppf)Cl2·DCM(25mg，0.03mmol)、磷酸钾(140mg，0.66mmol)，5mL二氧六环和1mL水，90℃反应3h。冷却至室温，加水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩，残余物经硅胶柱柱层析分离，得化合物2(35mg，产率19.23％)。2c (170 mg, 0.33 mmol), 1f (113 mg, 0.39 mmol), Pd(dppf)Cl 2 ·DCM (25 mg, 0.03 mmol), potassium phosphate (140 mg, 0.66 mmol), 5 mL of dioxane and 1 mL of water were added to a sealed tube and reacted at 90°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain compound 2 (35 mg, yield 19.23%).
LCMS m/z(ESI):553.3[M+H]+ LCMS m/z(ESI):553.3[M+H] +
实施例3：化合物3的制备
Example 3: Preparation of Compound 3
第一步：3b的制备Step 1: Preparation of 3b
氮气保护下，将3a(0.5g,6mmol)溶于5mL DMF中，加入(1.7mL,12mmol)三乙胺和(2.07mL,9mmol)，随后室温下反应3h，加入50mL乙酸乙酯稀释，分别用水(20mL×3)、饱和食盐水20mL洗。有机相干燥，浓缩，残余物经柱层析分离纯化得到3b(0.77g，收率：71％)。Under nitrogen protection, 3a (0.5 g, 6 mmol) was dissolved in 5 mL DMF, and triethylamine (1.7 mL, 12 mmol) and (2.07 mL, 9 mmol) were added. The mixture was then reacted at room temperature for 3 h, and 50 mL of ethyl acetate was added for dilution. The mixture was washed with water (20 mL × 3) and 20 mL of saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain 3b (0.77 g, yield: 71%).
LCMS m/z＝184.1[M+H]+ LCMS m/z＝184.1[M+H] +
第二步：3c的制备Step 2: Preparation of 3c
将3b(0.4g，2.2mmol)溶于10mL DMF中，氮气保护下依次加入溴甲基环丙烷(0.32mL，3.3mmol)、碳酸钾(912mg，6.6mmol)和碘化钾(365mg，2.2mmol)，80℃反应过夜。加入50mL乙酸乙酯稀释，分别用水(20mL×3)、饱和食盐水20mL洗。有机相干燥，浓缩，残余物经柱层析分离纯化得到3c(0.21g，收率：40％)。3b (0.4 g, 2.2 mmol) was dissolved in 10 mL DMF, and bromomethylcyclopropane (0.32 mL, 3.3 mmol), potassium carbonate (912 mg, 6.6 mmol) and potassium iodide (365 mg, 2.2 mmol) were added in sequence under nitrogen protection, and the mixture was reacted at 80°C overnight. 50 mL of ethyl acetate was added to dilute the mixture, and the mixture was washed with water (20 mL × 3) and 20 mL of saturated brine, respectively. The organic phase was dried and concentrated, and the residue was separated and purified by column chromatography to obtain 3c (0.21 g, yield: 40%).
LCMS m/z＝238.2[M+H]+ LCMS m/z＝238.2[M+H] +
第三步：3d的制备Step 3: 3D preparation
氮气保护下，将3c(0.21g,0.88mmol)溶于5mL二氯甲烷中，加入2mL三氟乙酸，随后体系室温下反应1h，减压浓缩，残留物直接经过反相纯化得到3d(98mg，收率：80％)。Under nitrogen protection, 3c (0.21 g, 0.88 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The system was then reacted at room temperature for 1 h and concentrated under reduced pressure. The residue was directly purified by reverse phase to obtain 3d (98 mg, yield: 80%).
LCMS m/z＝138.1[M+H]+ LCMS m/z＝138.1[M+H] +
第四步：3f的制备Step 4: Preparation of 3f
氮气保护下，将中间体3e(0.7g,3.07mmol)溶于8mL1,4-二氧六环中，加入3e-1(884mg，3.07mmol)和DIPEA(1.1mL，6.14mmol)，80℃反应1h，反应加入30mL乙酸乙酯，并用水(20mL×3)洗涤三次，饱和NaCl的水溶液20mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，得到3f(1.2g，收率：98％)。Under nitrogen protection, the intermediate 3e (0.7 g, 3.07 mmol) was dissolved in 8 mL of 1,4-dioxane, and 3e-1 (884 mg, 3.07 mmol) and DIPEA (1.1 mL, 6.14 mmol) were added. The reaction was carried out at 80 ° C for 1 h. 30 mL of ethyl acetate was added to the reaction, and the mixture was washed three times with water (20 mL×3) and once with 20 mL of a saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain 3f (1.2 g, yield: 98%).
LCMS m/z＝389.1[M+H]+ LCMS m/z＝389.1[M+H] +
第五步：3g的制备Step 5: Preparation of 3g
氮气保护下，将中间体3f(0.25g,0.64mmol)溶于15mL1,4-二氧六环1.5mL水中，加入1d(254mg，0.77mmol)、Pd(dppf)Cl2(47mg，0.064mmol)和碳酸钾(354mg，2.56mmol)，随后体系加热至100℃反应1h，反应加入20mL乙酸乙酯，并用水(20mL×3)洗涤，饱和NaCl的水溶液20mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，得到3g(198mg，收率：58％)。 Under nitrogen protection, intermediate 3f (0.25 g, 0.64 mmol) was dissolved in 15 mL 1,4-dioxane and 1.5 mL water, and 1d (254 mg, 0.77 mmol), Pd(dppf)Cl 2 (47 mg, 0.064 mmol) and potassium carbonate (354 mg, 2.56 mmol) were added. The system was then heated to 100 °C for 1 h. 20 mL of ethyl acetate was added to the reaction, and the mixture was washed with water (20 mL × 3) and 20 mL of a saturated NaCl aqueous solution once. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain 3g (198 mg, yield: 58%).
LCMS m/z＝513.2[M+H]+ LCMS m/z＝513.2[M+H] +
第六步：3h的制备Step 6: Preparation of 3h
氮气氛围下，将3g(198mg，0.386mmol)，3d(64mg，0.46mmol)，Pd2(dba)3(36mg，0.0386mmol)，S-phos(CAS:657408-07-6)(32mg，0.077mmol)，碳酸铯(252mg，0.77mmol)，溶于1,4-二氧六环(6mL)，120℃反应16h。将反应冷却至室温，加入20mL乙酸乙酯，用水(20mL×3)洗涤，饱和NaCl的水溶液20mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，得3h(166mg，产率：60％)Under nitrogen atmosphere, 3g (198 mg, 0.386 mmol), 3d (64 mg, 0.46 mmol), Pd 2 (dba) 3 (36 mg, 0.0386 mmol), S-phos (CAS: 657408-07-6) (32 mg, 0.077 mmol), cesium carbonate (252 mg, 0.77 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 120°C for 16 h. The reaction was cooled to room temperature, 20 mL of ethyl acetate was added, washed with water (20 mL × 3), and washed once with 20 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography to obtain 3h (166 mg, yield: 60%).
LCMS m/z＝614.2[M+H]+ LCMS m/z＝614.2[M+H] +
第七步：3i的制备Step 7: Preparation of 3i
氮气保护下，将3h(0.19g,0.27mmol)溶于5mL二氯甲烷中，加入2mL三氟乙酸，室温反应1h，减压浓缩除去溶剂，残留物直接经过反相纯化得到3i(50mg，收率：36％)。Under nitrogen protection, 3h (0.19 g, 0.27 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure. The residue was directly purified by reverse phase purification to obtain 3i (50 mg, yield: 36%).
LCMS m/z＝514.2[M+H]+ LCMS m/z＝514.2[M+H] +
第八步：化合物3的制备Step 8: Preparation of compound 3
氮气保护下，将3i(50mg,0.097mmol)溶于2mL DMF中，依次加入丙烯酸(7mg，0.097mmol)、N-甲基咪唑(16mg，0.194mmol)和TCFH(41mg，0.146mmol)，室温反应1h，反应加入20mL乙酸乙酯，用水(20mL×3)洗涤，饱和NaCl的水溶液20mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，得到化合物3(2.5mg，收率：4.5％)。Under nitrogen protection, 3i (50 mg, 0.097 mmol) was dissolved in 2 mL DMF, and acrylic acid (7 mg, 0.097 mmol), N-methylimidazole (16 mg, 0.194 mmol) and TCFH (41 mg, 0.146 mmol) were added in sequence. The reaction was carried out at room temperature for 1 h. 20 mL of ethyl acetate was added to the reaction, and the mixture was washed with water (20 mL × 3) and once with 20 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated by silica gel column chromatography to give compound 3 (2.5 mg, yield: 4.5%).
LCMS m/z＝568.2[M+H]+ LCMS m/z＝568.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.00(s,1H),7.82(s,1H),7.58(s,1H),7.32(t,1H),7.23(dd,1H),7.21-7.17(m,1H),7.12(d,1H),6.32-6.16(m,2H)5.70(dd,1H),4.39(s,2H),4.14(s,2H),4.07(s,4H),3.97(d,2H),2.46(s,3H),1.31-1.27(m,1H),0.66-0.58(m,2H),0.45-0.36(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 8.41 (d, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.32 (t, 1H), 7.23 (dd, 1H), 7.21-7.17 (m, 1H), 7.12 (d, 1H), 6.32-6.16 (m, 2H) 5.70 (dd, 1H), 4.39 (s, 2H), 4.14 (s, 2H), 4.07 (s, 4H), 3.97 (d, 2H), 2.46 (s, 3H), 1.31-1.27 (m, 1H), 0.66-0.58 (m, 2H), 0.45-0.36 (m, 2H).
实施例4：化合物4的合成
Example 4: Synthesis of Compound 4
第一步：4B的合成Step 1: Synthesis of 4B
将4A(10g，44.84mmol)、2-氯-4-甲基嘧啶(6.92g，53.81mmol)、碳酸钾(12.37g，89.68mmol)溶于120mL DMF中，80℃反应10h。加水稀释，乙酸乙酯萃取(50mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化得4B(7.5g，53.26％)。4A (10 g, 44.84 mmol), 2-chloro-4-methylpyrimidine (6.92 g, 53.81 mmol), potassium carbonate (12.37 g, 89.68 mmol) were dissolved in 120 mL DMF and reacted at 80 °C for 10 h. Diluted with water, extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 4B (7.5 g, 53.26%).
LC-Ms m/z(ESI):315.2[M+H]+ LC-Ms m/z(ESI):315.2[M+H] +
第二步：4C的合成 Step 2: Synthesis of 4C
将4B(6.0g，19.04mmol)、联硼酸频哪醇酯(7.25g，28.56mmol)、Pd(dppf)Cl2(1.38g，1.9mmol)、醋酸钾(3.73g，38.08mmol)溶于120mL1,4-二氧六环中，氮气置换保护，100℃反应3h。加水稀释，乙酸乙酯萃取(50mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得4C(6.0g，87.05％)。4B (6.0 g, 19.04 mmol), bipyralidin (7.25 g, 28.56 mmol), Pd(dppf)Cl 2 (1.38 g, 1.9 mmol), potassium acetate (3.73 g, 38.08 mmol) were dissolved in 120 mL 1,4-dioxane, replaced with nitrogen for protection, and reacted at 100°C for 3 h. Diluted with water, extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 4C (6.0 g, 87.05%).
LC-Ms m/z(ESI):363.1[M+H]+ LC-Ms m/z(ESI):363.1[M+H] +
第三步：4D的合成Step 3: 4D synthesis
在氮气氛围下，将4C(2.0g，5.52mmol)、4C-1(1.51g，5.52mmol)、Pd(dppf)Cl2(400mg，0.55mmol)、碳酸铯(3.60g，11.04mmol)溶于20mL1,4-二氧六环和4mL水中，100℃反应3h。加水稀释，乙酸乙酯萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得4D(0.8g，37.90％)。Under nitrogen atmosphere, 4C (2.0 g, 5.52 mmol), 4C-1 (1.51 g, 5.52 mmol), Pd(dppf)Cl 2 (400 mg, 0.55 mmol), cesium carbonate (3.60 g, 11.04 mmol) were dissolved in 20 mL 1,4-dioxane and 4 mL water, and reacted at 100°C for 3 h. The mixture was diluted with water, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4D (0.8 g, 37.90%).
LC-Ms m/z(ESI):383.6[M+H]+ LC-Ms m/z(ESI):383.6[M+H] +
第四步：4E的合成Step 4: Synthesis of 4E
在氮气氛围下，将4D(800mg，2.09mmol)溶于10mL二氯甲烷中，0℃加入三氟乙酸(477mg，4.18mmol)，NIS(940mg，4.18mmol)，室温搅拌2h，饱和碳酸氢钠淬灭，乙酸乙酯萃取(10mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得4E(0.5g，47.09％)。Under nitrogen atmosphere, 4D (800 mg, 2.09 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (477 mg, 4.18 mmol) and NIS (940 mg, 4.18 mmol) were added at 0°C, stirred at room temperature for 2 h, quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4E (0.5 g, 47.09%).
LC-Ms m/z(ESI):509.2[M+H]+ LC-Ms m/z(ESI):509.2[M+H] +
第五步：化合物4的合成Step 5: Synthesis of compound 4
将4E(120mg，0.236mmol)、1f(68mg，0.236mmol)、Pd(dppf)Cl2(17.4mg，0.024mmol)、碳酸铯(154mg，0.472mmol)溶于20mL1,4-二氧六环和4mL水中，氮气置换保护，100℃反应3h。加水稀释，乙酸乙酯萃取(10mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得化合物4(15mg，11.73％)。4E (120 mg, 0.236 mmol), 1f (68 mg, 0.236 mmol), Pd(dppf)Cl 2 (17.4 mg, 0.024 mmol), cesium carbonate (154 mg, 0.472 mmol) were dissolved in 20 mL 1,4-dioxane and 4 mL water, replaced with nitrogen, and reacted at 100°C for 3 h. Diluted with water, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 4 (15 mg, 11.73%).
LC-Ms m/z(ESI):542.2[M+H]+ LC-Ms m/z(ESI):542.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.39(d,1H),8.21(s,1H),7.91-7.77(s,3H),7.66-7.58(m,3H),7.42-7.35(m,1H),7.34-7.26(m,3H),7.11(d,1H),5.77(s,1H),5.50(s,1H),3.74(s,3H),2.46(s,3H),2.00(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.39 (d, 1H), 8.21 (s, 1H), 7.91-7.77 (s, 3H), 7.66-7.58 (m, 3H), 7.42-7.35 (m, 1H), 7.34-7.26 (m, 3H), 7.11 (d, 1H), 5.77 (s, 1H), 5.50 (s, 1H), 3.74 (s, 3H), 2.46 (s, 3H), 2.00 (s, 3H).
实施例5：化合物5的合成
Example 5: Synthesis of Compound 5
将4E(120mg，0.236mmol)、5A(65mg，0.236mmol)、Pd(dppf)Cl2(17.4mg，0.024mmol)和碳酸铯(154mg,0.472mmol)溶于20mL1,4-二氧六环和4mL水中，氮气置换保护，100℃反应3h。加水稀释，乙酸乙酯萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化(洗脱条件：二氯甲烷/甲醇(98：2-90：10)梯度洗脱)，洗脱液浓缩后，残余物加1mL乙腈溶解，加1mL水稀释后，冻干即得化合物5(15mg，11.73％)。 4E (120 mg, 0.236 mmol), 5A (65 mg, 0.236 mmol), Pd(dppf)Cl 2 (17.4 mg, 0.024 mmol) and cesium carbonate (154 mg, 0.472 mmol) were dissolved in 20 mL 1,4-dioxane and 4 mL water, and the mixture was replaced with nitrogen for protection. The mixture was reacted at 100°C for 3 h. The mixture was diluted with water, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (elution conditions: gradient elution with dichloromethane/methanol (98:2-90:10)). After the eluate was concentrated, the residue was dissolved in 1 mL acetonitrile, diluted with 1 mL water, and lyophilized to obtain compound 5 (15 mg, 11.73%).
LC-Ms m/z(ESI):528.2[M+H]+ LC-Ms m/z(ESI):528.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.46(d,1H),8.22(s,1H),7.92(d,1H),7.86(s,1H),7.82(d,1H),7.70-7.60(m,3H),7.38-7.27(m,4H),7.16(d,1H),6.47-6.35(m,1H),6.29-6.19(m,1H),6.13-5.60(m,3H),3.65(s,3H),2.41(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.46 (d, 1H), 8.22 (s, 1H), 7.92 (d, 1H), 7.86 (s, 1H), 7.82 (d, 1H), 7.70-7.60 (m, 3H), 7.38-7.27 (m, 4H), 7.16 (d, 1H), 6.47-6.35 (m, 1H), 6.29-6.19 (m, 1H), 6.13-5.60 (m, 3H), 3.65 (s, 3H), 2.41 (s, 3H).
实施例6：化合物6的合成
Example 6: Synthesis of Compound 6
第一步：6A的合成Step 1: Synthesis of 6A
将3b(250mg，1.36mmol)溶于DMF(6mL)中，加入2-溴乙基甲基醚(280mg，2.04mmol)，碘化钾(230mg，1.36mmol)和碳酸钾(560mg，4.08mmol)，70℃反应16h。将反应冷却至室温，反应加入200mL乙酸乙酯，并用水(200mL×3)洗涤，饱和NaCl的水溶液200mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，即得6A(169mg，产率51.50％)3b (250 mg, 1.36 mmol) was dissolved in DMF (6 mL), 2-bromoethyl methyl ether (280 mg, 2.04 mmol), potassium iodide (230 mg, 1.36 mmol) and potassium carbonate (560 mg, 4.08 mmol) were added, and the mixture was reacted at 70°C for 16 h. The reaction mixture was cooled to room temperature, 200 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (200 mL × 3), and once with 200 mL of a saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography to obtain 6A (169 mg, yield 51.50%).
LC-Ms m/z(ESI):242.2[M+H]+ LC-Ms m/z(ESI):242.2[M+H] +
第二步：6B的合成Step 2: Synthesis of 6B
将6A(165mg，0.68mmol)溶解于二氯甲烷(5mL)中，加入三氟乙酸(2mL)，室温下搅拌反应2h。减压浓缩，即得6B粗品(93mg，产率96.88％)Dissolve 6A (165 mg, 0.68 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 2 h. Concentrate under reduced pressure to obtain crude 6B (93 mg, yield 96.88%).
LC-Ms m/z(ESI):142.2[M+H]+ LC-Ms m/z(ESI):142.2[M+H] +
第三步：6C的合成Step 3: Synthesis of 6C
氮气氛围下，将3g(180mg，0.35mmol)，6B(59mg，0.42mmol)，Pd2(dba)3(32mg，0.035mmol)，S-phos(29mg，0.07mmol)，碳酸铯(230mg，0.70mmol)溶于1,4-二氧六环(10mL)中，120℃反应2h。将反应冷却至室温，加水稀释，用乙酸乙酯(50mL×3)萃取，饱和NaCl水溶液200mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，即得6A(97mg，产率44.87％)。Under nitrogen atmosphere, 3g (180mg, 0.35mmol), 6B (59mg, 0.42mmol), Pd 2 (dba) 3 (32mg, 0.035mmol), S-phos (29mg, 0.07mmol), cesium carbonate (230mg, 0.70mmol) were dissolved in 1,4-dioxane (10mL) and reacted at 120°C for 2h. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (50mL×3), washed once with 200mL of saturated NaCl aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain 6A (97mg, yield 44.87%).
LC-Ms m/z(ESI):618.2[M+H]+ LC-Ms m/z(ESI):618.2[M+H] +
第四步：6D的合成Step 4: 6D Synthesis
将化合物6C(88mg，0.14mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(1mL)，室温反应2h。减压浓缩，即得6D的三氟乙酸盐(62mg，产率85.57％)Compound 6C (88 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of 6D (62 mg, yield 85.57%).
LC-Ms m/z(ESI):518.2[M+H]+ LC-Ms m/z(ESI):518.2[M+H] +
第五步：化合物6的合成 Step 5: Synthesis of compound 6
将6D的三氟乙酸盐粗品(38mg，0.073mmol)溶于DMF(3mL)中，加入丙烯酸(5.3mg，0.073mmol)，TCFH(31mg，0.11mmol)，N-甲基咪唑(12mg，0.15mmol)，室温反应1h。加水稀释，并用乙酸乙酯(10mL×3)萃取，饱和NaCl的水溶液100mL洗2次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离纯化，即得化合物6(3mg，产率7.19％)The crude trifluoroacetate of 6D (38 mg, 0.073 mmol) was dissolved in DMF (3 mL), and acrylic acid (5.3 mg, 0.073 mmol), TCFH (31 mg, 0.11 mmol), and N-methylimidazole (12 mg, 0.15 mmol) were added, and the mixture was reacted at room temperature for 1 h. The mixture was diluted with water, extracted with ethyl acetate (10 mL × 3), and washed twice with 100 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain compound 6 (3 mg, yield 7.19%).
LC-Ms m/z(ESI):572.6[M+H]+ LC-Ms m/z(ESI):572.6[M+H] +
实施例7：化合物7的制备
Example 7: Preparation of Compound 7
第一步：7B的制备Step 1: Preparation of 7B
将7A(1.00g，2.84mmol)、三乙胺(0.86g，8.52mmol)、碘化亚铜(2.16g，11.36mmol)、无水氯化锂(0.96g，22.72mmol)、3-乙炔基-1-氮杂环丁烷甲酸叔丁酯(0.56g，3.12mmol)、Pd(PPh3)2Cl2(0.40g，0.56mmol)溶于DMF(20mL)，氮气氛围下，60℃反应3h。反应液中加入水(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相依次用水(20mL×2)、饱和NaCl水溶液(20mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析得到7B(0.56g，产率39.76％)。7A (1.00 g, 2.84 mmol), triethylamine (0.86 g, 8.52 mmol), cuprous iodide (2.16 g, 11.36 mmol), anhydrous lithium chloride (0.96 g, 22.72 mmol), tert-butyl 3-ethynyl-1-azetidinecarboxylate (0.56 g, 3.12 mmol), Pd(PPh 3 ) 2 Cl 2 (0.40 g, 0.56 mmol) were dissolved in DMF (20 mL) and reacted at 60° C. for 3 h under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with water (20 mL×2) and saturated aqueous NaCl solution (20 mL×1) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 7B (0.56 g, yield 39.76%).
LCMS m/z＝440.1[M-55]+ LCMS m/z＝440.1[M-55] +
第二步：7C的制备Step 2: Preparation of 7C
将7B(0.56g，1.12mmol)、1-甲基-1H-吡唑-4-胺(0.22g，2.24mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP)(0.07g，0.11mmol)、碳酸铯(0.72g，2.24mmol)、醋酸钯(0.05g，0.22mmol)溶于1,4-二氧六环(20mL)，氮气氛围100℃反应2h。将反应冷却至室温，减压浓缩后残余物用硅胶柱层析分离纯化得到7C(0.24g，产率38.50％)。7B (0.56 g, 1.12 mmol), 1-methyl-1H-pyrazol-4-amine (0.22 g, 2.24 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) (0.07 g, 0.11 mmol), cesium carbonate (0.72 g, 2.24 mmol), palladium acetate (0.05 g, 0.22 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 100° C. for 2 h in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 7C (0.24 g, yield 38.50%).
LCMS m/z＝557.70[M+H]+ LCMS m/z＝557.70[M+H] +
第三步：7D的制备Step 3: Preparation of 7D
将7C(0.10g，0.18mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(0.5mL)，室温反应2h。减压浓缩除去反应溶剂得到粗品7D的三氟乙酸盐(0.08g)7C (0.10 g, 0.18 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of crude product 7D (0.08 g)
LCMS m/z＝457.1[M+H]+ LCMS m/z＝457.1[M+H] +
第四步：化合物7的制备Step 4: Preparation of compound 7
将7D的三氟乙酸盐(0.06g，0.13mmol)溶于二氯甲烷(4mL)，氮气氛围0℃加入三乙胺(0.05g，0.52mmol)，缓慢逐滴加入丙烯酰氯(0.011g，0.13mmol)的二氯甲烷溶液(1mL)，室温反应2h。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析得到化合物7(0.014g，产率21.09％)。The trifluoroacetate of 7D (0.06 g, 0.13 mmol) was dissolved in dichloromethane (4 mL), triethylamine (0.05 g, 0.52 mmol) was added at 0°C under nitrogen atmosphere, and a dichloromethane solution (1 mL) of acryloyl chloride (0.011 g, 0.13 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 7 (0.014 g, yield 21.09%).
LCMS m/z＝511.2[M+H]+ LCMS m/z＝511.2[M+H] +
1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.40(d,1H),7.86(s,1H),7.51(s,1H),7.44-7.28(m,3H),7.12-7.00(m,1H),6.96(d,1H),6.37-6.24(m,1H),6.17-6.05(m,1H),5.72-5.62(m,1H),4.50-4.07(m,4H),3.92(s,3H),3.70-3.57(m,1H),2.53(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, 1H), 8.40 (d, 1H), 7.86 (s, 1H), 7.51 (s, 1H), 7.44-7.28 (m, 3H), 7.12-7.00 (m, 1H), 6.96 (d, 1H), 6.37-6.24 (m, 1H), 6.17-6.05 (m, 1H), 5.72-5.62 (m, 1H), 4.50-4.07 (m, 4H), 3.92 (s, 3H), 3.70-3.57 (m, 1H), 2.53 (s, 3H).
实施例8：化合物8的制备
Example 8: Preparation of Compound 8
将7D的三氟乙酸盐(0.1g，0.22mmol)溶于二氯甲烷(4mL)，氮气氛围0℃加入三乙胺(0.09g，0.88mmol)，缓慢逐滴加入甲基丙烯酰氯(0.023g，0.22mmol)的二氯甲烷溶液(1mL)，室温反应2h。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析得到化合物8(0.014g，产率12.13％)。The trifluoroacetate of 7D (0.1 g, 0.22 mmol) was dissolved in dichloromethane (4 mL), triethylamine (0.09 g, 0.88 mmol) was added at 0°C under nitrogen atmosphere, and a dichloromethane solution (1 mL) of methacryloyl chloride (0.023 g, 0.22 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 8 (0.014 g, yield 12.13%).
LCMS m/z＝525.50[M+H]+ LCMS m/z＝525.50[M+H] +
1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.39(d,1H),7.86(s,1H),7.50(s,1H),7.42(dd,1H),7.37-7.28(m,2H),7.02-6.85(m,2H),5.40-5.35(m,1H),5.29-5.25(m,1H),4.48-4.03(m,4H),3.92(s,3H),3.68-3.54(m,1H),2.52(s,3H),1.90(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, 1H), 8.39 (d, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.42 (dd, 1H), 7.37-7.28 (m, 2H), 7.02-6.85 (m, 2H), 5.40-5.35 (m, 1H), 5.29-5.25 (m, 1H), 4.48-4.03 (m, 4H), 3.92 (s, 3H), 3.68-3.54 (m, 1H), 2.52 (s, 3H), 1.90 (s, 3H).
实施例9：化合物9的制备
Example 9: Preparation of Compound 9
参照化合物7的合成路线及制备方法，得到化合物9(25mg)。Referring to the synthetic route and preparation method of compound 7, compound 9 (25 mg) was obtained.
LCMS m/z＝525.2[M+H]+ LCMS m/z＝525.2[M+H] +
1H NMR(400MHz,CDCl3)δ8.46(d,1H),8.37(t,1H),7.86(d,1H),7.51(d,1H),7.43-7.31(m,2H),7.30-7.27(m,1H),7.12-7.01(m,1H),6.95(d,1H),6.41-6.31(m,2H),5.71-5.62(m,1H),3.92(s,3H),3.88-3.79(m,1H),3.76-3.50(m,3H),3.33-3.17(m,1H),2.56-2.49(m,3H),2.31-2.17(m,1H),2.15-1.95(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, 1H), 8.37 (t, 1H), 7.86 (d, 1H), 7.51 (d, 1H), 7.43-7.31 (m, 2H), 7.30-7.27 (m, 1H), 7.12-7.01 (m, 1H), 6.95 (d, 1H), 6.41-6.31 (m, 2H), 5.71-5.62 (m, 1H), 3.92 (s, 3H), 3.88-3.79 (m, 1H), 3.76-3.50 (m, 3H), 3.33-3.17 (m, 1H), 2.56-2.49 (m, 3H), 2.31-2.17 (m, 1H), 2.15-1.95 (m, 1H).
实施例10：化合物10的制备
Example 10: Preparation of Compound 10
参照化合物7的合成路线及制备方法，得到化合物10(25mg)。Referring to the synthetic route and preparation method of compound 7, compound 10 (25 mg) was obtained.
LCMS m/z＝539.50[M+H]+ LCMS m/z＝539.50[M+H] +
1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.38(d,1H),7.86(s,1H),7.50(s,1H),7.43-7.27(m,3H),7.01-6.85(m,2H),5.29-5.22(m,1H),5.15-5.08(m,1H),3.92(s,3H),3.88-3.44(m,4H), 3.28-3.12(m,1H),2.52(s,3H),2.32-2.12(m,1H),2.07-1.97(m,1H),1.93(s,3H). 1 H NMR (400MHz,CDCl 3 )δ8.46(s,1H),8.38(d,1H),7.86(s,1H),7.50(s,1H),7.43-7.27(m,3H),7.01-6.85(m,2H),5.29-5.22(m,1H),5.15-5.08(m,1H),3.92(s,3H),3.88-3.44(m,4H), 3.28-3.12(m,1H),2.52(s,3H),2.32-2.12(m,1H),2.07-1.97(m,1H),1.93(s,3H).
实施例11：化合物11的制备
Example 11: Preparation of Compound 11
将9D(0.045g，0.096mmol)溶于DMF(4mL)，加入2-氟丙烯酸(0.011g，0.11mmol)、TCFH(0.04g，0.14mmol)、N-甲基咪唑(0.015g，0.19mmol)，室温反应16h。反应加入乙酸乙酯(20mL)，有机相依次用水(20mL×2)、饱和NaCl水溶液(20mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝25:1-8:1)得到化合物11(20mg，产率38.40％)。9D (0.045 g, 0.096 mmol) was dissolved in DMF (4 mL), and 2-fluoroacrylic acid (0.011 g, 0.11 mmol), TCFH (0.04 g, 0.14 mmol), and N-methylimidazole (0.015 g, 0.19 mmol) were added, and the mixture was reacted at room temperature for 16 h. Ethyl acetate (20 mL) was added to the reaction, and the organic phase was washed with water (20 mL × 2) and saturated aqueous NaCl solution (20 mL × 1) in sequence, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 25: 1-8: 1) to obtain compound 11 (20 mg, yield 38.40%).
