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WO2022037560A1 - Pyrimidone derivative and application thereof in drug - Google Patents

Pyrimidone derivative and application thereof in drug Download PDF

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Publication number
WO2022037560A1
WO2022037560A1 PCT/CN2021/112919 CN2021112919W WO2022037560A1 WO 2022037560 A1 WO2022037560 A1 WO 2022037560A1 CN 2021112919 W CN2021112919 W CN 2021112919W WO 2022037560 A1 WO2022037560 A1 WO 2022037560A1
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Prior art keywords
isopropyl
chf
oxo
och
amino
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PCT/CN2021/112919
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French (fr)
Chinese (zh)
Inventor
习宁
吴双
李敏雄
席云龙
廖敏
李晓波
杨芳
陈疏影
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a new class of compounds as KRAS activity inhibitors, a method for preparing them, a pharmaceutical composition comprising the compound, and the application of the compound and the pharmaceutical composition in the treatment of various diseases . More specifically, the compounds described in the present invention can act as inhibitors of the activity or function of KRAS G12C.
  • KRAS is a murine sarcoma virus gene.
  • K-ras is also known as p21 gene because it encodes a 21kD ras protein.
  • K-Ras has the greatest impact on human cancers, accounting for 86% of all RAS mutations. It acts like a molecular switch: when normal, it controls the pathway that regulates cell growth; when abnormal, it causes the cell to continue growing and Stop cells from self-destruction. It is involved in intracellular signal transmission.
  • the K-ras gene is mutated, the gene is permanently activated and normal ras protein cannot be produced, resulting in disordered intracellular signal transduction, uncontrolled cell proliferation and canceration.
  • KRAS G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine No. 12 to cysteine.
  • KRAS G12C mutation is the most common in lung cancer. According to the data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which acts as an inhibitor of KRAS.
  • the present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease and/or disorder by inhibiting the activity of KRAS by the compound.
  • the present invention further describes the synthesis of said compounds.
  • the compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • Z is N or CR 2e ;
  • R a and R b are each independently hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups;
  • R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, 5-6-membered heteroaryl, C 3-6 carbocyclic or 3-6-membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C1 -3 alkyl, C 1-3 haloalkyl, C 1-3
  • R 3 is C 6-12 aryl or 5-10-membered heteroaryl, wherein the C 6-12 aryl and 5-10-membered heteroaryl are independently optionally substituted by n R y ;
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 1-3 hydroxyalkoxy;
  • R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally selected from 1, 2, 3, 4 or 5 independently selected from Deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1 -3 hydroxyalkoxy groups are substituted;
  • R 2a , R 2b , R 2c , R 2d and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1- 3 alkoxy, C 1-3 haloalkoxy and
  • Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy Amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C
  • Each R y is independently deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms; C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, 3 -Heterocyclic groups consisting of 8 atoms, C 6-10 aryl groups and heteroaryl groups consisting of 5-10 atoms are independently optionally selected from 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen atoms , hydroxy, oxo, amino, nitro, cyano, C
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6 or 7;
  • p 0, 1, 2, 3, 4 or 5.
  • R and R are each independently hydrogen, deuterium , halogen, methyl, ethyl, n -propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, Ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl , difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups;
  • R c is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, - CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclo Butenyl, cyclopentenyl, cyclo
  • R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independently optionally separated by n R y replaced.
  • R is Among them, the said independently optionally substituted with n R ys .
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoro Methyl, difluoromethyl, methoxy, ethoxy, isopropoxy , trifluoromethoxy, -OCH2OH or -OCH2CH2OH .
  • R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne group, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxygen substituted, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups replaced by the group.
  • R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propylene group, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy , n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl
  • R 2a , R 2b , R 2c , R 2d , and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the Said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalk
  • R 2a , R 2b , R 2c , R 2d , and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl radical, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino;
  • each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocycle wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkane group and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 substituted by groups of alkyl, C 1-3 haloalkyl, C 1-3
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, alkene Propyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy , ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino , dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cycl
  • each R is independently deuterium , halogen, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 cycloalkyl, 3-6 atoms heterocyclyl, C 6-10 aryl or 5-6 atoms heterocycle Aryl; wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3- 6 -cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 aryl and heteroaryl of 5-6 atoms are independently optionally separated by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C
  • each R is independently deuterium , halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, Difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl , furanyl or triazolyl; wherein, the methyl, ethyl,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula (I) of the present invention, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compounds, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.
  • the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention, treatment or alleviation of a KRAS G12C mediated disease in a patient.
  • the KRAS G12C-mediated disease of the invention is cancer.
  • the cancer of the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma.
  • the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
  • the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless stated otherwise or otherwise clearly contradicted by context.
  • these articles refer to one or more than one (ie, at least one) object of the article.
  • a component refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
  • Chiral is a molecule that has the property of being non-superimposable with its mirror image; while “achiral” refers to a molecule that is superimposable with its mirror image.
  • Enantiomer refers to two nonsuperimposable, but mirror-image isomers of a compound.
  • Diastereomer refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
  • any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms) ) in the form of.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.
  • any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents.
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier.
  • a chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
  • substituents such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
  • optionally substituted by is used interchangeably with the term “unsubstituted or substituted by”, ie the structure is unsubstituted or substituted by one or more of the present invention group substitution; when the number of the substituents is greater than 1, the substituents may be the same or different from each other. For example, “optionally substituted by 1, 2, 3, 4 or 5 groups selected from " described in the present invention, when the number of the substituents is greater than 1, the substituents may
  • an optional substituent group may be substituted at each substitutable position of the group.
  • the substituents may be substituted at each position identically or differently.
  • the substituents described therein can be, but are not limited to, deuterium, oxo, halogen, cyano, nitro, hydroxyl, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkyne alkyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy, haloalkoxy, aryl Oxy, heteroaryloxy, alkylacyloxy, carboxyl, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkane Oxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, al
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 -4 carbon atoms; also in some embodiments, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the “cis” and “trans” positions, or the “E” and “Z” positions.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (propynyl, -C ⁇ C-CH) 3 ) and so on.
  • alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1 -pentyloxy (n - pentyloxy, -OCH2CH2CH2CH2CH2
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups, examples of which include, but are not limited to, -OCH2OH , -OCH2CH2OH , and the like.
  • Carbocyclyl or “carbocycle” refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms.
  • Carbobicyclyl groups include spirocarbobicyclyl, fused carbobicyclyl, and bridged carbobicyclyl groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • carbocyclyl groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloalkyl refers to a monovalent or polyvalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.
  • heterocycle refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3 to 14 ring atoms, wherein One or more atoms on the ring are independently replaced by a heteroatom having the meaning as defined in the present invention, the ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring may be not allowed.
  • a “heterocycle”, “heterocyclyl” or “heterocyclic” group is a 3-8 membered monocyclic ring (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms, where S or P are optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) , or a 7-12 membered bicyclic ring ( 4 - 9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to give like SO, SO 2 , PO, PO 2 groups).
  • a “heterocycle”, “heterocyclyl” or “heterocyclic” group is a 3-6 membered monocyclic ring (2-4 carbon atoms and selected from N, O, P, 1-3 heteroatoms of S, where S or P are optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) .
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Amyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperi
  • oxidized sulfur atoms in a heterocyclyl group include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic A family of rings in which each ring system contains a ring of 3-7 atoms with one or more points of attachment to the rest of the molecule.
  • aryl is used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl or “heteroaromatic ring” means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms A system in which at least one ring is aromatic and at least one ring contains one or more heteroatoms.
  • a heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl groups of 5-10 ring atoms contain 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, 5-6 rings Atomic heteroaryl is a monocyclic ring system and contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • jk ring atoms consisting of jk ring atoms or “jk-membered” are used interchangeably herein to mean that the cyclic group consists of jk ring atoms including carbon atoms and/or O, Hetero atoms such as N, S, P, etc.
  • the j and k are each independently any non-zero natural number, and k>j; the "j-k” includes j, k and any natural number in between.
  • 3-8 atoms or 3-8 elements means that the cyclic group consists of 3-8 (ie, 3, 4, 5, 6, 7 or 8), 3-6 (ie, 3, 4, 5 or 6), 5-10 (ie, 5, 6, 7, 8, 9 or 10) or 5-6 (ie, 5 or 6) ring atoms including carbon atoms and/or O , N, S, P and other heteroatoms.
  • heteroaryl of 5-10 ring atoms or “heteroaryl of 5-10 members” means that it includes a heteroaryl group of 5, 6, 7, 8, 9, or 10 ring atoms wherein 5, 6, 7, 8, 9 or 10 represent the number of ring atoms, eg pyridyl is a heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.
  • heteroatom refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring.
  • Hydrogen substituted form for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).
  • halogen or "halogen atom” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino” wherein the amino group is independently substituted with one or two alkyl groups, respectively.
  • the alkylamino group is an alkylamino group formed by one or two C1-6 alkyl groups attached to a nitrogen atom.
  • the alkylamino group is an amino group substituted with one or two C1-3 alkyl groups.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.
  • the substituent (R 4 ) p is attached to the central ring by a bond to form a ring system representing p substituents R 4 can be carried out at any substitutable position or any reasonable position on the ring in which they are located. replace.
  • Formula d represents that the G ring may be substituted with p R4s , and when p is greater than 1 , each R4 may be independently selected from the same or different substituent groups.
  • An attachment point can be attached to the rest of the molecule at any linkable position on the loop as described herein.
  • formula e represents that any position on the C-ring or the D-ring that may be attached can serve as a point of attachment.
  • protecting group refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups.
  • a “protecting group for an amino group” refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group
  • suitable protecting groups include acetyl and silyl.
  • Carboxyl protecting group means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like.
  • protecting groups reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like.
  • pharmaceutically acceptable as used herein means approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • prodrug refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters.
  • a compound that contains a hydroxyl group can be acylated to give the compound in prodrug form.
  • prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • phosphates such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • a complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51, 2328-2345.
  • Metal refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as Acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or obtain these salts by other methods described in books such as ion exchange.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of Groups I to XII of the periodic table, and organic base salts, such as those formed with primary, secondary, and tertiary amines. Salt.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association in which the solvent molecule is water.
  • any disease or disorder in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, “treating” refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect the treatment of such disease.
  • a “therapeutically effective amount” can vary depending on the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods.
  • such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a suitable base eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K
  • Such reactions are usually carried out in water or an organic solvent or a mixture of the two.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds disclosed herein, including their salts can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization.
  • a solvent eg, ethanol, DMSO, etc.
  • Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.
  • Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 15N , 17O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • Isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or as described in the Examples and Preparations of this invention, using a suitable isotopically labeled reagent in place of the previously used unlabeled reagent.
  • cancer refers to or describes a physiological condition in a patient that is often characterized by uncontrolled cell growth.
  • a “tumor” includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies.
  • cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), esophageal cancer, Peritoneal cancer, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, Liver cancer, anal cancer, penile cancer and head and neck cancer.
  • squamous cell carcinoma eg, epithelial squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinom
  • KRAS G12C inhibitor used in the present invention refers to a substance that can bind to KRAS G12C and inhibit its activity.
  • the present invention provides a compound or a pharmaceutical composition thereof, which can be used as a KRAS G12C inhibitor.
  • the present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease and/or disorder by inhibiting the activity of KRAS G12C with the compound.
  • the present invention further describes methods of synthesizing the compounds.
  • the compounds of the present invention exhibit improved biological activity and pharmacokinetic properties.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each of m, p, Z, R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , R 5 and R x has the meaning described in the present invention.
  • Z is N or CR 2e ; wherein R 2e has the meaning described herein.
  • R a is hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
  • Ra is hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropyl Propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted by 1, 2, 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.
  • R b is hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
  • R is hydrogen, deuterium , halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropyl Propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted by 1, 2, 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.
  • R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclic or 3-6 membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl group, C 3-6 carbocyclyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy
  • Rc is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2 , -CF3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, methylamino
  • R 3 is C 6-12 aryl or 5-10 membered heteroaryl, wherein said C 6-12 aryl and 5-10 membered heteroaryl are independently optionally separated by n R y is substituted; wherein n and R y have the meanings described in the present invention.
  • R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independently optionally surrounded by n R y is substituted; wherein, n and R y have the meanings described in the present invention.
  • R3 is Among them, the said independently optionally substituted with n R y ; wherein n and R y have the meanings described herein.
  • R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1 -3 alkoxy, C 1-3 haloalkoxy or C 1-3 hydroxyalkoxy.
  • R4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tris Fluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy , trifluoromethoxy, -OCH2OH or -OCH2CH2OH .
  • R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.
  • R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl,
  • R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.
  • R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.
  • R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.
  • R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.
  • R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.
  • R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • Rx is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 Alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; wherein , said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1 -6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino , nitro, cyano, C 1-3 alkyl,
  • R x is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; Wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl , C 1-3 haloalkyl, C 1-3 alkoxy,
  • Rx is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl , propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethyl Oxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, di- methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopen
  • R y is deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, 3-8 atoms heterocyclic group, C 6-10 aryl group or 5-10 atom heteroaryl group;
  • R y is deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1- 4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 cycloalkyl, 3-6 atoms heterocyclyl, C 6-10 aryl or 5-6 atoms heteroaryl ;
  • the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 ring Alkyl, heterocyclyl of 3-6 atoms, C 6-10 aryl, and heteroaryl of 5-6 atoms are independently optionally selected from 1, 2, 3, 4 or 5 independently Deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alk
  • R y is deuterium, halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoro Methyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Heterocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furan or triazolyl; wherein, the methyl, ethyl,
  • the present invention relates to one of the following compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, hydrates, metabolites, Esters, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to:
  • the present invention relates to pharmaceutical compositions comprising stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites of the aforementioned compounds Products, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or any combination thereof.
  • the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the manufacture of a medicament for preventing, treating or alleviating a KRAS G12C mediated disease in a patient.
  • the KRAS G12C mediated disease is cancer.
  • the cancer of the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma.
  • the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
  • the pharmaceutical composition of the present invention features a compound represented by formula (I), a compound listed in the present invention, or a compound of the examples, and a pharmaceutically acceptable carrier.
  • the amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate a KRAS G12C mediated disease in a patient.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form.
  • a pharmaceutically acceptable carrier including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, sorbitan Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants such as
  • the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (referred to herein as a pharmaceutical formulation) selected according to the form of administration and conventional pharmaceutical practice, which may be oral tablets, capsules , elixirs, syrups, etc.
  • a suitable pharmaceutical diluent, excipient, or carrier referred to herein as a pharmaceutical formulation
  • conventional pharmaceutical practice which may be oral tablets, capsules , elixirs, syrups, etc.
  • the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert filler such as lactose, starch, sucrose, glucose, methylcellulose , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical component may be wetted with any oral, non-toxic, pharmaceutically acceptable inert Agent combination, such as ethanol, glycerol, water, etc.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene Ethylene Glycol, Wax, etc.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of this invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms well known to those of ordinary skill in the art of pharmacy. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the chosen mode of administration and standard pharmaceutical practice.
  • oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms well known to those of ordinary skill in the art
  • the compounds of the present invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or transdermally via the use of transdermal patches.
  • a suitable intranasal vehicle or transdermally via the use of transdermal patches.
  • the dose administered is continuous rather than intermittent throughout the period of administration.
  • the compounds of the present invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
  • the compounds of the present invention are also conjugated to soluble polymers that serve as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate amine-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues amino acid.
  • the compounds of the present invention can be coupled with a class of biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly ⁇ caprolactone Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.
  • biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly ⁇ caprolactone Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.
  • Dosage regimens for compounds of the present invention will vary with known factors such as the pharmacokinetic profile of the particular agent and its mode of administration and route of administration; the race, age, sex, health, medical condition and weight of the recipient; Nature and extent of symptoms; type of concurrent therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effect.
  • a physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, offset, or stop the development of cancer.
  • the daily oral dose of each active ingredient employed is in the range of between about 0.001 to 1000 mg/kg of body weight.
  • the most preferred dosage range is from about 1 to about 10 mg/kg body weight/minute during conventional rate infusion.
  • the compounds of the present invention may be administered once a day, or may be administered in two, three or four times a day.
  • Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient.
  • the weight of the active ingredient will generally be about 0.5-95% by weight of the total weight of the pharmaceutical composition.
  • a compound of the present invention When a compound of the present invention is administered with other therapeutic agents, generally, the amounts of each component in a typical daily dose and in a typical dosage form, relative to the additive or synergistic effects of the therapeutic agents when administered in combination, are The usual dose when administered alone may be reduced.
  • the compounds involved in the present invention or their pharmaceutically acceptable salts or their hydrates can be effectively used for preventing, treating or alleviating diseases mediated by KRAS G12C in patients, in particular, they can effectively treat lung cancer, lymphoma, esophageal cancer, ovarian cancer and pancreatic cancer. , rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma, etc.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined herein.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 ⁇ m, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5 %-95% ( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
  • ESI electrospray ionization
  • the compound represented by formula ( 17 ) can be prepared by reaction scheme 1: the compound represented by formula ( 1 ) reacts with oxalyl chloride and ammonia water to obtain the compound represented by formula ( 2 ).
  • the compound represented by the formula ( 2 ), the compound represented by the formula ( 3 ) and the compound represented by the formula ( 4 ) are reacted to obtain the compound represented by the formula ( 5 ).
  • the compound represented by the formula ( 5 ) is reacted under the action of potassium bis(trimethylsilyl)amide to obtain the compound represented by the formula ( 6 ).
  • the compound represented by the formula ( 6 ) is reacted under the action of phosphorus oxychloride to obtain the compound represented by the formula ( 7 ).
  • the compound represented by the formula ( 7 ) and the compound represented by the formula ( 8 ) are reacted under the action of N,N-diisopropylethylamine to obtain the compound represented by the formula ( 9 ).
  • the compound represented by the formula ( 9 ) and the compound represented by the formula ( 10 ) react under the action of potassium acetate to obtain the compound represented by the formula ( 11 ); then, the compound represented by the formula ( 11 ) and the compound represented by the formula ( 12 )
  • the compound can react under the action of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex and cesium carbonate to obtain the compound represented by formula ( 14 ); or, formula
  • the compound represented by ( 11 ) and the compound represented by formula ( 13 ) are in chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[ Under the action of
  • the compound represented by the formula ( 14 ) is de-Boc removed under the action of trifluoroacetic acid to obtain the compound represented by the formula ( 15 ).
  • the compound represented by the formula ( 15 ) and the compound represented by the formula ( 16 ) can react under the action of N,N-diisopropylethylamine to obtain the compound represented by the formula ( 17 ).
  • the first step is the synthesis of 2,5,6-trichloropyridine-3-carboxamide
  • 2,5,6-Trichloropyridine-3-carboxylic acid (5.00g, 22.0mmol), dichloromethane (60.0mL) and N,N-dimethylformamide (0.05mL, 0.6mmol) were added to the reaction flask , cooled to 0 °C, and oxalyl chloride (2.4 mL, 28 mmol) was added dropwise. After dropping, stirring was carried out for 24h. An isopropanol solution of ammonia (17.0 mL, 34 mmol, 2.0 mol/L) was added, and stirring was continued for 4 h, and a large amount of white solid was precipitated. Suction filtration, the filter residue was washed with dichloromethane (50 mL ⁇ 2), and dried to obtain the title compound as a white solid (1.6 g, 32.0%).
  • the second step is the synthesis of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide
  • the fourth step is the synthesis of 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the ninth step 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-6-hydroxybenzene)-1-(2 Synthesis of -isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the fourth step 4-(4-acryloylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methyl) Synthesis of oxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the first step is the synthesis of 5-bromo-1,3-lutidine-2(1H)-one
  • Example A CTG method to detect the inhibitory activity of compounds on H358 (KRAS G12C) cell proliferation
  • the cells were cultured in a suitable medium and placed in a 37°C, 5% carbon dioxide incubator. The cells were observed with an inverted microscope once a day, and the culture medium was changed every 2-4 days. The cells were collected and centrifuged at 1200 rpm for 5 min, the supernatant was discarded, and the cells were transferred to a new sterile culture dish at a ratio of 1:3-1:8.
  • Cells in exponential growth phase were collected and counted with a cell counter. Resuspend the cells in the appropriate medium and adjust to the appropriate concentration. Add 90 ⁇ L of cell suspension to each well in a 96-well cell culture plate. Incubate overnight in a 37°C, 5% carbon dioxide incubator.
  • Preparation of stock solution Dissolve the test compound with DMSO to prepare a 10 mM stock solution.
  • the compound was diluted 3 times with DMSO to obtain 9 concentration gradient compounds.
  • the above gradient diluted compounds were diluted 20 times with complete medium, and mixed evenly to obtain a 10 ⁇ concentration drug working solution.
  • Growth inhibition rate % (V negative group- V experimental group )/(V negative group- V blank group ) ⁇ 100%, where V negative group is the average value of solvent control group, V experimental group is the reading of drug treatment group, The V blank group is the reading of the cell-free and drug-free group. Data were analyzed using GraphPad Prism 5.0 software and counted to obtain IC50 values. The results are shown in Table 1, and Table 1 is the results of the experiments of inhibiting the proliferation of H358 cells by the compounds provided in the examples of the present invention.
  • the experimental results show that in the test of inhibitory activity on H358 cell proliferation, the compound of the present invention has a strong inhibitory activity on H358 cell proliferation, and the activity is better than that of the positive control substance ARS1620.
  • Example B LC-MS method to detect the binding of compounds to KRAS G12C protein
  • the KRAS G12C protein stock solution (11.13 mg/mL, 550 ⁇ M) was diluted 5-fold to 110 ⁇ M with low Mg 2+ buffer. Take 1 mL of 110 ⁇ M KRAS G12C protein and add 1 mL of 2 ⁇ GDP loading buffer, mix gently, incubate at room temperature for 1.5 h, divide into 40 ⁇ L/tube, quickly freeze and store in -80 °C refrigerator.
  • the GDP-loaded KRAS G12C was diluted to 20 ⁇ M with 10 ⁇ incubation buffer and the reagents were mixed as shown in Table C below.
  • each reagent can be changed in a certain proportion as needed.
  • the incubation solution was mixed and transferred to the injection vial for LC-MS analysis and detection.
  • the analysis conditions are as follows:
  • KRAS G12C binding rate % complex peak area / (complex peak area + peak area not bound to KRAS G12C) ⁇ 100
  • Table 2 is the experimental result that the compound provided in the embodiment of the present invention binds to the KRAS G12C protein for 1 h.
  • the experimental results show that the compound of the present invention has a high binding rate to KRAS-4B-G12C protein.
  • 18-22g male ICR mice were taken and randomly divided into two groups.
  • One group was intravenously injected with the test compound at a dose of 2.0 mg/kg, and the other group was orally administered the test compound at a dose of 5 mg/kg;
  • Tail vein blood was collected at time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours; tail vein at time points 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration Blood collection.
  • the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters.