LCMS m/z＝543.20[M+H]+ LCMS m/z＝543.20[M+H] +
1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.40-8.34(m,1H),7.89-7.83(m,1H),7.51(s,1H),7.42-7.27(m,3H),7.11-7.01(m,1H),6.95(d,1H),5.52(dd,1H),5.16-5.06(m,1H),3.99-3.81(m,4H),3.78-3.53(s,3H),3.30-3.14(m,1H),2.52(s,3H),2.28-2.15(m,1H),2.12-1.94(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.40-8.34 (m, 1H), 7.89-7.83 (m, 1H), 7.51 (s, 1H), 7.42-7.27 (m, 3H), 7.11-7.01 (m, 1H), 6.95 (d, 1H), 5.52 (dd, 1H), 5.16-5.06 (m, 1H), 3.99-3.81 (m, 4H), 3.78-3.53 (s, 3H), 3.30-3.14 (m, 1H), 2.52 (s, 3H), 2.28-2.15 (m, 1H), 2.12-1.94 (m, 1H).
实施例12：化合物12的制备
Example 12: Preparation of Compound 12
第一步：12B的制备Step 1: Preparation of 12B
氮气氛围下，将12A(2g,8.99mmol)、频哪醇联硼酸酯(2g，8.99mmol)、乙酸钾(1.76g,17.89mmol)、Pd(dppf)Cl2.DCM(0.73g，0.89mmol)混悬于1,4-二氧六环(8mL)和水(1.5mL)的混合溶剂中，100℃下反应3h。反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析得到12B(2.3g，产率95.05％)。Under nitrogen atmosphere, 12A (2 g, 8.99 mmol), pinacol biborate (2 g, 8.99 mmol), potassium acetate (1.76 g, 17.89 mmol), Pd(dppf)Cl 2 .DCM (0.73 g, 0.89 mmol) were suspended in a mixed solvent of 1,4-dioxane (8 mL) and water (1.5 mL) and reacted at 100° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 12B (2.3 g, yield 95.05%).
LCMS m/z＝270.2[M+H]+ LCMS m/z＝270.2[M+H] +
第二步：12C的制备Step 2: Preparation of 12C
氮气氛围下，将12B(1g，3.72mmol)溶于二氯甲烷(15mL)，缓慢加入吡啶(0.59g，7.48mmol)，0℃下缓慢滴加甲基丙烯酰氯(0.58g，5.54mmol)的二氯甲烷溶液(2mL)，室温反应2h。加入水(10mL)，分液，有机相用饱和NaCl的水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层次得到12C(0.9g，产率71.74％)。Under nitrogen atmosphere, 12B (1 g, 3.72 mmol) was dissolved in dichloromethane (15 mL), pyridine (0.59 g, 7.48 mmol) was slowly added, and a dichloromethane solution (2 mL) of methacryloyl chloride (0.58 g, 5.54 mmol) was slowly added dropwise at 0°C, and the mixture was reacted at room temperature for 2 h. Water (10 mL) was added, and the liquid was separated. The organic phase was washed with a saturated aqueous solution of NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 12C (0.9 g, yield 71.74%).
LCMS m/z＝338.2[M+H]+ LCMS m/z＝338.2[M+H] +
第三步：化合物12的制备 Step 3: Preparation of compound 12
氮气氛围下，将12D(0.06g，0.13mmol)、12C(0.044g，0.13mmol)、乙酸钾(0.036g，0.26mmol)和Pd(dppf)Cl2.DCM(0.011g，0.013mmol)溶于1,4-二氧六环(4mL)和水(0.5mL)中，100℃反应3h。反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析得化合物12(21mg，产率28.87％)。Under nitrogen atmosphere, 12D (0.06 g, 0.13 mmol), 12C (0.044 g, 0.13 mmol), potassium acetate (0.036 g, 0.26 mmol) and Pd(dppf)Cl 2 .DCM (0.011 g, 0.013 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.5 mL) and reacted at 100° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 12 (21 mg, yield 28.87%).
LCMS m/z＝560.1[M+H]+ LCMS m/z＝560.1[M+H] +
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.35-8.29(d,2H),7.83-7.66(m,4H),7.52(dd,1H),7.33(dd,1H),7.21-7.14(m,1H),7.12-7.03(m,2H),6.91(d,1H),5.86(s,1H),5.52(s,1H),5.15(s,2H),3.76(s,3H),2.47(s,3H),2.11(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.35-8.29 (d, 2H), 7.83-7.66 (m, 4H), 7.52 (dd, 1H), 7.33 (dd, 1H), 7.21-7.14 (m, 1H), 7.12-7.03 (m, 2H), 6.91 (d, 1H), 5.86 (s, 1H), 5.52 (s, 1H), 5.15 (s, 2H), 3.76 (s, 3H), 2.47 (s, 3H), 2.11 (s, 3H).
实施例13：化合物13的制备
Example 13: Preparation of Compound 13
第一步：13A的制备Step 1: Preparation of 13A
氮气氛围下，将12A(1g,4.50mmol)溶于二氯甲烷(10mL)，缓慢加入三乙胺(0.59g，5.85mmol)，0℃缓慢滴加丙烯酰氯(0.43g，4.70mmol)的二氯甲烷溶液(2mL)，继续反应2h。加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶色谱柱柱层次得到13A(1.2g，产率96.57％)。Under nitrogen atmosphere, 12A (1 g, 4.50 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.59 g, 5.85 mmol) was slowly added, and a dichloromethane solution (2 mL) of acryloyl chloride (0.43 g, 4.70 mmol) was slowly added dropwise at 0°C, and the reaction was continued for 2 h. Water was added to quench, and DCM was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 13A (1.2 g, yield 96.57%).
LCMS m/z＝276.0[M+H]+ LCMS m/z＝276.0[M+H] +
第二步：13B的制备Step 2: Preparation of 13B
封管中加入13A(200mg，0.72mmol),用二氧六环(10mL)溶解后，加入频哪醇联硼酸酯(370mg，1.44mmol)、乙酸钾(280mg,2.88mmol)、Pd(dppf)Cl2.DCM(0.73g，0.89mmol)，氮气保护90℃反应16h，冷却至室温，加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物经过柱层析分离纯化得13B(200mg，产率85.95％)。13A (200 mg, 0.72 mmol) was added to a sealed tube, dissolved with dioxane (10 mL), and then pinacol borate (370 mg, 1.44 mmol), potassium acetate (280 mg, 2.88 mmol), and Pd(dppf)Cl 2 .DCM (0.73 g, 0.89 mmol) were added. The reaction was carried out at 90° C. under nitrogen protection for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 13B (200 mg, yield 85.95%).
LCMS m/z＝324.50[M+H]+ LCMS m/z＝324.50[M+H] +
第三步：化合物13的制备Step 3: Preparation of compound 13
封管中加入12D(70mg，0.15mmol)、13B(68mg，0.21mmol)、碳酸钾(41mg，0.30mmol)和Pd(dppf)Cl2.DCM(12mg，0.015mmol)溶于1,4-二氧六环(4mL)和水(1mL)中，置换氮气保护。100℃反应5h。反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析得产物粗品，再经过反相柱层析纯化，冻干后得化合物13(36mg，产率43.99％)。12D (70 mg, 0.15 mmol), 13B (68 mg, 0.21 mmol), potassium carbonate (41 mg, 0.30 mmol) and Pd(dppf)Cl 2 .DCM (12 mg, 0.015 mmol) were added to the sealed tube and dissolved in 1,4-dioxane (4 mL) and water (1 mL), and nitrogen was replaced for protection. The reaction was carried out at 100°C for 5 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain a crude product, which was then purified by reverse phase column chromatography and freeze-dried to obtain compound 13 (36 mg, yield 43.99%).
LCMS m/z＝546.1[M+H]+ LCMS m/z＝546.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.44(d,1H),8.42(s,1H),8.23(s,1H),7.92-7.84(m,3H),7.68(dd,1H),7.43(dd,1H),7.30(t,1H),7.21(dd,1H),7.15(d,1H),7.13(d,1H),6.50(dd,1H),6.31(dd,1H),6.00(brs,2H),5.80(dd,1H),3.65(s,3H),2.38(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.44 (d, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.92-7.84 (m, 3H), 7.68 (dd, 1H), 7.43 (dd, 1H), 7.30 (t, 1H), 7.21 (dd, 1H), 7.15 (d, 1H), 7.13 (d, 1H), 6.50 (dd, 1H), 6.31 (dd, 1H), 6.00 (brs, 2H), 5.80 (dd, 1H), 3.65 (s, 3H), 2.38 (s, 3H).
实施例14：化合物14的制备
Example 14: Preparation of Compound 14
第一步：14A的制备Step 1: Preparation of 14A
氮气氛围下，将2-氟丙烯酸(430mg,4.78mmol)溶于二氯甲烷(12mL)，加入TCFH(1.89g，6.75mmol)，N-甲基咪唑(0.74g，9.00mmol)，置换氮气保护30分钟后，加入12A(1g,4.50mmol)，继续反应2h。加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物经过柱层析分离得14A(580mg，产率43.82％)。Under nitrogen atmosphere, 2-fluoroacrylic acid (430 mg, 4.78 mmol) was dissolved in dichloromethane (12 mL), TCFH (1.89 g, 6.75 mmol) and N-methylimidazole (0.74 g, 9.00 mmol) were added, and after replacing nitrogen for 30 minutes, 12A (1 g, 4.50 mmol) was added and the reaction was continued for 2 h. Water was added to quench, and DCM was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 14A (580 mg, yield 43.82%).
LCMS m/z＝294.1[M+H]+ LCMS m/z＝294.1[M+H] +
第二步：14B的制备Step 2: Preparation of 14B
封管中加入14A(200mg，0.68mmol),用二氧六环(10mL)溶解后，加入频哪醇联硼酸酯(350mg，1.36mmol)、乙酸钾(270mg,2.72mmol)、Pd(dppf)Cl2.DCM(0.56g，0.068mmol)，置换氮气保护，90℃反应16h，冷却至室温，加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物经过柱层析分离纯化得14B(195mg，产率84.05％)。14A (200 mg, 0.68 mmol) was added to a sealed tube, dissolved with dioxane (10 mL), and then pinacol borate (350 mg, 1.36 mmol), potassium acetate (270 mg, 2.72 mmol), and Pd(dppf)Cl 2 .DCM (0.56 g, 0.068 mmol) were added. The atmosphere was replaced with nitrogen for protection. The reaction was carried out at 90° C. for 16 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 14B (195 mg, yield 84.05%).
LCMS m/z＝342.40[M+H]+ LCMS m/z＝342.40[M+H] +
第三步：化合物14的制备Step 3: Preparation of compound 14
封管中加入12D(70mg，0.15mmol)、14B(72mg，0.21mmol)、碳酸钾(41mg，0.30mmol)和Pd(dppf)Cl2.DCM(12mg，0.015mmol)溶于1,4-二氧六环(4mL)和水(1mL)中，置换氮气保护。100℃反应5h。反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析得产物粗品，再经过反相柱层析纯化，冻干后得化合物14(37mg，产率43.77％)。12D (70 mg, 0.15 mmol), 14B (72 mg, 0.21 mmol), potassium carbonate (41 mg, 0.30 mmol) and Pd(dppf)Cl 2 .DCM (12 mg, 0.015 mmol) were added to the sealed tube and dissolved in 1,4-dioxane (4 mL) and water (1 mL), and nitrogen was replaced for protection. The reaction was carried out at 100°C for 5 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain a crude product, which was then purified by reverse phase column chromatography and freeze-dried to obtain compound 14 (37 mg, yield 43.77%).
LCMS m/z＝546.1[M+H]+ LCMS m/z＝546.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.44(d,1H),8.40(s,1H),8.24(s,1H),7.94-7.86(m,3H),7.82(dd,1H),7.45(dd,1H),7.30(t,1H),7.21(dd,1H),7.15(d,1H),7.14-7.10(m,1H),6.01(brs,2H),5.77(dd,1H),5.47(dd,1H),3.66(s,3H),2.38(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.44 (d, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.94-7.86 (m, 3H), 7.82 (dd, 1H), 7.45 (dd, 1H), 7.30 (t, 1H), 7.21 (dd, 1H), 7.15 (d, 1H), 7.14-7.10 (m, 1H), 6.01 (brs, 2H), 5.77 (dd, 1H), 5.47 (dd, 1H), 3.66 (s, 3H), 2.38 (s, 3H).
实施例15：化合物15的合成
Example 15: Synthesis of Compound 15
第一步：15b的制备Step 1: Preparation of 15b
氮气保护下，0℃将15a(5.0g,21.12mmol)溶于50mL二氯甲烷中，加入三乙胺(4.28g，42.27mmol)，滴加丙烯酰氯(1.91g，21.12mmol)，室温反应1h，反应加入水50mL淬灭，二氯甲烷(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，得到15b(3.0g，收率：48.80％)。 Under nitrogen protection, 15a (5.0 g, 21.12 mmol) was dissolved in 50 mL of dichloromethane at 0°C, triethylamine (4.28 g, 42.27 mmol) was added, and acryloyl chloride (1.91 g, 21.12 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 h. 50 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain 15b (3.0 g, yield: 48.80%).
LCMS m/z＝292.1[M+H]+ LCMS m/z＝292.1[M+H] +
第二步：15c的制备Step 2: Preparation of 15c
将15b(1.0g，3.44mmol)、联硼酸频哪醇酯(1.75g，6.88mmol)、Pd(dppf)Cl2(0.28g，0.34mmol)、醋酸钾(1.01g，10.32mmol)溶于20mL1,4-二氧六环中，氮气置换保护，100℃反应1h。加水稀释，乙酸乙酯萃取(50mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化得15c(0.15g，19.98％)。15b (1.0 g, 3.44 mmol), bipyralidin (1.75 g, 6.88 mmol), Pd(dppf)Cl 2 (0.28 g, 0.34 mmol), potassium acetate (1.01 g, 10.32 mmol) were dissolved in 20 mL 1,4-dioxane, replaced with nitrogen, and reacted at 100°C for 1 h. Diluted with water, extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 15c (0.15 g, 19.98%).
LC-Ms m/z(ESI):292.1[M+H]+ LC-Ms m/z(ESI):292.1[M+H] +
第三步：化合物15的制备Step 3: Preparation of compound 15
将4E(120mg，0.236mmol)、15c(70mg，0.236mmol)、Pd(dppf)Cl2(17.4mg，0.024mmol)和碳酸铯(154mg,0.472mmol)溶于5mL1,4-二氧六环和1mL水中，氮气置换保护，100℃反应3h。加水稀释，乙酸乙酯萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得化合物15(10mg，7.64％)。4E (120 mg, 0.236 mmol), 15c (70 mg, 0.236 mmol), Pd(dppf)Cl 2 (17.4 mg, 0.024 mmol) and cesium carbonate (154 mg, 0.472 mmol) were dissolved in 5 mL 1,4-dioxane and 1 mL water, replaced with nitrogen, and reacted at 100°C for 3 h. Diluted with water, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 15 (10 mg, 7.64%).
LC-Ms m/z(ESI):546.2[M+H]+ LC-Ms m/z(ESI):546.2[M+H] +
1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.35(d,1H),7.85-7.69(m,4H),7.64-7.59(m,1H),7.42(s,1H),7.38-7.30(m,2H),7.07-6.99(m,2H),6.92(d,1H),6.45(d,1H),6.22(dd,1H),5.81(d,1H),5.07(br.s,2H),3.70(s,3H),2.52(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.35 (d, 1H), 7.85-7.69 (m, 4H), 7.64-7.59 (m, 1H), 7.42 (s, 1H), 7.38-7.30 (m, 2H), 7.07-6.99 (m, 2H), 6.92 (d, 1H), 6.45 (d, 1H), 6.22 (dd, 1H), 5.81 (d, 1H), 5.07 (br. s, 2H), 3.70 (s, 3H), 2.52 (s, 3H).
实施例16：化合物16的合成
Example 16: Synthesis of Compound 16
第一步：16b的合成Step 1: Synthesis of 16b
将16a(0.9g，3.72mmol)、2-氯-4-甲基嘧啶(0.96g，7.43mmol)、碳酸钾(1.54g,11.14mmol)溶于20mL DMF中，80℃反应10h。加水稀释，乙酸乙酯萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得16b(0.6g，48.41％)。16a (0.9 g, 3.72 mmol), 2-chloro-4-methylpyrimidine (0.96 g, 7.43 mmol), potassium carbonate (1.54 g, 11.14 mmol) were dissolved in 20 mL DMF and reacted at 80 °C for 10 h. The mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 16b (0.6 g, 48.41%).
LC-Ms m/z(ESI):333.1[M+H]+ LC-Ms m/z(ESI):333.1[M+H] +
第二步：16c的合成Step 2: Synthesis of 16c
将16b(0.6g，1.80mmol)、联硼酸频哪醇酯(0.91g，3.60mmol)、Pd(dppf)Cl2(0.15g，0.18mmol)、醋酸钾(0.53g，5.4mmol)溶于20mL1,4-二氧六环中，氮气置换保护，100℃反应3h。加水稀释，乙酸乙酯萃取(50mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化得16c(0.55g，80.36％)。16b (0.6 g, 1.80 mmol), bipyralidin (0.91 g, 3.60 mmol), Pd(dppf)Cl 2 (0.15 g, 0.18 mmol), potassium acetate (0.53 g, 5.4 mmol) were dissolved in 20 mL 1,4-dioxane, replaced with nitrogen, and reacted at 100°C for 3 h. The mixture was diluted with water, extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16c (0.55 g, 80.36%).
LC-Ms m/z(ESI):381.2[M+H]+ LC-Ms m/z(ESI):381.2[M+H] +
第三步：16d的合成Step 3: Synthesis of 16d
在氮气氛围下，将16c(0.56g，1.47mmol)、4C-1(0.60g，2.21mmol)、Pd(dppf)Cl2(0.12g，0.15mmol)、碳酸铯(0.61g，4.41mmol)溶于20mL1,4-二氧六环和4mL水中，100℃反应3h。加 水稀释，乙酸乙酯萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得16d(0.3g，50.97％)。Under nitrogen atmosphere, 16c (0.56 g, 1.47 mmol), 4C-1 (0.60 g, 2.21 mmol), Pd(dppf)Cl 2 (0.12 g, 0.15 mmol), and cesium carbonate (0.61 g, 4.41 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water and reacted at 100°C for 3 h. The mixture was diluted with water, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16d (0.3 g, 50.97%).
LC-Ms m/z(ESI):401.2[M+H]+ LC-Ms m/z(ESI):401.2[M+H] +
第四步：16e的合成Step 4: Synthesis of 16e
在氮气氛围下，将16d(0.3g，0.75mmol)溶于10mL二氯甲烷中，0℃加入三氟乙酸(0.17mg，1.50mmol)，NIS(CAS 516-12-1)(0.34g，1.50mmol)，室温搅拌2h，饱和碳酸氢钠淬灭，乙酸乙酯萃取(10mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化得16e(0.24g，60.80％)。Under nitrogen atmosphere, 16d (0.3 g, 0.75 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (0.17 mg, 1.50 mmol) and NIS (CAS 516-12-1) (0.34 g, 1.50 mmol) were added at 0°C, stirred at room temperature for 2 h, quenched with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 16e (0.24 g, 60.80%).
LC-Ms m/z(ESI):527.1[M+H]+ LC-Ms m/z(ESI):527.1[M+H] +
第五步：化合物16的合成Step 5: Synthesis of compound 16
将16e(120mg，0.24mmol)、5A(70mg，0.24mmol)、Pd(dppf)Cl2(17.4mg，0.024mmol)、碳酸铯(154mg，0.472mmol)溶于20mL1,4-二氧六环和4mL水中，氮气置换保护，100℃反应3h。加水稀释，乙酸乙酯萃取(10mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得化合物16(10mg，7.64％)。16e (120 mg, 0.24 mmol), 5A (70 mg, 0.24 mmol), Pd(dppf)Cl 2 (17.4 mg, 0.024 mmol), cesium carbonate (154 mg, 0.472 mmol) were dissolved in 20 mL 1,4-dioxane and 4 mL water, replaced with nitrogen, and reacted at 100°C for 3 h. Diluted with water, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 16 (10 mg, 7.64%).
LC-Ms m/z(ESI):546.2[M+H]+ LC-Ms m/z(ESI):546.2[M+H] +
实施例17：化合物17的制备：
Example 17: Preparation of Compound 17:
参照化合物3的合成路线及制备方法，得到化合物17(8mg)。Referring to the synthetic route and preparation method of compound 3, compound 17 (8 mg) was obtained.
LCMS m/z＝582.3[M+H]+ LCMS m/z＝582.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.00(s,1H),7.82(s,1H),7.59(s,1H),7.32(t,1H),7.23(dd,1H),7.19(dd,1H),7.13(d,1H),5.43-5.39(m,1H),5.35-5.32(m,1H),4.39(s,2H),4.12(s,2H),4.06(s,4H),3.97(d,2H),2.46(s,3H),1.86(s,3H),1.31-1.27(m,1H),0.66-0.59(m,2H),0.43-0.38(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 8.41 (d, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.32 (t, 1H), 7.23 (dd, 1H), 7.19 (dd, 1H), 7.13 (d, 1H), 5.43-5.39 (m, 1H), 5.35-5.32 (m, 1H), 4.39 (s, 2H), 4.12 (s, 2H), 4.06 (s, 4H), 3.97 (d, 2H), 2.46 (s, 3H), 1.86 (s, 3H), 1.31-1.27 (m, 1H), 0.66-0.59 (m, 2H), 0.43-0.38 (m, 2H).
实施例18：化合物18的制备：
Example 18: Preparation of Compound 18:
氮气保护下，将3i(120mg,0.23mmol)溶于5mL DMF中，依次加入2-氟丙烯酸(25mg，0.28mmol)、N-甲基咪唑(38mg，0.46mmol)和TCFH(97mg，0.35mmol)，室温反应1h，反应加入20mL乙酸乙酯，并用水(20mL×3)洗涤，饱和NaCl的水溶液20mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，得到化合物18(31mg，收率：23.02％)。Under nitrogen protection, 3i (120 mg, 0.23 mmol) was dissolved in 5 mL DMF, and 2-fluoroacrylic acid (25 mg, 0.28 mmol), N-methylimidazole (38 mg, 0.46 mmol) and TCFH (97 mg, 0.35 mmol) were added in sequence. The reaction was carried out at room temperature for 1 h. 20 mL of ethyl acetate was added to the reaction, and the mixture was washed with water (20 mL × 3) and once with 20 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated by silica gel column chromatography to give compound 18 (31 mg, yield: 23.02%).
LCMS m/z＝586.2[M+H]+ LCMS m/z＝586.2[M+H] +
实施例19：化合物19的制备：
Example 19: Preparation of Compound 19:
第一步:19B的制备Step 1: Preparation of 19B
将19A(1g,5.81mmol)溶于10mL DMF中，加入三乙胺(0.97mL，6.97mmol)，置换氮气保护，冰浴下，缓慢滴入丙烯酰氯(0.53mL,6.39mmol)，室温反应1h，加水淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤2次，有机相无水硫酸钠干燥，过滤，减压浓缩除去溶剂，残留物经过柱层析分离得产物19B(1g，收率：76.06％)。19A (1 g, 5.81 mmol) was dissolved in 10 mL of DMF, and triethylamine (0.97 mL, 6.97 mmol) was added. The nitrogen atmosphere was replaced and protected. Acryloyl chloride (0.53 mL, 6.39 mmol) was slowly added dropwise under ice bath. The mixture was reacted at room temperature for 1 h, quenched with water, extracted with ethyl acetate three times, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography to obtain the product 19B (1 g, yield: 76.06%).
LCMS m/z＝171.2[M+H-56]+ LCMS m/z＝171.2[M+H-56] +
第二步:19C的制备Step 2: Preparation of 19C
将19B(600mg,2.65mmol)溶于10mL DCM中,冰浴下，滴入2mL三氟乙酸，继续反应3h，加入饱和碳酸氢钠溶液调节pH至7，用DCM/MeOH(10/1)的混合体系萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得产物19C(280mg，收率：83.70％)19B (600 mg, 2.65 mmol) was dissolved in 10 mL DCM. 2 mL trifluoroacetic acid was added dropwise under ice bath. The reaction was continued for 3 h. Saturated sodium bicarbonate solution was added to adjust the pH to 7. The mixture was extracted three times with a DCM/MeOH (10/1) mixture. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain product 19C (280 mg, yield: 83.70%).
LCMS m/z＝127.1[M+H]+ LCMS m/z＝127.1[M+H] +
第三步:19E的制备Step 3: Preparation of 19E
在高压釜中，将19D(300mg,0.63mmol)溶于6mL甲醇中，加入三乙胺(0.19mL,1.39mmol)，Pd(dppf)Cl2(103mg，0.13mmol)，置换CO气体氛围，60℃反应24h。冷却至室温，减压浓缩，残余物经过柱层析分离纯化得产物19E(230mg，收率：89.49％) In an autoclave, 19D (300 mg, 0.63 mmol) was dissolved in 6 mL of methanol, triethylamine (0.19 mL, 1.39 mmol) and Pd(dppf)Cl 2 (103 mg, 0.13 mmol) were added, the CO gas atmosphere was replaced, and the reaction was carried out at 60°C for 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain product 19E (230 mg, yield: 89.49%).
LCMS m/z＝409.40[M+H]+ LCMS m/z＝409.40[M+H] +
第四步:19F的制备Step 4: Preparation of 19F
将19E(230mg,0.56mmol)溶于6mL乙醇和2mL水中，加入一水合氢氧化锂(24mg,5.63mmol)，室温下搅拌反应3h，减压浓缩，残余物经过反相柱层析分离纯化，冻干得19F(100mg，收率：45.05％)19E (230 mg, 0.56 mmol) was dissolved in 6 mL of ethanol and 2 mL of water, and lithium hydroxide monohydrate (24 mg, 5.63 mmol) was added. The mixture was stirred at room temperature for 3 h, and concentrated under reduced pressure. The residue was separated and purified by reverse phase column chromatography and freeze-dried to obtain 19F (100 mg, yield: 45.05%).
LCMS m/z＝395.40[M+H]+ LCMS m/z＝395.40[M+H] +
第五步:化合物19的制备Step 5: Preparation of Compound 19
将19F(60mg,0.15mmol)溶于3mL DMF中，加入TCFH(TCFH)(64mg，0.23mmol),N-甲基咪唑(25mg,0.30mmol)，置换氮气保护，室温反应30分钟，加入19C(29mg,0.23mmol)，继续反应2h，加水淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤2次，有机相无水硫酸钠干燥，过滤后减压浓缩，残余物经过反相柱层析分离纯化，冻干得化合物19(4mg，收率：5.23％)19F (60 mg, 0.15 mmol) was dissolved in 3 mL DMF, TCFH (TCFH) (64 mg, 0.23 mmol) and N-methylimidazole (25 mg, 0.30 mmol) were added, and nitrogen protection was replaced. The reaction was carried out at room temperature for 30 minutes, and 19C (29 mg, 0.23 mmol) was added. The reaction was continued for 2 hours, and water was added to quench the reaction. The mixture was extracted with ethyl acetate three times, and the organic phases were combined and washed with saturated brine twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by reverse phase column chromatography and freeze-dried to obtain compound 19 (4 mg, yield: 5.23%).
LCMS m/z＝503.70[M+H]+ LCMS m/z＝503.70[M+H] +
1H NMR(400MHz,CD3OD)δ8.45(d,1H),8.38(s,1H),7.52(t,1H),7.45-7.34(m,2H),7.19(d,1H),6.25-6.09(m,1H),5.73-5.64(m,1H),4.50-4.33(m,2H),4.05-3.83(m,5H),3.52-3.41(m,1H),2.52(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.45 (d, 1H), 8.38 (s, 1H), 7.52 (t, 1H), 7.45-7.34 (m, 2H), 7.19 (d, 1H), 6.25-6.09 (m, 1H), 5.73-5.64 (m, 1H), 4.50-4.33 (m, 2H), 4.05-3.83 (m, 5H), 3.52-3.41 (m, 1H), 2.52 (s, 3H).
实施例20：化合物20的制备：
Example 20: Preparation of Compound 20:
参照化合物19的合成路线及制备方法，得到化合物20(3mg)。Referring to the synthetic route and preparation method of compound 19, compound 20 (3 mg) was obtained.
LCMS m/z＝517.3[M+H]+ LCMS m/z＝517.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.45(d,1H),8.36(s,1H),7.52(t,1H),7.44-7.33(m,2H),7.19(d,1H),5.67(s,1H),5.41(s,1H),4.48-4.30(m,2H),4.12-4.02(m,1H),3.93(s,3H),3.88-3.78(m,1H),3.57-3.45(m,1H),2.52(s,3H),1.89(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.45 (d, 1H), 8.36 (s, 1H), 7.52 (t, 1H), 7.44-7.33 (m, 2H), 7.19 (d, 1H), 5.67 (s, 1H), 5.41 (s, 1H), 4.48-4.30 (m, 2H), 4.12-4.02 (m, 1H), 3.93 (s, 3H), 3.88-3.78 (m, 1H), 3.57-3.45 (m, 1H), 2.52 (s, 3H), 1.89 (s, 3H).