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Abstract

A pyrimidone derivative and an application thereof in a drug, in particular, relating to a novel pyrimidone derivative and a pharmaceutical composition containing the compound. The present invention also relates to a method for preparing the compound and the pharmaceutical composition, and use in preparation of a drug for treating KRAS G12C-mediated disease and/or disorder, in particular to use in preparation of a drug for treating cancer.

Description

嘧啶酮衍生物及其在药物中的应用Pyrimidone derivatives and their application in medicine 发明领域Field of Invention

本发明属于药物领域，具体涉及一类作为KRAS活性抑制剂的新化合物、制备它们的方法、包含所述化合物的药物组合物以及所述化合物及其药物组合物在治疗多种不同疾病中的应用。更具体地说，本发明所述的化合物可以作为KRAS G12C的活性或功能的抑制剂。The invention belongs to the field of medicine, and specifically relates to a new class of compounds as KRAS activity inhibitors, a method for preparing them, a pharmaceutical composition comprising the compound, and the application of the compound and the pharmaceutical composition in the treatment of various diseases . More specifically, the compounds described in the present invention can act as inhibitors of the activity or function of KRAS G12C.

背景技术Background technique

KRAS是一种鼠类肉瘤病毒基因，ras基因家族与人类肿瘤相关的基因有三种——H-ras、K-ras和N-ras，分别定位在11、12和1号染色体上。K-ras因编码21kD的ras蛋白又名p21基因。在ras基因中，K-Ras对人类癌症影响最大，占所有RAS突变中的86％，它好像分子开关：当正常时能控制调控细胞生长的路径；发生异常时，则导致细胞持续生长，并阻止细胞自我毁灭。它参与细胞内的信号传递，当K-ras基因突变时，该基因永久活化，不能产生正常的ras蛋白，使细胞内信号传导紊乱，细胞增殖失控而癌变。KRAS is a murine sarcoma virus gene. There are three genes in the ras gene family associated with human tumors—H-ras, K-ras, and N-ras, which are located on chromosomes 11, 12, and 1, respectively. K-ras is also known as p21 gene because it encodes a 21kD ras protein. Of the ras genes, K-Ras has the greatest impact on human cancers, accounting for 86% of all RAS mutations. It acts like a molecular switch: when normal, it controls the pathway that regulates cell growth; when abnormal, it causes the cell to continue growing and Stop cells from self-destruction. It is involved in intracellular signal transmission. When the K-ras gene is mutated, the gene is permanently activated and normal ras protein cannot be produced, resulting in disordered intracellular signal transduction, uncontrolled cell proliferation and canceration.

G12C突变是KRAS基因突变中比较常见的一个亚型，它是指12号甘氨酸突变为半胱氨酸。KRAS G12C突变在肺癌中最为常见，根据文献(Nat Rev Drug Discov 2014；13:828-851)报道数据可知，KRAS G12C突变占所有肺癌患者的10％左右。G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine No. 12 to cysteine. KRAS G12C mutation is the most common in lung cancer. According to the data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients.

目前，科研工作者已经开展了一些研究以期找到能够有效抑制KRAS G12C突变蛋白的治疗药剂。PCT申请WO2014152588、WO2015054572、WO2016049524、WO2016164675、WO2016168540、WO2017015562、WO2017058915、WO2017058807、WO2017058792、WO2017058902、WO2017087528、WO2017201161、WO2018064510、WO2018068017、WO2018119183、WO2018140600、WO2018140512、WO2018143315、WO2018206539、WO2018217651、WO2018218070、WO2019051291、WO2019099524、WO2019110751、WO2019137985和WO2019141250披露了诸多小分子化合物，其作为KRAS G12C突变蛋白抑制剂用于预防或治疗癌症。然而，临床仍然亟需更多更好的KRAS G12C突变蛋白抑制剂。At present, researchers have carried out some studies to find therapeutic agents that can effectively inhibit the KRAS G12C mutant protein. PCT Application WO2014152588, WO2015054572, WO2016049524, WO2016164675, WO2016168540, WO2017015562, WO2017058915, WO2017058807, WO2017058792, WO2017058902, WO2017087528, WO2017201161, WO2018064510, WO2018068017, WO2018119183, WO2018140600, WO2018140512, WO2018143315, WO2018206539, WO2018217651, WO2018218070, WO2019051291, WO2019099524, WO2019110751, WO2019137985 and WO2019141250 disclose a number of small molecule compounds as KRAS G12C mutein inhibitors for the prevention or treatment of cancer. However, there is still an urgent need for more and better KRAS G12C mutant protein inhibitors.

发明内容SUMMARY OF THE INVENTION

本发明提供一种化合物，或其药物组合物，其可作为KRAS的抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过所述化合物抑制KRAS活性来治疗疾病和/或病症。本发明又进一步描述了所述化合物的合成方法。本发明的化合物显示出优良的生物活性及药代动力学性质。The present invention provides a compound, or a pharmaceutical composition thereof, which acts as an inhibitor of KRAS. The present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease and/or disorder by inhibiting the activity of KRAS by the compound. The present invention further describes the synthesis of said compounds. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

具体地说：Specifically:

一方面，本发明涉及一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Figure PCTCN2021112919-appb-000001
Figure PCTCN2021112919-appb-000001

其中：in:

Z为N或CR 2e； Z is N or CR 2e ;

R 1为-C(＝O)-CR a＝CR b-R c、-C(＝O)-C≡C-R c、-S(＝O) 2-CR a＝CR b-R c或-S(＝O) 2-C≡C-R c； R 1 is -C(=O)-CR a =CR b -R c , -C(=O)-C≡CR c , -S(=O) 2 -CR a =CR b -R c or -S (=O) 2 -C≡CR c ;

R a和R b各自独立地为氢、氘、卤原子、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基，其中，所述的C 1-3烷基、C 1-3卤代烷基和C 1-3烷氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； R a and R b are each independently hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups;

R c为氢、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、5-6元杂芳基、C 3-6碳环基或3-6元杂环基，其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、5-6元杂芳基、C 3-6碳环基和3-6元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟基烷氧基和3-6元杂环基的基团所取代； R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, 5-6-membered heteroaryl, C 3-6 carbocyclic or 3-6-membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C1 -3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkoxy and 3-6 membered heterocyclic groups;

R 3为C 6-12芳基或5-10元杂芳基，其中，所述的C 6-12芳基和5-10元杂芳基独立任选地被n个R y取代； R 3 is C 6-12 aryl or 5-10-membered heteroaryl, wherein the C 6-12 aryl and 5-10-membered heteroaryl are independently optionally substituted by n R y ;

R 4为氢、氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-3羟基烷氧基； R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 1-3 hydroxyalkoxy;

R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally selected from 1, 2, 3, 4 or 5 independently selected from Deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1 -3 hydroxyalkoxy groups are substituted;

R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； R 2a , R 2b , R 2c , R 2d and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1- 3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups;

各R x独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基和3-8元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy Amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups;

各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟基烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中，所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟基烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； Each R y is independently deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms; C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, 3 -Heterocyclic groups consisting of 8 atoms, C 6-10 aryl groups and heteroaryl groups consisting of 5-10 atoms are independently optionally selected from 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen atoms , hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy substituted with an oxy group;

m为0、1、2、3、4、5、6、7或8；m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

n为1、2、3、4、5、6或7；n is 1, 2, 3, 4, 5, 6 or 7;

p为0、1、2、3、4或5。p is 0, 1, 2, 3, 4 or 5.

在一些实施方案中，R a和R b各自独立地为氢、氘、卤原子、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基，其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰 基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代； In some embodiments, R and R are each independently hydrogen, deuterium , halogen, methyl, ethyl, n -propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, Ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl , difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups;

R c为氢、氘、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、-OCH 2OH、-OCH 2CH 2OH、异丙氧基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基的基团所取代。 R c is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, - CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclo Butenyl, cyclopentenyl, cyclohexenyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, tris Azazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; wherein the methyl, ethyl, n-propyl , isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methyl Oxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, di- methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidine, pyrrolidinyl, Tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl , pyrimidinyl, pyrazinyl and pyridazinyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl , ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, isopropyl oxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups .

在一些实施方案中，R 3为C 6-10芳基或5-10元杂芳基，其中，所述的C 6-10芳基和5-10元杂芳基独立任选地被n个R y取代。 In some embodiments, R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independently optionally separated by n R y replaced.

在一些实施方案中，R 3为

Figure PCTCN2021112919-appb-000002
Figure PCTCN2021112919-appb-000003
Figure PCTCN2021112919-appb-000004
其中，所述的
Figure PCTCN2021112919-appb-000005
Figure PCTCN2021112919-appb-000006
Figure PCTCN2021112919-appb-000007
独立任选地被n个R y取代。 In some embodiments, R is
Figure PCTCN2021112919-appb-000002
Figure PCTCN2021112919-appb-000003
Figure PCTCN2021112919-appb-000004
Among them, the said
Figure PCTCN2021112919-appb-000005
Figure PCTCN2021112919-appb-000006
Figure PCTCN2021112919-appb-000007
independently optionally substituted with n R ys .

在一些实施方案中，R 4为氢、氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、 正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH或-OCH 2CH 2OH。 In some embodiments, R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoro Methyl, difluoromethyl, methoxy, ethoxy, isopropoxy , trifluoromethoxy, -OCH2OH or -OCH2CH2OH .

在一些实施方案中，R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne group, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxygen substituted, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups replaced by the group.

在一些实施方案中，R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In some embodiments, R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propylene group, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy , n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxygen Substitute, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl oxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

在一些实施方案中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 2a , R 2b , R 2c , R 2d , and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the Said C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.

在一些实施方案中，R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In some embodiments, R 2a , R 2b , R 2c , R 2d , and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl radical, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propyl Alkynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy group, -OCHF2 , -OCHFCH2F , -OCF2CHF2 , -OCH2CF3 , -OCH2CF2CHF2 , methylamino , dimethylamino and ethylamino independently optionally replaced by 1 , 2 , 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

在一些实施方案中，各R x独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基或3-6元杂环基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基和3-6元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocycle wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkane group and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 substituted by groups of alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.

在一些实施方案中，各R x独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、 甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In some embodiments, each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, alkene Propyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy , ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino , dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidine wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine , oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally selected from 1, 2, 3, 4 or 5 independently selected from Deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, substituted with groups of isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.

在一些实施方案中，各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟基烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟基烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, each R is independently deuterium , halogen, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 cycloalkyl, 3-6 atoms heterocyclyl, C 6-10 aryl or 5-6 atoms heterocycle Aryl; wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3- 6 -cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 aryl and heteroaryl of 5-6 atoms are independently optionally separated by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.

在一些实施方案中，各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH、-OCH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三唑基；其中，所述的甲基、乙基、正丙基、异丙基、叔丁基、二氟甲基、甲氧基、乙氧基、异丙氧基、-OCH 2OH、-OCH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三唑基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In some embodiments, each R is independently deuterium , halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, Difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl , furanyl or triazolyl; wherein, the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, - OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl , phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl or triazolyl independently optionally selected by 1, 2, 3, 4 or 5 independently From deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy , isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)所示的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的组合。In one aspect, the present invention relates to a pharmaceutical composition comprising the compound represented by formula (I) of the present invention, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compounds, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.

一方面，本发明涉及前面所述的化合物或其药物组合物在制备用于预防、治疗或减轻患者KRAS G12C介导的疾病的药物中的用途。In one aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention, treatment or alleviation of a KRAS G12C mediated disease in a patient.

其中一些实施方案是，本发明所述的KRAS G12C介导的疾病为癌症。In some embodiments, the KRAS G12C-mediated disease of the invention is cancer.

其中一些实施方案是，本发明所述的癌症为肺癌、淋巴瘤、食道癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、白血病和黑色素瘤。In some embodiments, the cancer of the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma.

另一方面，本发明涉及式(I)所示的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).

前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below.

本发明的详细说明书Detailed Description of the Invention

定义和一般术语Definitions and General Terms

现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以 在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It will further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions as used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , the entire contents of which are incorporated herein by reference.

除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to one or more than one (ie, at least one) object of the article. For example, "a component" refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.

本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .

“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。"Chiral" is a molecule that has the property of being non-superimposable with its mirror image; while "achiral" refers to a molecule that is superimposable with its mirror image.

“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"Diastereomer" refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and methods, the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms) ) in the form of. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.

可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。 Any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其它不出现的情况。例如，“任选的键”是指该键可以存在或可以不存在，并且该描述包括单键、双键或三键。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and other instances where it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.

术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。术语“任选地被…….所取代”，可以与术语“未取代或被…..所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代；当所述取代基个数大于1时，所述的取代基相互之间可以是相同或不同的。例如，本发明所述的“任选地被1、2、3、4或5个选自……的基团所取代”，当所述取代基的个数大于1时，所述取代基可以是相同或者不同的。The term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. The term "optionally substituted by" is used interchangeably with the term "unsubstituted or substituted by", ie the structure is unsubstituted or substituted by one or more of the present invention group substitution; when the number of the substituents is greater than 1, the substituents may be the same or different from each other. For example, "optionally substituted by 1, 2, 3, 4 or 5 groups selected from ..." described in the present invention, when the number of the substituents is greater than 1, the substituents may be be the same or different.

除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘、氧代、卤素、氰基、硝基、羟基、巯基、氨基、烷氨基、芳氨基、氨基烷基、烷基、烯基、炔基、烷基硫基、羟基烷基、卤代烷基、环烷基、杂环基、芳基、杂芳基、烷酰基、芳基酰基、杂芳基酰基、烷氧基、卤代烷氧基、芳氧基、杂芳基氧基、烷基酰氧基、羧基、烷氧基酰基、芳氧基酰基、杂芳氧基酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷氧基磺酰基、氨基酰基、烷氨基酰基、氨基磺酰基、烷氨基磺酰基等。Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position identically or differently. The substituents described therein can be, but are not limited to, deuterium, oxo, halogen, cyano, nitro, hydroxyl, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkyne alkyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy, haloalkoxy, aryl Oxy, heteroaryloxy, alkylacyloxy, carboxyl, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkane Oxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl and the like.

另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other.

在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .

在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.

本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一些实施方案中，烷基基团含有1-12个碳原子；在另一些实施方案中，烷基基团含有1-6个碳原子；在又一些实施方案中，烷基基团含有1-4个碳原子；还在一些实施方案中，烷基基团含有1-3个碳原子。The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 -4 carbon atoms; also in some embodiments, the alkyl group contains 1-3 carbon atoms.

烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、 -CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl -2-butyl(-C(CH3)2CH2CH3), 3 -methyl- 2-butyl(-CH(CH3)CH(CH3)2 ) , 3 - methyl -1- Butyl ( -CH2CH2CH ( CH3 ) 2 ), 2 -methyl- 1 -butyl (-CH2CH( CH3 ) CH2CH3 ) , n - hexyl ( -CH2CH2CH2 CH2CH2CH3 ), 2 -hexyl (-CH( CH3 ) CH2CH2CH2CH3 ) , 3 - hexyl (-CH( CH2CH3 ) ( CH2CH2CH3 ) ) , 2-methyl-2-pentyl(-C( CH3 )2CH2CH2CH3), 3 -methyl- 2 -pentyl(-CH( CH3 ) CH ( CH3 ) CH2CH3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like.

术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、1-丙烯基(丙烯基，-CH＝CH-CH 3)等等。 The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the "cis" and "trans" positions, or the "E" and "Z" positions. In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (propenyl, -CH=CH-CH 3 ) and so on.

术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，炔基基团包含2-8个碳原子；在另一些实施方案中，炔基基团包含2-6个碳原子；在又一些实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(丙炔基，-C≡C-CH 3)等等。 The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1 -propynyl (propynyl, -C≡C-CH) 3 ) and so on.

术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1 -pentyloxy (n - pentyloxy, -OCH2CH2CH2CH2CH3), 2 - pentyloxy (-OCH ( CH3 ) CH2CH2CH3 ) , 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy group (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), etc.

术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、三氟甲氧基等。The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy Wait.

术语“羟基烷氧基”表示烷氧基基团被一个或多个羟基所取代，这样的实例包含，但并不限于，-OCH 2OH、-OCH 2CH 2OH等。 The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, examples of which include, but are not limited to, -OCH2OH , -OCH2CH2OH , and the like.

术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基、稠合碳双环基和桥碳双环基，合适的碳环基基团包括，但并不限于，环烷基、环烯基和环炔基。碳环基基团的实例进一步包括，环丙基、环丁基、环戊基、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-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Carbobicyclyl groups include spirocarbobicyclyl, fused carbobicyclyl, and bridged carbobicyclyl groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclyl groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

术语“环烷基”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和单环、双环或三环体系。在一些实施方案中，环烷基包含3-12个碳原子；在另一些实施方案中，环烷基包含3-8个碳原子；在又一些实施方案中，环烷基包含3-6个碳原子。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、 环己基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。The term "cycloalkyl" refers to a monovalent or polyvalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

术语“杂环”、“杂环基”或“杂环的”在此处可交换使用，是指包含3-14个环原子的，单价或多价的单环、双环或者三环体系，其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。在一些实施方案中，“杂环”，“杂环基”或“杂环的”基团是3-8元环的单环(2-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团)，或7-12元的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团)。在另一些实施方案中，“杂环”，“杂环基”或“杂环的”基团是3-6元环的单环(2-4个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团)。所述杂环基基团任选地被一个或多个本发明所描述的取代基所取代。 The terms "heterocycle,""heterocyclyl," or "heterocyclic" are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3 to 14 ring atoms, wherein One or more atoms on the ring are independently replaced by a heteroatom having the meaning as defined in the present invention, the ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring may be not allowed. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-8 membered monocyclic ring (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms, where S or P are optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) , or a 7-12 membered bicyclic ring ( 4 - 9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to give like SO, SO 2 , PO, PO 2 groups). In other embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-6 membered monocyclic ring (2-4 carbon atoms and selected from N, O, P, 1-3 heteroatoms of S, where S or P are optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) . The heterocyclyl group is optionally substituted with one or more substituents described herein.