实施例21：化合物21的合成
Example 21: Synthesis of Compound 21
第一步:21b的制备Step 1: Preparation of 21b
将3a(10g,120.29mmol)溶于50mL DMF中，依次加入三乙胺(24.35g,240.58mmol)，N-[2-(三甲基硅基)乙氧羰氧基]琥珀酰亚胺(40.55g,156.38mmol)，室温反应16h。反应加入50mL水，乙酸乙酯(50mL×2)萃取，合并乙酸乙酯层，乙酸乙酯层依次用水(80mL×2)洗，饱和NaCl水溶液100mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝50:1)，即得21b(19g，收率：69.48％)。3a (10 g, 120.29 mmol) was dissolved in 50 mL DMF, triethylamine (24.35 g, 240.58 mmol) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (40.55 g, 156.38 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 h. 50 mL of water was added to the reaction, and ethyl acetate (50 mL × 2) was used for extraction. The ethyl acetate layers were combined, and the ethyl acetate layers were washed with water (80 mL × 2) and 100 mL of saturated NaCl aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 50:1) to obtain 21b (19 g, yield: 69.48%).
LCMS m/z＝228.1[M+H]+ LCMS m/z＝228.1[M+H] +
第二步:21d的制备Step 2: Preparation of 21d
将21b(5g,21.99mmol)溶于20mL DMF中，依次加入中间体21c(6.53g,32.98mmol)，碳酸钾(6.08g,43.98mmol)，80℃反应16h。冷却至室温，加入40mL水，加入乙酸乙酯(40mL×2)萃取，合并乙酸乙酯层，乙酸乙酯层依次用水(50mL×2)洗，饱和NaCl水溶液50mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝50:1)得21d(3.6g，收率：55.04％)。21b (5 g, 21.99 mmol) was dissolved in 20 mL DMF, and intermediate 21c (6.53 g, 32.98 mmol) and potassium carbonate (6.08 g, 43.98 mmol) were added in sequence, and the mixture was reacted at 80°C for 16 h. After cooling to room temperature, 40 mL of water was added, and ethyl acetate (40 mL × 2) was added for extraction. The ethyl acetate layers were combined, and the ethyl acetate layers were washed with water (50 mL × 2) and 50 mL of saturated NaCl aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 50:1) to obtain 21d (3.6 g, yield: 55.04%).
LCMS m/z＝298.1[M+H]+ LCMS m/z＝298.1[M+H] +
第三步:21e的制备Step 3: Preparation of 21e
将21d(3.6g,12.10mmol)溶于30mL四氢呋喃中，加入四丁基氟化铵(4.75g,18.17mmol)，室温反应16h。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝50:1)，即得21e(1.4g，收率：75.53％)。21d (3.6 g, 12.10 mmol) was dissolved in 30 mL of tetrahydrofuran, and tetrabutylammonium fluoride (4.75 g, 18.17 mmol) was added, and the mixture was reacted at room temperature for 16 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 50:1) to obtain 21e (1.4 g, yield: 75.53%).
LCMS m/z＝154.1[M+H]+ LCMS m/z＝154.1[M+H] +
第四步:21f的制备Step 4: Preparation of 21f
将3g(0.18g,0.35mmol)溶于超干1,4-二氧六环6mL中，依次加入21e(0.08g,0.52mmol)，Pd2(dba)3(0.032g,0.035mmol)，碳酸铯(0.23g,0.70mmol)，S-phos(0.029g,0.07mmol)，氮气氛围下，100℃反应1h。将反应冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝20:1)，即得21f(0.09g，收率：40.84％)。3g (0.18g, 0.35mmol) was dissolved in 6mL of ultra-dry 1,4-dioxane, and 21e (0.08g, 0.52mmol), Pd 2 (dba) 3 (0.032g, 0.035mmol), cesium carbonate (0.23g, 0.70mmol), S-phos (0.029g, 0.07mmol) were added in sequence, and the mixture was reacted at 100°C for 1h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 20:1) to obtain 21f (0.09g, yield: 40.84%).
LCMS m/z＝630.3[M+H]+ LCMS m/z＝630.3[M+H] +
第五步:21g的制备Step 5: Preparation of 21g
将21f(0.05g,0.079mmol)溶解于5mL二氯甲烷中，室温下加入三氟乙酸1mL，室温反应3h。减压浓缩除去反应溶剂，残余物即为21g，直接用于下一步反应。21f (0.05 g, 0.079 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at room temperature. The reaction was allowed to react for 3 h at room temperature. The reaction solvent was removed by concentration under reduced pressure, and the residue was 21 g, which was directly used in the next step.
LCMS m/z＝530.4[M+H]+ LCMS m/z＝530.4[M+H] +
第六步:化合物21的制备Step 6: Preparation of Compound 21
将粗品21g溶于5mL二氯甲烷中，氮气氛围下，0℃依次缓慢滴入三乙胺(0.15g,1.44mmol)，丙烯酰氯(7.2mg,0.081mmol)的二氯甲烷溶液1mL，室温反应1h。反应加入10mL水，加入二氯甲烷(10mL×2)萃取两次，合并二氯甲烷层，二氯甲烷用无水硫酸钠干燥，过滤，滤液减压浓缩后，残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝50:1)，即得化合物21(14mg，两步收率：30.43％)。Dissolve 21 g of the crude product in 5 mL of dichloromethane, and slowly add triethylamine (0.15 g, 1.44 mmol) and 1 mL of dichloromethane solution of acryloyl chloride (7.2 mg, 0.081 mmol) at 0°C in a nitrogen atmosphere, and react at room temperature for 1 hour. Add 10 mL of water to the reaction, add dichloromethane (10 mL×2) to extract twice, combine the dichloromethane layers, dry the dichloromethane with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue on a silica gel column (dichloromethane: methanol = 50:1) to obtain compound 21 (14 mg, two-step yield: 30.43%).
LCMS m/z＝584.40[M+H]+ LCMS m/z＝584.40[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.13(s,1H),7.83(s,1H),7.61(s,1H),7.32(t,1H),7.26-7.18(m,2H),7.13(d,1H),6.32-6.24(m,1H),6.23-6.17(m,1H),5.70(dd,1H),5.16-5.09 (m,1H),4.66-4.58(m,1H),4.40-4.37(m,3H),4.34(dd,2H),4.14(s,2H),4.07(s,4H),2.76-2.66(m,1H),2.46(s,3H),2.44-2.39(m,1H). 1 H NMR (400 MHz, CD 3 OD) δ8.41 (d, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 7.32 (t, 1H), 7.26-7.18 (m, 2H), 7.13 (d, 1H), 6.32-6.24 (m, 1H), 6.23-6.17 (m, 1H), 5.70 (dd, 1H), 5.16-5.09 (m, 1H), 4.66-4.58 (m, 1H), 4.40-4.37 (m, 3H), 4.34 (dd, 2H), 4.14 (s, 2H), 4.07 (s, 4H), 2.76-2.66 (m, 1H), 2.46 (s, 3H), 2.44-2.39 (m, 1H).
实施例22：化合物22的合成
Example 22: Synthesis of Compound 22
第一步:21g的制备Step 1: Preparation of 21g
将21f(0.05g,0.079mmol)溶于5mL二氯甲烷中，室温加入三氟乙酸1mL，室温反应3h。减压浓缩除去反应溶剂，残余物即为21g，直接用于下一步反应。21f (0.05 g, 0.079 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at room temperature. The reaction was allowed to react for 3 h at room temperature. The reaction solvent was removed by concentration under reduced pressure, and the residue was 21 g, which was directly used in the next step.
LCMS m/z＝530.4[M+H]+ LCMS m/z＝530.4[M+H] +
第二步:化合物22的制备Step 2: Preparation of compound 22
氮气保护下，将粗品21g溶于5mL DMF中，依次加入2-氟丙烯酸(10.72mg，0.12mmol)、N-甲基咪唑(20mg，0.24mmol)和TCFH(33mg，0.12mmol)，室温反应1h，反应加入20mL乙酸乙酯，并用水(20mL×3)洗涤，饱和NaCl水溶液20mL洗，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残余物用硅胶色谱柱柱层析分离，得到化合物22(15mg，两步收率：31.25％)。Under nitrogen protection, 21 g of the crude product was dissolved in 5 mL of DMF, and 2-fluoroacrylic acid (10.72 mg, 0.12 mmol), N-methylimidazole (20 mg, 0.24 mmol) and TCFH (33 mg, 0.12 mmol) were added in sequence. The reaction was carried out at room temperature for 1 h. 20 mL of ethyl acetate was added to the reaction, and the mixture was washed with water (20 mL × 3) and 20 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated by silica gel column chromatography to give compound 22 (15 mg, two-step yield: 31.25%).
LCMS m/z＝602.2[M+H]+ LCMS m/z＝602.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.13(s,1H),7.82(s,1H),7.61(s,1H),7.32(t,1H),7.26-7.17(m,2H),7.13(d,1H),5.49(dd,1H),5.20-5.11(m 2H),4.67-4.59(m,1H),4.53(d,2H),4.42-4.38(m,1H),4.37-4.29(m,2H),4.17(s,2H),4.07(s,4H),2.77-2.66(m,1H),2.46(s,3H),2.45-2.37(m,1H). 1 H NMR (400 MHz, CD 3 OD) δ 8.41 (d, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.32 (t, 1H), 7.26-7.17 (m, 2H), 7.13 (d, 1H), 5.49 (dd, 1H), 5.20-5.11 (m 2H), 4.67-4.59 (m, 1H), 4.53 (d, 2H), 4.42-4.38 (m, 1H), 4.37-4.29 (m, 2H), 4.17 (s, 2H), 4.07 (s, 4H), 2.77-2.66 (m, 1H), 2.46 (s, 3H), 2.45-2.37 (m, 1H).
实施例23：化合物23的合成
Example 23: Synthesis of Compound 23
第一步:23b的制备Step 1: Preparation of 23b
将23a(2g,7.29mmol)溶于15mL1,4-二氧六环和1mL水中，依次加入1d(3.13g,9.48mmol),碳酸钾(2.02g,14.58mmol),Pd(dppf)Cl2·DCM(0.6g，0.73mmol),氮气氛围下，100℃反应3h。将反应冷却至室温，减压浓缩残余物用硅胶色谱柱柱层析(石油醚:乙酸乙酯＝5:1)得23b(1.17g，收率：39.06％)。23a (2 g, 7.29 mmol) was dissolved in 15 mL 1,4-dioxane and 1 mL water, and 1d (3.13 g, 9.48 mmol), potassium carbonate (2.02 g, 14.58 mmol), and Pd(dppf)Cl 2 ·DCM (0.6 g, 0.73 mmol) were added in sequence, and the mixture was reacted at 100°C for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the residue was concentrated under reduced pressure and chromatographed on a silica gel column (petroleum ether:ethyl acetate=5:1) to obtain 23b (1.17 g, yield: 39.06%).
LCMS m/z＝351.1[M+H]+ LCMS m/z＝351.1[M+H] +
第二步:23c的制备 Step 2: Preparation of 23c
将23b(1.1g,3.13mmol)溶于12mL 1,4-二氧六环和1mL水中，依次加入4-(BOC-氨基)-2-氟苯硼酸频哪醇酯(1.06g,3.13mmol),碳酸钾(0.87g,6.29mmol),Pd(dppf)Cl2·DCM(0.51g，0.62mmol),氮气氛围下，100℃下反应2h。将反应冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析(石油醚：乙酸乙酯＝2:1)，即得23c(0.7g，收率：42.52％)。23b (1.1 g, 3.13 mmol) was dissolved in 12 mL 1,4-dioxane and 1 mL water, and 4-(BOC-amino)-2-fluorophenylboronic acid pinacol ester (1.06 g, 3.13 mmol), potassium carbonate (0.87 g, 6.29 mmol), and Pd(dppf)Cl 2 ·DCM (0.51 g, 0.62 mmol) were added in sequence, and the mixture was reacted at 100° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain 23c (0.7 g, yield: 42.52%).
LCMS m/z＝526.1[M+H]+ LCMS m/z＝526.1[M+H] +
第三步:23d的制备Step 3: Preparation of 23d
将23c(0.46g,0.87mmol)溶于超干1,4-二氧六环10mL中，依次加入6B(0.18g,1.28mmol)，Pd2(dba)3(0.08g,0.087mmol)，碳酸铯(0.57g,1.75mmol)，S-phos(0.036g,0.087mmol)，氮气氛围下，100℃反应1h。将反应冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析(二氯甲烷：甲醇＝20:1)得23d(0.12g，收率：21.87％)。23c (0.46 g, 0.87 mmol) was dissolved in 10 mL of ultra-dry 1,4-dioxane, and 6B (0.18 g, 1.28 mmol), Pd 2 (dba) 3 (0.08 g, 0.087 mmol), cesium carbonate (0.57 g, 1.75 mmol), S-phos (0.036 g, 0.087 mmol) were added in sequence, and the mixture was reacted at 100°C for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column (dichloromethane: methanol = 20:1) to obtain 23d (0.12 g, yield: 21.87%).
LCMS m/z＝631.1[M+H]+ LCMS m/z＝631.1[M+H] +
第四步：23e的制备Step 4: Preparation of 23e
将23d(0.075g,0.12mmol)溶于4mL二氯甲烷中，加入1mL三氟乙酸，室温反应1h，减压浓缩除去溶剂，残留物即为23e(61mg，收率：95.82％)。23d (0.075 g, 0.12 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure. The residue was 23e (61 mg, yield: 95.82%).
LCMS m/z＝531.3[M+H]+ LCMS m/z＝531.3[M+H] +
第五步：化合物23的制备Step 5: Preparation of compound 23
将23e(61mg,0.11mmol)溶于4mL二氯甲烷中，氮气氛围下，加入三乙胺(44mg,0.44mmol),0℃缓慢滴加丙烯酰氯(10mg,0.14mmol)的二氯甲烷溶液0.5mL，室温反应1h，反应加入10mL水，并用二氯甲烷(10mL×2)萃取，合并有机相，有机相用饱和NaCl的水溶液10mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残余物用硅胶色谱柱柱层析分离(二氯甲烷：甲醇＝15:1)即得化合物23(6mg，收率：9.33％)。23e (61 mg, 0.11 mmol) was dissolved in 4 mL of dichloromethane. Triethylamine (44 mg, 0.44 mmol) was added under nitrogen atmosphere. 0.5 mL of dichloromethane solution of acryloyl chloride (10 mg, 0.14 mmol) was slowly added dropwise at 0°C. The mixture was reacted for 1 h at room temperature. 10 mL of water was added to the reaction, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, washed once with 10 mL of saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography (dichloromethane: methanol = 15:1) to obtain compound 23 (6 mg, yield: 9.33%).
LCMS m/z＝585.2[M+H]+ LCMS m/z＝585.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.49(s,1H),8.38(d,1H),8.05(s,1H),7.64(s,1H),7.60-7.49(m,2H),7.44(dd,1H),7.17(t,1H),7.09(d,1H),7.06-6.97(m,2H),6.42-6.37(m,2H),5.79(dd,1H),4.25(t,2H),3.72(t,2H),3.31(s,3H),2.44(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (s, 1H), 8.38 (d, 1H), 8.05 (s, 1H), 7.64 (s, 1H), 7.60-7.49 (m, 2H), 7.44 (dd, 1H), 7.17 (t, 1H), 7.09 (d, 1H), 7.06-6.97 (m, 2H), 6.42-6.37 (m, 2H), 5.79 (dd, 1H), 4.25 (t, 2H), 3.72 (t, 2H), 3.31 (s, 3H), 2.44 (s, 3H).
实施例24：化合物24的合成
Example 24: Synthesis of Compound 24
第一步:24b的制备Step 1: Preparation of 24b
将24a(1.5g,8.94mmol)溶于10mL二氯甲烷和4mL乙腈中，加入NIS(3.02g,13.42mmol)，50℃应3h。将反应冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析(石油醚： 乙酸乙酯＝5：1)得24b(1.43g，收率：54.37％)。Dissolve 24a (1.5 g, 8.94 mmol) in 10 mL of dichloromethane and 4 mL of acetonitrile, add NIS (3.02 g, 13.42 mmol), and incubate at 50°C for 3 h. Cool the reaction to room temperature, concentrate under reduced pressure to remove the reaction solvent, and chromatograph the residue on a silica gel column (petroleum ether: Ethyl acetate = 5:1) to give 24b (1.43 g, yield: 54.37%).
LCMS m/z＝295.0[M+H]+ LCMS m/z＝295.0[M+H] +
第二步:24c的制备Step 2: Preparation of 24c
将24b(0.5g,1.70mmol)溶于乙腈8mL中，依次加入DIPEA(0.66g,5.10mmol)，氧氯化磷(1.31g,8.55mmol)，氮气氛围下，85℃反应2h。将反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析(石油醚：乙酸乙酯＝5:1)即得24c(0.4g，收率：75.18％)。24b (0.5 g, 1.70 mmol) was dissolved in 8 mL of acetonitrile, and DIPEA (0.66 g, 5.10 mmol) and phosphorus oxychloride (1.31 g, 8.55 mmol) were added in sequence, and the mixture was reacted at 85°C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain 24c (0.4 g, yield: 75.18%).
LCMS m/z＝313.1[M+H]+ LCMS m/z＝313.1[M+H] +
第三步:24d的制备Step 3: Preparation of 24d
将24c(0.4g,1.28mmol)溶于8mL 1,4-二氧六环和1mL水中，依次加入中间体1d(0.42g,1.28mmol)，碳酸铯(0.83g,2.55mmol)，PdCl2(dppf).DCM(CAS:95464-05-4)(0.10g，0.12mmol)，氮气氛围下，100℃反应3h。将反应冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析(石油醚：乙酸乙酯＝1：1)即得目标化合物24d(0.3g，收率：62.70％)。24c (0.4 g, 1.28 mmol) was dissolved in 8 mL 1,4-dioxane and 1 mL water, and intermediate 1d (0.42 g, 1.28 mmol), cesium carbonate (0.83 g, 2.55 mmol), PdCl2(dppf).DCM (CAS: 95464-05-4) (0.10 g, 0.12 mmol) were added in sequence, and the mixture was reacted at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain the target compound 24d (0.3 g, yield: 62.70%).
LCMS m/z＝389.1[M+H]+ LCMS m/z＝389.1[M+H] +
第四步:24e的制备Step 4: Preparation of 24e
将24d(0.053g,0.14mmol)溶于2mL 1,4-二氧六环中，依次加入1f(0.048g,0.17mmol)，碳酸钾(0.039g,0.28mmol)，PdCl2(dppf).DCM(0.011g，0.013mmol)，氮气氛围100℃反应2h。将反应冷却至室温，减压浓缩后,残余物用硅胶色谱柱柱层析(石油醚：乙酸乙酯＝1:1)得24e(0.048g，收率：66.77％)。24d (0.053 g, 0.14 mmol) was dissolved in 2 mL 1,4-dioxane, and 1f (0.048 g, 0.17 mmol), potassium carbonate (0.039 g, 0.28 mmol), PdCl2(dppf).DCM (0.011 g, 0.013 mmol) were added in sequence, and the mixture was reacted at 100 °C in a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain 24e (0.048 g, yield: 66.77%).
LCMS m/z＝514.2[M+H]+ LCMS m/z＝514.2[M+H] +
第五步:24f的制备Step 5: Preparation of 24f
将24e(0.048g,0.093mmol)溶于2mL乙醇和0.2mL水的混合溶剂中，加入氢氧化锂(0.039g,0.93mmol)，室温反应2h。减压浓缩除去反应溶剂，用1N HCl调节PH为4，二氯甲烷(5mL×2)萃取两次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后得到24f(0.014g，收率：33.33％)。24e (0.048 g, 0.093 mmol) was dissolved in a mixed solvent of 2 mL ethanol and 0.2 mL water, and lithium hydroxide (0.039 g, 0.93 mmol) was added. The reaction was allowed to react at room temperature for 2 h. The reaction solvent was removed by concentration under reduced pressure, the pH was adjusted to 4 with 1N HCl, and the mixture was extracted twice with dichloromethane (5 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 24f (0.014 g, yield: 33.33%).
LCMS m/z＝486.1[M+H]+ LCMS m/z＝486.1[M+H] +
第六步:化合物24的制备Step 6: Preparation of Compound 24
将24f(0.014g,0.029mmol)溶于1.5mL DMF中，依次加入DIPEA(0.011g,0.085mmol)，HATU(0.022g,0.058mmol),氯化铵(0.015g,0.28mmol)，室温反应16h。反应加入10mL水，乙酸乙酯(10mL×2)萃取，有机相依次用水(10mL×2)洗两次，饱和NaCl水溶液10mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析(二氯甲烷:甲醇＝30:1-10:1)，即得化合物24(7mg，收率：49.82％)。24f (0.014 g, 0.029 mmol) was dissolved in 1.5 mL DMF, and DIPEA (0.011 g, 0.085 mmol), HATU (0.022 g, 0.058 mmol), and ammonium chloride (0.015 g, 0.28 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 h. 10 mL of water was added to the reaction, and ethyl acetate (10 mL × 2) was used for extraction. The organic phase was washed twice with water (10 mL × 2) and once with 10 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane: methanol = 30: 1-10: 1) to obtain compound 24 (7 mg, yield: 49.82%).
LCMS m/z＝485.0[M+H]+ LCMS m/z＝485.0[M+H] +
1H NMR(400MHz,CDCl3)δ9.26(s,1H),8.40(d,1H),7.52(d,2H),7.36(d,2H),7.22(t,1H),7.03-6.94(m,2H),6.92(d,1H),5.78(s,1H),5.48(d,1H),2.49(s,3H),2.05(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.26 (s, 1H), 8.40 (d, 1H), 7.52 (d, 2H), 7.36 (d, 2H), 7.22 (t, 1H), 7.03-6.94 (m, 2H), 6.92 (d, 1H), 5.78 (s, 1H), 5.48 (d, 1H), 2.49 (s, 3H), 2.05 (s, 3H).
实施例25：化合物25的合成
Example 25: Synthesis of Compound 25
第一步：25A的合成Step 1: Synthesis of 25A
封管中加入3f(670mg，1.72mmol)溶于二氧六环(10mL)和水(2mL)中，加入4C(720mg，1.89mmol)，Pd(dppf)Cl2.DCM(140mg，0.17mmol)和碳酸钾(480mg，3.47mmol)，置换氮气保护。100℃反应5h。将反应冷却至室温，反应加入100mL水稀释，并用乙酸乙酯(100mL×3)萃取，合并有机相，饱和NaCl的水溶液200mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，即得25A(603mg，产率62.27％)Add 3f (670 mg, 1.72 mmol) dissolved in dioxane (10 mL) and water (2 mL) to the sealed tube, add 4C (720 mg, 1.89 mmol), Pd(dppf)Cl 2 .DCM (140 mg, 0.17 mmol) and potassium carbonate (480 mg, 3.47 mmol), replace nitrogen protection. React at 100 ° C for 5 h. Cool the reaction to room temperature, add 100 mL of water to dilute the reaction, and extract with ethyl acetate (100 mL × 3), combine the organic phases, wash once with 200 mL of saturated NaCl aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel chromatography to obtain 25A (603 mg, yield 62.27%)
LC-Ms m/z(ESI):545.60[M+H]+ LC-Ms m/z(ESI):545.60[M+H] +
第二步：25B的合成Step 2: Synthesis of 25B
封管中加入25A(600mg，1.10mmol)，6B(230mg，1.65mmol)，Pd2(dba)3(100mg，0.11mmol)，S-phos(90mg，0.22mmol)，碳酸铯(720mg，2.2mmol)溶于1,4-二氧六环(12mL)中，置换氮气保护，110℃反应2h。将反应冷却至室温，加水稀释，用乙酸乙酯(50mL×3)萃取，饱和NaCl水溶液200mL洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离，即得25B(210mg，产率29.38％)25A (600 mg, 1.10 mmol), 6B (230 mg, 1.65 mmol), Pd 2 (dba) 3 (100 mg, 0.11 mmol), S-phos (90 mg, 0.22 mmol), cesium carbonate (720 mg, 2.2 mmol) were added to the sealed tube and dissolved in 1,4-dioxane (12 mL), replaced with nitrogen protection, and reacted at 110°C for 2 h. The reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate (50 mL×3), washed once with 200 mL of saturated NaCl aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel chromatography to obtain 25B (210 mg, yield 29.38%).
LC-Ms m/z(ESI):650.70[M+H]+ LC-Ms m/z(ESI):650.70[M+H] +
第三步：25C的合成Step 3: Synthesis of 25C
将6C(117mg，0.18mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(1mL)，室温反应2h。减压浓缩，残余物经过反相柱层析纯化，冻干后得25C(62mg，产率62.67％)6C (117 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography and freeze-dried to obtain 25C (62 mg, yield 62.67%).
LC-Ms m/z(ESI):550.3[M+H]+ LC-Ms m/z(ESI):550.3[M+H] +
第四步：化合物25的合成Step 4: Synthesis of compound 25
将25C(16mg，0.029mmol)溶于DCM(3mL)中，加入三乙胺(5.9mg，0.058mmol)，冰浴下缓慢加入丙烯酰氯(2.6mg，0.029mmol)的二氯甲烷溶液1mL，反应1h。加水稀释，用乙酸乙酯(10mL×3)萃取，饱和NaCl的水溶液100mL洗2次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离纯化，即得化合物25(5mg，产率：28.56％)25C (16 mg, 0.029 mmol) was dissolved in DCM (3 mL), triethylamine (5.9 mg, 0.058 mmol) was added, and 1 mL of dichloromethane solution of acryloyl chloride (2.6 mg, 0.029 mmol) was slowly added under ice bath, and the reaction was continued for 1 h. The mixture was diluted with water, extracted with ethyl acetate (10 mL×3), and washed twice with 100 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 25 (5 mg, yield: 28.56%).
LC-Ms m/z(ESI):604.2[M+H]+ LC-Ms m/z(ESI):604.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),8.02(s,1H),7.97(d,1H),7.90(d,1H),7.88(s,1H), 7.85(s,1H),7.66(d,1H),7.61(s,1H),7.51(dd,1H),7.35(dd,1H),7.12(d,1H),6.28-6.12(m,2H),5.67(dd,1H),4.54(s,2H),4.28(t,2H),4.08(s,2H),4.01(s,4H),3.75(t,2H),3.34(s,3H),2.47(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.41 (d, 1H), 8.02 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.88 (s, 1H), 7.85(s,1H),7.66(d,1H),7.61(s,1H),7.51(dd,1H),7.35(dd,1H),7.12(d,1H),6.28-6.12(m,2H),5.67(dd,1H),4.54(s,2H),4.28(t,2H),4.08(s,2H),4.01(s,4H),3.75(t,2H),3.34(s,3H),2.47(s,3H).
实施例26：化合物26的合成
Example 26: Synthesis of Compound 26
参照化合物6的合成路线及制备方法，得到化合物26(3mg)。Referring to the synthetic route and preparation method of compound 6, compound 26 (3 mg) was obtained.
LC-Ms m/z(ESI):586.3[M+H]+ LC-Ms m/z(ESI):586.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),7.99(s,1H),7.82(s,1H),7.59(s,1H),7.32(t,1H),7.27-7.17(m,2H),7.13(d,1H),5.49(dd,1H),5.16(dd,1H),4.54(d,2H),4.27(t,2H),4.18(s,2H),4.07(s,4H),3.74(t,2H),3.33(s,3H),2.46(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.41 (d, 1H), 7.99 (s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.32 (t, 1H), 7.27-7.17 (m, 2H), 7.13 (d, 1H), 5.49 (dd, 1H), 5.16 (dd, 1H), 4.54 (d, 2H), 4.27 (t, 2H), 4.18 (s, 2H), 4.07 (s, 4H), 3.74 (t, 2H), 3.33 (s, 3H), 2.46 (s, 3H).
实施例27：化合物27的合成
Example 27: Synthesis of Compound 27
参照化合物6的合成路线及制备方法，得到化合物27(4mg)。Referring to the synthetic route and preparation method of compound 6, compound 27 (4 mg) was obtained.
LC-Ms m/z(ESI):590.2[M+H]+ LC-Ms m/z(ESI):590.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.49(d,1H),7.89(s,2H),7.52(s,1H),7.38(t,1H),7.31(dd,1H),7.20(d,1H),7.17(dd,1H),5.39-5.35(m,1H),5.30-5.26(m,1H),4.33(s,2H),4.21(t,2H),4.09-3.88(m,6H),3.66(t,2H),3.24(s,3H),2.43(s,3H),1.77(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.16 (s, 1H), 8.49 (d, 1H), 7.89 (s, 2H), 7.52 (s, 1H), 7.38 (t, 1H), 7.31 (dd, 1H), 7.20 (d, 1H), 7.17 (dd, 1H), 5.39-5.35 (m, 1H), 5.30-5.26 (m, 1H), 4.33 (s, 2H), 4.21 (t, 2H), 4.09-3.88 (m, 6H), 3.66 (t, 2H), 3.24 (s, 3H), 2.43 (s, 3H), 1.77 (s, 3H).
实施例28：化合物28的合成
Example 28: Synthesis of Compound 28
第一步：28B的合成：Step 1: Synthesis of 28B:
在氮气保护下，依次将28A(1.0g，5.74mmol)、中间体28(2.0g，6.31mmol)，PdCl2(dppf)(CAS:72287-26-4)(420.0mg，0.57mmol)和碳酸钾(2.4g，17.22mmol)溶于1,4-二氧六环(10mL)和水(2mL)中，80℃反应过夜。冷却至室温，减压除去溶剂，加入80mL水，用乙酸乙酯(80mL×3)萃取，合并有机相后用无水硫酸钠干燥，过滤，减压浓缩滤液后，经硅胶柱层析纯化(PE:EA＝5:1),获得28B(1.20g,产率：63.20％)。Under nitrogen protection, 28A (1.0 g, 5.74 mmol), intermediate 28 (2.0 g, 6.31 mmol), PdCl2 (dppf) (CAS: 72287-26-4) (420.0 mg, 0.57 mmol) and potassium carbonate (2.4 g, 17.22 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) in turn, and reacted at 80°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, 80 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA=5:1) to obtain 28B (1.20 g, yield: 63.20%).
Ms m/z(ESI):331.1[M+H]+ Ms m/z(ESI):331.1[M+H] +
第二步：28C的合成Step 2: Synthesis of 28C
将28B(500.0mg，1.51mmol)溶于1,4-二氧六环(5mL)中，依次加入1-甲基-1H-吡唑-4-胺(175.98mg，1.81mmol)、Pd2(dba)3(138.27mg，0.15mmol)，Sphos(123.98mg，0.30mmol)和碳酸铯(983.98g，3.02mmol)，100℃持续反应过夜。冷却至室温，减压除去溶剂，加入30mL水，再用乙酸乙酯(50mL×2)萃取，合并有机相后用无水硫酸钠干燥，过滤，减压浓缩滤液后，经硅胶柱层析纯化(DCM:MeOH＝20:1),获得28C(400.0mg,产率：67.68％)。28B (500.0 mg, 1.51 mmol) was dissolved in 1,4-dioxane (5 mL), and 1-methyl-1H-pyrazol-4-amine (175.98 mg, 1.81 mmol), Pd 2 (dba) 3 (138.27 mg, 0.15 mmol), Sphos (123.98 mg, 0.30 mmol) and cesium carbonate (983.98 g, 3.02 mmol) were added in sequence, and the reaction was continued at 100°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, 30 mL of water was added, and then extracted with ethyl acetate (50 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 28C (400.0 mg, yield: 67.68%).
Ms m/z(ESI):390.3[M-H]+ Ms m/z(ESI):390.3[MH] +
第三步：28D的合成Step 3: Synthesis of 28D
将28C(200.0mg，0.51mmol)溶于二氯甲烷(5mL)中，依次加入NIS(229.48mg，1.02mmol)和三氟乙酸(116.30mg，1.02mmol)，室温反应30分钟，减压浓缩，残余物经硅胶柱层析纯化(DCM:MeOH＝20:1),获得28D(200.0mg,产率：75.81％)。28C (200.0 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL), and NIS (229.48 mg, 1.02 mmol) and trifluoroacetic acid (116.30 mg, 1.02 mmol) were added in sequence. The mixture was reacted at room temperature for 30 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 28D (200.0 mg, yield: 75.81%).
Ms m/z(ESI):518.5[M+H]+ Ms m/z(ESI):518.5[M+H] +
第四步：28E的合成Step 4: Synthesis of 28E
将28D(400.0mg，0.88mmol)溶于DMF(10mL)溶剂中，依次加入1d(319.59mg，0.97mmol)、RuPhos Pd G3(CAS:1445085-77-7)(74.0mg，0.088mmol)和磷酸钾(560.0mg，2.64mmol),氮气保护80℃反应过夜。冷却至室温，减压除去溶剂，加入30mL水，用乙酸乙酯(50mL×2)萃取，合并有机相后用无水硫酸钠干燥后过滤，减压浓缩滤液后经硅胶柱层析纯化(DCM:MeOH＝20:1)得28E(200.0mg,产率：42.64％)。28D (400.0 mg, 0.88 mmol) was dissolved in DMF (10 mL) solvent, and 1d (319.59 mg, 0.97 mmol), RuPhos Pd G3 (CAS: 1445085-77-7) (74.0 mg, 0.088 mmol) and potassium phosphate (560.0 mg, 2.64 mmol) were added in sequence. The mixture was reacted at 80°C under nitrogen protection overnight. The mixture was cooled to room temperature, the solvent was removed under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH = 20:1) to obtain 28E (200.0 mg, yield: 42.64%).
Ms m/z(ESI):594.3[M+H]+ Ms m/z(ESI):594.3[M+H] +
第五步：28F的合成Step 5: Synthesis of 28F
将28E(200.0mg，0.38mmol)溶于DCM(3mL)中，加入盐酸-1,4-二氧六环溶液(2mL)。室温反应1h，加入三乙胺，调节pH＝7-8左右，除去溶剂得28F固体粗品(0.1g)。28E (200.0 mg, 0.38 mmol) was dissolved in DCM (3 mL), and a hydrochloric acid-1,4-dioxane solution (2 mL) was added. The mixture was reacted at room temperature for 1 h, and triethylamine was added to adjust the pH to about 7-8. The solvent was removed to obtain a solid crude product of 28F (0.1 g).
Ms m/z(ESI):494.6[M+H]+ Ms m/z(ESI):494.6[M+H] +
第六步：化合物28的合成Step 6: Synthesis of compound 28
在氮气保护下，将28F粗品(100.0mg，0.201mmol)溶于DCM(4mL)中，加入三乙胺(30.36mg，0.30mmol)，缓慢滴加丙烯酰氯(20.0mg，0.22mmol)的二氯甲烷溶液1mL，室温反应30min，减压浓缩滤液后，经硅胶柱层析纯化(DCM:MeOH＝20:1)得化合物28(15.0mg,产率：11.34％)。Under nitrogen protection, the crude product of 28F (100.0 mg, 0.201 mmol) was dissolved in DCM (4 mL), triethylamine (30.36 mg, 0.30 mmol) was added, and 1 mL of a dichloromethane solution of acryloyl chloride (20.0 mg, 0.22 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 30 min. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain compound 28 (15.0 mg, yield: 11.34%).
Ms m/z(ESI):548.3[M+H]+ Ms m/z(ESI):548.3[M+H] +
1H NMR(400MHz,CDCl3)δ8.41(d,1H),8.25(s,1H),8.06(d,2H),7.76(d,2H),7.46(t,1H),7.38(s,2H),7.00(d,1H),6.88(s,1H),6.50(d,1H),6.28(dd,1H),5.86(d,1H),3.90(s,3H),2.55(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (d, 1H), 8.25 (s, 1H), 8.06 (d, 2H), 7.76 (d, 2H), 7.46 (t, 1H), 7.38 (s, 2H), 7.00 (d, 1H), 6.88 (s, 1H), 6.50 (d, 1H), 6.28 (dd, 1H), 5.86 (d, 1H), 3.90 (s, 3H), 2.55 (s, 3H).
实施例29：化合物29的合成
Example 29: Synthesis of Compound 29
参考化合物4的合成得化合物29(40mg)Compound 29 (40 mg) was obtained by the synthesis of reference compound 4
LC-Ms m/z(ESI):564.6[M+H]+ LC-Ms m/z(ESI):564.6[M+H] +
1H NMR(400MHz,CDCl3)δ8.38(s,1H),8.36(d,1H),7.95(d,1H),7.86-7.70(m,4H),7.62(d,1H),7.35(dd,1H),7.10-7.04(m,2H),6.93(d,1H),5.85(dd,1H),5.29(dd,1H),3.72(s,3H),2.53(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 1H), 8.36 (d, 1H), 7.95 (d, 1H), 7.86-7.70 (m, 4H), 7.62 (d, 1H), 7.35 (dd, 1H), 7.10-7.04 (m, 2H), 6.93 (d, 1H), 5.85 (dd, 1H), 5.29 (dd, 1H), 3.72 (s, 3H), 2.53 (s, 3H).
实施例30：化合物30的合成
Example 30: Synthesis of Compound 30
参考化合物16的合成得化合物30(50mg)Compound 30 (50 mg) was obtained by the synthesis of reference compound 16
LC-Ms m/z(ESI):582.6[M+H]+ LC-Ms m/z(ESI):582.6[M+H] +
1H NMR(400MHz,CDCl3)δ8.36(s,1H),8.35(d,1H),8.03(d,1H),7.97(d,1H),7.82-7.74(m,2H),7.61(d,1H),7.44-7.36(m,2H),7.13-7.05(m,2H),6.94(d,1H),5.85(dd,1H),5.51(brs,2H),5.29(dd,1H),3.72(s,3H),2.52(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 1H), 8.35 (d, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.82-7.74 (m, 2H), 7.61 (d, 1H), 7.44-7.36 (m, 2H), 7.13-7.05 (m, 2H), 6.94 (d, 1H), 5.85 (dd, 1H), 5.51 (brs, 2H), 5.29 (dd, 1H), 3.72 (s, 3H), 2.52 (s, 3H).
实施例31：化合物31的合成
Example 31: Synthesis of Compound 31
第一步：31B的合成： Step 1: Synthesis of 31B:
封管中加入23b(967mg，2.75mmol)、31A(合成参考专利WO2022206939)(570mg，2.61mmol)，DIPEA(710mg，5.5mmol)溶于乙醇(12mL)中，置换氮气保护，80℃反应过夜。冷却至室温，减压除去溶剂，残余物经硅胶柱层析纯化，获得31B(780mg,产率：53.41％)。23b (967 mg, 2.75 mmol), 31A (synthesis reference patent WO2022206939) (570 mg, 2.61 mmol), DIPEA (710 mg, 5.5 mmol) were added to the sealed tube and dissolved in ethanol (12 mL), replaced with nitrogen protection, and reacted at 80 ° C overnight. Cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 31B (780 mg, yield: 53.41%).
Ms m/z(ESI):531.50[M+H]+ Ms m/z(ESI):531.50[M+H] +
第二步：31C的合成：Step 2: Synthesis of 31C:
封管中加入31B(470mg，0.89mmol)、6B(160mg，1.16mmol)，Pd2(dba)3(81mg，0.089mmol)，S-phos(73mg，0.18mmol)和碳酸铯(580mg，1.78mmol)，溶于1,4-二氧六环(10mL)中，置换氮气保护，110℃反应2h。冷却至室温，加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化，获得31C(211mg,产率：37.39％)。31B (470 mg, 0.89 mmol), 6B (160 mg, 1.16 mmol), Pd 2 (dba) 3 (81 mg, 0.089 mmol), S-phos (73 mg, 0.18 mmol) and cesium carbonate (580 mg, 1.78 mmol) were added to the sealed tube, dissolved in 1,4-dioxane (10 mL), replaced with nitrogen for protection, and reacted at 110° C. for 2 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 31C (211 mg, yield: 37.39%).
Ms m/z(ESI):636.80[M+H]+ Ms m/z(ESI):636.80[M+H] +
第三步：31D的合成Step 3: Synthesis of 31D
将31C(200mg，0.31mmol)溶于四氢呋喃(4mL)中，加入三氟乙酸(1.5mL)，70℃下搅拌反应6h。减压浓缩，即得31D(170mg，粗品)。31C (200 mg, 0.31 mmol) was dissolved in tetrahydrofuran (4 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at 70°C for 6 h. The mixture was concentrated under reduced pressure to obtain 31D (170 mg, crude product).
LC-Ms m/z(ESI):532.9[M+H]+ LC-Ms m/z(ESI):532.9[M+H] +
第四步：化合物31的合成Step 4: Synthesis of compound 31
将31D粗品(170mg，Crude)溶于DCM(3mL)中，加入三乙胺(65mg，0.64mmol)，冰浴下缓慢加入丙烯酰氯(26mg，0.29mmol)的二氯甲烷溶液1mL，反应1h。加水稀释，用乙酸乙酯(10mL×3)萃取三次，饱和NaCl的水溶液100mL洗2次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶色谱柱柱层析分离纯化，即得化合物31(27mg，两步产率：14.87％)The crude product of 31D (170 mg, Crude) was dissolved in DCM (3 mL), triethylamine (65 mg, 0.64 mmol) was added, and 1 mL of dichloromethane solution of acryloyl chloride (26 mg, 0.29 mmol) was slowly added under ice bath, and the reaction was continued for 1 h. The mixture was diluted with water, extracted three times with ethyl acetate (10 mL×3), and washed twice with 100 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 31 (27 mg, two-step yield: 14.87%).
LC-Ms m/z(ESI):586.50[M+H]+ LC-Ms m/z(ESI):586.50[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(d,1H),7.99(s,1H),7.83(s,1H),7.60(s,1H),7.33(t,1H),7.27-7.18(m,2H),7.12(d,1H),6.39-6.16(m,2H),5.78-5.64(m,1H),4.64-4.39(m,1H),4.38-4.30(m,1H),4.30-4.23(m,2H),4.17-3.97(m,4H),3.91-3.82(m,1H),3.77-3.71(m,2H),3.36-3.32(m,3H),2.46(s,3H),1.50-1.41(m,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.41 (d, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.33 (t, 1H), 7.27-7.18 (m, 2H), 7.12 (d, 1H), 6.39-6.16 (m, 2H), 5.78-5.64 (m, 1H), 4.64-4.39 (m, 1H), 4.38-4.30 (m, 1H), 4.30-4.23 (m, 2H), 4.17-3.97 (m, 4H), 3.91-3.82 (m, 1H), 3.77-3.71 (m, 2H), 3.36-3.32 (m, 3H), 2.46 (s, 3H), 1.50-1.41 (m, 3H).
实施例32：化合物32的合成
Example 32: Synthesis of Compound 32
化合物32A的合成参考专利WO2020/231990中Example 28中间体3的合成The synthesis of compound 32A refers to the synthesis of intermediate 3 in Example 28 in patent WO2020/231990
第一步：32B的合成：Step 1: Synthesis of 32B:
封管中加入4E(720mg，1.42mmol)、32A(510mg，1.85mmol)，Pd(dppf)Cl2.DCM(120mg，0.14mmol)和碳酸钠(300mg，2.84mmol)，溶于乙二醇二甲醚(8mL)和水(1mL)中，置换氮气保护，90℃反应1.5h。冷却至室温，加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压除去溶剂，残余物经硅胶柱层析纯化，获得32B(200mg,产率：22.98％)。 4E (720 mg, 1.42 mmol), 32A (510 mg, 1.85 mmol), Pd(dppf)Cl 2 .DCM (120 mg, 0.14 mmol) and sodium carbonate (300 mg, 2.84 mmol) were added to the sealed tube, dissolved in ethylene glycol dimethyl ether (8 mL) and water (1 mL), replaced with nitrogen protection, and reacted at 90° C. for 1.5 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 32B (200 mg, yield: 22.98%).
Ms m/z(ESI):613.2[M+H]+ Ms m/z(ESI):613.2[M+H] +
第二步：化合物32的合成：Step 2: Synthesis of compound 32:
单口瓶中加入32B(108mg，0.18mmol)，用12mL四氢呋喃溶解，加入四丁基氟化铵三水合物(110mg，0.36mmol)，置换氮气保护，室温反应1h。加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化，获得化合物32(50mg,产率：55.72％)。32B (108 mg, 0.18 mmol) was added to a single-mouth bottle, dissolved in 12 mL of tetrahydrofuran, and tetrabutylammonium fluoride trihydrate (110 mg, 0.36 mmol) was added, replaced with nitrogen protection, and reacted at room temperature for 1 h. The mixture was diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 32 (50 mg, yield: 55.72%).
Ms m/z(ESI):499.1[M+H]+ Ms m/z(ESI):499.1[M+H] +
1H NMR(400MHz,CD3OD)δ8.73(s,1H),8.43(s,1H),8.39(d,1H),7.91(d,2H),7.86(s,1H),7.67(d,1H),7.40-7.33(m,2H),7.11(d,1H),3.87(s,1H),3.74(s,3H),2.45(s,3H),2.22(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.73 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H), 7.91 (d, 2H), 7.86 (s, 1H), 7.67 (d, 1H), 7.40-7.33 (m, 2H), 7.11 (d, 1H), 3.87 (s, 1H), 3.74 (s, 3H), 2.45 (s, 3H), 2.22 (s, 3H).
实施例33：化合物33的合成
Example 33: Synthesis of Compound 33
参考化合物16的合成得化合物33(50mg)Compound 33 (50 mg) was obtained by the synthesis of reference compound 16
LC-Ms m/z(ESI):564.1[M+H]+ LC-Ms m/z(ESI):564.1[M+H] +
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.34(d,1H),8.01(d,1H),7.82-7.75(m,2H),7.60(d,1H),7.50(s,1H),7.45-7.35(m,2H),7.10-7.00(m,2H),6.94(d,1H),6.45(dd,1H),6.23(dd,1H),5.81(dd,1H),5.02(s,2H),3.71(s,3H),2.52(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 7.82-7.75 (m, 2H), 7.60 (d, 1H), 7.50 (s, 1H), 7.45-7.35 (m, 2H), 7.10-7.00 (m, 2H), 6.94 (d, 1H), 6.45 (dd, 1H), 6.23 (dd, 1H), 5.81 (dd, 1H), 5.02 (s, 2H), 3.71 (s, 3H), 2.52 (s, 3H).
实施例34：化合物34的合成
Example 34: Synthesis of Compound 34
第一步：34B的合成Step 1: Synthesis of 34B
将34A(3.6g，16.91mmol)、环丙基硼酸(2.91g，33.82mmol)、2,2'-联吡啶(2.64g，16.91mmol)、乙酸铜(3.07g，16.91mmol)、碳酸钠(3.58g，33.82mmol)溶于35mL 1,2-二氯乙烷中，70℃反应16h。冷却至室温，过滤，用乙酸乙酯洗涤滤饼，滤液加水稀释，乙酸乙酯萃取(40mL×3)，合并有机相，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得34B(560mg，13.08％)。34A (3.6 g, 16.91 mmol), cyclopropylboronic acid (2.91 g, 33.82 mmol), 2,2'-bipyridine (2.64 g, 16.91 mmol), cupric acetate (3.07 g, 16.91 mmol), sodium carbonate (3.58 g, 33.82 mmol) were dissolved in 35 mL 1,2-dichloroethane and reacted at 70 °C for 16 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was diluted with water, extracted with ethyl acetate (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34B (560 mg, 13.08%).
LC-Ms m/z(ESI):253.1[M+H]+ LC-Ms m/z(ESI):253.1[M+H] +
第二步：34C的合成Step 2: Synthesis of 34C
将34B(560mg，2.21mmol)、4C(1.44g，3.98mmol)、Pd(dppf)Cl2(140mg，0.22mmol)、碳酸钾(610mg，4.42mmol)溶于10mL1,4-二氧六环和3mL水中，置换氮气保护，100℃反应2h。 冷却至室温，加水稀释，乙酸乙酯萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得34C(0.9g，99.70％)。34B (560 mg, 2.21 mmol), 4C (1.44 g, 3.98 mmol), Pd(dppf)Cl2 (140 mg, 0.22 mmol), and potassium carbonate (610 mg, 4.42 mmol) were dissolved in 10 mL of 1,4-dioxane and 3 mL of water, and the atmosphere was replaced with nitrogen for protection, and the reaction was carried out at 100 °C for 2 h. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34C (0.9 g, 99.70%).
LC-Ms m/z(ESI):409.2[M+H]+ LC-Ms m/z(ESI):409.2[M+H] +
第三步：34D的合成Step 3: 34D synthesis
在氮气氛围下，将34C(1.04g，2.55mmol)溶于40mL二氯甲烷中，0℃加入三氟乙酸(0.38mL，5.1mmol)，NIS(1.15g，5.1mmol)，室温搅拌2h，加水稀释，饱和碳酸氢钠淬灭，二氯甲烷萃取(20mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得34D(0.67g，49.17％)。Under nitrogen atmosphere, 34C (1.04 g, 2.55 mmol) was dissolved in 40 mL of dichloromethane. Trifluoroacetic acid (0.38 mL, 5.1 mmol) and NIS (1.15 g, 5.1 mmol) were added at 0°C. The mixture was stirred at room temperature for 2 h, diluted with water, quenched with saturated sodium bicarbonate, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 34D (0.67 g, 49.17%).
LC-Ms m/z(ESI):535.0[M+H]+ LC-Ms m/z(ESI):535.0[M+H] +
第四步：化合物34的合成Step 4: Synthesis of compound 34
将34D(135mg，0.25mmol)、中间体5A(100mg，0.38mmol)、Pd(dppf)Cl2(20mg，0.025mmol)、碳酸钾(69mg，0.5mmol)溶于4mL1,4-二氧六环和1mL水中，氮气置换保护，100℃反应3h。冷却至室温，加水稀释，乙酸乙酯萃取(10mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化后，再经过反相柱层析纯化，冻干即得化合物34(45mg，32.51％)。34D (135 mg, 0.25 mmol), intermediate 5A (100 mg, 0.38 mmol), Pd(dppf)Cl 2 (20 mg, 0.025 mmol), potassium carbonate (69 mg, 0.5 mmol) were dissolved in 4 mL 1,4-dioxane and 1 mL water, and nitrogen was replaced for protection, and the reaction was carried out at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, and then purified by reverse phase column chromatography, and lyophilized to obtain compound 34 (45 mg, 32.51%).
LC-Ms m/z(ESI):554.3[M+H]+ LC-Ms m/z(ESI):554.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.39(d,1H),8.22(s,1H),7.90-7.80(m,3H),7.64(d,1H),7.60(d,2H),7.40-7.30(m,4H),7.11(d,1H),6.45-6.29(m,2H),5.75(dd,1H),3.49-3.41(m,1H),2.46(s,3H),1.04-0.92(m,2H),0.78-0.65(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 8.39 (d, 1H), 8.22 (s, 1H), 7.90-7.80 (m, 3H), 7.64 (d, 1H), 7.60 (d, 2H), 7.40-7.30 (m, 4H), 7.11 (d, 1H), 6.45-6.29 (m, 2H), 5.75 (dd, 1H), 3.49-3.41 (m, 1H), 2.46 (s, 3H), 1.04-0.92 (m, 2H), 0.78-0.65 (m, 2H).
实施例35：化合物35的合成
Example 35: Synthesis of Compound 35
第一步：35B的合成Step 1: Synthesis of 35B
将35A(1.2g，5.45mmol)溶于25mL二氯甲烷中，0℃下，加入三乙胺(1.13mL，8.15mmol)、置换氮气保护，缓慢滴加丙烯酰氯(0.54g，6.0mmol)，冰浴下继续反应1h。加水稀释，二氯甲烷萃取(40mL×3)，合并有机相，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得35B(1g，95.58％)。35A (1.2 g, 5.45 mmol) was dissolved in 25 mL of dichloromethane, triethylamine (1.13 mL, 8.15 mmol) was added at 0°C, nitrogen was replaced for protection, acryloyl chloride (0.54 g, 6.0 mmol) was slowly added dropwise, and the reaction was continued for 1 h under ice bath. Water was added for dilution, and dichloromethane was extracted (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 35B (1 g, 95.58%).
LC-Ms m/z(ESI):193.2[M+H]+ LC-Ms m/z(ESI):193.2[M+H] +
第二步：化合物35的合成Step 2: Synthesis of compound 35
将34D(120mg，0.22mmol)、35B(76mg，0.4mmol)、Pd(dppf)Cl2(18mg，0.022mmol)、碳酸钾(61mg，0.44mmol)溶于4mL1,4-二氧六环和1mL水中，氮气置换保护，100℃反应3h。冷却至室温，加水稀释，乙酸乙酯萃取(10mL×3)，饱和氯化钠洗涤，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化后，再经过反相柱层析纯化，冻干即得35(38mg，31.14％)。 34D (120 mg, 0.22 mmol), 35B (76 mg, 0.4 mmol), Pd(dppf)Cl 2 (18 mg, 0.022 mmol), potassium carbonate (61 mg, 0.44 mmol) were dissolved in 4 mL 1,4-dioxane and 1 mL water, and the mixture was replaced with nitrogen and reacted at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and then by reverse phase column chromatography, and lyophilized to obtain 35 (38 mg, 31.14%).
LC-Ms m/z(ESI):555.3[M+H]+ LC-Ms m/z(ESI):555.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.42(d,1H),8.26(s,1H),8.25-8.18(m,2H),7.94-7.86(m,4H),7.68(d,1H),7.44-7.33(m,2H),7.13(d,1H),6.55-6.36(m,2H),5.81(dd,1H),3.55-3.46(m,1H),2.48(s,3H),1.10-1.01(m,2H),0.82-0.73(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 8.42 (d, 1H), 8.26 (s, 1H), 8.25-8.18 (m, 2H), 7.94-7.86 (m, 4H), 7.68 (d, 1H), 7.44-7.33 (m, 2H), 7.13 (d, 1H), 6.55-6.36 (m, 2H), 5.81 (dd, 1H), 3.55-3.46 (m, 1H), 2.48 (s, 3H), 1.10-1.01 (m, 2H), 0.82-0.73 (m, 2H).
实施例36：化合物36的合成
Example 36: Synthesis of Compound 36
第一步：36A的合成Step 1: Synthesis of 36A
将35A(1.3g，5.89mmol)，2-氟丙烯酸(0.8g，8.88mmol)溶于25mL二氯甲烷中，随后加入HATU(3.36g，8.83mmol)、DIPEA(1.52g，11.78mmol)，置换氮气保护，室温反应16h。加水稀释，二氯甲烷萃取(40mL×3)，合并有机相，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得36A(0.8g，64.69％)。35A (1.3 g, 5.89 mmol) and 2-fluoroacrylic acid (0.8 g, 8.88 mmol) were dissolved in 25 mL of dichloromethane, followed by the addition of HATU (3.36 g, 8.83 mmol) and DIPEA (1.52 g, 11.78 mmol), and the mixture was replaced with nitrogen for protection, and reacted at room temperature for 16 h. The mixture was diluted with water, extracted with dichloromethane (40 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 36A (0.8 g, 64.69%).
LC-Ms m/z(ESI):211.1[M+H]+ LC-Ms m/z(ESI):211.1[M+H] +
第二步：化合物36的合成Step 2: Synthesis of compound 36
参考化合物35的合成得化合物36(50mg)Compound 36 (50 mg) was obtained by the synthesis of reference compound 35
LC-Ms m/z(ESI):573.3[M+H]+ LC-Ms m/z(ESI):573.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.42(d,1H),8.29(d,1H),8.26(s,1H),8.17(d,1H),7.98-7.87(m,4H),7.68(d,1H),7.45-7.32(m,2H),7.13(d,1H),5.78(dd,1H),5.35(dd,1H),3.54-3.46(m,1H),2.48(s,3H),1.10-1.01(m,2H),0.82-0.73(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ8.42 (d, 1H), 8.29 (d, 1H), 8.26 (s, 1H), 8.17 (d, 1H), 7.98-7.87 (m, 4H), 7.68 (d, 1H), 7.45-7.32 (m, 2H), 7.13 (d, 1H), 5.78 (dd, 1H), 5.35 (dd, 1H), 3.54-3.46 (m, 1H), 2.48 (s, 3H), 1.10-1.01 (m, 2H), 0.82-0.73 (m, 2H).
实施例37：化合物37的合成
Example 37: Synthesis of Compound 37
参考化合物35的合成得化合物37(50mg)Compound 37 (50 mg) was obtained by the synthesis of reference compound 35
LC-Ms m/z(ESI):529.2[M+H]+ LC-Ms m/z(ESI):529.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.41(s,1H),8.40(d,1H),8.31-8.20(m,2H),7.94-7.84(m,4H),7.68(d,1H),7.42-7.35(m,2H),7.12(d,1H),6.54-6.37(m,2H),5.81(dd,1H),3.87(s,3H),2.46(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.41 (s, 1H), 8.40 (d, 1H), 8.31-8.20 (m, 2H), 7.94-7.84 (m, 4H), 7.68 (d, 1H), 7.42-7.35 (m, 2H), 7.12 (d, 1H), 6.54-6.37 (m, 2H), 5.81 (dd, 1H), 3.87 (s, 3H), 2.46 (s, 3H).
实施例38：化合物38的合成
Example 38: Synthesis of Compound 38
参考化合物36的合成得化合物38(30mg)Compound 38 (30 mg) was obtained by the synthesis of reference compound 36
LC-Ms m/z(ESI):547.2[M+H]+ LC-Ms m/z(ESI):547.2[M+H] +
1H NMR(400MHz,CD3OD)δ8.42(s,1H),8.40(d,1H),8.27(d,1H),8.22(d,1H),7.95-7.86(m,4H),7.67(s,1H),7.40(dd,1H),7.36(dd,1H),7.12(d,1H),5.76(dd,1H),5.35(dd,1H),3.87(s,3H),2.46(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ 8.42 (s, 1H), 8.40 (d, 1H), 8.27 (d, 1H), 8.22 (d, 1H), 7.95-7.86 (m, 4H), 7.67 (s, 1H), 7.40 (dd, 1H), 7.36 (dd, 1H), 7.12 (d, 1H), 5.76 (dd, 1H), 5.35 (dd, 1H), 3.87 (s, 3H), 2.46 (s, 3H).
实施例39：化合物39的合成
Example 39: Synthesis of Compound 39
第一步：39A的合成Step 1: Synthesis of 39A
将35A(1g，4.56mmol)溶于25mL二氯甲烷中，0℃下，加入三乙胺(1.14mL，8.21mmol)、置换氮气保护，缓慢滴加甲基丙烯酰氯(0.51g，4.83mmol)，冰浴下继续反应1h。加水稀释，二氯甲烷萃取(40mL×3)，合并有机相，无水硫酸钠干燥，过滤后，减压浓缩，残余物经柱层析纯化即得39A(0.45g，47.90％)。35A (1 g, 4.56 mmol) was dissolved in 25 mL of dichloromethane, triethylamine (1.14 mL, 8.21 mmol) was added at 0°C, nitrogen was replaced for protection, methacryloyl chloride (0.51 g, 4.83 mmol) was slowly added dropwise, and the reaction was continued for 1 h under ice bath. Water was added for dilution, dichloromethane was extracted (40 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 39A (0.45 g, 47.90%).
LC-Ms m/z(ESI):193.2[M+H]+ LC-Ms m/z(ESI):193.2[M+H] +
第二步：化合物39的合成Step 2: Synthesis of compound 39
参考化合物35的合成得化合物39(30mg)Compound 39 (30 mg) was obtained by the synthesis of reference compound 35
LC-Ms m/z(ESI):543.3[M+H]+ LC-Ms m/z(ESI):543.3[M+H] +
1H NMR(400MHz,CD3OD)δ8.42(d,1H),8.25(s,1H),8.24-8.16(m,2H),7.94-7.83(m,4H),7.67(d,1H),7.42(dd,1H),7.35(dd,1H),7.13(d,1H),5.87(s,1H),5.58(d,1H),3.79(s,3H),2.48(s,3H),2.03(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ8.42 (d, 1H), 8.25 (s, 1H), 8.24-8.16 (m, 2H), 7.94-7.83 (m, 4H), 7.67 (d, 1H), 7.42 (dd, 1H), 7.35 (dd, 1H), 7.13 (d, 1H), 5.87 (s, 1H), 5.58 (d, 1H), 3.79 (s, 3H), 2.48 (s, 3H), 2.03 (s, 3H).
参考前述实施例的合成方法，制备了如下表格化合物：