杂环基可以是碳基或杂原子基；其中，环的-CH 2-基团可以任选地被-C(＝O)-替代，环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于，环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂

Figure PCTCN2021112919-appb-000008
基，二氮杂
Figure PCTCN2021112919-appb-000009
基，硫氮杂
Figure PCTCN2021112919-appb-000010
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述杂环基基团任选地被一个或多个本发明所描述的取代基所取代。 The heterocyclyl group can be a carbonyl group or a heteroatom group; wherein, the -CH2- group of the ring can be optionally replaced by -C(=O)-, and the sulfur atom of the ring can be optionally oxidized to S-oxidation compound, the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Amyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl, Oxazepine
Figure PCTCN2021112919-appb-000008
base, diazepine
Figure PCTCN2021112919-appb-000009
base, thiazepine
Figure PCTCN2021112919-appb-000010
yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and the like. Examples of heterocyclyl groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of oxidized sulfur atoms in a heterocyclyl group include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic A family of rings in which each ring system contains a ring of 3-7 atoms with one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

术语“杂芳基”或“杂芳环”表示含有5-14个环原子，或5-10个环原子，或5-6个环原子的，单价或多价的单环、双环或三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，5-10个环原子组成的杂芳基包含1、2、3或4个独立选自O、S和N的杂原子；在另一些实施方案中，5-6个环原子组成的杂芳基为单环体系且包含1、2、3或4个独立选自O、S和N的杂原子。The term "heteroaryl" or "heteroaromatic ring" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms A system in which at least one ring is aromatic and at least one ring contains one or more heteroatoms. A heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, heteroaryl groups of 5-10 ring atoms contain 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, 5-6 rings Atomic heteroaryl is a monocyclic ring system and contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、氮杂喹啉、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also including, but in no way limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), nitrogen Heteroquinoline, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b ]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2 ,4]Triazolo[1,5-a]pyridyl, etc.

术语“j-k个环原子组成的”或“j-k元”在此处可交换使用，表示所述环状基团由j-k个成环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。所述j和k各自独立地为任意非零的自然数，且k>j；所述“j-k”包括j、k和两者之间的任意自然数。例如，“3-8个原子组成的或3-8元”、“3-6个原子组成的或3-6元”、“5-10个原子组成的或5-10元”或“5-6个原子组成的或5-6元”表示所述环状基团由3-8(即，3、4、5、6、7或8)、3-6(即，3、4、5或6)、5-10(即，5、6、7、8、9或10)或5-6(即，5或6)个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。具体来说，例如，“5-10个环原子组成的杂芳基”或“5-10元杂芳基”代表其包括5、6、7、8、9或10个环原子组成的杂芳基，其中5、6、7、8、9或10表示成环原子数目，如吡啶基是由6个环原子组成的杂芳基或6元杂芳基。The terms "consisting of jk ring atoms" or "jk-membered" are used interchangeably herein to mean that the cyclic group consists of jk ring atoms including carbon atoms and/or O, Hetero atoms such as N, S, P, etc. The j and k are each independently any non-zero natural number, and k>j; the "j-k" includes j, k and any natural number in between. For example, "3-8 atoms or 3-8 elements", "3-6 atoms or 3-6 elements", "5-10 atoms or 5-10 elements" or "5- 6 atoms or 5-6 members" means that the cyclic group consists of 3-8 (ie, 3, 4, 5, 6, 7 or 8), 3-6 (ie, 3, 4, 5 or 6), 5-10 (ie, 5, 6, 7, 8, 9 or 10) or 5-6 (ie, 5 or 6) ring atoms including carbon atoms and/or O , N, S, P and other heteroatoms. Specifically, for example, "heteroaryl of 5-10 ring atoms" or "heteroaryl of 5-10 members" means that it includes a heteroaryl group of 5, 6, 7, 8, 9, or 10 ring atoms wherein 5, 6, 7, 8, 9 or 10 represent the number of ring atoms, eg pyridyl is a heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.

在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。The term "unsaturated" as used herein means that the group contains one or more degrees of unsaturation.

术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R为本发明所述的取代基)。The term "heteroatom" refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring. Hydrogen substituted form, for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).

术语“卤素”或“卤原子”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

术语“烷基氨基”或“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C 1-6烷基连接到氮原子上形成的烷基氨基基团。另外一些实施例是，烷基氨基是被一个或两个C 1-3的烷基取代的氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基(甲氨基)，N-乙氨基(乙氨基)，N,N-二甲氨基(二甲氨基)，N,N-二乙氨基(二乙氨基)等等。 The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino group is independently substituted with one or two alkyl groups, respectively. In some embodiments, the alkylamino group is an alkylamino group formed by one or two C1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is an amino group substituted with one or two C1-3 alkyl groups. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.

如本发明所描述，取代基(R 4) p由一个键连接到中心的环上形成的环体系代表p个取代基R 4可以在所在的环上任何可取代的位置或任何合理的位置进行取代。例如，式d代表G环可被p个R 4取代，当p大于1时，各R 4可独立地选自相同或不同的取代基团。 As described in the present invention, the substituent (R 4 ) p is attached to the central ring by a bond to form a ring system representing p substituents R 4 can be carried out at any substitutable position or any reasonable position on the ring in which they are located. replace. For example, Formula d represents that the G ring may be substituted with p R4s , and when p is greater than 1 , each R4 may be independently selected from the same or different substituent groups.

Figure PCTCN2021112919-appb-000011
Figure PCTCN2021112919-appb-000011

如本发明所描述，附着点可以在环上任何可连接的位置与分子其余部分连接。例如，式e代表C环或D环上任何可能被连接的位置均可作为连接的点。An attachment point can be attached to the rest of the molecule at any linkable position on the loop as described herein. For example, formula e represents that any position on the C-ring or the D-ring that may be attached can serve as a point of attachment.

Figure PCTCN2021112919-appb-000012
Figure PCTCN2021112919-appb-000012

术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005. The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. For example, a "protecting group for an amino group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本发明所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、特别在人体中使用的。The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein means approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly in humans.

术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。The term "carrier" refers to a diluent, adjuvant, excipient or base with which the compound is administered. These pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如，一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。 The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound that contains a hydroxyl group can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51, 2328-2345.

“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，无机酸盐，如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐，如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。可药用碱加成盐包括，但不限于，无机碱盐，例如铵盐和周期表的I族至XII族的金属盐，和有机碱盐，例如与伯胺、仲胺和叔胺形成的盐。As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as Acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or obtain these salts by other methods described in books such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of Groups I to XII of the periodic table, and organic base salts, such as those formed with primary, secondary, and tertiary amines. Salt.

本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" any disease or disorder, as used herein, in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

术语“治疗有效量”是指当给药于主体来治疗疾病时，化合物的分量足够对这种疾病的治疗起效。“治疗有效量”可以随着化合物，疾病和严重程度，以及有待治疗的主体的条件，年龄，体重，性别等而改变。The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect the treatment of such disease. A "therapeutically effective amount" can vary depending on the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.

本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing  Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required. In, e.g., "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Additional lists of suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇，DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。同位素富集的本发明化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。 Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 15N , 17O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or as described in the Examples and Preparations of this invention, using a suitable isotopically labeled reagent in place of the previously used unlabeled reagent.

除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

本发明所用的术语“癌症”是指或描述患者中通常以失控的细胞生长为特征的生理学病症。“肿瘤”包含一种或多种癌细胞。癌症的实例包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤、肉瘤和白血病，或恶性淋巴增殖性疾病(lymphoid malignancies)。此类癌症的更具体的实例包括鳞状细胞癌(如上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌和肺鳞状癌)、食管癌、腹膜癌、肝细胞癌(hepatocellular cancer)、胃癌(gastric or stomach cancer)(包括胃肠癌)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾脏癌(kidney or renal cancer)、前列腺癌、外阴癌、甲状腺癌、肝脏癌(hepatic carcinoma)、肛门癌、阴茎癌以及头颈癌。The term "cancer" as used herein refers to or describes a physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), esophageal cancer, Peritoneal cancer, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, Liver cancer, anal cancer, penile cancer and head and neck cancer.

本发明所用的术语“KRAS G12C抑制剂”是指能与KRAS G12C结合并抑制其活性的物质。The term "KRAS G12C inhibitor" used in the present invention refers to a substance that can bind to KRAS G12C and inhibit its activity.

本发明的化合物的详细描述DETAILED DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

本发明提供一种化合物或其药物组合物，其可作为KRAS G12C抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过用所述化合物抑制KRAS G12C的活性来治疗疾病和/或病症。本发明又进一步描述了合成所述化合物的方法。本发明的化合物显示出改善的生物活性及药代动力学性质。The present invention provides a compound or a pharmaceutical composition thereof, which can be used as a KRAS G12C inhibitor. The present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease and/or disorder by inhibiting the activity of KRAS G12C with the compound. The present invention further describes methods of synthesizing the compounds. The compounds of the present invention exhibit improved biological activity and pharmacokinetic properties.

一方面，本发明涉及一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Figure PCTCN2021112919-appb-000013
Figure PCTCN2021112919-appb-000013

其中，各m、p、Z、R 1、R 2a、R 2b、R 2c、R 2d、R 3、R 4、R 5和R x均具有本发明所描述的含义。 Wherein, each of m, p, Z, R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , R 5 and R x has the meaning described in the present invention.

在一些实施方案中，Z为N或CR 2e；其中R 2e具有本发明所述的含义。 In some embodiments, Z is N or CR 2e ; wherein R 2e has the meaning described herein.

在一些实施方案中，R 1为-C(＝O)-CR a＝CR b-R c、-C(＝O)-C≡C-R c、-S(＝O) 2-CR a＝CR b-R c或-S(＝O) 2-C≡C-R c；其中R a、R b和R c具有本发明所述的含义。 In some embodiments, R 1 is -C(=O)-CR a =CR b -R c , -C(=O)-C≡CR c , -S(=O) 2 -CR a =CR b -R c or -S(=O) 2 -C≡CR c ; wherein R a , R b and R c have the meanings described in the present invention.

在一些实施方案中，R a为氢、氘、卤原子、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基，其中，所述的C 1-3烷基、C 1-3卤代烷基和C 1-3烷氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R a is hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.

在另一些实施方案中，R a为氢、氘、卤原子、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基，其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, Ra is hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropyl Propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted by 1, 2, 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

在一些实施方案中，R b为氢、氘、卤原子、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基，其中，所述的C 1-3烷基、C 1-3卤代烷基和C 1-3烷氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R b is hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.

在另一些实施方案中，R b为氢、氘、卤原子、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基，其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R is hydrogen, deuterium , halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropyl Propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted by 1, 2, 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

在一些实施方案中，R c为氢、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、5-6元杂芳基、C 3-6碳环基或3-6元杂环基，其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、5-6元杂芳基、C 3-6碳环基和3-6元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟基烷氧基和3-6元杂环基的基团所取代。 In some embodiments, R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclic or 3-6 membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl group, C 3-6 carbocyclyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkoxy and 3-6 membered heterocyclyl substituted groups.

在另一些实施方案中，R c为氢、氘、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、-OCH 2OH、-OCH 2CH 2OH、异丙氧基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷 基、四氢呋喃基、哌啶基、哌嗪基和吗啉基的基团所取代。 In other embodiments, Rc is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2 , -CF3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyridine azolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; wherein, the methyl , ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azacycle Butyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl , oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro radical, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, isopropoxy, oxiranyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and substituted with alkynyl groups.

在一些实施方案中，R 3为C 6-12芳基或5-10元杂芳基，其中，所述的C 6-12芳基和5-10元杂芳基独立任选地被n个R y取代；其中，n和R y具有本发明所述的含义。 In some embodiments, R 3 is C 6-12 aryl or 5-10 membered heteroaryl, wherein said C 6-12 aryl and 5-10 membered heteroaryl are independently optionally separated by n R y is substituted; wherein n and R y have the meanings described in the present invention.

在另一些实施方案中，R 3为C 6-10芳基或5-10元杂芳基，其中，所述的C 6-10芳基和5-10元杂芳基独立任选地被n个R y取代；其中，n和R y具有本发明所述的含义。 In other embodiments, R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independently optionally surrounded by n R y is substituted; wherein, n and R y have the meanings described in the present invention.

在另一些实施方案中，R 3为

Figure PCTCN2021112919-appb-000014
Figure PCTCN2021112919-appb-000015
Figure PCTCN2021112919-appb-000016
其中，所述的
Figure PCTCN2021112919-appb-000017
Figure PCTCN2021112919-appb-000018
Figure PCTCN2021112919-appb-000019
独立任选地被n个R y取代；其中，n和R y具有本发明所述的含义。 In other embodiments, R3 is
Figure PCTCN2021112919-appb-000014
Figure PCTCN2021112919-appb-000015
Figure PCTCN2021112919-appb-000016
Among them, the said
Figure PCTCN2021112919-appb-000017
Figure PCTCN2021112919-appb-000018
Figure PCTCN2021112919-appb-000019
independently optionally substituted with n R y ; wherein n and R y have the meanings described herein.

在一些实施方案中，R 4为氢、氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-3羟基烷氧基。 In some embodiments, R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1 -3 alkoxy, C 1-3 haloalkoxy or C 1-3 hydroxyalkoxy.

在另一些实施方案中，R 4为氢、氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH或-OCH 2CH 2OH。 In other embodiments, R4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tris Fluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy , trifluoromethoxy, -OCH2OH or -OCH2CH2OH .

在一些实施方案中，R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4 卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.

在另一些实施方案中，R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoro methoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

在一些实施方案中，R 2a为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R 2a为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.

在另一些实施方案中，R 2a为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, substituted with groups of trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.

在一些实施方案中，R 2b为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R 2b为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟 基烷氧基的基团所取代。 In other embodiments, R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.

在另一些实施方案中，R 2b为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, substituted with groups of trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.

在一些实施方案中，R 2c为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R 2c为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.

在另一些实施方案中，R 2c为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, substituted with groups of trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.

在一些实施方案中，R 2d为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R 2d为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.

在另一些实施方案中，R 2d为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正 丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, substituted with groups of trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.

在一些实施方案中，R 2e为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R 2e为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 1-4 haloalkane group, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy group substituted.

在另一些实施方案中，R 2e为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, substituted with groups of trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.

在一些实施方案中，R x为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基和3-8元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, Rx is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 Alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclyl; wherein , said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1 -6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino , nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy .

在另一些实施方案中，R x为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基或3-6元杂环基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基和3-6元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R x is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; Wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl , C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups.

在另一些实施方案中，R x为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、 -OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, Rx is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl , propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethyl Oxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, di- methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl or morpholinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F , -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxygen Heterobutyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, Halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyl oxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

在一些实施方案中，R y为氘、卤原子、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟基烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中，所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟基烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In some embodiments, R y is deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, 3-8 atoms heterocyclic group, C 6-10 aryl group or 5-10 atom heteroaryl group; Wherein, the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkane radicals, heterocyclyl groups of 3-8 atoms, C 6-10 aryl groups, and heteroaryl groups of 5-10 atoms independently optionally selected from 1, 2, 3, 4, or 5 atoms independently selected from deuterium , halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1- 3 hydroxyalkoxy groups are substituted.

在另一些实施方案中，R y为氘、卤原子、羟基、氨基、硝基、氰基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟基烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟基烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 In other embodiments, R y is deuterium, halogen, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1- 4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 cycloalkyl, 3-6 atoms heterocyclyl, C 6-10 aryl or 5-6 atoms heteroaryl ; Wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 ring Alkyl, heterocyclyl of 3-6 atoms, C 6-10 aryl, and heteroaryl of 5-6 atoms are independently optionally selected from 1, 2, 3, 4 or 5 independently Deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1 -3 hydroxyalkoxy groups are substituted.

在另一些实施方案中，R y为氘、卤原子、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH、-OCH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三唑基；其中，所述的甲基、乙基、正丙基、异丙基、叔丁基、二氟甲基、甲氧基、乙氧基、异丙氧基、-OCH 2OH、-OCH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三唑基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 In other embodiments, R y is deuterium, halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoro Methyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Heterocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furan or triazolyl; wherein, the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, benzene radical, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or triazolyl independently optionally selected from 1, 2, 3, 4 or 5 deuterium , halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyl Propoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.

另一方面，本发明涉及以下其中之一的化合物或以下其中之一的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、水合物、代谢产物、酯、药学上可接受的盐或它的前药，但绝不限于：In another aspect, the present invention relates to one of the following compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, hydrates, metabolites, Esters, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to:

Figure PCTCN2021112919-appb-000020
Figure PCTCN2021112919-appb-000020

Figure PCTCN2021112919-appb-000021
Figure PCTCN2021112919-appb-000021

Figure PCTCN2021112919-appb-000022
Figure PCTCN2021112919-appb-000022

Figure PCTCN2021112919-appb-000023
Figure PCTCN2021112919-appb-000023

Figure PCTCN2021112919-appb-000024
Figure PCTCN2021112919-appb-000024

另一方面，本发明涉及药物组合物，该药物组合物，包含前面所述的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，及其药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物，或它们的任意组合。In another aspect, the present invention relates to pharmaceutical compositions comprising stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites of the aforementioned compounds Products, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or any combination thereof.

另一方面，本发明涉及前面所述化合物或其药物组合物在制备用于预防、治疗或减轻患者KRAS G12C介导的疾病的药物中的用途。In another aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the manufacture of a medicament for preventing, treating or alleviating a KRAS G12C mediated disease in a patient.

其中一些实施例是，KRAS G12C介导的疾病为癌症。In some embodiments, the KRAS G12C mediated disease is cancer.

其中一些实施方案是，本发明所述的癌症为肺癌、淋巴瘤、食道癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、白血病和黑色素瘤。In some embodiments, the cancer of the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma.

另一方面，本发明涉及式(I)所示的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).

本发明化合物的药物组合物，制剂，给药和用途PHARMACEUTICAL COMPOSITIONS, FORMULATIONS, ADMINISTRATION AND USE OF THE COMPOUNDS OF THE INVENTION

根据另一方面，本发明的药物组合物的特点包括式(I)所示的化合物，本发明所列出的化合物，或实施例的化合物，和药学上可接受的载体。本发明的药物组合物中化合物的量能有效地治疗或减轻患者KRAS G12C介导的疾病。According to another aspect, the pharmaceutical composition of the present invention features a compound represented by formula (I), a compound listed in the present invention, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate a KRAS G12C mediated disease in a patient.

本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。The compounds of the present invention exist in free form, or as suitable, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.

像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999 , Marcel Dekker, New York, synthesizing the contents of the documents herein, shows that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except to the extent that any conventional carrier vehicle is incompatible with the compounds of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of a pharmaceutically acceptable composition, they The use of is also within the scope of the present invention.

可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米 油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, sorbitan Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, Sweeteners, Flavours and Fragrances, Preservatives and Antioxidants.

优选地，该化合物与根据施用的形式和常规的药学实践来选择的合适的药物稀释剂，赋形剂，或者载体(在此是指药物制剂)混合施用，施用方式可以是口服片剂，胶囊，酏剂，糖浆等等。Preferably, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (referred to herein as a pharmaceutical formulation) selected according to the form of administration and conventional pharmaceutical practice, which may be oral tablets, capsules , elixirs, syrups, etc.

例如，对于以片剂或者胶囊形式口服施用，活性药物组分可以和一种口服的、非毒性的、药学上可接受的惰性填充剂结合，如乳糖，淀粉，蔗糖，葡萄糖，甲基纤维素，硬脂酸镁，磷酸二钙，硫酸钙，甘露醇，山梨醇等等；对于以液体形式口服施用，口服药物组分可以和任何口服的、非毒性的、药学上可以接受的惰性润湿剂结合，如乙醇，甘油，水等等。而且，当需要或必需时，合适的粘合剂、滑润剂、分解试剂以及着色剂也可以加入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖如葡萄糖或者β-乳糖，玉米甜味剂，天然的和合成的树胶如阿拉伯胶，黄芪胶，或者藻酸钠，羧甲基纤维素，聚乙烯乙二醇，蜡等等。在这些剂型中应用的润滑剂包括油酸钠，硬脂酸钠，硬脂酸镁，苯甲酸钠，乙酸钠，氯化钠等等。分解剂包括，但不限于，淀粉，甲基纤维素，琼脂，膨润土，黄原胶，等等。For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert filler such as lactose, starch, sucrose, glucose, methylcellulose , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical component may be wetted with any oral, non-toxic, pharmaceutically acceptable inert Agent combination, such as ethanol, glycerol, water, etc. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene Ethylene Glycol, Wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

本发明化合物可以以口服剂的形式被施用，如片剂，胶囊(其中的每一个都包括持续释放或者定时释放的配方)，丸剂，粉剂，粒剂，酏剂，酊剂，悬浮剂，糖浆剂，和乳化剂。它们也可以以静脉内(大丸剂或者输液)，腹膜内，皮下或者肌肉内的形式施用，所有使用的剂量形式都是药学领域的普通技术人员所熟知的。它们可以单独施用，但一般将基于所选择的施用方式和标准的药学实践选择一种药学载体一起施用。The compounds of this invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms well known to those of ordinary skill in the art of pharmacy. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the chosen mode of administration and standard pharmaceutical practice.