With reference to the synthetic method of the above-mentioned embodiment, the following table compounds were prepared:

生物测试例Biological test cases
FGFR1激酶抑制活性测试FGFR1 kinase inhibitory activity assay
受试化合物使用DMSO进行稀释，稀释至检测浓度的2.5×。用电动移液器转移4μL的化合物至384反应板中(784075,Greiner)。用激酶反应缓冲液(5×Buffer,5mM MgCl2,1mM DTT,1％ Tween 20)，准备FGFR1激酶溶液(工作浓度:0.3nM)，转移2μL的激酶溶液到384反应板中。使用离心机在1000rpm离心1分钟，25℃孵育10分钟。用激酶反应缓冲液准备底物(TK-sub工作浓度:1μM)和ATP(工作浓度：50μM)的混合液，向反应板中加入4μL的底物和ATP的混合液用来开始反应，使用离心机在1000rpm离心1分钟。使用封板膜封住板子，25℃孵育60min。用检测缓冲液配置XL665和抗体检测试剂。每孔加入5μL激酶检测试剂加入到384反应板中，1000rpm离心60秒，25℃孵育60min。用酶标仪读620nm(Cryptate)和665nm(XL665)的荧光信号。The test compound was diluted with DMSO to 2.5× the detection concentration. 4 μL of the compound was transferred to a 384 reaction plate (784075, Greiner) using an electric pipette. The kinase reaction buffer (5× Buffer, 5 mM MgCl 2 , 1 mM DTT, 1% Tween 20), prepare FGFR1 kinase solution (working concentration: 0.3nM), transfer 2μL of kinase solution to 384 reaction plate. Centrifuge at 1000rpm for 1 minute and incubate at 25℃ for 10 minutes. Prepare substrate (TK-sub working concentration: 1μM) and ATP (working concentration: 50μM) mixture in kinase reaction buffer, add 4μL of substrate and ATP mixture to the reaction plate to start the reaction, centrifuge at 1000rpm for 1 minute. Seal the plate with sealing film and incubate at 25℃ for 60min. Prepare XL665 and antibody detection reagents with detection buffer. Add 5μL of kinase detection reagent to each well of the 384 reaction plate, centrifuge at 1000rpm for 60 seconds, and incubate at 25℃ for 60min. Read the fluorescence signal at 620nm (Cryptate) and 665nm (XL665) with a microplate reader.
FGFR2激酶抑制活性测试FGFR2 kinase inhibitory activity assay
化合物使用DMSO进行稀释，稀释至检测浓度的200×。用Echo 665转移25nL的化合物的384反应板中(784075,Greiner)。用激酶反应缓冲液(5X Buffer,5mM Mgcl2,1mM DTT)，准备激酶溶液(工作浓度:0.3nM)，转移2.5μL的激酶溶液到384反应板中。使用离心机在1000rpm离心1分钟，25℃孵育10分钟。用激酶反应缓冲液准备底物(TK-sub工作浓度:1μM)和ATP(工作浓度：50μM)的混合液，向反应板中加入2.5μL的底物和ATP的混合液用来开始反应，使用离心机在1000rpm离心1分钟。使用封板膜封住板子，25℃孵育50min。用检测缓冲液配置XL665和抗体检测试剂。每孔加入5μL激酶检测试剂加入到384反应板中，1000rpm离心60秒，25℃孵育1小时。用酶标仪读620nm(Cryptate)和665nm(XL665)的荧光信号。Compounds were diluted in DMSO to 200× the assay concentration. 25 nL of compound was transferred to a 384-well plate (784075, Greiner) using Echo 665. Kinase solution (working concentration: 0.3 nM) was prepared using kinase reaction buffer (5X Buffer, 5 mM Mgcl2, 1 mM DTT) and 2.5 μL of kinase solution was transferred to the 384-well plate. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 10 min. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 50 μM) was prepared using kinase reaction buffer. 2.5 μL of the mixture of substrate and ATP was added to the plate to start the reaction. Centrifuge at 1000 rpm for 1 min. The plate was sealed with a sealing film and incubated at 25°C for 50 min. XL665 and antibody detection reagents were prepared using assay buffer. Add 5 μL of kinase detection reagent to each well of the 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25° C. for 1 hour. Read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) using an ELISA reader.
表1化合物对FGFR1和FGFR2激酶抑制活性
Table 1 Inhibitory activity of compounds on FGFR1 and FGFR2 kinases
FGFR3激酶抑制活性测试FGFR3 kinase inhibitory activity assay
化合物使用DMSO进行稀释，稀释至检测浓度的200×。用Echo 665转移25nL的化合物的384反应板中(784075,Greiner)。用激酶反应缓冲液(5X Buffer,5mM Mgcl2,1mM DTT)，准备激酶溶液(工作浓度:0.6nM)，转移2.5μL的激酶溶液到384反应板中。使用离心机在1000rpm离心1分 钟，25℃孵育10分钟。用激酶反应缓冲液准备底物(TK-sub工作浓度:1μM)和ATP(工作浓度：50μM)的混合液，向反应板中加入2.5μL的底物和ATP的混合液用来开始反应，使用离心机在1000rpm离心1分钟。使用封板膜封住板子，25℃孵育50min。用检测缓冲液配置XL665和抗体检测试剂。每孔加入5μL激酶检测试剂加入到384反应板中，1000rpm离心60秒，25℃孵育1小时。用酶标仪读620nm(Cryptate)和665nm(XL665)的荧光信号。Compounds were diluted with DMSO to 200× the assay concentration. 25 nL of compound was transferred to a 384-well plate (784075, Greiner) using an Echo 665. Kinase solution (working concentration: 0.6 nM) was prepared using kinase reaction buffer (5X Buffer, 5 mM Mgcl2, 1 mM DTT) and 2.5 μL of kinase solution was transferred to the 384-well plate. Centrifuge at 1000 rpm for 1 minute. 1 minute, incubate at 25°C for 10 minutes. Prepare a mixture of substrate (TK-sub working concentration: 1μM) and ATP (working concentration: 50μM) in kinase reaction buffer, add 2.5μL of the substrate and ATP mixture to the reaction plate to start the reaction, and centrifuge at 1000rpm for 1 minute. Seal the plate with a sealing film and incubate at 25°C for 50min. Prepare XL665 and antibody detection reagents in detection buffer. Add 5μL of kinase detection reagent to each well of the 384 reaction plate, centrifuge at 1000rpm for 60 seconds, and incubate at 25°C for 1 hour. Read the fluorescence signals at 620nm (Cryptate) and 665nm (XL665) using an enzyme reader.
FGFR2 N549H激酶抑制活性测试FGFR2 N549H kinase inhibitory activity assay
化合物使用DMSO进行稀释，稀释至检测浓度的200×。用Echo 665转移25nL的化合物的384反应板中(784075,Greiner)。用激酶反应缓冲液(5X Buffer,5mM Mgcl2,1mM DTT)，准备激酶溶液(工作浓度:0.3nM)，转移2.5μL的激酶溶液到384反应板中。使用离心机在1000rpm离心1分钟，25℃孵育10分钟。用激酶反应缓冲液准备底物(TK-sub工作浓度:1μM)和ATP(工作浓度：5μM)的混合液，向反应板中加入2.5μL的底物和ATP的混合液用来开始反应，使用离心机在1000rpm离心1分钟。使用封板膜封住板子，25℃孵育50min。用检测缓冲液配置XL665和抗体检测试剂。每孔加入5μL激酶检测试剂加入到384反应板中，1000rpm离心60秒，25℃孵育1小时。用酶标仪读620nm(Cryptate)和665nm(XL665)的荧光信号。Compounds were diluted in DMSO to 200× the assay concentration. 25 nL of compound was transferred to a 384-well plate (784075, Greiner) using Echo 665. Kinase solution (working concentration: 0.3 nM) was prepared using kinase reaction buffer (5X Buffer, 5 mM Mgcl2, 1 mM DTT) and 2.5 μL of kinase solution was transferred to the 384-well plate. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 10 min. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 5 μM) was prepared using kinase reaction buffer. 2.5 μL of the mixture of substrate and ATP was added to the plate to start the reaction. Centrifuge at 1000 rpm for 1 min. The plate was sealed with a sealing film and incubated at 25°C for 50 min. XL665 and antibody detection reagents were prepared using detection buffer. Add 5 μL of kinase detection reagent to each well of the 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25° C. for 1 hour. Read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) using an ELISA reader.
FGFR2 V564F激酶抑制活性测试FGFR2 V564F kinase inhibitory activity assay
化合物使用DMSO进行稀释，稀释至检测浓度的200×。用Echo 665转移25nL的化合物的384反应板中(784075,Greiner)。用激酶反应缓冲液(5X Buffer,5mM Mgcl2,1mM DTT)，准备激酶溶液(工作浓度:0.3nM)，转移2.5μL的激酶溶液到384反应板中。使用离心机在1000rpm离心1分钟，25℃孵育10分钟。用激酶反应缓冲液准备底物(TK-sub工作浓度:1μM)和ATP(工作浓度：10μM)的混合液，向反应板中加入2.5μL的底物和ATP的混合液用来开始反应，使用离心机在1000rpm离心1分钟。使用封板膜封住板子，25℃孵育50min。用检测缓冲液配置XL665和抗体检测试剂。每孔加入5μL激酶检测试剂加入到384反应板中，1000rpm离心60秒，25℃孵育1小时。用酶标仪读620nm(Cryptate)和665nm(XL665)的荧光信号。Compounds were diluted in DMSO to 200× the assay concentration. 25 nL of compound was transferred to a 384-well plate (784075, Greiner) using Echo 665. Kinase solution (working concentration: 0.3 nM) was prepared using kinase reaction buffer (5X Buffer, 5 mM Mgcl2, 1 mM DTT) and 2.5 μL of kinase solution was transferred to the 384-well plate. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 10 min. A mixture of substrate (TK-sub working concentration: 1 μM) and ATP (working concentration: 10 μM) was prepared using kinase reaction buffer. 2.5 μL of the mixture of substrate and ATP was added to the plate to start the reaction. Centrifuge at 1000 rpm for 1 min. The plate was sealed with a sealing film and incubated at 25°C for 50 min. XL665 and antibody detection reagents were prepared using detection buffer. Add 5 μL of kinase detection reagent to each well of the 384 reaction plate, centrifuge at 1000 rpm for 60 seconds, and incubate at 25° C. for 1 hour. Read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) using an ELISA reader.
结论：本发明化合物，例如实施例化合物，具体的如化合物1至化合物46具有良好的FGFR2激酶抑制活性，相较于FGFR1，对FGFR2激酶具有良好的选择性。Conclusion: The compounds of the present invention, such as the example compounds, specifically compounds 1 to 46, have good FGFR2 kinase inhibitory activity and have good selectivity for FGFR2 kinase compared to FGFR1.
SNU16细胞增殖抑制SNU16 cell proliferation inhibition
SNU16细胞(ATCC,CRL-5974)使用DMEM完全培养基(+10％FBS)于CO2培养箱中37℃培养48h。胰酶消化细胞并计数，然后调整密度为4.44×104个/mL。每孔接种细胞90μL(4000个)至底部透明96孔板中，转移至CO2培养箱中37℃条件下培养过夜。细胞孵育过夜后，使用排枪每孔加入10μL稀释好的化合物(终浓度1μM起始，3倍稀释，11个浓度)，阳性对照为含DMSO无血清培养基，混合均匀后放于CO2培养箱37℃条件下5天。孵育结束后，取出试剂盒检测液(Vazyme，DD1101-03)恢复室温，每个孔加入100μL CellCounting-Lite2.0检测液，封板膜封好，将板放在振荡器上面振荡15min(整个过程需避光操作)，使用酶标仪(BMG LRBTECH)的Luminescence模块检测各孔的荧光信号值LUM。通过公式计算化合物的抑制率。使用Graphpad软件log(inhibitor)vs.response--Variable slope(four parameters)方程进行拟合分析，计算样品的IC50数值。数据纵坐标为抑制率百 分比，横坐标为样品浓度的对数值(Log10)。SNU16 cells (ATCC, CRL-5974) were cultured in a CO2 incubator at 37°C for 48h using DMEM complete medium (+10% FBS). The cells were trypsinized and counted, and then the density was adjusted to 4.44× 104 /mL. 90μL (4000) of cells were inoculated into each well of a transparent 96-well plate at the bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10μL of the diluted compound (starting at a final concentration of 1μM, 3-fold dilution, 11 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO. After mixing evenly, it was placed in a CO2 incubator at 37°C for 5 days. After the incubation, remove The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on an oscillator for 15 minutes (the whole process must be protected from light), and the Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well. Calculate the inhibition rate of the compound. Use Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation for fitting analysis and calculate the IC 50 value of the sample. The vertical axis of the data is the percentage of inhibition rate. The horizontal axis is the logarithm of the sample concentration (Log 10 ).
表2化合物对SNU16细胞增殖抑制活性
Table 2 Inhibitory activity of compounds on SNU16 cell proliferation
结论：本发明化合物，特别是实施例化合物，具体的如化合物1至化合物46对SNU16细胞增殖具有良好的抑制活性。Conclusion: The compounds of the present invention, especially the compounds of the examples, specifically compounds 1 to 46, have good inhibitory activity on the proliferation of SNU16 cells.
KATO III细胞增殖抑制KATO III cell proliferation inhibition
KATO III细胞(ATCC,HTB-103)使用IMDM完全培养基(+10％FBS)于CO2培养箱中37℃培养48h。胰酶消化细胞并计数，然后调整密度为1.67×104个/mL。每孔接种细胞90μL(1500个)至底部透明96孔板中，转移至CO2培养箱中37℃条件下培养过夜。细胞孵育过夜后，使用排枪每孔加入10μL稀释好的化合物(终浓度1μM起始，3倍稀释，10个浓度)，阳性对照为含DMSO无血清培养基，混合均匀后放于CO2培养箱37℃条件下96h。孵育结束后，取出试剂盒检测液(Vazyme，DD1101-03)恢复室温，每个孔加入100μL CellCounting-Lite2.0检测液，封板膜封好，将板放在振荡器上面振荡15min(整个过程需避光操作)，使用酶标仪(BMG LRBTECH)的Luminescence模块检测各孔的荧光信号值LUM。通过公式计算化合物的抑制率。使用Graphpad软件log(inhibitor)vs.response--Variable slope(four parameters)方程进行拟合分析，计算样品的IC50数值。数据纵坐标为抑制率百分比，横坐标为样品浓度的对数值(Log10)。KATO III cells (ATCC, HTB-103) were cultured in a CO2 incubator at 37°C for 48 h using IMDM complete medium (+10% FBS). The cells were trypsinized and counted, and then the density was adjusted to 1.67× 104 /mL. 90 μL (1500) of cells were inoculated into each well of a 96-well plate with a transparent bottom, and transferred to a CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 μL of the diluted compound (starting at a final concentration of 1 μM, 3-fold dilution, 10 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO. After mixing evenly, the cells were placed in a CO2 incubator at 37°C for 96 h. After the incubation, the cells were removed. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on an oscillator for 15 minutes (the whole process must be protected from light), and the Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well. Calculate the inhibition rate of the compound. Use Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation for fitting analysis and calculate the IC 50 value of the sample. The vertical axis of the data is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log 10 ).
表3化合物对KATO III细胞增殖抑制活性
Table 3 Inhibitory activity of compounds on KATO III cell proliferation
结论：本发明化合物，例如实施例化合物1至化合物46对KATO III细胞增殖具有良好的抑制活性，具体的如表格3所示。Conclusion: The compounds of the present invention, such as Example compounds 1 to 46, have good inhibitory activity against KATO III cell proliferation, as shown in Table 3.
Li7细胞增殖抑制Li7 cell proliferation inhibition
Li7细胞(明舟生物,MZ-0519)使用RPMI-1640完全培养基(+10％FBS)于CO2培养箱中37℃培养48h。胰酶消化细胞并计数，然后调整密度为1.67×104个/mL。每孔接种细胞90μL(3000 个)至底部透明96孔板中，转移至CO2培养箱中37℃条件下培养过夜。细胞孵育过夜后，使用排枪每孔加入10μL稀释好的化合物(终浓度10μM起始，3倍稀释，10个浓度)，受试化合物为含DMSO无血清培养基，混合均匀后放于CO2培养箱37℃条件下96h。孵育结束后，取出试剂盒检测液(Vazyme，DD1101-03)恢复室温，每个孔加入100μL CellCounting-Lite2.0检测液，封板膜封好，将板放在振荡器上面振荡15min(整个过程需避光操作)，使用酶标仪(BMG LRBTECH)的Luminescence模块检测各孔的荧光信号值LUM。通过公式计算化合物的抑制率。使用Graphpad软件log(inhibitor)vs.response--Variable slope(four parameters)方程进行拟合分析，计算样品的IC50数值。数据纵坐标为抑制率百分比，横坐标为样品浓度的对数值(Log10)。Li7 cells (Mingzhou Bio, MZ-0519) were cultured in RPMI-1640 complete medium (+10% FBS) in a CO 2 incubator at 37°C for 48 h. The cells were trypsinized and counted, and then the density was adjusted to 1.67×10 4 cells/mL. 90 μL (3000 cells) of cells were inoculated into each well. ) to a transparent 96-well plate at the bottom, and transfer to a CO2 incubator and culture overnight at 37°C. After the cells were incubated overnight, 10 μL of the diluted compound (starting at a final concentration of 10 μM, 3-fold dilution, 10 concentrations) was added to each well using a spray gun. The test compound was a serum-free medium containing DMSO. After mixing evenly, the plate was placed in a CO2 incubator at 37°C for 96 hours. After the incubation, the cells were taken out. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on an oscillator for 15 minutes (the whole process must be protected from light), and the Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well. Calculate the inhibition rate of the compound. Use Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation for fitting analysis and calculate the IC 50 value of the sample. The vertical axis of the data is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log 10 ).
结论：相对于Li-7细胞，本发明化合物，例如实施例化合物1至化合物46对SUN-16细胞和KATO III细胞具有选择性的抑制作用。Conclusion: Compared with Li-7 cells, the compounds of the present invention, such as Example compounds 1 to compound 46, have selective inhibitory effects on SUN-16 cells and KATO III cells.
4.CYP450酶抑制测试4.CYP450 enzyme inhibition test
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型CYP1A2、CYP2C9、CYP2D6、CYP3A4-M(以咪达唑仑为底物)的抑制潜能。The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (with midazolam as substrate).
结论：本发明化合物，例如实施例化合物1至化合物46对CYP酶各亚型均无明显的抑制作用。Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have no significant inhibitory effect on any subtype of CYP enzymes.
5.小鼠药代动力学测试5. Pharmacokinetic Test in Mice
试验动物：雄性BALB/c小鼠，20～25g，6只/化合物。购于成都达硕实验动物有限公司。Experimental animals: Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验设计：试验当天，6只BALB/c小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Experimental design: On the day of the experiment, 6 BALB/c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
表4.给药信息
Table 4. Dosing Information
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MCNote: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose
于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。 Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
表5：受试化合物小鼠要药代动力学结果
Table 5: Pharmacokinetic results of the test compounds in mice
结论：本发明化合物，例如实施例化合物1至化合物46具有良好的药代动力学性能，具体的如化合物15在小鼠体内具有较好的口服吸收性能和清除率更低。Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good pharmacokinetic properties. Specifically, Compound 15 has good oral absorption performance and lower clearance rate in mice.
对照化合物1为 The control compound 1 is
6.大鼠药代动力学测试6. Pharmacokinetic Test in Rats
试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验设计：试验当天，6只SD大鼠/化合物，按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Experimental design: On the day of the experiment, 6 SD rats/compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
表6.给药信息
Table 6. Dosing Information
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MCNote: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。MC：(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose. MC:
于给药前及给药后异氟烷麻醉经眼眶取血0.10mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after drug administration, 0.10 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
表7:受试化合物大鼠药代动力学结果
Table 7: Pharmacokinetic results of test compounds in rats
结论：本发明化合物，例如实施例化合物1至化合物46具有良好的药代动力学性能，具体 的如化合物5在大鼠体内具有较好的口服吸收性能或/和清除率更低。Conclusion: The compounds of the present invention, such as Example compounds 1 to 46, have good pharmacokinetic properties. For example, compound 5 has better oral absorption performance and/or lower clearance rate in rats.
7.比格犬药代动力学测试7. Beagle dog pharmacokinetic test
试验动物：雄性比格犬，8～11kg左右，5-6只/化合物，购于北京玛斯生物技术有限公司。Experimental animals: Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
试验方法：试验当天，比格犬5-6只/化合物按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Test method: On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.
表8：给药信息
Table 8: Dosing Information
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC：(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 0.5% MC: (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; 0.5% MC: 0.5% methylcellulose aqueous solution.
于给药前及给药后通过颈静脉或四肢静脉取血1ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。G1和G2组静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24h,48,72h。G3和G4组静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm, 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group in G1 and G2 groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h, 48, 72 h. The blood collection time points for the intravenous group and the gavage group in G3 and G4 groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
结论：本发明化合物，例如实施例化合物1至化合物46在比格犬体内具有较好的口服吸收性能。Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good oral absorption properties in beagle dogs.
8.猴药代动力学测试8. Monkey Pharmacokinetic Test
试验动物：雄性食蟹猴，3～5kg，3～6年龄，4-6只/化合物。购于苏州西山生物技术有限公司。Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
试验方法：试验当天，猴4-6只/化合物按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。Test method: On the test day, 4-6 monkeys/compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.
表9：给药信息
Table 9: Dosing Information
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。 Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 0.5% MC (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% methylcellulose aqueous solution.
*剂量以游离碱计。*Dosage is based on free base.
于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5min,15min,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
结论：本发明化合物，例如实施例化合物1至化合物46在猴体内具有较好的口服吸收性能。Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have good oral absorption properties in monkeys.
9.hERG钾离子通道作用测试9. hERG potassium channel action test
实验平台：电生理手动膜片钳系统Experimental platform: electrophysiological manual patch clamp system
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion of the electrode liquid was about 2-5MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz. After obtaining the whole-cell recording, the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s. This voltage stimulus was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute). Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n≥2) were tested at each concentration.
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Inhibition％＝[1-(I/Io)]×100％Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis. The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:
Inhibition%＝[1-(I/Io)]×100%
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))The IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:
Y = Bottom + (Top-Bottom) / (1 + 10^(( LogIC50 -X) × HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。Among them, X is the Log value of the test sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.
结论：本发明化合物，例如实施例化合物1至化合物46无明显的hERG抑制活性。Conclusion: The compounds of the present invention, such as Example Compounds 1 to 46, have no significant hERG inhibitory activity.
10.化合物灌胃小鼠稳态的血磷检测10. Steady-state blood phosphorus detection in mice given oral administration of compounds
D0分组前称重，每只动物采集全血约250μL/只，保证离心后提取血清不少于60μL，采用全自动生化分析仪(Cobas；Cat:C311)测定血磷基础值，据此进行分组，分组当天不给药；Weigh the animals before grouping on D0, collect about 250 μL of whole blood from each animal, and ensure that no less than 60 μL of serum is extracted after centrifugation. Use an automatic biochemical analyzer (Cobas; Cat: C311) to measure the basic value of blood phosphorus, and group them accordingly. No drug is administered on the day of grouping;
分组之后的第一天记为D1，开始化合物一天两次给药，D1给药后0.5、1、4、7、24h测伴随PK，第2次给药在首次给药6h后进行；Day1、2、3、4、5记录动物体重并填写给药记录；给药D5，当天第一次给药后4h测血磷，给药后0.5、1、4、7、24h测伴随PK。The first day after grouping was recorded as D1. The compound was initially administered twice a day. The concomitant PK was measured 0.5, 1, 4, 7, and 24 h after administration on D1, and the second administration was performed 6 h after the first administration. The animal body weight was recorded and the administration record was filled in on Days 1, 2, 3, 4, and 5. On D5, blood phosphorus was measured 4 h after the first administration of the day, and concomitant PK was measured 0.5, 1, 4, 7, and 24 h after administration.
结论：本发明化合物例如实施化合物1至化合物46不会显著的引起小鼠血磷的升高。 Conclusion: The compounds of the present invention, such as compound 1 to compound 46, do not significantly cause an increase in blood phosphorus in mice.