本发明的化合物可以经过合适的鼻内载体的局部使用以鼻内形式施用，或者通过使用经皮药贴以经皮途径施用。当以经皮传递系统的形式施用时，在整个用药期间施用的剂量是连续的而不是间歇的。The compounds of the present invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or transdermally via the use of transdermal patches. When administered in the form of a transdermal delivery system, the dose administered is continuous rather than intermittent throughout the period of administration.

本发明化合物也可以以脂质体传递系统的形式施用，如小的单层的囊泡，大的单层的囊泡以及多层囊泡。脂质体可以通过不同的磷脂形成，如胆固醇，硬脂胺，或者磷脂酰胆碱。The compounds of the present invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

本发明化合物也与可溶性的聚合物偶联，该多聚物作为靶向的药物载剂。这样的多聚物包括聚乙烯吡咯烷酮，吡喃共聚物，聚羟基丙基甲基丙烯酸胺-酚，聚羟基乙基天冬酰胺酚，或者用棕榈酰残基取代的聚乙烯氧化物-聚赖氨酸。而且，本发明化合物可以与一类生物可降解的聚合物偶联，用于完成可控制的药物释放，例如，聚乳酸，聚羟基乙酸，聚乳酸和聚羟基乙酸的共聚物，聚ε己内酯，聚羟基丁酸，聚原酸酯，聚缩醛，聚二氢吡喃，聚氰基丙烯酸酯，和水凝胶的交联的或者两亲性的阻断共聚物。The compounds of the present invention are also conjugated to soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate amine-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues amino acid. Furthermore, the compounds of the present invention can be coupled with a class of biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyεcaprolactone Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

本发明化合物的给药方案将随已知的各种因素而不同，如特定试剂的药动学特征及其模式和施用途径；接受者的种族，年龄，性别，健康状况，医疗状况和体重；症状的性质和程度；并行的治疗的种类；治疗的频率；施药的途径，病人的肾和肝功能，和希望达到的效果。一个医师或者兽医可以作出决定并开出有效量的药物来预防、抵销或者阻止癌症的发展。Dosage regimens for compounds of the present invention will vary with known factors such as the pharmacokinetic profile of the particular agent and its mode of administration and route of administration; the race, age, sex, health, medical condition and weight of the recipient; Nature and extent of symptoms; type of concurrent therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, offset, or stop the development of cancer.

根据一般的指导原则，为了达到指定的效果，所使用的每一种活性成分的日口服剂量的范围为大约0.001到1000mg/kg体重之间。对于静脉内的施用，在常规速率的输液过程中最优选的剂量范围为大约1到大约10mg/kg体重/分钟。本发明化合物可以以每日一次来施用，或者可以以每日分两次，三次或者四次进行施用。As a general guideline, to achieve the indicated effect, the daily oral dose of each active ingredient employed is in the range of between about 0.001 to 1000 mg/kg of body weight. For intravenous administration, the most preferred dosage range is from about 1 to about 10 mg/kg body weight/minute during conventional rate infusion. The compounds of the present invention may be administered once a day, or may be administered in two, three or four times a day.

适于施用的剂型(药物组合物)的每一单位剂量，可以含有大约1mg到大约1000mg的活性成分。在这些药物组合物中，活性成分的重量一般将占药物组合物的总重量的大约0.5-95％。Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be about 0.5-95% by weight of the total weight of the pharmaceutical composition.

当本发明化合物与其他治疗剂一起施用时，一般地，考虑到联合施用时治疗剂的附加的或者协同的效果，在典型的日剂量和典型的剂型中的每一个组分的量，相对于单独施用时的通常剂量，可以有所下降。When a compound of the present invention is administered with other therapeutic agents, generally, the amounts of each component in a typical daily dose and in a typical dosage form, relative to the additive or synergistic effects of the therapeutic agents when administered in combination, are The usual dose when administered alone may be reduced.

本发明涉及的化合物或者其药用盐或其水合物能有效用于预防、治疗或减轻患者由KRAS G12C介导 的疾病，特别是能有效治疗肺癌、淋巴瘤、食道癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、白血病和黑色素瘤等。The compounds involved in the present invention or their pharmaceutically acceptable salts or their hydrates can be effectively used for preventing, treating or alleviating diseases mediated by KRAS G12C in patients, in particular, they can effectively treat lung cancer, lymphoma, esophageal cancer, ovarian cancer and pancreatic cancer. , rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma, etc.

一般合成过程General synthetic procedure

为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.

一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如本发明所述。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined herein. The following reaction schemes and examples serve to further illustrate the content of the present invention.

所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in this invention may be used to suitably prepare other compounds of this invention, and that other methods for preparing compounds of this invention are considered to be within the scope of this invention . For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化。除非其他方面表明，一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification. Unless otherwise indicated, the general reagents are from Shantou Xilong Chemical Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd. Company, Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿均是经过干燥的。The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.

色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、q(quartet，四重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽的单峰)、dd(doublet of doublets，双二重峰)、ddd(doublet doublet of doublets，双双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数J，用赫兹(Hz)表示。 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublet), ddd (doublet doublet of doublets, double double doublet), dt ( doublet of triplets). The coupling constant, J, is expressed in Hertz (Hz).

低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-MS(柱子型号：Zorbax SB-C18,2.1×30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。 The measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1×30 mm, 3.5 μm, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 %-95% ( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.

纯的化合物使用Agilent 1260 pre-HPLC或Calesep pump 250 pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm下，用UV检测。Pure compounds were detected by UV at 210nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC).

下面简写词的使用贯穿本发明：The following abbreviations are used throughout this disclosure:

Figure PCTCN2021112919-appb-000025
Figure PCTCN2021112919-appb-000025

Figure PCTCN2021112919-appb-000026
Figure PCTCN2021112919-appb-000026

下列反应方案描述了制备本发明化合物的步骤。除非另外说明，其中各Z、R x、R 2a、R 2b、R 2c、R 2d、R 3、R 4、m和p具有本发明所述的定义。 The following reaction schemes describe steps for the preparation of compounds of the present invention. wherein each of Z, Rx, R2a , R2b , R2c , R2d , R3 , R4, m and p has the definitions described herein unless otherwise specified .

反应方案1Reaction scheme 1

Figure PCTCN2021112919-appb-000027
Figure PCTCN2021112919-appb-000027

式( 17)所示的化合物可以通过反应方案1制备得到：式( 1)所示化合物和草酰氯、氨水反应得到式( 2)所示的化合物。式( 2)所示的化合物、式( 3)所示化合物和式( 4)所示的化合物反应得到式( 5)所示的化合物。式( 5)所示的化合物在二(三甲基硅基)氨基钾的作用下反应得到式( 6)所示的化合物。式( 6)所示的化合物在三氯氧磷的作用下反应得到式( 7)所示的化合物。式( 7)所示的化合物和式( 8)所示的化合物在N,N-二异丙基乙胺的作用下反应得到式( 9)所示的化合物。式( 9)所示的化合物和式( 10)所示 化合物在醋酸钾的作用下反应得到式( 11)所示的化合物；然后，式( 11)所示的化合物和式( 12)所示化合物在[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物和碳酸铯的作用下可以反应得到式( 14)所示的化合物；或者，式( 11)所示的化合物和式( 13)所示化合物在氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)和碳酸钠的作用下也可以反应得到式( 14)所示的化合物。式( 14)所示的化合物在三氟乙酸的作用下脱Boc得到式( 15)所示的化合物。式( 15)所示的化合物和式( 16)所示化合物在N,N-二异丙基乙胺的作用下可以反应得到式( 17)所示的化合物。 The compound represented by formula ( 17 ) can be prepared by reaction scheme 1: the compound represented by formula ( 1 ) reacts with oxalyl chloride and ammonia water to obtain the compound represented by formula ( 2 ). The compound represented by the formula ( 2 ), the compound represented by the formula ( 3 ) and the compound represented by the formula ( 4 ) are reacted to obtain the compound represented by the formula ( 5 ). The compound represented by the formula ( 5 ) is reacted under the action of potassium bis(trimethylsilyl)amide to obtain the compound represented by the formula ( 6 ). The compound represented by the formula ( 6 ) is reacted under the action of phosphorus oxychloride to obtain the compound represented by the formula ( 7 ). The compound represented by the formula ( 7 ) and the compound represented by the formula ( 8 ) are reacted under the action of N,N-diisopropylethylamine to obtain the compound represented by the formula ( 9 ). The compound represented by the formula ( 9 ) and the compound represented by the formula ( 10 ) react under the action of potassium acetate to obtain the compound represented by the formula ( 11 ); then, the compound represented by the formula ( 11 ) and the compound represented by the formula ( 12 ) The compound can react under the action of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex and cesium carbonate to obtain the compound represented by formula ( 14 ); or, formula The compound represented by ( 11 ) and the compound represented by formula ( 13 ) are in chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[ Under the action of 2-(2'-amino-1,1'-biphenyl)]palladium(II) and sodium carbonate, the compound represented by formula ( 14 ) can also be obtained by reaction. The compound represented by the formula ( 14 ) is de-Boc removed under the action of trifluoroacetic acid to obtain the compound represented by the formula ( 15 ). The compound represented by the formula ( 15 ) and the compound represented by the formula ( 16 ) can react under the action of N,N-diisopropylethylamine to obtain the compound represented by the formula ( 17 ).

以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below with reference to the examples.

实施例Example

实施例1 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-6-羟基苯)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 1 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-6-hydroxybenzene)-1-(2 -Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000028
Figure PCTCN2021112919-appb-000028

第一步2,5,6-三氯吡啶-3-甲酰胺的合成The first step is the synthesis of 2,5,6-trichloropyridine-3-carboxamide

反应瓶中加入2,5,6-三氯吡啶-3-羧酸(5.00g,22.0mmol)，二氯甲烷(60.0mL)和N,N-二甲基甲酰胺(0.05mL,0.6mmol)，降温至0℃，滴加草酰氯(2.4mL,28mmol)。滴毕，搅拌24h。加入氨的异丙醇溶液(17.0mL,34mmol,2.0mol/L)，继续搅拌4h，有大量白色固体析出。抽滤，滤渣用二氯甲烷(50mL×2)洗涤，干燥后得到标题化合物白色固体(1.6g,32.0％)。2,5,6-Trichloropyridine-3-carboxylic acid (5.00g, 22.0mmol), dichloromethane (60.0mL) and N,N-dimethylformamide (0.05mL, 0.6mmol) were added to the reaction flask , cooled to 0 °C, and oxalyl chloride (2.4 mL, 28 mmol) was added dropwise. After dropping, stirring was carried out for 24h. An isopropanol solution of ammonia (17.0 mL, 34 mmol, 2.0 mol/L) was added, and stirring was continued for 4 h, and a large amount of white solid was precipitated. Suction filtration, the filter residue was washed with dichloromethane (50 mL×2), and dried to obtain the title compound as a white solid (1.6 g, 32.0%).

MS(ESI,pos.ion)m/z:224.9[M+H] +. MS(ESI,pos.ion)m/z:224.9[M+H] + .

第二步2,5,6-三氯-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰基)烟酰胺的合成The second step is the synthesis of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide

反应瓶中加入2,5,6-三氯吡啶-3-甲酰胺(1.46g,6.48mmol)，四氢呋喃(10mL)，升温至75℃，滴加草酰氯(1.0g,7.9mmol)，搅拌1h。冷却至室温，浓缩除去溶剂，降温至0℃，加入THF(5mL)溶解。将2-异丙基-4-甲基-吡啶-3-胺(1.0g,6.7mmol)溶解在四氢呋喃(5mL)中，滴加到上述混合物中，搅拌过夜。加入饱和氯化铵(10mL)淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相，浓缩得到标题化合物黄色固体(1.4g,54.0％)。2,5,6-Trichloropyridine-3-carboxamide (1.46g, 6.48mmol) and tetrahydrofuran (10mL) were added to the reaction flask, the temperature was raised to 75°C, oxalyl chloride (1.0g, 7.9mmol) was added dropwise, and the mixture was stirred for 1h . It was cooled to room temperature, concentrated to remove the solvent, cooled to 0°C, and dissolved by adding THF (5 mL). 2-Isopropyl-4-methyl-pyridin-3-amine (1.0 g, 6.7 mmol) was dissolved in tetrahydrofuran (5 mL), added dropwise to the above mixture, and stirred overnight. It was quenched by adding saturated ammonium chloride (10 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined and concentrated to give the title compound as a yellow solid (1.4 g, 54.0%).

MS(ESI,pos.ion)m/z:401.0[M+H] +. MS(ESI,pos.ion)m/z:401.0[M+H] + .

第三步6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成The third step 6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-di Synthesis of Ketones

反应瓶中加入2,5,6-三氯-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰基)烟酰胺(1.4g,3.5mmol)，四氢呋 喃(10.0mL)，降温至0℃，滴加二(三甲基硅基)氨基钾的四氢呋喃溶液(8.7mL,1mol/L,8.7mmol)，滴毕，转移至常温，搅拌过夜。加入饱和氯化铵(5mL)淬灭，乙酸乙酯(50mL)萃取，浓缩，得到标题化合物黄色固体(0.30g,24％)。2,5,6-Trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (1.4g, 3.5mmol), tetrahydrofuran (10.0 mL), cooled to 0° C., added dropwise a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (8.7 mL, 1 mol/L, 8.7 mmol), after dropping, transferred to room temperature and stirred overnight. Quenched by addition of saturated ammonium chloride (5 mL), extracted with ethyl acetate (50 mL), and concentrated to give the title compound as a yellow solid (0.30 g, 24%).

第四步4,6,7-三氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step is the synthesis of 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入6,7-二氯-1-(2-异丙基-4-甲基-3-吡啶基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.20g,0.55mmol)，N,N-二异丙基乙胺(0.6mL,4mmol)和乙腈(2.0mL)，搅拌溶解，滴加三氯氧磷(0.3mL,3mmol)，升温至回流，搅拌过夜。减压除去溶剂，得到标题化合物棕色油状物(210.1mg,100％)，不进行纯化，直接用于下一步。6,7-Dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)- Diketone (0.20g, 0.55mmol), N,N-diisopropylethylamine (0.6mL, 4mmol) and acetonitrile (2.0mL) were stirred to dissolve, phosphorus oxychloride (0.3mL, 3mmol) was added dropwise, and the temperature was increased. to reflux and stirring overnight. The solvent was removed under reduced pressure to give the title compound as a brown oil (210.1 mg, 100%) which was used in the next step without purification.

第五步(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The fifth step (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido Synthesis of [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入4,6,7-三氯-1-(2-异丙基-4-甲基-3-吡啶基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.53g,1.37mmol)，(S)-3-甲基哌嗪-1-羧酸叔丁酯(0.41g,2.05mmol)，N,N-二异丙基乙胺(1.2mL,7.2mmol)和乙腈(6mL)，升温至80℃，搅拌过夜。浓缩除去溶剂，所得残留物经柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.46g,60.82％)4,6,7-Trichloro-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2(1H)-one ( 0.53g, 1.37mmol), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.41g, 2.05mmol), N,N-diisopropylethylamine (1.2mL, 7.2mmol) and acetonitrile (6 mL), warmed to 80°C, and stirred overnight. The solvent was removed by concentration, and the obtained residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (0.46 g, 60.82%)

MS(ESI,pos.ion)m/z:547.2[M+H] +. MS(ESI,pos.ion)m/z:547.2[M+H] + .

第六步(3S)-4-(6-氯-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The sixth step (3S)-4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.43g,0.78mmol)，(2-氟-6-羟基苯基)硼酸(0.18g,1.17mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(63.8mg,0.078mmol)，醋酸钾(0.33g,3.11mmol)和1,4-二氧六环(10mL)，升温至100℃，搅拌24h。浓缩除去溶剂，所得残留物经柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0-0/1)，得到标题化合物黄色固体(0.24g,48.9％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.43 g, 0.78 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid ( 0.18g, 1.17mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (63.8mg, 0.078mmol), potassium acetate (0.33g, 3.11mmol) ) and 1,4-dioxane (10 mL), the temperature was raised to 100 °C, and stirred for 24 h. The solvent was removed by concentration, and the obtained residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-0/1) to obtain the title compound as a yellow solid (0.24 g, 48.9%).

MS(ESI,pos.ion)m/z:623.3[M+H] +. MS(ESI,pos.ion)m/z:623.3[M+H] + .

第七步(3S)-4-(6-环丙基-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The seventh step (3S)-4-(6-cyclopropyl-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(3S)-4-(6-氯-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(12.5mg,0.02mmol)，环丙基硼酸(6.9mg,0.08mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(63.8mg,0.078mmol)，碳酸铯(13.2mg,0.04mmol)和1,4-二氧六环(2.0mL)，升温至100℃，搅拌10h。冷却至常温，继续搅拌过夜。浓缩除去溶剂，所得残留物经柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0-0/1)，得到标题化合物黄色固体(6.4mg,51％)。Add (3S)-4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the reaction flask - tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (12.5 mg, 0.02 mmol), cyclopropane boronic acid (6.9mg, 0.08mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (63.8mg, 0.078mmol), cesium carbonate (13.2mg , 0.04 mmol) and 1,4-dioxane (2.0 mL), the temperature was raised to 100 °C and stirred for 10 h. Cool to room temperature and continue stirring overnight. The solvent was removed by concentration, and the obtained residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-0/1) to obtain the title compound as a yellow solid (6.4 mg, 51%).

MS(ESI,pos.ion)m/z:629.3[M+H] +. MS(ESI,pos.ion)m/z:629.3[M+H] + .

第八步6-环丙基-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-((S)-2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The eighth step 6-cyclopropyl-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)- Synthesis of 2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(3S)-4-(6-环丙基-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁基酯(95.5mg,0.15mmol)，二氯甲烷(5.0mL)，滴加三氟乙酸(1.0mL,13mmol)，常温搅拌1.5h。直接减压浓缩，得到标题化合物黄色粘稠液体(80.3mg,100％)。MS(ESI,pos.ion)m/z:529.3[M+H] +. Add (3S)-4-(6-cyclopropyl-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (95.5 mg, 0.15 mmol) , dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL, 13 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 h. Direct concentration under reduced pressure gave the title compound as a yellow viscous liquid (80.3 mg, 100%). MS(ESI,pos.ion)m/z:529.3[M+H] + .

第九步4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-6-羟基苯)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The ninth step 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-6-hydroxybenzene)-1-(2 Synthesis of -isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入6-环丙基-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-((S)-2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(80.3mg,0.085mmol)，二氯甲烷(2mL)，降温至-30℃，缓慢滴加丙烯酰氯(15.1mg,0.17mmol)的DCM(1mL)溶液，滴毕，搅拌2h，浓缩除去溶剂，经制备柱分离得到标题化合物白色固体(10.9mg,12.31％)。Add 6-cyclopropyl-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S) to the reaction flask -2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (80.3 mg, 0.085 mmol), dichloromethane (2 mL), cooled to -30°C, A solution of acryloyl chloride (15.1 mg, 0.17 mmol) in DCM (1 mL) was slowly added dropwise, the drop was completed, stirred for 2 h, concentrated to remove the solvent, and separated by a preparative column to obtain the title compound as a white solid (10.9 mg, 12.31%).

1H NMR(400MHz,CDCl 3)δ(ppm)9.02(s,1H),8.61(d,J＝4.9Hz,1H),7.77(s,1H),7.19(d,J＝5.4Hz,2H),6.75-6.60(m,3H),6.42(d,J＝16.0Hz,1H),5.82(dd,J＝10.5,1.7Hz,1H),5.43-5.21(m,1H),4.84-4.66(m,1H),4.61-4.42(m,1H),3.97-3.79(m,1H),3.77-3.40(m,3H),3.25(dd,J＝19.8,15.3Hz,1H),2.91-2.71(m,1H),2.04(s,3H),1.34-1.28(m,4H),1.23(s,6H),1.05(d,J＝6.5Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.02 (s, 1H), 8.61 (d, J=4.9 Hz, 1H), 7.77 (s, 1H), 7.19 (d, J=5.4 Hz, 2H) ,6.75-6.60(m,3H),6.42(d,J＝16.0Hz,1H),5.82(dd,J＝10.5,1.7Hz,1H),5.43-5.21(m,1H),4.84-4.66(m ,1H),4.61-4.42(m,1H),3.97-3.79(m,1H),3.77-3.40(m,3H),3.25(dd,J=19.8,15.3Hz,1H),2.91-2.71(m ,1H),2.04(s,3H),1.34-1.28(m,4H),1.23(s,6H),1.05(d,J=6.5Hz,3H).