Claims (12)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中
    A compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein
    环A、环B、环C各自独立的选自苯基、苯并C4-6碳环、5至6元杂芳基或8-10元并环杂芳基，所述环A任选被1至4个Ra取代，所述环B任选被1至4个Rb取代，所述环C任选被1至4个Rc取代；Ring A, Ring B, and Ring C are each independently selected from phenyl, benzoC 4-6 carbocycle, 5- to 6-membered heteroaryl, or 8-10-membered cycloheteroaryl, wherein Ring A is optionally substituted by 1 to 4 Ra , Ring B is optionally substituted by 1 to 4 Rb , and Ring C is optionally substituted by 1 to 4 Rc ;
    Q选自键、-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、C4-10碳环、4至10元杂环，所述的碳环或杂环任选被1至4个Rk取代；Q is selected from the key, -O-, -N(R q3 )-, -C(═O)N(R q3 )-, -N(R q3 )C(═O), -C(═O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    m选自0或1；m is selected from 0 or 1;
    Rq1、Rq2、Rq3各自独立的选自H、C1-6烷基，所述的烷基任选被1至4个Rk取代；R q1 , R q2 , and R q3 are each independently selected from H, C 1-6 alkyl, and the alkyl is optionally substituted by 1 to 4 R k ;
    D选自键、-NRn1-、所述D任选被1至6个Rd取代，D1或D2右侧与R1直接连接；D is selected from a bond, -NR n1 -, The D is optionally substituted by 1 to 6 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
    Q与D不能同时为键；Q and D cannot be bonds at the same time;
    Q与D的连接键不能形成N-N、N-O；The bond between Q and D cannot form N-N or N-O;
    D1选自4至14元含氮杂环基； D1 is selected from 4 to 14-membered nitrogen-containing heterocyclic groups;
    D2选自C3-14碳环基、4至14元杂环基； D2 is selected from C3-14 carbocyclyl, 4 to 14 membered heterocyclyl;
    D3选自C7-14碳环基； D3 is selected from C7-14 carbocyclic group;
    Rn1选自H、C1-4烷基；R n1 is selected from H, C 1-4 alkyl;
    Ra、Rb、Rc、Rd各自独立的选自H、氘、卤素、CN、OH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、-OC1-6烷基、-SC1-6烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-NH-5至6元杂芳基-C1-4烷基、-NH-3至7元杂环-C3-6碳环、-NH-3至7元杂环-4至6元杂环、-C1-4亚烷基-C3-6碳环、-C1-4亚烷基-3至7元杂环、-C(＝O)NH2、-C(＝O)NH-C1-6烷基、-C(＝O)NH-C3-6碳环、-NHC(＝O)-C1-6烷基、-NHC(＝O)-C3-6碳环、C3-6碳环、3至7元杂环，所述烷基、亚烷基、烯基、炔基、杂芳基、碳环或杂环任选被1至4个Rk取代； Ra , Rb , Rc , and Rd are each independently selected from H, deuterium, halogen, CN, OH , NH2, NHC1-6 alkyl, N( C1-6 alkyl) 2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OC1-6 alkyl, -SC1-6 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH -C3-6 carbocycle , -NH-3 to 7 membered heterocycle, -NH-5 to 6 membered heteroaryl- C1-4 alkyl, -NH-3 to 7 membered heterocycle- C3-6 carbocycle, -NH-3 to 7 membered heterocycle-4 to 6 membered heterocycle, -C1-4 alkylene- C3-6 carbocycle, -C1-4 alkylene-3 to 7 membered heterocycle, -C(=O) NH2 , -C(=O)NH-C R k is substituted with 1 to 4 R k ;
    R1选自卤素、CN、 R1 is selected from halogen, CN,
    R1a、R1b、R1c、R1d各自独立的选自H、氘、卤素、CN、-C(＝O)R、-C(＝O)OR、-C(＝O)N(R)2、C(＝O)N(R)OR、C1-6烷基、C2-6烯基、C2-6炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, -C(═O)R, -C(═O)OR, -C(═O)N(R) 2 , C(═O)N(R)OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
    R1e选自卤素或-OS(＝O)2R；R 1e is selected from halogen or -OS(=O) 2 R;
    R选自H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
    作为选择，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    作为选择，Rn1与Rd直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R n1 and R d are directly linked to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    Rk选自氘、卤素、CN、OH、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、-OC1-6烷基、-SC1-6烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C(＝O)-C3-6碳环、-C(＝O)-3至7元杂环、-C1-4亚烷基-C3-6碳环、-C1-4亚烷基-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代。R k is selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C(＝O)-C 3-6 carbocycle, -C(＝O)-3 to 7 membered heterocycle, -C 1-4 alkylene-C 3-6 carbocycle, -C 1-4 alkylene-3 to 7 membered heterocycle, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 members selected from deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C The moiety is substituted by 1-6 alkoxy substituents.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，通式(I)所示的化合物选自通式(II)、通式(III)、通式(IV)、通式(V)、通式(VI)、通式(VII)、通式(VIII)所示的化合物，