实施例2(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(5-氟-2-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 2(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(5-fluoro-2-hydroxyphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000029
Figure PCTCN2021112919-appb-000029

第一步(S)-4-(6-氯-7-(5-氟-2-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(5-fluoro-2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基-哌嗪-1-羧酸叔丁酯(0.24g,0.44mmol)，(5-氟-2-羟基苯基)硼酸(0.10g,0.67mmol)，Pd(dppf)Cl 2(35.8mg,0.044mmol)，醋酸钾(0.19g,1.75mmol)和1,4-二氧六环(10.0mL)，升温至100℃，搅拌24h。浓缩除去溶剂。所得残留物经硅胶柱层析分离纯化(PE/EtOAc(v/v)＝1/0-0/1)，得到标题化合物黄色固体(0.18 g,66.9％)。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate tert-butyl ester (0.24 g, 0.44 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (0.10g, 0.67mmol), Pd(dppf)Cl 2 (35.8mg, 0.044mmol), potassium acetate (0.19g, 1.75mmol) and 1,4-dioxane (10.0mL), warmed to 100°C, Stir for 24h. Concentrate to remove solvent. The obtained residue was separated and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/0-0/1) to obtain the title compound as a yellow solid (0.18 g, 66.9%).

MS(ESI,pos.ion)m/z:623.3[M+H] +. MS(ESI,pos.ion)m/z:623.3[M+H] + .

第二步(S)-4-(6-环丙基-7-(5-氟-2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成Second step (S)-4-(6-cyclopropyl-7-(5-fluoro-2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(5-氟-2-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.18g,0.29mmol)，环丙基硼酸(0.50g,5.78mmol)，Pd(dppf)Cl 2(47.2mg,0.058mmol)，碳酸钾(0.12g,0.87mmol)，水(0.10g)和1,4-二氧六环(6.0mL)，升温至100℃，搅拌24h。冷却至常温，减压除去溶剂。所得残余物中加入水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，减压浓缩得到标题化合物黄色固体(0.18g,100％)。 Add (S)-4-(6-chloro-7-(5-fluoro-2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the reaction flask -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.18g, 0.29mmol), cyclopropane boronic acid (0.50 g, 5.78 mmol), Pd(dppf)Cl 2 (47.2 mg, 0.058 mmol), potassium carbonate (0.12 g, 0.87 mmol), water (0.10 g) and 1,4-dioxane (6.0 mL), the temperature was raised to 100 °C, and stirred for 24 h. After cooling to room temperature, the solvent was removed under reduced pressure. Water (30 mL) was added to the obtained residue, stirred for 10 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain the title compound as a yellow solid (0.18 g, 100%).

第三步(S)-6-环丙基-7-(5-氟-2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(5-fluoro-2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-( Synthesis of 2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(5-氟-2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.18g,0.29mmol)，二氯甲烷(10.0mL)和三氟乙酸(2.0mL)，搅拌5h。减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(DCM/MeOH(v/v)＝20/1)，得到标题化合物棕色固体(0.15g,100％)。Add (S)-4-(6-cyclopropyl-7-(5-fluoro-2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.18 g, 0.29 mmol), Dichloromethane (10.0 mL) and trifluoroacetic acid (2.0 mL) were stirred for 5 h. The solvent was removed by concentration under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a brown solid (0.15 g, 100%).

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(5-氟-2-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(5-fluoro-2-hydroxyphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(5-氟-2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.16g,0.29mmol)，N,N-二异丙基乙胺(0.38g,2.93mmol)，二氯甲烷(4mL)。体系降温至-30℃，缓慢滴加丙烯酰氯(31.9mg,0.35mmol)的二氯甲烷(2mL)溶液，滴毕，保温搅拌3h。待原料反应完全后，减压浓缩除去溶剂。所得残留物经硅胶柱层析分离纯化(DCM/MeOH(v/v)＝100/1-20/1)，得到标题化合物黄色固体(3.9mg,2.3％)。Add (S)-6-cyclopropyl-7-(5-fluoro-2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4- (2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.16g, 0.29mmol), N,N-diisopropylethylamine (0.38g) , 2.93 mmol), dichloromethane (4 mL). The system was cooled to -30°C, and a solution of acryloyl chloride (31.9 mg, 0.35 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the reaction of the raw materials was completed, the solvent was removed by concentration under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (3.9 mg, 2.3%).

MS(ESI,pos.ion)m/z:583.3[M+H] +. MS(ESI,pos.ion)m/z:583.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)10.53-10.33(m,1H),8.66(d,J＝4.8Hz,1H),8.38-8.21(m,1H),7.00-6.84(m,2H),6.80-6.65(m,2H),6.46-6.32(m,1H),5.92-5.79(m,1H),5.40-5.29(m,1H),4.78-4.64(m,1H),4.54-4.40(m,1H),3.90(ddd,J＝10.0,7.3,5.5Hz,1H),3.73-3.49(m,2H),3.31-2.95(m,2H),2.91-2.74(m,1H),2.30-1.96(m,4H),1.44(dd,J＝5.0,2.1Hz,2H),1.33-1.27(m,6H),1.10(d,J＝6.7Hz,3H),0.89-0.80(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 10.53-10.33 (m, 1H), 8.66 (d, J=4.8Hz, 1H), 8.38-8.21 (m, 1H), 7.00-6.84 (m, 2H) ),6.80-6.65(m,2H),6.46-6.32(m,1H),5.92-5.79(m,1H),5.40-5.29(m,1H),4.78-4.64(m,1H),4.54-4.40 (m,1H),3.90(ddd,J＝10.0,7.3,5.5Hz,1H),3.73-3.49(m,2H),3.31-2.95(m,2H),2.91-2.74(m,1H),2.30 -1.96(m,4H),1.44(dd,J=5.0,2.1Hz,2H),1.33-1.27(m,6H),1.10(d,J=6.7Hz,3H),0.89-0.80(m,2H) ).

实施例3(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 3 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluorophenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000030
Figure PCTCN2021112919-appb-000030

第一步(S)-4-(6-氯-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 Synthesis of ,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.20g,0.37mmol)，(2-氟苯基)硼酸(0.10g,0.74mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(30.1mg,0.037mmol)，碳酸铯(0.14g,0.73mmol)和1,4-二氧六环(10.0mL)，水(0.20g,11.10mmol)，升温至100℃，搅拌3h。冷却至室温，浓缩除去溶剂。加入水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，浓缩。所得残留物经柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物黄色固体(223.7mg,100％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3- d] pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.37 mmol), (2-fluorophenyl)boronic acid (0.10 g, 0.74 mmol), [1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30.1 mg, 0.037 mmol), cesium carbonate (0.14 g, 0.73 mmol) and 1,4-dioxane (10.0 mL), water (0.20 g, 11.10 mmol), warmed to 100° C. and stirred for 3 h. It was cooled to room temperature and concentrated to remove the solvent. Water (30 mL) was added, stirred for 10 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined and concentrated. The obtained residue was separated and purified by column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound as a yellow solid (223.7 mg, 100%).

MS(ESI,pos.ion)m/z:607.3[M+H] +. MS(ESI,pos.ion)m/z:607.3[M+H] + .

第二步(S)-4-(6-环丙基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.36g,0.59mmol)，1,4-二氧六环(6.0mL)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(73.6mg,0.094mmol)，碳酸钠(0.36g,4.32mmol)，置换氮气并保护，快速加入环丙基溴化锌的四氢呋喃溶液(12.0mL,0.5mol/L,6.00mmol)，升温至100℃，搅拌24h。浓缩除去溶剂，所得残留物经柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0-0/1)，再用反相制备分离得到标题化合物黄色固体(85.3mg,23.5％)。Add (S)-4-(6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.36 g, 0.59 mmol), 1,4-dioxo Hexacyclic (6.0 mL), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1 ,1'-biphenyl)] palladium (II) (73.6 mg, 0.094 mmol), sodium carbonate (0.36 g, 4.32 mmol), replaced with nitrogen and protected, quickly added a solution of cyclopropylzinc bromide in tetrahydrofuran (12.0 mL, 0.5mol/L, 6.00mmol), heated to 100°C, and stirred for 24h. The solvent was concentrated and removed, and the obtained residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0-0/1), and then separated by reverse-phase preparation to obtain the title compound as a yellow solid (85.3 mg, 23.5%).

MS(ESI,pos.ion)m/z:613.3[M+H] +. MS(ESI,pos.ion)m/z:613.3[M+H] + .

第三步(S)-6-环丙基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) Synthesis of piperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

单口瓶中加入(S)-4-(6-环丙基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(40.0mg,0.065mmol)，三氟乙酸(0.5mL,7mmol)和二氯甲烷(4.0mL)，常温搅拌1h。浓缩除去溶剂，得到标题化合物棕色固体(33.5mg,100％)。Add (S)-4-(6-cyclopropyl-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the single-necked bottle Substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (40.0 mg, 0.065 mmol), trifluoroacetic acid ( 0.5 mL, 7 mmol) and dichloromethane (4.0 mL), stirred at room temperature for 1 h. Concentration to remove the solvent gave the title compound as a brown solid (33.5 mg, 100%).

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并 [2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluorophenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

单口瓶中加入(S)-6-环丙基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(33.5mg,0.065mmol)，二氯甲烷(4mL)，降温至0℃，缓慢滴加丙烯酰氯(7.2mg,0.080mmol)的二氯甲烷(2mL)溶液，滴毕，搅拌3h。待原料反应完全后，浓缩除去溶剂。所得残留物经柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物黄色固体(22.8mg,61.6％)。Add (S)-6-cyclopropyl-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) into the single-necked bottle ylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (33.5 mg, 0.065 mmol), dichloromethane (4 mL), cooled to 0 °C, slowly added dropwise acryloyl chloride (7.2 mg, 0.080 mmol) in dichloromethane (2 mL), dropwise completed, and stirred for 3 h. After the reaction of the raw materials was completed, the solvent was removed by concentration. The obtained residue was separated and purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a yellow solid (22.8 mg, 61.6%).

MS(ESI,pos.ion)m/z:567.3[M+H] +. MS(ESI,pos.ion)m/z:567.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.47(d,J＝4.9Hz,1H),7.66(d,J＝10.6Hz,1H),7.40-7.34(m,1H),7.16-7.12(m,2H),7.08(t,J＝8.4Hz,2H),6.69-6.56(m,1H),6.41(d,J＝16.7Hz,1H),5.81(d,J＝10.5Hz,1H),5.12(s,1H),4.75(s,1H),3.68(dd,J＝73.0,60.2Hz,3H),3.26(s,1H),3.07(s,1H),2.75(s,1H),2.02(d,J＝4.4Hz,3H),1.89-1.85(m,1H),1.56(s,2H),1.48(s,2H),1.27-1.20(m,6H),1.05(d,J＝6.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.47 (d, J=4.9 Hz, 1H), 7.66 (d, J=10.6 Hz, 1H), 7.40-7.34 (m, 1H), 7.16-7.12 ( m, 2H), 7.08(t, J＝8.4Hz, 2H), 6.69-6.56(m, 1H), 6.41(d, J＝16.7Hz, 1H), 5.81(d, J＝10.5Hz, 1H), 5.12(s, 1H), 4.75(s, 1H), 3.68(dd, J=73.0, 60.2Hz, 3H), 3.26(s, 1H), 3.07(s, 1H), 2.75(s, 1H), 2.02 (d, J=4.4Hz, 3H), 1.89-1.85(m, 1H), 1.56(s, 2H), 1.48(s, 2H), 1.27-1.20(m, 6H), 1.05(d, J=6.4 Hz, 3H).

实施例4(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 4(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(4-fluorophenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000031
Figure PCTCN2021112919-appb-000031

第一步(S)-4-(6-氯-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 Synthesis of ,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-吡啶并[2,3-d]嘧啶-4-基)-3-甲基-哌嗪-1-羧酸叔丁酯(0.50g,0.91mmol)，(4-氟苯基)硼酸(0.14g,1.01mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(74.9mg,0.092mmol)，碳酸铯(0.23g,1.19mmol)和1,4-二氧六环(10.0mL)，升温至100℃，搅拌4h。冷却至室温，浓缩除去溶剂，得到棕色固体。加入水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，浓缩。所得残留物经柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(480.1mg,86.59％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3- d] pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), (4-fluorophenyl)boronic acid (0.14 g, 1.01 mmol), [1 , 1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (74.9mg, 0.092mmol), cesium carbonate (0.23g, 1.19mmol) and 1 , 4-dioxane (10.0 mL), warmed to 100° C. and stirred for 4 h. Cooled to room temperature and concentrated to remove solvent to give a brown solid. Water (30 mL) was added, stirred for 10 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined and concentrated. The obtained residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (480.1 mg, 86.59%).

MS(ESI,pos.ion)m/z:607.3[M+H] +. MS(ESI,pos.ion)m/z:607.3[M+H] + .

第二步(S)-4-(6-环丙基-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧 啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.11g,0.19mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(21.8mg,0.028mmol)和碳酸钠(76.8mg,0.93mmol)，氮气保护，快速加入环丙基溴化锌的四氢呋喃溶液(10.0mL,0.5mol/L,5.0mmol)，升温至70℃，搅拌过夜。浓缩除去溶剂，所得残留物经柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.11g,94.23％)。MS(ESI,pos.ion)m/z:613.3[M+H] +. Add (S)-4-(6-chloro-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.11 g, 0.19 mmol), chloro (2-bicyclic Hexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)( 21.8mg, 0.028mmol) and sodium carbonate (76.8mg, 0.93mmol), under nitrogen protection, quickly add a solution of cyclopropylzinc bromide in tetrahydrofuran (10.0mL, 0.5mol/L, 5.0mmol), warm to 70°C, stir overnight. The solvent was removed by concentration, and the obtained residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (0.11 g, 94.23%). MS(ESI,pos.ion)m/z:613.3[M+H] + .

第三步(S)-6-环丙基-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) Synthesis of piperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

单口瓶中加入(S)-4-(6-环丙基-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.13g,0.21mmol)，三氟乙酸(0.5mL)和二氯甲烷(4.0mL)，常温搅拌3h。浓缩除去溶剂，真空干燥，得到标题化合物棕色固体(0.11g,100.0％)。Add (S)-4-(6-cyclopropyl-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the single-necked bottle Substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.13 g, 0.21 mmol), trifluoroacetic acid ( 0.5 mL) and dichloromethane (4.0 mL), and stirred at room temperature for 3 h. Concentration to remove solvent and drying in vacuo gave the title compound as a brown solid (0.11 g, 100.0%).

MS(ESI,pos.ion)m/z:513.3[M+H] +. MS(ESI,pos.ion)m/z:513.3[M+H] + .

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(4-fluorophenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

单口瓶中加入(S)-6-环丙基-7-(4-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.11g,0.21mmol)，二氯甲烷(2mL)，降温至0℃，缓慢滴加丙烯酰氯(23.2mg,0.26mmol)的二氯甲烷(2mL)溶液，滴毕，搅拌3h。浓缩除去溶剂，所得残留物经柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物黄色固体(84.3mg,70.6％)。Add (S)-6-cyclopropyl-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) into the single-necked bottle ylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.11 g, 0.21 mmol), dichloromethane (2 mL), cooled to 0 °C, slowly added dropwise acryloyl chloride (23.2 mg, 0.26 mmol) in dichloromethane (2 mL), the dropwise addition was completed, and the mixture was stirred for 3 h. The solvent was removed by concentration, and the obtained residue was separated and purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a yellow solid (84.3 mg, 70.6%).

MS(ESI,pos.ion)m/z:567.3[M+H] +. MS(ESI,pos.ion)m/z:567.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.52(d,J＝4.4Hz,1H),7.69(s,1H),7.55(s,2H),7.18-6.97(m,3H),6.72-6.53(m,1H),6.40(d,J＝16.5Hz,1H),5.81(d,J＝10.3Hz,1H),4.41(ddd,J＝33.1,18.9,6.6Hz,2H),4.11-3.42(m,4H),3.16(dd,J＝79.9,6.9Hz,1H),2.72(dd,J＝33.3,9.1Hz,1H),2.03(s,3H),1.80(s,2H),1.52(d,J＝29.6Hz,3H),1.38-1.15(m,5H),1.14-1.01(m,4H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.52(d, J=4.4Hz, 1H), 7.69(s, 1H), 7.55(s, 2H), 7.18-6.97(m, 3H), 6.72- 6.53(m,1H),6.40(d,J=16.5Hz,1H),5.81(d,J=10.3Hz,1H),4.41(ddd,J=33.1,18.9,6.6Hz,2H),4.11-3.42 (m,4H),3.16(dd,J=79.9,6.9Hz,1H),2.72(dd,J=33.3,9.1Hz,1H),2.03(s,3H),1.80(s,2H),1.52( d, J=29.6Hz, 3H), 1.38-1.15(m, 5H), 1.14-1.01(m, 4H).

实施例5(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 5(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-methoxyphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000032
Figure PCTCN2021112919-appb-000032

第一步(S)-4-(6-氯-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-吡啶并[2,3-d]嘧啶-4-基)-3-甲基-哌嗪-1-羧酸叔丁酯(0.50g,0.91mmol)，(2-甲氧基苯)硼酸(0.15g,1.01mmol)，Pd(dppf)Cl 2(74.8mg,0.092mmol)，碳酸钾(0.43g,4.30mmol)和1,4-二氧六环(10.0mL)，升温至100℃搅拌24h。冷却至室温，浓缩除去溶剂，得到棕色固体。再加入水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，浓缩。残余物经硅胶柱层析分离纯化(PE/EtOAc(v/v)＝1/0-0/1)，得到标题化合物黄色固体(0.42g,74.38％)。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3- d] pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), (2-methoxybenzene)boronic acid (0.15 g, 1.01 mmol), Pd (dppf)Cl 2 (74.8 mg, 0.092 mmol), potassium carbonate (0.43 g, 4.30 mmol) and 1,4-dioxane (10.0 mL), warmed to 100° C. and stirred for 24 h. Cooled to room temperature and concentrated to remove solvent to give a brown solid. Water (30 mL) was added, stirred for 10 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined and concentrated. The residue was separated and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/0-0/1) to obtain the title compound as a yellow solid (0.42 g, 74.38%).

MS(ESI,pos.ion)m/z:619.4[M+H] +. MS(ESI,pos.ion)m/z:619.4[M+H] + .

第二步(S)-4-(6-环丙基-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6-氯-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.42g,0.68mmol)，xphos Pd G2(82.9mg,0.11mmol)，碳酸钠(0.29g,3.44mmol)和环丙基溴化锌(10.0mL,1.0mol/L,10.0mmol)，升温至60℃，搅拌过夜。体系减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(PE/EtOAc(v/v)＝1/0-0/1)，得到标题化合物黄色固体(0.39g,92.21％)。Add (S)-4-(6-chloro-7-(2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the reaction flask Substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.42g, 0.68mmol), xphos Pd G2 ( 82.9 mg, 0.11 mmol), sodium carbonate (0.29 g, 3.44 mmol) and cyclopropylzinc bromide (10.0 mL, 1.0 mol/L, 10.0 mmol), warmed to 60° C. and stirred overnight. The system was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/0-0/1) to obtain the title compound as a yellow solid (0.39 g, 92.21%).

MS(ESI,pos.ion)m/z:625.4[M+H] +. MS(ESI,pos.ion)m/z:625.4[M+H] + .

第三步(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(2- Synthesis of Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.13g，0.22mmol)，三氟乙酸(1.0mL)和二氯甲烷(6.0mL)，常温搅拌过夜。浓缩除去溶剂，得到标题化合物黄色固体(0.11g,100.0％)。Add (S)-4-(6-cyclopropyl-7-(2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the reaction flask -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.13 g, 0.22 mmol), trifluoro Acetic acid (1.0 mL) and dichloromethane (6.0 mL) were stirred at room temperature overnight. Concentration to remove the solvent gave the title compound as a yellow solid (0.11 g, 100.0%).

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-methoxyphenyl)-1-(2- Synthesis of isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.11g,0.22mmol)，二氯甲烷(2mL)。体系降温至0℃，缓慢滴加丙烯酰氯(21.5mg,0.24mmol)的二氯甲烷(1mL)溶液，滴加完毕后，保温搅拌6h。浓缩除去溶剂。残余物经硅胶柱层析分离纯化(DCM/MeOH(v/v)＝30/1)，得到标题化合物黄色固体(28.7mg,23.0％)。Add (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(2 to the reaction flask -Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.11 g, 0.22 mmol), dichloromethane (2 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (21.5 mg, 0.24 mmol) in dichloromethane (1 mL) was slowly added dropwise. Concentrate to remove solvent. The residue was separated and purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow solid (28.7 mg, 23.0%).

MS(ESI,pos.ion)m/z:579.4[M+H] +. MS(ESI,pos.ion)m/z:579.4[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.45(d,J＝4.8Hz,1H),7.57(s,1H),7.34(t,J＝7.1Hz,1H),7.09-6.80(m,4H),6.71-6.53(m,1H),6.40(d,J＝16.5Hz,1H),5.85-5.75(m,1H),5.27-4.91(m,1H),4.76(dd,J＝9.6, 7.0Hz,1H),4.65-4.20(m,2H),4.10-3.46(m,7H),3.30-3.01(m,1H),2.03(s,3H),1.75(dd,J＝12.0,6.8Hz,1H),1.47(d,J＝1.7Hz,2H),1.25(dd,J＝20.3,9.2Hz,6H),1.05(d,J＝6.4Hz,3H),0.86-0.77(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.45 (d, J=4.8 Hz, 1H), 7.57 (s, 1H), 7.34 (t, J=7.1 Hz, 1H), 7.09-6.80 (m, 4H), 6.71-6.53(m, 1H), 6.40(d, J=16.5Hz, 1H), 5.85-5.75(m, 1H), 5.27-4.91(m, 1H), 4.76(dd, J=9.6, 7.0Hz, 1H), 4.65-4.20(m, 2H), 4.10-3.46(m, 7H), 3.30-3.01(m, 1H), 2.03(s, 3H), 1.75(dd, J=12.0, 6.8Hz ,1H),1.47(d,J＝1.7Hz,2H),1.25(dd,J＝20.3,9.2Hz,6H),1.05(d,J＝6.4Hz,3H),0.86-0.77(m,2H) .

实施例6(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 6(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(pyridin-3-yl)-1-(2-isopropyl yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000033
Figure PCTCN2021112919-appb-000033

第一步(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(吡啶-3-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(pyridin-3-yl)-1 Synthesis of ,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中分别加(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.20g,0.36mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(60.2mg,0.07mmol)，醋酸钾(0.18g,1.90mmol)，1,4-二氧六环(5.0mL)。体系置换氮气三次后90℃下搅拌10min，再取3-吡啶硼酸(82.3mg,0.7mmol)溶解于1,4-二氧六环(1.0mL)中，加入体系后再加入水(0.5mL)继续反应3h。停止加热，冷却至室温，将体系抽滤，滤液减压旋干，所得残余物经硅胶柱层析分离纯化(PE/EA(v/v)＝1/4)，得到标题化合物深绿色固体(90.0mg,41.8％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydrogen to the reaction flask respectively Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.36 mmol), [1,1'-[1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (60.2 mg, 0.07 mmol), potassium acetate (0.18 g, 1.90 mmol), 1,4-dioxane (5.0 mL) ). The system was replaced with nitrogen three times and stirred at 90°C for 10 min, then 3-pyridineboronic acid (82.3 mg, 0.7 mmol) was dissolved in 1,4-dioxane (1.0 mL), and the system was added followed by water (0.5 mL) Continue to react for 3h. The heating was stopped, cooled to room temperature, the system was suction filtered, the filtrate was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (PE/EA (v/v)=1/4) to obtain the title compound as a dark green solid ( 90.0 mg, 41.8%).

MS(ESI,pos.ion)m/z:590.3[M+H] +. MS(ESI,pos.ion)m/z:590.3[M+H] + .

第二步(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(吡啶-3-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(pyridin-3-yl) Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(吡啶-3-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(90.0mg,0.15mmol)，XPhos Pd G3(15.6mg,0.017mmol)，Na 2CO 3(60.5mg,0.73mmol)，置换氮气后加入环丙基溴化锌的四氢呋喃溶液(3.5mL,2mmol)，加热至70℃下反应10h。待反应完全后，停止加热，冷却至室温，抽滤。滤液减压旋干，残余物经硅胶柱层析分离纯化(PE/EtOAc(v/v)＝1/9)，得到标题化合物深绿色固体(65.0mg,64.4％)。 Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(pyridin-3-yl)- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (90.0 mg, 0.15 mmol), XPhos Pd G3 (15.6 mg , 0.017 mmol), Na 2 CO 3 (60.5 mg, 0.73 mmol), replaced with nitrogen, added a solution of cyclopropylzinc bromide in tetrahydrofuran (3.5 mL, 2 mmol), heated to 70° C. to react for 10 h. After the reaction was completed, the heating was stopped, cooled to room temperature, and filtered with suction. The filtrate was spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/9) to obtain the title compound as a dark green solid (65.0 mg, 64.4%).

MS(ESI,pos.ion)m/z:596.4[M+H] +. MS(ESI,pos.ion)m/z:596.4[M+H] + .

第三步(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-(吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮The third step (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7- (Pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(吡啶-3-基)-1,2-二氢吡啶并 [2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(60.0mg,0.10mmol)，CH 2Cl 2(2.5mL)，三氟乙酸(0.5mL)，室温下反应2h。将体系直接旋干后，真空干燥，得到标题化合物浅棕色粘稠物(73.0mg,119％)。 Add (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(pyridin-3-yl) to the reaction flask )-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (60.0 mg, 0.10 mmol), CH 2 Cl 2 (2.5 mL), trifluoroacetic acid (0.5 mL), and reacted at room temperature for 2 h. The system was directly spin-dried and then dried in vacuo to give the title compound as a light brown viscous substance (73.0 mg, 119%).

MS(ESI,pos.ion)m/z:496.3[M+H] +. MS(ESI,pos.ion)m/z:496.3[M+H] + .

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- yl)-7-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

在-1℃下向反应瓶中加入(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-(吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(73.0mg,0.12mmol)，CH 2Cl 2(20.0mL)，Et 3N(32.5mg,0.32mmol)，再加入丙烯酰氯(13.0mg,0.14mmol)。体系保温反应30min后，减压旋干，残余物经硅胶柱层析分离纯化(PE/EA(v/v)＝1/0-0/1)，得到标题化合物浅黄色固体(17.0mg,25.8％)。 Add (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine- 1-yl)-7-(pyridin-3-yl)pyrido[2,3-d]pyrimidin- 2 (1H)-one (73.0 mg, 0.12 mmol), CH2Cl2 (20.0 mL), Et3 N (32.5 mg, 0.32 mmol) followed by acryloyl chloride (13.0 mg, 0.14 mmol). After the system was incubated for 30 min, it was spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE/EA (v/v)=1/0-0/1) to obtain the title compound as a pale yellow solid (17.0 mg, 25.8 mg). %).

MS(ESI,pos.ion)m/z:550.3[M+H] +. MS(ESI,pos.ion)m/z:550.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.89(s,1H),8.62(d,J＝3.6Hz,1H),8.55(d,J＝4.9Hz,1H),7.84-7.74(m,2H),7.31-7.34(m,1H),7.12(d,J＝4.9Hz,1H),6.68–6.60(m,1H),6.44-6.37(m,1H),5.83(dd,J＝10.4,1.5Hz,1H),4.62-4.76(m,1H),4.29-4.49(m,1H),3.89-4.05(m,1H),3.66-3.73(m,2H),3.52-3.50(m,1H),3.29-3.33(m,1H),3.10(dd,J＝14.6,7.3Hz,1H),2.65-2.80(m,1H),2.05(s,3H),1.27(s,3H),1.26-1.23(m,3H),1.09-1.11(m,2H),1.02-1.05(m,3H),0.91-0.84(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.89 (s, 1H), 8.62 (d, J=3.6 Hz, 1H), 8.55 (d, J=4.9 Hz, 1H), 7.84-7.74 (m, 2H), 7.31-7.34(m, 1H), 7.12(d, J=4.9Hz, 1H), 6.68-6.60(m, 1H), 6.44-6.37(m, 1H), 5.83(dd, J=10.4, 1.5Hz, 1H), 4.62-4.76(m, 1H), 4.29-4.49(m, 1H), 3.89-4.05(m, 1H), 3.66-3.73(m, 2H), 3.52-3.50(m, 1H) ,3.29-3.33(m,1H),3.10(dd,J=14.6,7.3Hz,1H),2.65-2.80(m,1H),2.05(s,3H),1.27(s,3H),1.26-1.23 (m,3H),1.09-1.11(m,2H),1.02-1.05(m,3H),0.91-0.84(m,2H).

实施例7(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-苯基吡啶并[2,3-d]嘧啶-2(1H)-酮Example 7(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- yl)-7-phenylpyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000034
Figure PCTCN2021112919-appb-000034

第一步(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-苯基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-phenyl-1,2-dihydro Synthesis of pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-吡啶并[2,3-d]嘧啶-4-基)-3-甲基-哌嗪-1-羧酸叔丁酯(1.02g,1.86mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.15g,0.19mmol)，碳酸铯(0.92g,2.80mmol)，1,4-二氧六环(20.0mL)，苯硼酸(0.25g,2.04mmol)。体系置换氮气三次后100℃下反应2h。经硅藻土过滤。滤液减压旋干，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝3/0-3/1)，得到标题化合物浅黄色固体(0.85g,77.4％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-pyrido[2,3- d] pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate tert-butyl ester (1.02 g, 1.86 mmol), [1,1′-[1,1′-bis(diphenylphosphine) ) ferrocene]dichloropalladium dichloromethane complex (0.15g, 0.19mmol), cesium carbonate (0.92g, 2.80mmol), 1,4-dioxane (20.0mL), phenylboronic acid (0.25 g, 2.04 mmol). After the system was replaced with nitrogen three times, the reaction was carried out at 100 °C for 2 h. Filter through diatomaceous earth. The filtrate was spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/0-3/1) to obtain the title compound as a pale yellow solid (0.85 g, 77.4%) .

MS(ESI,pos.ion)m/z:589.3[M+H] +. MS(ESI,pos.ion)m/z:589.3[M+H] + .

第二步(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-苯基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-phenyl-1,2- Synthesis of tert-butyl dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-苯基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.44g,0.74mmol)，XPhos Pd G3(75.6mg,0.08mmol)，Na 2CO 3(0.20g,2.40mmol)，置换氮气后加入环丙基溴化锌的四氢呋喃溶液(20mL,10mmol)。体系加热至70℃下反应7h。反应结束后，冷却至室温，抽滤。滤液减压旋干，残余物经制备柱(43％CAN-57％H 2O,0.2％TFA)，得到标题化合物白色固体(0.22g,49.07％)。 Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-phenyl-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.44 g, 0.74 mmol), XPhos Pd G3 (75.6 mg, 0.08 mmol), Na 2 CO 3 (0.20 g, 2.40 mmol) was replaced with nitrogen and a solution of cyclopropylzinc bromide in tetrahydrofuran (20 mL, 10 mmol) was added. The system was heated to 70°C and reacted for 7h. After the reaction was completed, it was cooled to room temperature and filtered with suction. The filtrate was spin-dried under reduced pressure, and the residue was passed through a preparative column (43% CAN-57% H2O , 0.2% TFA) to give the title compound as a white solid (0.22 g, 49.07%).

MS(ESI,pos.ion)m/z:595.4[M+H] +. MS(ESI,pos.ion)m/z:595.4[M+H] + .

第三步(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-苯基吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7- Synthesis of Phenylpyrido[2,3-d]pyrimidin-2(1H)-one

向反应瓶中加入(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-苯基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.22g,0.36mmol)，二氯甲烷(3.5mL)，三氟乙酸(1.5mL)。体系室温下反应2h。待原料反应完毕后，体系直接旋干后，真空60℃干燥过夜，得到标题化合物浅棕色粘稠物(0.30g,134％)。Add (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-phenyl-1 to the reaction flask, 2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.22 g, 0.36 mmol), dichloromethane (3.5 mL), Trifluoroacetic acid (1.5 mL). The system was reacted at room temperature for 2h. After the reaction of the raw materials was completed, the system was directly rotated to dry, and then dried in vacuum at 60° C. overnight to obtain the title compound as a light brown viscous substance (0.30 g, 134%).

MS(ESI,pos.ion)m/z:495.3[M+H] +. MS(ESI,pos.ion)m/z:495.3[M+H] + .

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-苯基吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- Synthesis of yl)-7-phenylpyrido[2,3-d]pyrimidin-2(1H)-one

在-5℃下向反应瓶中加入(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-苯基吡啶并[2,3-d]嘧啶-2(1H)-酮(0.25mg,0.41mmol)，二氯甲烷(20.0mL)，三乙胺(0.11g,1.07mmol)，再加入丙烯酰氯(46.5mg,0.5mmol)，保温反应20min。减压旋干，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/0-10/3)，得到标题化合物白色固体(10.0mg,44.5％)。Add (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine- 1-yl)-7-phenylpyrido[2,3-d]pyrimidin-2(1H)-one (0.25 mg, 0.41 mmol), dichloromethane (20.0 mL), triethylamine (0.11 g, 1.07 mmol), then acryloyl chloride (46.5 mg, 0.5 mmol) was added, and the reaction was incubated for 20 min. Spin to dryness under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/0-10/3) to obtain the title compound as a white solid (10.0 mg, 44.5%).

MS(ESI,pos.ion)m/z:549.3[M+H] +. MS(ESI,pos.ion)m/z:549.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.55(d,J＝4.9Hz,1H),7.68(s,1H),7.57-7.52(m,2H),7.34-7.39(m,3H),7.12(d,J＝4.9Hz,1H),6.71-6.56(m,1H),6.23-6.13(m,1H),5.82(d,J＝12.0Hz,1H),4.77-4.47(m,2H),4.04-3.88(m,2H),3.68-3.55(m,2H),3.13(d,J＝7.3Hz,2H),2.81-2.69(m,1H),2.06(s,3H),1.58-1.50(m,3H),1.30(d,J＝7.3Hz,3H),1.25(d,J＝6.7Hz,3H),1.07-1.04(m,4H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.55(d, J=4.9Hz, 1H), 7.68(s, 1H), 7.57-7.52(m, 2H), 7.34-7.39(m, 3H), 7.12(d,J＝4.9Hz,1H),6.71-6.56(m,1H),6.23-6.13(m,1H),5.82(d,J＝12.0Hz,1H),4.77-4.47(m,2H) ,4.04-3.88(m,2H),3.68-3.55(m,2H),3.13(d,J=7.3Hz,2H),2.81-2.69(m,1H),2.06(s,3H),1.58-1.50 (m,3H),1.30(d,J=7.3Hz,3H),1.25(d,J=6.7Hz,3H),1.07-1.04(m,4H).

实施例8(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 8 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-hydroxyphenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000035
Figure PCTCN2021112919-appb-000035

第一步(S)-6-环丙基-7-(2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The first step (S)-6-cyclopropyl-7-(2-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) Synthesis of piperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.13g,0.21mmol)，二氯甲烷(5.0mL)，无水氯化铝(0.13g,2.10mmol)，搅拌10min后，滴加乙硫醇(0.13g,2.08mmol)，常温搅拌过夜。缓慢滴加水(10mL)，用二氯甲烷萃取(50mL×3)。合并有机相，减压浓缩，所得残余物经硅胶柱层析分离纯化(DCM/MeOH(v/v)＝20/1)，得到标题化合物黄色固体(0.11g,100％)。Add (S)-4-(6-cyclopropyl-7-(2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the reaction flask -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.13 g, 0.21 mmol), dichloro Methane (5.0 mL), anhydrous aluminum chloride (0.13 g, 2.10 mmol), and after stirring for 10 min, ethanethiol (0.13 g, 2.08 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. Water (10 mL) was slowly added dropwise, and extracted with dichloromethane (50 mL×3). The organic phases were combined and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (0.11 g, 100%).

第二步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The second step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-hydroxyphenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(2-甲氧基-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.11g,0.21mmol)，二氯甲烷(2mL)，N,N-二异丙基乙胺(0.27g,2.08mmol)。降温至-30℃，缓慢滴加丙烯酰氯(20.7mg,0.23mmol)的二氯甲烷(1mL)溶液，滴加完毕后，保温搅拌5h。待原料反应完全后，减压浓缩。残余物经硅胶柱层析分离纯化(DCM/MeOH(v/v)＝20/1)，得到标题化合物黄色固体(15.3mg,13.1％)。Add (S)-6-cyclopropyl-7-(2-methoxy-phenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-( 2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.11 g, 0.21 mmol), dichloromethane (2 mL), N,N-diisopropyl Ethylamine (0.27 g, 2.08 mmol). The temperature was lowered to -30°C, and a solution of acryloyl chloride (20.7 mg, 0.23 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the reaction of the raw materials was completed, the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (15.3 mg, 13.1%).

MS(ESI,pos.ion)m/z:565.3[M+H] +. MS(ESI,pos.ion)m/z:565.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.61(d,J＝4.7Hz,1H),7.69(s,1H),7.48(d,J＝7.2Hz,1H),7.33(t,J＝7.5Hz,1H),7.17(s,1H),6.92(dd,J＝16.0,8.1Hz,2H),6.71-6.54(m,1H),6.41(d,J＝16.5Hz,1H),5.81(d,J＝10.3Hz,1H),5.10(s,1H),4.84-4.65(m,1H),4.59-4.38(m,1H),4.33-4.17(m,1H),4.03(dd,J＝10.5,5.5Hz,1H),3.87(dd,J＝10.8,5.5Hz,1H),3.73-3.64(m,1H),3.30-3.00(m,1H),2.85-2.66(m,1H),2.05(s,3H),1.66-1.61(m,1H),1.47(dd,J＝4.7,2.6Hz,2H),1.26(s,6H),1.07(dd,J＝15.9,9.6Hz,5H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.61 (d, J=4.7 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.33 (t, J= 7.5Hz, 1H), 7.17(s, 1H), 6.92(dd, J=16.0, 8.1Hz, 2H), 6.71-6.54(m, 1H), 6.41(d, J=16.5Hz, 1H), 5.81( d, J=10.3Hz, 1H), 5.10(s, 1H), 4.84-4.65(m, 1H), 4.59-4.38(m, 1H), 4.33-4.17(m, 1H), 4.03(dd, J= 10.5,5.5Hz,1H),3.87(dd,J=10.8,5.5Hz,1H),3.73-3.64(m,1H),3.30-3.00(m,1H),2.85-2.66(m,1H),2.05 (s,3H),1.66-1.61(m,1H),1.47(dd,J=4.7,2.6Hz,2H),1.26(s,6H),1.07(dd,J=15.9,9.6Hz,5H).

实施例9(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 9 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1 -(2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000036
Figure PCTCN2021112919-appb-000036

第一步(S)-4-(6-氯-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.50g,0.92mmol)，2-氟-5-甲氧基苯硼酸(0.21g,1.21mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(78.0mg,0.096mmol)，醋酸钾(0.14g,1.38mmol)和1,4-二氧六环(40.0mL)，升温至100℃，搅拌3h。冷却至室温，浓缩除去溶剂。残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，减压浓缩，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物淡黄色固体(0.44g,75.3％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.92 mmol), 2-fluoro-5-methoxybenzeneboronic acid (0.21 g, 1.21 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (78.0 mg, 0.096 mmol), potassium acetate ( 0.14 g, 1.38 mmol) and 1,4-dioxane (40.0 mL), the temperature was raised to 100 °C and stirred for 3 h. It was cooled to room temperature and concentrated to remove the solvent. Saturated brine (30 mL) was added to the residue, stirred for 10 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.44 g, 75.3%).

第二步(S)-4-(6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.40g,0.63mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(57.0mg,0.073mmol)和环丙基溴化锌(10.0mL,5.0mmol)，升温至68℃，反应7小时。原料反应完全后，冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.19g,47.1％)。Add (S)-4-(6-chloro-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.40 g, 0.63 mmol), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ] Palladium (II) (57.0 mg, 0.073 mmol) and cyclopropyl zinc bromide (10.0 mL, 5.0 mmol), the temperature was raised to 68° C., and reacted for 7 hours. After the reaction of the raw materials was completed, it was cooled to room temperature, saturated brine (10.0 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=1/1) to give the title compound as a yellow solid (0.19 g, 47.1%).

MS(ESI,pos.ion)m/z:643.3[M+H] +. MS(ESI,pos.ion)m/z:643.3[M+H] + .