    The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the group consisting of compounds represented by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII) and general formula (VIII),

    环B选自苯基、萘环、苯并C4-6碳环、苯并4至6元杂环、5至6元杂芳基、8至10元并环杂芳基，所述环B任选被1至4个Rb取代；Ring B is selected from phenyl, naphthalene, benzoC 4-6 carbon ring, benzo 4-6 membered heterocyclic ring, 5-6 membered heteroaryl, 8-10 membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;
    Q3选自C4-10碳环、4至10元杂环，所述Q3任选被1至4个Rk取代；Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said Q 3 is optionally substituted by 1 to 4 R k ;
    环B1选自Q3选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Ring B 1 is selected from Q3 is selected from C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
    B2选自C4-6碳环，B3选自C4-6碳环； B2 is selected from C4-6 carbocyclic ring, B3 is selected from C4-6 carbocyclic ring;
    或者Q3选自环B1选自C4-10碳环、4至10元杂环，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Or Q3 is selected from Ring B1 is selected from C4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
    环C选自 Ring C is selected from
    F1或F2选自N或CH； F1 or F2 is selected from N or CH;
    Q选自-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、C4-10碳环、4至10元杂环，所述的碳环或杂环任选被1至4个Rk取代；Q is selected from -O-, -N(R q3 )-, -C(═O)N(R q3 )-, -N(R q3 )C(═O), -C(═O)-, C 4-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    Q1选自-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-、任选被1至4个Rk取代的 Q1 is selected from -O-, -N( Rq3 )-, -C(=O)N( Rq3 )-, -N( Rq3 )C(=O), -C(=O)-, optionally substituted with 1 to 4 Rk
    D选自-NRn1-、所述D任选被1至4个Rd取代，D1或D2右侧与R1直接连接；D is selected from -NR n1 -, The D is optionally substituted by 1 to 4 R d , and the right side of D 1 or D 2 is directly connected to R 1 ;
    D1选自4至7元含氮杂单环烷基、4至7元含氮杂单环烯基、5至14元含氮杂螺环烷基、5至14元含氮杂并环烷基、5至14元含氮杂桥环烷基； D1 is selected from 4 to 7 membered nitrogen-containing heteromonocyclic alkyl, 4 to 7 membered nitrogen-containing heteromonocyclic alkenyl, 5 to 14 membered nitrogen-containing heterospirocyclic alkyl, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged cycloalkyl;
    D2选自苯基、苯并C4-7碳环基、苯并4至7元杂环基、5至6元杂芳基、C3-7单环烷基、C3-7单环烯基、C5-14螺环烷基、C5-14并环烷基、C5-14桥环烷基、4至7元含氮杂单环基、5至14元含氮杂螺环基、5至14元含氮杂并环基、5至14元含氮杂桥环基； D2 is selected from phenyl, benzo C4-7 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl, C3-7 monocycloalkyl, C3-7 monocycloalkenyl, C5-14 spirocycloalkyl , C5-14 cycloalkyl, C5-14 bridged cycloalkyl, 4 to 7 membered nitrogen-containing heteromonocyclic group, 5 to 14 membered nitrogen-containing heterospirocyclic group, 5 to 14 membered nitrogen-containing heterocycloalkyl, 5 to 14 membered nitrogen-containing heterobridged ring group;
    D3选自苯并C4-7碳环基、C7-14螺环烷基、C7-14并环烷基、C7-14桥环烷基； D3 is selected from benzo C4-7 carbocyclyl, C7-14 spirocycloalkyl, C7-14 cycloalkyl, C7-14 bridged cycloalkyl;
    Rc1选自H、C1-4烷基、C3-6环烷基或4至7元杂环烷基，所述烷基、环烷基或杂环烷基任选被1至4个Rk取代；R c1 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl or 4 to 7 membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
    Rc2各自独立的选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4 烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-C(＝O)NH-C1-4烷基、-C(＝O)NH-C3-6碳环、-NHC(＝O)-C1-4烷基、-NHC(＝O)-C3-6碳环、C3-6碳环、3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R c2 is independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7-membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7-membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7-membered heterocycle, -C (= O) NH-C 1-4 alkyl, -C (= O) NH-C 3-6 carbocycle, -NHC (= O) -C 1-4 alkyl, -NHC (= O) -C 3-6 carbocycle, C 3-6 carbocycle, 3 to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
    Rc3各自独立的选自H、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R c3 is each independently selected from H, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
    Rc4选自H、NH2、卤素、CN、OH、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环，所述的烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R c4 is selected from H, NH 2 , halogen, CN, OH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
    Rc5选自H、氘、卤素、CN、羟基、NH2、-NHC1-4烷基、-NH-C3-7碳环、-NH-3至7元杂环、C1-4烷基、C1-4烷氧基、C3-6环烷基、-NH-5至6元杂芳基-C1-3亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a,所述烷基、亚烷基、烷氧基、环烷基、碳环基、杂环基、杂芳基任选地被1至4个Rk取代；R c5 is selected from H, deuterium, halogen, CN, hydroxyl, NH 2 , -NHC 1-4 alkyl, -NH-C 3-7 carbocycle, -NH-3 to 7-membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -NH-5 to 6-membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
    Rc6选自H、卤素、OH、NH2、C1-4烷基、CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环或3至7元杂环，所述烷基、亚烷基、烯基、炔基、碳环、杂环任选地被1至4个Rk取代；R c6 is selected from H, halogen, OH, NH 2 , C 1-4 alkyl, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle or 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R k ;
    当Rc6选自H、卤素、OH、NH2或C1-4烷基时，Rc5选自-NH-5至6元杂芳基-C1-3亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a，所述的烷基、杂芳基、亚烷基、碳环基或杂环基任选被1至3个Rk取代；When R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-3 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , and the alkyl, heteroaryl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 3 R k ;
    Rc5a选自CN、-O-C1-3烷基、-S-C1-3烷基、C3-6碳环、-O-C3-6碳环、4至6元杂环、-O-4至6元杂环、-C(＝O)C3-6碳环、-C(＝O)-4至6元杂环，所述的烷基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R c5a is selected from CN, -OC 1-3 alkyl, -SC 1-3 alkyl, C 3-6 carbocycle, -OC 3-6 carbocycle, 4- to 6-membered heterocycle, -O-4- to 6-membered heterocycle, -C(=O)C 3-6 carbocycle, -C(=O)-4- to 6-membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
    当Rc6选自CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-O-C3-6碳环、-O-3至7元杂环、C3-6碳环或3至7元杂环时，Rc5选自H、氘、卤素、CN、羟基、NH2、-NHC1-4烷基、-NH-C3-7碳环、-NH-3至7元杂环、C1-4烷基、C1-4烷氧基或C3-6环烷基，所述烷基、亚烷基、烯基、炔基、烷氧基、环烷基、碳环、杂环任选地被1至4个Rk取代；When R c6 is selected from CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, C 3-6 carbocycle or 3 to 7 membered heterocycle, R c5 is selected from H, deuterium, halogen, CN, hydroxyl , NH 2 , -NHC 1-4 alkyl, -NH -C 3-7 carbocycle, -NH-3 to 7 membered heterocycle, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocycle, heterocycle are optionally substituted with 1 to 4 R k ;
    Rc7选自H或Rc2；R c7 is selected from H or R c2 ;
    p1或p2选自0、1、2或3。p1 or p2 is selected from 0, 1, 2 or 3.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound according to claim 2 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,
    Q选自苯基、萘基、苯并C4-6碳环、苯并4至6元杂环、-O-、-N(Rq3)-、-C(＝O)N(Rq3)-、-N(Rq3)C(＝O)、-C(＝O)-，所述的苯基、萘基、苯并C4-6碳环、苯 并4至6元杂环任选被1至4个Rk取代；Q is selected from Phenyl, naphthyl, benzo C 4-6 carbon ring, benzo 4 to 6 membered heterocycle, -O-, -N(R q3 )-, -C(=O)N(R q3 )-, -N(R q3 )C(=O), -C(=O)-, the phenyl, naphthyl, benzo C 4-6 carbon ring, benzo and the 4- to 6-membered heterocyclic ring is optionally substituted by 1 to 4 R k ;
    Rq1、Rq2、Rq3各自独立的选自H、C1-4烷基，所述的烷基任选被1至4个Rk取代；R q1 , R q2 , and R q3 are each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted with 1 to 4 R k ;
    Ra、Rb、Rd各自独立的选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、-C(＝O)NH-C1-6烷基、-C(＝O)NH-C3-6碳环、C3-6碳环、3至7元杂环，所述烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代； Ra , Rb , and Rd are each independently selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl , C2-4 alkenyl, C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -OC3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH- C3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C1-2 alkylene- C3-6 carbocycle, -C1-2 alkylene-3 to 7 membered heterocycle, -C(=O)NH- C1-6 alkyl, -C(=O)NH- C3-6 carbocycle, C3-6 carbocycle , 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 Rk ;
    Rc3各自独立的选自H、NH2、-C(＝O)NH2、甲基、乙基、环丙基、环丁基、环戊基；R c3 is each independently selected from H, NH 2 , -C(=O)NH 2 , methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl;
    Rc4选自H、NH2、卤素、CN、C1-4烷基、C2-4炔基或-NH-5至6元杂芳环，所述的烷基、炔基或杂芳环任选被1至4个Rk取代；R c4 is selected from H, NH 2 , halogen, CN, C 1-4 alkyl, C 2-4 alkynyl or -NH-5 to 6 membered heteroaromatic ring, wherein the alkyl, alkynyl or heteroaromatic ring is optionally substituted with 1 to 4 R k ;
    Rc5选自-NH-C3-6碳环、-NH-3至6元杂环、-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a,所述烷基、亚烷基、烷氧基、环烷基、碳环基、杂环基、杂芳基任选地被1至4个Rk取代；R c5 is selected from -NH-C 3-6 carbocycle, -NH-3 to 6-membered heterocycle, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the alkyl, alkylene, alkoxy, cycloalkyl, carbocyclyl, heterocyclyl, heteroaryl is optionally substituted with 1 to 4 R k ;
    Rc6选自H、卤素、OH、NH2、C1-4烷基、CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-4至6元杂环、-O-C3-6碳环、-O-4至6元杂环、C3-6碳环或4至7元杂环烷环，所述烷基、亚烷基、烯基、炔基、碳环、杂环、杂环烷环任选地被1至4个Rk取代；R c6 is selected from H, halogen, OH, NH 2 , C 1-4 alkyl, CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(＝O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-4 to 6 membered heterocycle, -OC 3-6 carbocycle, -O-4 to 6 membered heterocycle, C 3-6 carbocycle or 4 to 7 membered heterocycloalkane ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle, heterocycle, heterocycloalkane ring is optionally substituted by 1 to 4 R k ;
    当Rc6选自H、卤素、OH、NH2或C1-4烷基时，Rc5选自-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6环烷基-Rc5a、-NH-5至6元杂芳基-4至6元杂环烷基-Rc5a，所述的烷基、杂芳基、亚烷基、环烷基或杂环烷基任选被1至3个Rk取代；When R c6 is selected from H, halogen, OH, NH 2 or C 1-4 alkyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , wherein the alkyl, heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
    当Rc6选自CN、NHC1-4烷基、N(C1-4烷基)2、C2-4烯基、C2-4炔基、-OC1-4烷基、-C(＝O)NH2、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-4至6元杂环、-O-C3-6碳环、-O-4至6元杂环、C3-6环烷基或4至7元杂环烷环时，Rc5选自-NH-C3-6碳环、-NH-5至6元杂芳环，所述烷基、亚烷基、烯基、炔基、烷氧基、碳环、杂环、环烷基或杂环烷基任选地被1至4个Rk取代；When R c6 is selected from CN, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -C(=O)NH 2 , -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-4 to 6-membered heterocycle, -OC 3-6 carbocycle, -O-4 to 6-membered heterocycle, C 3-6 cycloalkyl or 4 to 7-membered heterocycloalkyl ring, R c5 is selected from -NH-C 3-6 carbocycle, -NH-5 to 6-membered heteroaryl ring, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, carbocycle, heterocycle, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 4 R k ;
    R1a、R1b、R1c、R1d各自独立的选自H、氘、卤素、CN、C1-4烷基、C2-4烯基、C2-4炔基、C3-6碳环、3至7元杂环，所述烷基、烯基、炔基、碳环或杂环任选被1至4个Rk取代；R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, halogen, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k ;
    作为选择，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    R1e选自卤素或-OS(＝O)2C1-4烷基，所述烷基任选被1至4个Rk取代；R 1e is selected from halogen or -OS(=O) 2 C 1-4 alkyl, which is optionally substituted with 1 to 4 R k ;
    Rk选自氘、卤素、CN、OH、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C2-4烯基、C2-4炔基、-OC1-4烷基、-SC1-4烷基、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C1-2亚烷基-C3-6碳环、-C1-2亚烷基-3至7元杂环、C3-6碳环、3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。R k is selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -OC 3-6 carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 7 membered heterocycle, -C 1-2 alkylene-C 3-6 carbocycle, -C 1-2 alkylene-3 to 7 membered heterocycle, C 3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中， The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:
    D1选自 D 1 is selected from
    D2选自 苯基、苯并C4-6碳环基、苯并4至6元杂环基、5至6元杂芳基；D 2 is selected from Phenyl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl;
    D3选自 D 3 is selected from
    Q3选自C6-10芳基、5至10元杂芳基，所述Q3任选被1至4个Rk取代；Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said Q3 is optionally substituted by 1 to 4 R k ;
    环B1选自Q3选自C6-10芳基、5至10元杂芳基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Ring B 1 is selected from Q3 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, the ring B 1 is optionally substituted by 1 to 4 R b , and the Q 3 is optionally substituted by 1 to 4 R k ;
    B2选自C4-6碳环，B3选自C4-6碳环； B2 is selected from C4-6 carbocyclic ring, B3 is selected from C4-6 carbocyclic ring;
    或者Q3选自环B1选自苯基、苯并C4-6碳环、苯并4至6元杂环，5至6元杂芳基、8至10元杂芳基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代；Or Q3 is selected from Ring B1 is selected from phenyl, benzo C4-6 carbocycle, benzo 4 to 6-membered heterocycle, 5 to 6-membered heteroaryl, 8 to 10-membered heteroaryl, said ring B1 is optionally substituted by 1 to 4 Rb , said Q3 is optionally substituted by 1 to 4 Rk ;
    n1、n3、n5各自独立的选自0、1或2；n1, n3, n5 are each independently selected from 0, 1 or 2;
    n2、n4各自独立的选自0或1；n2 and n4 are each independently selected from 0 or 1;
    n6自0、1、2或3；n6 is 0, 1, 2 or 3;
    Rq1、Rq2、Rq3各自独立的选自H、甲基、乙基；R q1 , R q2 , and R q3 are each independently selected from H, methyl, and ethyl;
    Rn1选自H、甲基、乙基；R n1 is selected from H, methyl, ethyl;
    Ra、Rb、Rd各自独立的选自氘、F、Cl、Br、I、氰基、OH、NH2、NH(CH3)、N(CH3)2、CF3、甲基、乙基、丙基、异丙基、丁基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基； Ra , Rb , and Rd are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, NH2 , NH( CH3 ), N( CH3 ) 2 , CF3 , methyl, ethyl, propyl, isopropyl, butyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
    Rc1选自H、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基，所述甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个Rk取代；R c1 is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 R k ;
    Rc2各自独立的选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、-O-环丙基、-NH-环丙基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑、-CH2-环丙基、-CH2-环丁基、 -CH2-环戊基、-CH2-环己基、-C(＝O)NH-甲基、-C(＝O)NH-乙基、-C(＝O)NH-环丙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、吡唑、咪唑、噁唑、噻唑，所述的甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、吡唑、咪唑、噁唑、噻唑任选被1至4个Rk取代；R c2 is each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, -C(=O)NH-cyclopropyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole, the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, azetyl, oxetyl, oxetyl, piperazinyl, morpholinyl, pyrazole, imidazole, oxazole, thiazole are optionally substituted by 1 to 4 R k replaces;
    Rc4选自H、NH2、F、Cl、Br、I、CN、甲基、乙基、乙炔基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑，所述的甲基、乙基、乙炔基、吡唑、咪唑、噁唑、噻唑任选被1至4个Rk取代；R c4 is selected from H, NH 2 , F, Cl, Br, I, CN, methyl, ethyl, ethynyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, wherein the methyl, ethyl, ethynyl, pyrazole, imidazole, oxazole, thiazole is optionally substituted by 1 to 4 R k ;
    环B选自 Ring B is selected from
    Rc5选自-NH-C3-6碳环、-NH-吡唑、-NH-吡咯、-NH-咪唑、-NH-三氮唑、-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6碳环基-Rc5a、-NH-5至6元杂芳基-4至6元杂环基-Rc5a,所述的5至6元杂芳基选自吡唑基、吡咯基、咪唑基或三氮唑基，所述亚烷基、碳环基、杂环基、杂芳基、吡唑基、吡咯基、咪唑基或三氮唑基任选地被1至4个Rk取代；R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 carbocyclyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocyclyl-R c5a , wherein the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the alkylene, carbocyclyl, heterocyclyl, heteroaryl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
    Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基、乙基、CN、乙炔基、-CH2-乙炔基、丙炔基、甲氧基、乙氧基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基，所述甲基、乙基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、环丁基或环戊基任选地被1至4个Rk取代；R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl, ethyl, CN, ethynyl, -CH 2 -ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted with 1 to 4 R k ;
    当Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基或乙基时，Rc5选自-NH-5至6元杂芳基-C1-2亚烷基-Rc5a、-NH-5至6元杂芳基-C3-6环烷基-Rc5a、-NH-5至6元杂芳基-4至6元杂环烷基-Rc5a，所述的5至6元杂芳基选自吡唑基、吡咯基、咪唑基或三氮唑基，所述的杂芳基、亚烷基、环烷基或杂环烷基任选被1至3个Rk取代；When R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from -NH-5 to 6-membered heteroaryl-C 1-2 alkylene-R c5a , -NH-5 to 6-membered heteroaryl-C 3-6 cycloalkyl-R c5a , -NH-5 to 6-membered heteroaryl-4 to 6-membered heterocycloalkyl-R c5a , the 5 to 6-membered heteroaryl is selected from pyrazolyl, pyrrolyl, imidazolyl or triazolyl, and the heteroaryl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 R k ;
    Rc5a选自CN或任选取代的如下基团之一：-O-甲基、-O-乙基、-S-甲基、-S-乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-O-环丙基、-O-环丁基、-O-环戊基、-O-环己基、-O-氮杂环丁基、-O-氮杂环戊基、-O-氮杂环己基、-C(＝O)-环丙基、-C(＝O)-环丁基、-C(＝O)-环戊基、-C(＝O)-环己基、-C(＝O)-氮杂环丁基、-C(＝O)-氮杂环戊基、-C(＝O)-氮杂环己基、-C(＝O)-氧杂环丁基、-C(＝O)-氧杂环戊基、-C(＝O)-氧杂环己基，当被取代时，被1至4个选自氘、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、甲氧基或乙氧基的取代基所取代；R c5a is selected from CN or one of the following optionally substituted groups: -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetyl, oxetyl, oxetyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-azetidinyl, -O-azacyclopentyl, -O-azacyclohexyl, -C (═O)-cyclopropyl, —C(═O)-cyclobutyl, —C(═O)-cyclopentyl, —C(═O)-cyclohexyl, —C(═O)-azetidinyl, —C(═O)-azacyclopentyl, —C(═O)-azetidinyl, —C(═O)-azacyclohexyl, —C(═O)-oxetanyl, —C(═O)-oxolanyl, —C(═O)-oxhexyl, when substituted, by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, methoxy or ethoxy;
    当Rc6选自CN、乙炔基、-CH2-乙炔基、丙炔基、甲氧基、乙氧基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基时，Rc5选自-NH-C3-6碳环、-NH-吡唑、-NH-吡咯、-NH-咪唑、-NH-三氮唑，所述的CH2、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、吡唑基、吡咯基、咪唑基或三氮唑基任选地被1至4个Rk取代；When R c6 is selected from CN, ethynyl, -CH 2 -ethynyl, propynyl, methoxy, ethoxy, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, R c5 is selected from -NH-C 3-6 carbocycle, -NH-pyrazole, -NH-pyrrole, -NH-imidazole, -NH-triazole, and the CH 2 , ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl, pyrrolyl, imidazolyl or triazolyl is optionally substituted with 1 to 4 R k ;
    R1a、R1b、R1c、R1d各自独立的选自H、氘、F、Cl、Br、I、CN、甲基、乙基、乙烯基、乙炔基、环丙基、环丁基、环戊基或环己基，所述甲基、乙基、乙烯基、乙炔基、环丙基、环丁基、 环戊基、环己基任选被1至4个Rk取代；R 1a , R 1b , R 1c , and R 1d are each independently selected from H, deuterium, F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, Cyclopentyl and cyclohexyl are optionally substituted by 1 to 4 R k ;
    作为选择，R1b与R1c、R1a与R1b直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R 1b and R 1c , R 1a and R 1b are directly linked to form a C 3-6 carbocyclic ring or a 3- to 7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    作为选择，Rn1与Rd直接连接形成C3-6碳环或3至7元杂环，所述碳环或杂环任选被1至4个Rk取代；Alternatively, R n1 and R d are directly linked to form a C 3-6 carbocyclic ring or a 3 to 7 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k ;
    R1e选自F、Cl、Br、I、-OS(＝O)2CH3、-OS(＝O)2CF3；R 1e is selected from F, Cl, Br, I, -OS(=O) 2 CH 3 , -OS(=O) 2 CF 3 ;
    Rk选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、甲硫基、-O-环丙基、-NH-环丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基任选被1至4个选自卤素、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。R k is selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from halogen, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy.
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein
    Q选自-O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-，所述任选被1至4个Rk取代；Q is selected from -O-, -NH-, -N(CH 3 )-, -C(=O)NH-, -NHC(=O), -C(=O)-, the Optionally substituted with 1 to 4 R k ;
    Q1选自-O-、-NH-、-N(CH3)-、-C(＝O)NH-、-NHC(＝O)、-C(＝O)-、 Q1 is selected from -O-, -NH-, -N( CH3 )-, -C(=O)NH-, -NHC(=O), -C(=O)-,
    选自 Selected from
    选自 Selected from
    D选自-NH-、-N(Rn1)-、或者任选被1至4个Rd取代的如下基团之一： 右侧与R1直接连接；D is selected from -NH-, -N( Rn1 )-, or one of the following groups optionally substituted by 1 to 4 R d : The right side is directly connected to R 1 ;
    D3选自任选被1至4个Rd取代的如下基团之一： D3 is selected from one of the following groups optionally substituted by 1 to 4 Rd :
    R1选自CN、 R1 is selected from CN,
    p1或p2选自0、1或2。p1 or p2 is selected from 0, 1 or 2.
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound according to claim 5 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,
    Ra各自独立的选自氘、F、Cl、Br、氰基、CF3、甲基；Ra is independently selected from deuterium, F, Cl, Br, cyano, CF3 , and methyl;
    Rb各自独立的选自氘、F、Cl、Br、氰基、CF3、甲基；R b is each independently selected from deuterium, F, Cl, Br, cyano, CF 3 , methyl;
    Rd各自独立的选自氘、F、Cl、Br、I、氰基、OH、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基； R d is each independently selected from deuterium, F, Cl, Br, I, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;
    Rc1选自CD3、CF3、甲基、乙基、丙基、异丙基、环丙基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、 R c1 is selected from CD 3 , CF 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl,
    Rc2选自氘、F、Cl、Br、OH、CN、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基、-NH-吡唑、-NH-咪唑、-NH-噁唑、-NH-噻唑、-C(＝O)NH-甲基、-C(＝O)NH-乙基、-C(＝O)NH-环丙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基，所述的甲基、乙基、异丙基、乙烯基、丙烯基、乙炔基、甲氧基、乙氧基、甲硫基、环丙基、环丁基、环戊基、环己基、吡唑、咪唑、噁唑、噻唑、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、哌嗪基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、CN、OH、NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2、N(CH2CH3)2、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基的取代基所取代；R c2 is selected from deuterium, F, Cl, Br, OH, CN, NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl, -NH-pyrazole, -NH-imidazole, -NH-oxazole, -NH-thiazole, -C(═O)NH-methyl, -C(═O)NH-ethyl, -C(═O)NH-cyclopropyl, -NHC(═O)NH- )-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, wherein the methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazole, imidazole, oxazole, thiazole, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 , N ( CH2CH3 ) 2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
    Rc4选自H、NH2、F、CN、甲基、 R c4 is selected from H, NH 2 , F, CN, methyl,
    Rc5选自 R c5 is selected from
    当Rc6选自H、F、Cl、Br、I、OH、NH2、CF3、甲基或乙基时，Rc5选自 When R c6 is selected from H, F, Cl, Br, I, OH, NH 2 , CF 3 , methyl or ethyl, R c5 is selected from
    Rc5a选自CN、-O-甲基、-O-乙基、-S-甲基、-S-乙基、环丙基、 R c5a is selected from CN, -O-methyl, -O-ethyl, -S-methyl, -S-ethyl, cyclopropyl,
    当Rc6选自CN、乙炔基、-CH2-乙炔基、丙炔基、-C(＝O)NH2、-CH2-环丙基、-O-环丙基、环丙基、环丁基或环戊基时，Rc5选自 When R c6 is selected from CN, ethynyl, -CH 2 -ethynyl, propynyl, -C(=O)NH 2 , -CH 2 -cyclopropyl, -O-cyclopropyl, cyclopropyl, cyclobutyl or cyclopentyl, R c5 is selected from
    Q3选自苯基、吡啶基或嘧啶基，所述Q3任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代；Q 3 is selected from phenyl, pyridyl or pyrimidinyl, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
    环B1选自Q3选自苯基、吡啶基或嘧啶基，所述环B1任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代，所述Q3任选被1至4个选自F、Cl、Br、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ring B 1 is selected from Q 3 is selected from phenyl, pyridyl or pyrimidinyl, the ring B 1 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy, and Q 3 is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
    或者Q3选自环B1选自苯基或吡啶基，所述环B1任选被1至4个Rb取代，所述Q3任选被1至4个Rk取代。Or Q3 is selected from Ring B 1 is selected from phenyl or pyridyl, said ring B 1 is optionally substituted by 1 to 4 R b , and said Q 3 is optionally substituted by 1 to 4 R k .
  7. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound according to claim 6 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,
    选自 Selected from
    通式(VI)中-D-选自 In the general formula (VI), -D- is selected from
    环B1选自Q3选自 Ring B 1 is selected from Q 3 Selected
    或者Q3选自环B1选自 Or Q 3 is selected from Ring B 1 is selected from
    通式(VII)中D选自-NH-；In the general formula (VII), D is selected from -NH-;
    通式(VIII)中 General formula (VIII) middle
  8. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表E-1所示结构之一。The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1.
  9. 一种药物组合物，包括权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及要学上可接受的载体，优选地，药物组合物中包含1-1500mg权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  10. 权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与FGFR2活性或表达量相关疾病的药物中的应用。Use of the compound according to any one of claims 1 to 8 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a medicament for treating a disease associated with FGFR2 activity or expression.
  11. 根据权利要求10所述的应用，所述的疾病选自肿瘤。The use according to claim 10, wherein the disease is selected from tumors.
  12. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-8任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选FGFR2活性或表达量相关疾病。 A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a disease related to FGFR2 activity or expression.
PCT/CN2023/133209 2022-11-22 2023-11-22 Pyrimidine derivative and application thereof in medicine WO2024109799A1 (en)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN202211462384.X 2022-11-22
CN202211462384 2022-11-22
CN202310209167 2023-03-07
CN202310209167.8 2023-03-07
CN202310366196.5 2023-04-07
CN202310366196 2023-04-07
CN202310680732 2023-06-09
CN202310680732.9 2023-06-09
CN202311238097.5 2023-09-25
CN202311238097 2023-09-25