第三步(S)-6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4 Synthesis of -(2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(79.7mg,0.13mmol)，三氟乙酸(3.0mL,40mmol)和二氯甲烷(4.0mL)，常温搅拌1h。待原料反应完全后，减压浓缩除去溶剂，真空60℃干燥得到标题化合物棕色固体(67.0mg,100.0％)，直接用于下一步反应。Add (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3- yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (79.7 mg, 0.13 mmol ), trifluoroacetic acid (3.0 mL, 40 mmol) and dichloromethane (4.0 mL), and stirred at room temperature for 1 h. After the reaction of the raw materials was completed, the solvent was removed by concentration under reduced pressure, and dried under vacuum at 60° C. to obtain the title compound as a brown solid (67.0 mg, 100.0%), which was directly used in the next reaction.

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基) 吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1 Synthesis of -(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮(63.3mg,0.117mmol)，N,N-二异丙基乙胺(0.1mL,1.0mmol)，二氯甲烷(4.0mL)，降温至0℃，缓慢滴加丙烯酰氯(0.1g,1.0mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10min。反应完毕后，减压浓缩除去溶剂。所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1–20/1)，得到标题化合物黄色固体(69.3mg,99.6％)。Add (S)-6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 4-(2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (63.3 mg, 0.117 mmol), N,N-diisopropylethylamine (0.1 mL, 1.0 mmol), dichloromethane (4.0 mL), cooled to 0° C., slowly added dropwise a solution of acryloyl chloride (0.1 g, 1.0 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 min. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (69.3 mg, 99.6%).

MS(ESI,pos.ion)m/z:597.3[M+H] +. MS(ESI,pos.ion)m/z:597.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.60(d,J＝5.0Hz,1H),7.67(s,1H),7.18(d,J＝4.9Hz,1H),7.00(t,J＝9.1Hz,1H),6.92–6.86(m,1H),6.64(dd,J＝5.4,3.1Hz,2H),6.41(d,J＝16.6Hz,1H),5.84–5.79(m,1H),4.54(ddd,J＝70.3,59.2,12.8Hz,4H),3.69(s,3H),2.78(s,1H),2.11–2.03(m,4H),1.97–1.88(m,1H),1.53(d,J＝28.6Hz,3H),1.26(t,J＝7.3Hz,5H),1.11(d,J＝6.4Hz,3H),0.94(s,2H),0.55(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.60 (d, J=5.0 Hz, 1H), 7.67 (s, 1H), 7.18 (d, J=4.9 Hz, 1H), 7.00 (t, J= 9.1Hz, 1H), 6.92–6.86 (m, 1H), 6.64 (dd, J=5.4, 3.1Hz, 2H), 6.41 (d, J=16.6Hz, 1H), 5.84–5.79 (m, 1H), 4.54(ddd,J=70.3,59.2,12.8Hz,4H),3.69(s,3H),2.78(s,1H),2.11–2.03(m,4H),1.97–1.88(m,1H),1.53( d, J=28.6Hz, 3H), 1.26(t, J=7.3Hz, 5H), 1.11(d, J=6.4Hz, 3H), 0.94(s, 2H), 0.55(s, 2H).

实施例10(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 10(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1- (2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000037
Figure PCTCN2021112919-appb-000037

第一步(S)-4-(6-氯-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.30g,0.55mmol)，2-氟-5-甲基苯硼酸(0.11g,0.73mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(48.3mg,0.059mmol)，醋酸钾(71.4mg,0.73mmol)和1,4-二氧六环(30.0mL)，氮气保护下，升温至100℃，搅拌3h。冷却至室温，减压浓缩除去溶剂。残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.32g,92.8％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.55 mmol), 2-fluoro-5-methylphenylboronic acid (0.11 g , 0.73 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (48.3 mg, 0.059 mmol), potassium acetate (71.4 mg, 0.73 mmol) and 1,4-dioxane (30.0 mL), under nitrogen protection, the temperature was raised to 100 °C and stirred for 3 h. It was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Saturated brine (30 mL) was added to the residue, stirred for 10 min, extracted with ethyl acetate (30 mL×3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=1/1) to obtain the title compound as a yellow solid (0.32 g, 92.8%).

MS(ESI,pos.ion)m/z:622.3[M+H] +. MS(ESI,pos.ion)m/z:622.3[M+H] + .

第二步(S)-4-(6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) -Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6-氯-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.30g,0.48mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(44.3mg,0.056mmol)，环丙基溴化锌(15.0mL,8.0mmol)。体系升温至68℃，反应7小时。反应完毕后，冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30.0mL×3)，合并有机相，减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.16g,53.5％)。Add (S)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.48 mmol), chloro (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium(II) (44.3 mg, 0.056 mmol), cyclopropylzinc bromide (15.0 mL, 8.0 mmol). The temperature of the system was raised to 68°C, and the reaction was carried out for 7 hours. After the reaction was completed, it was cooled to room temperature, saturated brine (10.0 mL) was added, extracted with ethyl acetate (30.0 mL×3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to give the title compound as a yellow solid (0.16 g, 53.5%).

MS(ESI,pos.ion)m/z:627.4[M+H] +. MS(ESI,pos.ion)m/z:627.4[M+H] + .

第三步(S)-6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4- Synthesis of (2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.16g,0.26mmol)，三氟乙酸(5.0mL,50mmol)和二氯甲烷(6.0mL)，常温搅拌1h。反应完毕后，减压浓缩除去溶剂，真空60℃干燥得到标题化合物棕色固体(0.14g,100.0％)，直接用于下一步。Add (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.16 g, 0.26 mmol) , trifluoroacetic acid (5.0 mL, 50 mmol) and dichloromethane (6.0 mL), stirred at room temperature for 1 h. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, and dried under vacuum at 60° C. to obtain the title compound as a brown solid (0.14 g, 100.0%), which was directly used in the next step.

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮(0.14g,0.26mmol)，N,N-二异丙基乙胺(0.1mL,1.0mmol)，二氯甲烷(8.0mL)，降温至0℃，缓慢滴加丙烯酰氯(0.1g,1.0mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10min。反应完全贵阳，减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1–20/1)，得到标题化合物黄色固体(0.11g,71.6％)。Add (S)-6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4 to the reaction flask -(2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (0.14 g, 0.26 mmol), N,N-diisopropylethylamine (0.1 mL) , 1.0 mmol), dichloromethane (8.0 mL), cooled to 0 °C, slowly added dropwise a solution of acryloyl chloride (0.1 g, 1.0 mmol) in dichloromethane (1 mL), the addition was completed, and stirred for 10 min. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (0.11 g, 71.6%).

MS(ESI,pos.ion)m/z:581.3[M+H] +. MS(ESI,pos.ion)m/z:581.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.39(d,J＝3.5Hz,1H),7.73(s,1H),7.27–7.12(m,3H),6.99(d,J＝5.9Hz,1H),6.86(dd,J＝23.1,11.5Hz,1H),6.20(dd,J＝16.7,5.6Hz,1H),5.76(d,J＝9.8Hz,1H),4.85(s,1H),3.75–3.55(m,2H),3.09(s,1H),2.67(s,2H),2.24(s,3H),1.93–1.87(m,3H),1.67(s,1H),1.37(d,J＝5.6Hz,3H),1.29–1.20(m,2H),1.06(s,3H),0.95(d,J＝5.3Hz,3H),0.84(d,J＝7.9Hz,2H),0.73(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.39 (d, J=3.5Hz, 1H), 7.73 (s, 1H), 7.27-7.12 (m, 3H), 6.99 (d, J=5.9Hz, 1H), 6.86(dd, J＝23.1, 11.5Hz, 1H), 6.20(dd, J＝16.7, 5.6Hz, 1H), 5.76(d, J＝9.8Hz, 1H), 4.85(s, 1H), 3.75–3.55(m, 2H), 3.09(s, 1H), 2.67(s, 2H), 2.24(s, 3H), 1.93–1.87(m, 3H), 1.67(s, 1H), 1.37(d, J=5.6Hz, 3H), 1.29–1.20(m, 2H), 1.06(s, 3H), 0.95(d, J=5.3Hz, 3H), 0.84(d, J=7.9Hz, 2H), 0.73( s, 2H).

实施例11(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 11(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-3-hydroxyphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000038
Figure PCTCN2021112919-appb-000038

第一步(S)-4-(6-氯-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2-fluoro-3-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-[6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸叔丁酯(0.30g,0.55mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(52.0mg,0.06mmol)，醋酸钾(0.28g,2.80mmol)，1,4-二氧六环(18.0mL)，置换氮气三次后90℃下搅拌10min，再加入(2-氟-3-羟基苯基)硼酸(0.17g,1.10mmol)的1,4-二氧六环(2.0mL)溶液，和三滴水。体系继续反应2.5h后，冷却至室温，过滤，滤液减压旋干，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝10/0–20/1)，得到标题化合物黄色固体(0.28g,82.0％)。Add (S)-4-[6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate tert-butyl ester (0.30 g, 0.55 mmol), [1,1′-[1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (52.0 mg, 0.06 mmol), potassium acetate (0.28 g, 2.80 mmol), 1,4-dioxane (18.0 mL) ), replaced nitrogen three times and stirred at 90 °C for 10 min, then added (2-fluoro-3-hydroxyphenyl)boronic acid (0.17 g, 1.10 mmol) in 1,4-dioxane (2.0 mL) solution, and three dripping. After the system continued to react for 2.5 hours, it was cooled to room temperature, filtered, the filtrate was spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10/0-20/1) to obtain The title compound was a yellow solid (0.28 g, 82.0%).

MS(ESI,pos.ion)m/z:623.2[M+H] +. MS(ESI,pos.ion)m/z:623.2[M+H] + .

第二步(S)-4-(6-氯-7-(2-氟-3-((4-甲氧基苯基)氧基)-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成Second step (S)-4-(6-Chloro-7-(2-fluoro-3-((4-methoxyphenyl)oxy)-phenyl)-1-(2-isopropyl- 4-Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert. Synthesis of Butyl Ester

反应瓶中加入(S)-4-(6-氯-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.25g,0.40mmol)，乙腈(10.0mL)，碳酸钾(65.8mg,0.48mmol)。体系加热至85℃，向其中分批加入4-甲氧基苄溴(0.15g,0.75mmol)，保温反应。待反应完全后，冷却至室温，加入甲醇(10.0mL)，搅拌2min，经硅藻土过滤，滤液减压旋干，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/0–2/1)，得到标题化合物黄色固体(0.26g,86.5％)。Add (S)-4-(6-chloro-7-(2-fluoro-3-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the reaction flask -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.25g, 0.40mmol), acetonitrile ( 10.0 mL), potassium carbonate (65.8 mg, 0.48 mmol). The system was heated to 85° C., 4-methoxybenzyl bromide (0.15 g, 0.75 mmol) was added thereto in portions, and the reaction was kept warm. After the reaction was completed, it was cooled to room temperature, methanol (10.0 mL) was added, stirred for 2 min, filtered through celite, the filtrate was spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/ v) = 2/0 - 2/1) to give the title compound as a yellow solid (0.26 g, 86.5%).

MS(ESI,pos.ion)m/z:743.4[M+H] +. MS(ESI,pos.ion)m/z:743.4[M+H] + .

第三步(S)-4-(6-环丙基-7-(2-氟-3-((4-甲氧基苯基)氧基)-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The third step (S)-4-(6-cyclopropyl-7-(2-fluoro-3-((4-methoxyphenyl)oxy)-phenyl)-1-(2-isopropyl) (yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate Synthesis of tert-butyl acid

反应瓶中加入(S)-4-(6-氯-7-(2-氟-3-((4-甲氧基苯基)氧基)-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.25g,0.34mmol),Xphos Pd G3(35.8mg,0.04mmol)，碳酸钠(0.14g,1.72mmol)，氮气保护下加入环丙基溴化锌四氢呋喃溶液(10.0mL,0.5mol/L,5.0mmol)，加热至70℃反应12h，冷却至室温，过滤。过滤的母液减压旋干，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0–0/1)，得到标题化合物白色固体(0.19g,75.4％)。Add (S)-4-(6-chloro-7-(2-fluoro-3-((4-methoxyphenyl)oxy)-phenyl)-1-(2-isopropyl) to the reaction flask -4-Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid Tert-butyl ester (0.25g, 0.34mmol), Xphos Pd G3 (35.8mg, 0.04mmol), sodium carbonate (0.14g, 1.72mmol), under nitrogen protection was added cyclopropyl zinc bromide tetrahydrofuran solution (10.0mL, 0.5mol /L, 5.0 mmol), heated to 70 °C for 12 h, cooled to room temperature, and filtered. The filtered mother liquor was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-0/1) to obtain the title compound as a white solid (0.19 g, 75.4 g) %).

MS(ESI,pos.ion)m/z:749.5[M+H] +. MS(ESI,pos.ion)m/z:749.5[M+H] + .

第四步(S)-4-(6-环丙基-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The fourth step (S)-4-(6-cyclopropyl-7-(2-fluoro-3-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-环丙基-7-(2-氟-3-((4-甲氧基苯基)氧基)-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.18g,0.24mmol)，10％Pd/C(0.15g)，甲醇(20.0mL)，置换氢气后室温反应6.5h，过滤，滤液减压旋干，得到标题化合物灰色固体(0.12g,82.1％)，直接投下一步。Add (S)-4-(6-cyclopropyl-7-(2-fluoro-3-((4-methoxyphenyl)oxy)-phenyl)-1-(2-iso) to the reaction flask Propyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- tert-Butyl carboxylate (0.18g, 0.24mmol), 10% Pd/C (0.15g), methanol (20.0mL), hydrogen was replaced and reacted at room temperature for 6.5h, filtered, and the filtrate was spin-dried under reduced pressure to obtain the title compound as a grey solid (0.12g, 82.1%), directly cast to the next step.

MS(ESI,pos.ion)m/z:629.3[M+H] +. MS(ESI,pos.ion)m/z:629.3[M+H] + .

第五步(S)-6-环丙基-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮The fifth step (S)-6-cyclopropyl-7-(2-fluoro-3-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-( 2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.12g,0.20mmol)，二氯甲烷(15.0mL)，三氟乙酸(2.0mL)，室温下反应1.5h。待反应完全后，体系直接减压旋干，得到标题化合物浅褐色粘稠液体(0.10g,100.0％)，直接投下一步。Add (S)-4-(6-cyclopropyl-7-(2-fluoro-3-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.12 g, 0.20 mmol), Dichloromethane (15.0 mL) and trifluoroacetic acid (2.0 mL) were reacted at room temperature for 1.5 h. After the reaction was completed, the system was directly spin-dried under reduced pressure to obtain the title compound as a light brown viscous liquid (0.10 g, 100.0%), which was directly used in the next step.

MS(ESI,pos.ion)m/z:529.3[M+H] +. MS(ESI,pos.ion)m/z:529.3[M+H] + .

第六步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The sixth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-3-hydroxyphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

在-20℃下向反应瓶中加入(S)-6-环丙基-7-(2-氟-3-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.10g,0.16mmol)，二氯甲烷(10.0mL)，三乙胺(58.5mg,0.58mmol)，再加入丙烯酰氯(15.5mg,0.17mmol)，保温反应30min。待原料反应完全后，体系减压旋干，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/0–10/3)，得到标题化合物浅棕色固体(20.0mg,22.1％)。Add (S)-6-cyclopropyl-7-(2-fluoro-3-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3 to the reaction flask at -20°C) -yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.10 g, 0.16 mmol), dichloromethane (10.0 mL) , triethylamine (58.5mg, 0.58mmol), then acryloyl chloride (15.5mg, 0.17mmol) was added, and the reaction was incubated for 30min. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/0-10/3) to obtain the title compound as a light brown solid ( 20.0 mg, 22.1%).

MS(ESI,pos.ion)m/z:583.3[M+H] +. MS(ESI,pos.ion)m/z:583.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.53–8.38(m,1H),7.67(s,1H),7.06–6.93(m,3H),6.68-6.57(m,2H),6.43(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),4.78-4.70(m,1H),4.11–3.89(m,2H),3.76–3.65(m,2H),3.17-3.08(m,2H),2.85–2.70(m,2H),2.02(d,J＝14.6Hz,3H),1.27(s,9H),1.10-1.98(m,4H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.53-8.38(m, 1H), 7.67(s, 1H), 7.06-6.93(m, 3H), 6.68-6.57(m, 2H), 6.43(d , J=16.5Hz, 1H), 5.83(d, J=10.5Hz, 1H), 4.78-4.70(m, 1H), 4.11-3.89(m, 2H), 3.76-3.65(m, 2H), 3.17- 3.08(m, 2H), 2.85-2.70(m, 2H), 2.02(d, J=14.6Hz, 3H), 1.27(s, 9H), 1.10-1.98(m, 4H).

实施例12(S)-2-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-6-甲氧基苯基乙酸酯Example 12(S)-2-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-6-methoxyphenyl acetate

Figure PCTCN2021112919-appb-000039
Figure PCTCN2021112919-appb-000039

第一步(S)-4-(6-氯-7-(2-羟基-3-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-Chloro-7-(2-hydroxy-3-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.50g,0.91mmol)，(2-羟基-3-甲氧基)苯硼酸(0.17g,0.95mmol)，Pd(dppf)Cl 2(78.6mg,0.096mmol)，碳酸钾(0.45g,4.57mmol)和1,4-二氧六环(10.0mL)，升温至100℃，反应24h。冷却至室温，减压浓缩除去溶剂。残余物中加入水(50mL)，搅拌10min，用乙酸乙酯萃取(200mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0–1/1)，得到标题化合物黄色固体(0.20g,34.6％)。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), (2-hydroxy-3-methoxy)benzeneboronic acid (0.17g, 0.95mmol), Pd(dppf)Cl 2 (78.6mg, 0.096mmol), potassium carbonate (0.45g, 4.57mmol) and 1,4-dioxane (10.0mL), warmed to 100°C, Reaction for 24h. It was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (50 mL) was added to the residue, stirred for 10 min, extracted with ethyl acetate (200 mL×3), the organic phases were combined and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/ v) = 1/0 - 1/1) to give the title compound as a yellow solid (0.20 g, 34.6%).

MS(ESI,pos.ion)m/z:635.2[M+H] +. MS(ESI,pos.ion)m/z:635.2[M+H] + .

第二步(S)-4-(7-(2-乙酰氧基-3-甲氧基苯基)-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(7-(2-acetoxy-3-methoxyphenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(2-羟基-3-甲氧基-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.43g,0.67mmol)，三乙胺(1.0mL,7.2mmol)，二氯甲烷(10mL)。再缓慢滴加乙酰氯(0.1mL,1.0mmol)，常温搅拌6h。待原料反应完全后，体系减压旋干，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/1–0/1)，得到标题化合物黄色固体(0.39g,85.8％)。Add (S)-4-(6-chloro-7-(2-hydroxy-3-methoxy-phenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.43 g, 0.67 mmol) , triethylamine (1.0 mL, 7.2 mmol), dichloromethane (10 mL). Then slowly add acetyl chloride (0.1 mL, 1.0 mmol) dropwise, and stir at room temperature for 6 h. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1-0/1) to obtain the title compound as a yellow solid ( 0.39g, 85.8%).

MS(ESI,pos.ion)m/z:677.3[M+H] +. MS(ESI,pos.ion)m/z:677.3[M+H] + .

第三步(S)-4-(7-(2-乙酰氧基-3-甲氧基苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The third step (S)-4-(7-(2-acetoxy-3-methoxyphenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3 -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(7-(2-乙酰氧基-3-甲氧基苯基)-6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.10g,0.15mmol)，xphos Pd G2(23.2mg,0.030mmol)，碳酸钾(29.6mg,0.30mmol)，环丙基溴化锌(10.0mL,0.5mol/L,5mmol)，升温至60℃，搅拌过夜。待原料反应完全后，体系减压旋干，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0-1/1)，得到标题化合物黄色固体(69.2mg,68.4％)。Add (S)-4-(7-(2-acetoxy-3-methoxyphenyl)-6-chloro-1-(2-isopropyl-4-methylpyridine-3- (0.10 g, 0.15 mmol ), xphos Pd G2 (23.2 mg, 0.030 mmol), potassium carbonate (29.6 mg, 0.30 mmol), cyclopropylzinc bromide (10.0 mL, 0.5 mol/L, 5 mmol), warmed to 60° C. and stirred overnight. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-1/1) to obtain the title compound as a yellow solid ( 69.2 mg, 68.4%).

MS(ESI,pos.ion)m/z:683.4[M+H] +. MS(ESI,pos.ion)m/z:683.4[M+H] + .