Publications (1)

Publication Number Publication Date
WO2024109799A1 true WO2024109799A1 (en) 2024-05-30

Family

ID=91195185

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/133209 WO2024109799A1 (en) 2022-11-22 2023-11-22 Pyrimidine derivative and application thereof in medicine

Country Status (1)

Country Link
WO (1) WO2024109799A1 (en)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109384790A (en) * 2017-08-08 2019-02-26 南京药捷安康生物科技有限公司 Fibroblast growth factor acceptor inhibitor and application thereof
CN113490666A (en) * 2018-12-19 2021-10-08 奥瑞生物药品公司 Substituted pyrazolo [1,5-A ] pyridine compounds as inhibitors of FGFR tyrosine kinases
CN114127051A (en) * 2019-05-17 2022-03-01 金耐特生物制药公司 Inhibitors of fibroblast growth factor receptor kinase
CN114126620A (en) * 2019-05-13 2022-03-01 传达治疗有限公司 FGFR inhibitors and methods of use thereof
WO2022109577A1 (en) * 2020-11-18 2022-05-27 Relay Therapeutics, Inc. Fgfr inhibitors and methods of making and using the same
WO2022109551A1 (en) * 2020-11-17 2022-05-27 Relay Therapeutics, Inc. Src inhibitors and uses thereof
WO2022206939A1 (en) * 2021-04-03 2022-10-06 海南耀臻生物医药科技有限公司 Heterocyclic compound serving as fgfr inhibitor and application thereof
CN115594682A (en) * 2022-10-26 2023-01-13 苏州浦合医药科技有限公司（Cn） FGFR2 inhibitors
WO2023046117A1 (en) * 2021-09-23 2023-03-30 3H Pharmaceuticals Co., Ltd. Fgfr inhibitors and methods of use thereof
WO2023104035A1 (en) * 2021-12-06 2023-06-15 英矽智能科技(上海)有限公司 Substituted monocyclic or bicyclic heterocyclic compound, preparation method therefor and medical use thereof
WO2023192502A1 (en) * 2022-03-31 2023-10-05 Acerand Therapeutics (Usa) Limited Spirobicyclic compounds

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109384790A (en) * 2017-08-08 2019-02-26 南京药捷安康生物科技有限公司 Fibroblast growth factor acceptor inhibitor and application thereof
CN113490666A (en) * 2018-12-19 2021-10-08 奥瑞生物药品公司 Substituted pyrazolo [1,5-A ] pyridine compounds as inhibitors of FGFR tyrosine kinases
CN114126620A (en) * 2019-05-13 2022-03-01 传达治疗有限公司 FGFR inhibitors and methods of use thereof
CN114127051A (en) * 2019-05-17 2022-03-01 金耐特生物制药公司 Inhibitors of fibroblast growth factor receptor kinase
WO2022109551A1 (en) * 2020-11-17 2022-05-27 Relay Therapeutics, Inc. Src inhibitors and uses thereof
WO2022109577A1 (en) * 2020-11-18 2022-05-27 Relay Therapeutics, Inc. Fgfr inhibitors and methods of making and using the same
WO2022206939A1 (en) * 2021-04-03 2022-10-06 海南耀臻生物医药科技有限公司 Heterocyclic compound serving as fgfr inhibitor and application thereof
WO2023046117A1 (en) * 2021-09-23 2023-03-30 3H Pharmaceuticals Co., Ltd. Fgfr inhibitors and methods of use thereof
WO2023104035A1 (en) * 2021-12-06 2023-06-15 英矽智能科技(上海)有限公司 Substituted monocyclic or bicyclic heterocyclic compound, preparation method therefor and medical use thereof
WO2023192502A1 (en) * 2022-03-31 2023-10-05 Acerand Therapeutics (Usa) Limited Spirobicyclic compounds
CN115594682A (en) * 2022-10-26 2023-01-13 苏州浦合医药科技有限公司（Cn） FGFR2 inhibitors

Similar Documents

Publication Publication Date Title
CN105524048B (en) As the indazole compounds of FGFR kinase inhibitor and its preparation and application
WO2023051716A1 (en) Heteroaryl derivative parp inhibitor and use thereof
TWI762769B (en) Peptidylarginine deiminase inhibitor and use thereof
CN115304623A (en) Pyrimido-cyclic derivative and application thereof in medicine
WO2023280237A1 (en) Synthesis and application of phosphatase degrader
WO2023284838A1 (en) Aak1 inhibitor and use thereof
CN106674202A (en) Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate
CN112469720A (en) Dual ATM and DNA-PK inhibitors for use in antitumor therapy
WO2023143424A1 (en) Azacyclic derivative and medical application thereof
TW201917129A (en) Triacyclic derivatives containing pyrazole, their preparation methods and applications thereof
WO2023227052A1 (en) Bicyclic derivative parp inhibitor and use thereof
WO2023030453A1 (en) Compound for degradation of bcl-2 family proteins and medical application thereof
WO2022063212A1 (en) Pyrimidyl derivative, preparation method therefor and use thereof
WO2023066363A1 (en) Parp-1 degradation agent and use thereof
TW202214615A (en) Egfr inhibitor, preparation method therefor and application thereof
WO2024008176A1 (en) Heterocyclic compound capable of inhibiting prmt5•mta and use thereof
WO2023131167A1 (en) Compound for inhibiting and degrading irak4, and pharmaceutical composition and pharmaceutical application thereof
WO2021057796A1 (en) Substituted fused tricyclic derivative, and composition and use thereof
WO2023198180A1 (en) Egfr degradation agent
WO2024109799A1 (en) Pyrimidine derivative and application thereof in medicine
WO2023155866A1 (en) Pyrazolopyridine derivative and application thereof in medicine
WO2022206730A1 (en) Pyrimidopyrazine compound and use thereof
WO2022063050A1 (en) Pyrazole compound and preparation method therefor and use thereof
TW202434592A (en) Pyrimidine derivatives and their applications in medicine
WO2024032600A1 (en) Heterocyclic derivative, and composition thereof and pharmaceutical use thereof

Legal Events

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

Ref document number: 23893887

Country of ref document: EP

Kind code of ref document: A1