第四步(S)-2-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-6-甲氧基苯基乙酸酯The fourth step (S)-2-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl) -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-6-methoxyphenyl acetate

反应瓶中加入(S)-4-(7-(2-乙酰氧基-3-甲氧基苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(20.5mg,0.030mmol)，二氯甲烷(4.0mL)和三氟乙酸(2.5mL)，常温搅拌4.5h。待原料反应完全后，体系减压旋干，得到标题化合物棕色液体(17.5mg,100％)。Add (S)-4-(7-(2-acetoxy-3-methoxyphenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (20.5mg, 0.030 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (2.5 mL), stirred at room temperature for 4.5 h. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure to obtain the title compound as a brown liquid (17.5 mg, 100%).

第五步(S)-2-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-6-甲氧基苯基乙酸酯The fifth step (S)-2-(4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-6-methoxyphenyl acetate

反应瓶中加入(S)-2-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-6-甲氧基苯基乙酸酯(17.5mg,0.030mmol)，二氯甲烷(2mL)，降温至0℃，缓慢滴加丙烯酰氯(6.6mg,0.073mmol)的二氯甲烷(2mL)溶液，滴毕，搅拌3h。待原料反应完全后，体系减压旋干，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1-20/1)，得到标题化合物黄色固体(5.6mg,29.0％)。Add (S)-2-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-6-methoxyphenyl acetate (17.5 mg, 0.030 mmol), dichloromethane (2 mL), cooled to 0°C, slowly added dropwise a solution of acryloyl chloride (6.6 mg, 0.073 mmol) in dichloromethane (2 mL), the drop was completed, and stirred for 3 h. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (5.6 mg, 29.0%).

MS(ESI,pos.ion)m/z:637.2[M+H] +. MS(ESI,pos.ion)m/z:637.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.48(d,J＝4.8Hz,1H),7.55(dd,J＝8.7,5.0Hz,1H),7.24–7.17(m,1H),7.05(dd,J＝30.0,6.3Hz,2H),6.74(d,J＝5.3Hz,1H),6.63(dd,J＝20.7,6.0Hz,1H),6.43(d,J＝16.1Hz,1H),5.84(d,J＝9.9Hz,1H),3.86(s,3H),3.80–3.72(m,2H),3.63(dd,J＝6.6,3.4Hz,2H),2.29–2.19(m,2H),2.09–2.02(m,4H),2.02–1.94(m,3H),1.45(d,J＝5.4Hz,2H),1.15–1.09(m,4H),1.07–1.01(m,4H),0.88(d,J＝3.9Hz,3H),0.86(s,4H),0.75(dd,J＝13.6,6.2Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.48 (d, J=4.8 Hz, 1H), 7.55 (dd, J=8.7, 5.0 Hz, 1H), 7.24-7.17 (m, 1H), 7.05 ( dd,J＝30.0,6.3Hz,2H),6.74(d,J＝5.3Hz,1H),6.63(dd,J＝20.7,6.0Hz,1H),6.43(d,J＝16.1Hz,1H), 5.84(d,J=9.9Hz,1H),3.86(s,3H),3.80-3.72(m,2H),3.63(dd,J=6.6,3.4Hz,2H),2.29-2.19(m,2H) , 2.09–2.02 (m, 4H), 2.02–1.94 (m, 3H), 1.45 (d, J=5.4Hz, 2H), 1.15–1.09 (m, 4H), 1.07–1.01 (m, 4H), 0.88 (d, J=3.9Hz, 3H), 0.86 (s, 4H), 0.75 (dd, J=13.6, 6.2Hz, 2H).

实施例13(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 13 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2,3-dimethoxyphenyl)-1- (2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000040
Figure PCTCN2021112919-appb-000040

第一步(S)-4-(6-氯-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2,3-dimethoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.28g,0.51mmol)，2,3-二甲氧基苯硼酸(0.30g,1.67mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(47.3mg,0.058mmol)，醋酸钾(70.0mg,0.71mmol)和1,4-二氧六环(10.0mL)，升温至90℃，搅拌10min，再加入二氧六环与水的混合溶液(v/v＝1/1,0.5mL)，再保温搅拌3h。冷却至室温，减压浓缩除去溶剂，得到的残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，减压浓缩，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1–1/1)，得到标题化合物淡黄色固体(0.21g,63.1％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.28 g, 0.51 mmol), 2,3-dimethoxybenzeneboronic acid (0.30 g , 1.67 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (47.3 mg, 0.058 mmol), potassium acetate (70.0 mg, 0.71 mmol) and 1,4-dioxane (10.0 mL), warmed to 90°C, stirred for 10 min, and then added a mixed solution of dioxane and water (v/v=1/1, 0.5 mL) , and then keep stirring for 3h. Cooled to room temperature, concentrated under reduced pressure to remove the solvent, added saturated brine (30 mL) to the obtained residue, stirred for 10 min, extracted with ethyl acetate (100 mL×3), combined the organic phases and concentrated under reduced pressure, the obtained residue was filtered through silica gel Separation and purification by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1-1/1) gave the title compound as a pale yellow solid (0.21 g, 63.1%).

MS(ESI,pos.ion)m/z:649.3[M+H] +. MS(ESI,pos.ion)m/z:649.3[M+H] + .

第二步(S)-4-(6-环丙基-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(2,3-dimethoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) -Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6-氯-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.21g,0.32mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(26.0mg,0.033mmol)，环丙基溴化锌(15.0mL,8.0mmol)，升温至66℃，反应5小时。冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(85.8mg,40.9％)。Add (S)-4-(6-chloro-7-(2,3-dimethoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.21 g, 0.32 mmol), chloro (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium (II) (26.0 mg, 0.033 mmol), cyclopropyl zinc bromide (15.0 mL, 8.0 mmol), the temperature was raised to 66° C., and the reaction was performed for 5 hours. It was cooled to room temperature, saturated brine (10.0 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v /v)=1/1) to give the title compound as a yellow solid (85.8 mg, 40.9%).

MS(ESI,pos.ion)m/z:655.4[M+H] +. MS(ESI,pos.ion)m/z:655.4[M+H] + .

第三步(S)-6-环丙基-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(2,3-dimethoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4- Synthesis of (2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(50.9mg,0.078mmol)，三氟乙酸(3.0mL)和二氯甲烷(5.0mL)，常温搅拌1h。待原料反应完全后，减压旋干，真空干燥，得到标题化合物棕色固体(43.2mg,100.0％)，直接用于下一步。Add (S)-4-(6-cyclopropyl-7-(2,3-dimethoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (50.9 mg, 0.078 mmol) , trifluoroacetic acid (3.0 mL) and dichloromethane (5.0 mL), stirred at room temperature for 1 h. After the reaction of the raw materials was completed, it was spin-dried under reduced pressure and dried in vacuo to obtain the title compound as a brown solid (43.2 mg, 100.0%), which was directly used in the next step.

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2,3-dimethoxyphenyl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(2,3-二甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(43.2mg,0.078mmol)，N,N-二异丙基乙胺(0.1mL，0.6mmol)，二氯甲烷(4.0mL)，降温至-30℃，缓慢滴加丙烯酰氯(0.1mL,0.1mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10min。待原料反应完全后，体系减压旋干，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1–20/1)，得到标题化合物黄色固体(26.8mg,56.5％)。Add (S)-6-cyclopropyl-7-(2,3-dimethoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4 to the reaction flask -(2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (43.2 mg, 0.078 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), dichloromethane (4.0 mL), cooled to -30°C, slowly added dropwise a solution of acryloyl chloride (0.1 mL, 0.1 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 min. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (26.8 mg, 56.5%).

MS(ESI,pos.ion)m/z:609.3[M+H] +. MS(ESI,pos.ion)m/z:609.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.47(d,J＝4.7Hz,1H),7.63(s,1H),7.05(t,J＝6.6Hz,2H),6.95(d,J＝8.0Hz,1H),6.63(t,J＝16.0Hz,2H),6.42(d,J＝16.6Hz,1H),5.83(d,J＝10.8Hz,1H),3.89(s,3H),3.76–3.62(m,2H),3.42(s,3H),1.81(s,6H),1.65(s,1H),1.58(s,2H),1.50(s,2H),1.34(d,J＝10.3Hz,2H),1.23(d,J＝6.4Hz,3H),1.04(s,3H),0.89(d,J＝6.7Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.47 (d, J=4.7 Hz, 1H), 7.63 (s, 1H), 7.05 (t, J=6.6 Hz, 2H), 6.95 (d, J= 8.0Hz, 1H), 6.63(t, J＝16.0Hz, 2H), 6.42(d, J＝16.6Hz, 1H), 5.83(d, J＝10.8Hz, 1H), 3.89(s, 3H), 3.76 –3.62(m, 2H), 3.42(s, 3H), 1.81(s, 6H), 1.65(s, 1H), 1.58(s, 2H), 1.50(s, 2H), 1.34(d, J=10.3 Hz, 2H), 1.23(d, J=6.4Hz, 3H), 1.04(s, 3H), 0.89(d, J=6.7Hz, 4H).

实施例14(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 14 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-hydroxyphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000041
Figure PCTCN2021112919-appb-000041

第一步(S)-4-(6-氯-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯The first step (S)-4-(6-chloro-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.20g,0.37mmol)，(2-氟-5-甲氧基)苯硼酸(0.19g,1.13mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(33.4mg,0.041mmol)，醋酸钾(50.2mg,0.51mmol)和1,4-二氧六环(20.0mL)，氮气保护下，升温至90℃，搅拌3h。冷却至室温，减压浓缩除去溶剂，得到的残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(100mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.15g,61.7％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.37 mmol), (2-fluoro-5-methoxy)benzeneboronic acid (0.19 g, 1.13 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33.4 mg, 0.041 mmol), acetic acid Potassium (50.2 mg, 0.51 mmol) and 1,4-dioxane (20.0 mL) were heated to 90 °C under nitrogen protection and stirred for 3 h. Cooled to room temperature, concentrated under reduced pressure to remove the solvent, added saturated brine (30 mL) to the obtained residue, stirred for 10 min, extracted with ethyl acetate (100 mL×3), combined the organic phases and concentrated under reduced pressure, the residue was filtered through a silica gel column Purification by chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (0.15 g, 61.7%).

第二步(S)-4-(6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯The second step (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.33g,0.52mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(45.0mg,0.057mmol)和环丙基溴化锌(30.0mL,20.0mmol)，升温至66℃，反应7小时。冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.14g,40.9％)。Add (S)-4-(6-chloro-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.33 g, 0.52 mmol), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ] Palladium(II) (45.0 mg, 0.057 mmol) and cyclopropylzinc bromide (30.0 mL, 20.0 mmol), the temperature was raised to 66° C., and the reaction was carried out for 7 hours. It was cooled to room temperature, saturated brine (10.0 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=1/1) to give the title compound as a yellow solid (0.14 g, 40.9%).

MS(ESI,pos.ion)m/z:643.4[M+H] +. MS(ESI,pos.ion)m/z:643.4[M+H] + .

第三步(S)-6-环丙基-7-(2-氟-5-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d] 嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(2-fluoro-5-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-( Synthesis of 2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(2-氟-5-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(63.2mg,0.098mmol)，二氯甲烷(8.0mL)，置于-78℃中搅拌5min，缓慢滴加三溴化硼的二氯甲烷溶液(0.1mL)，滴加完毕后转移至冰水浴中，搅拌10min。待原料反应完全后，体系减压旋干，干燥，得到标题化合物棕色固体(37.6mg,72.3％)，直接用于下一步。MS(ESI,pos.ion)m/z:529.2[M+H] +. Add (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3- yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (63.2 mg, 0.098 mmol ), dichloromethane (8.0 mL), placed at -78°C and stirred for 5 min, slowly added boron tribromide in dichloromethane solution (0.1 mL) dropwise, transferred to an ice-water bath and stirred for 10 min. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure and dried to obtain the title compound as a brown solid (37.6 mg, 72.3%), which was directly used in the next step. MS(ESI,pos.ion)m/z:529.2[M+H] + .

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-hydroxyphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(2-氟-5-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(37.6mg,0.071mmol)，N,N-二异丙基乙胺(0.1mL，0.6mmol)，二氯甲烷(5.0mL)，降温至-30℃，缓慢滴加丙烯酰氯(0.1mL,0.1mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10分钟。待原料反应完全后，体系减压旋干，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1–20/1)，得到标题化合物黄色固体(26.1mg,63.0％)。Add (S)-6-cyclopropyl-7-(2-fluoro-5-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4- (2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (37.6 mg, 0.071 mmol), N,N-diisopropylethylamine (0.1 mL) , 0.6 mmol), dichloromethane (5.0 mL), cooled to -30°C, slowly added dropwise a solution of acryloyl chloride (0.1 mL, 0.1 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 minutes. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (26.1 mg, 63.0%).

MS(ESI,pos.ion)m/z:583.2[M+H] +. MS(ESI,pos.ion)m/z:583.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.25(d,J＝18.1Hz,1H),7.65(s,1H),6.88(dd,J＝21.2,12.1Hz,2H),6.76(d,J＝8.1Hz,1H),6.60(d,J＝1.7Hz,2H),6.43(d,J＝16.5Hz,1H),5.83(d,J＝11.5Hz,1H),5.50–5.30(m,1H),5.12(d,J＝71.1Hz,1H),4.74(t,J＝18.2Hz,1H),4.58–4.40(m,1H),3.95–3.79(m,1H),3.68(dd,J＝19.4,13.4Hz,2H),2.81(s,1H),2.04–1.86(m,6H),1.66–1.47(m,4H),1.07(d,J＝6.2Hz,3H),0.95–0.84(m,3H),0.54(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.25 (d, J=18.1 Hz, 1H), 7.65 (s, 1H), 6.88 (dd, J=21.2, 12.1 Hz, 2H), 6.76 (d, J＝8.1Hz, 1H), 6.60(d, J＝1.7Hz, 2H), 6.43(d, J＝16.5Hz, 1H), 5.83(d, J＝11.5Hz, 1H), 5.50–5.30(m, 1H), 5.12 (d, J=71.1Hz, 1H), 4.74 (t, J=18.2Hz, 1H), 4.58–4.40 (m, 1H), 3.95–3.79 (m, 1H), 3.68 (dd, J =19.4,13.4Hz,2H),2.81(s,1H),2.04-1.86(m,6H),1.66-1.47(m,4H),1.07(d,J=6.2Hz,3H),0.95-0.84( m,3H),0.54(s,2H).

实施例15(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 15 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1 -(2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000042
Figure PCTCN2021112919-appb-000042

第一步(S)-4-(6-氯-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3- 甲基哌嗪-1-羧酸叔丁酯(0.20g,0.37mmol)，4-氟-2-甲氧基苯硼酸(70mg,0.4mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(61mg,0.073mmol)，醋酸钾(0.19g,1.8mmol)和1,4-二氧六环(6mL)，升温至90℃，搅拌3h。冷却至室温，浓缩除去溶剂。浓缩物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物黄色固体(0.14g,60.0％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.37 mmol), 4-fluoro-2-methoxyphenylboronic acid (70 mg , 0.4mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (61mg, 0.073mmol), potassium acetate (0.19g , 1.8 mmol) and 1,4-dioxane (6 mL), the temperature was raised to 90 °C and stirred for 3 h. It was cooled to room temperature and concentrated to remove the solvent. The concentrate was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow solid (0.14 g, 60.0%).

MS(ESI,pos.ion)m/z:637.3[M+H] +. MS(ESI,pos.ion)m/z:637.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.49(d,J＝4.9Hz,1H),8.04(s,1H),7.08(d,J＝4.9Hz,1H),7.03–6.93(m,1H),6.69–6.59(m,2H),5.22–4.54(m,1H),4.54–4.21(m,2H),4.21–3.85(m,2H),3.74(s,3H),3.47–2.97(m,2H),2.84–2.59(m,1H),2.05(s,3H),1.52(s,9H),1.27–1.16(m,6H),1.05(dd,J＝6.7,2.8Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.49 (d, J=4.9 Hz, 1H), 8.04 (s, 1H), 7.08 (d, J=4.9 Hz, 1H), 7.03-6.93 (m, 1H), 6.69–6.59 (m, 2H), 5.22–4.54 (m, 1H), 4.54–4.21 (m, 2H), 4.21–3.85 (m, 2H), 3.74 (s, 3H), 3.47–2.97 ( m, 2H), 2.84–2.59 (m, 1H), 2.05 (s, 3H), 1.52 (s, 9H), 1.27–1.16 (m, 6H), 1.05 (dd, J=6.7, 2.8Hz, 3H) .

第二步(S)-4-(6-环丙基-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.26g,0.41mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(33mg,0.041mmol)，环丙基溴化锌四氢呋喃溶液(8.5mL,4.3mmol)和碳酸钠(0.22g,2.1mmol)，氮气置换，升温至65℃，反应过夜。冷却至室温，浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物黄色固体(0.10g,38.0％)。Add (S)-4-(6-chloro-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.26 g, 0.41 mmol), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ] Palladium (II) (33 mg, 0.041 mmol), cyclopropylzinc bromide tetrahydrofuran solution (8.5 mL, 4.3 mmol) and sodium carbonate (0.22 g, 2.1 mmol), nitrogen was replaced, the temperature was raised to 65 ° C, and the reaction was performed overnight. It was cooled to room temperature, concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow solid (0.10 g, 38.0%).

MS(ESI,pos.ion)m/z:643.3[M+H] +. MS(ESI,pos.ion)m/z:643.3[M+H] + .

第三步(S)-6-环丙基-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4 Synthesis of -(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(95mg,0.15mmol)，三氟乙酸(1mL)和二氯甲烷(2mL)，常温搅拌2h。浓缩除去溶剂，浓缩物直接用于下一步反应。Add (S)-4-(6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3- yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (95 mg, 0.15 mmol) , trifluoroacetic acid (1 mL) and dichloromethane (2 mL), stirred at room temperature for 2 h. The solvent was removed by concentration, and the concentrate was directly used in the next reaction.

MS(ESI,pos.ion)m/z:543.3[M+H] +. MS(ESI,pos.ion)m/z:543.3[M+H] + .

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1 Synthesis of -(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(4-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.16g,0.29mmol)，DIPEA(80mg,0.61mmol)，二氯甲烷(2mL)，降温至0℃，缓慢滴加丙烯酰氯(40mg,0.43mmol)，滴加完毕，室温搅拌2小时。浓缩除去溶剂。残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝200/1)，得到标题化合物黄色固体(50mg,28.0％)。Add (S)-6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 4-(2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.16 g, 0.29 mmol), DIPEA (80 mg, 0.61 mmol), dichloromethane (2 mL), the temperature was lowered to 0° C., acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise, the dropwise addition was completed, and the mixture was stirred at room temperature for 2 hours. Concentrate to remove solvent. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=200/1) to obtain the title compound as a yellow solid (50 mg, 28.0%).

MS(ESI,pos.ion)m/z:597.3[M+H] +. MS(ESI,pos.ion)m/z:597.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.53–8.43(m,1H),7.58(d,J＝3.7Hz,1H),7.08(d,J＝4.6Hz,1H),7.03 –6.92(m,1H),6.67–6.62(m,3H),6.40(d,J＝16.8Hz,1H),5.81(d,J＝10.5Hz,1H),4.52–4.37(m,1H),4.38–4.19(m,1H),4.10–3.94(m,1H),3.70(s,3H),3.61–3.43(m,1H),3.37–3.19(m,1H),3.16–2.95(m,1H),2.87–2.69(m,1H),2.10–2.00(m,1H),1.81–1.68(m,1H),1.61–1.43(m,4H),1.25(d,J＝5.7Hz,6H),1.05(d,J＝6.5Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.53-8.43 (m, 1H), 7.58 (d, J=3.7Hz, 1H), 7.08 (d, J=4.6Hz, 1H), 7.03-6.92 ( m, 1H), 6.67–6.62 (m, 3H), 6.40 (d, J=16.8Hz, 1H), 5.81 (d, J=10.5Hz, 1H), 4.52–4.37 (m, 1H), 4.38–4.19 (m, 1H), 4.10–3.94 (m, 1H), 3.70 (s, 3H), 3.61–3.43 (m, 1H), 3.37–3.19 (m, 1H), 3.16–2.95 (m, 1H), 2.87 –2.69(m,1H),2.10-2.00(m,1H),1.81-1.68(m,1H),1.61-1.43(m,4H),1.25(d,J=5.7Hz,6H),1.05(d ,J=6.5Hz,3H).

实施例16 4-(4-丙烯酰基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 16 4-(4-Acryloylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methyl) oxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000043
Figure PCTCN2021112919-appb-000043

第一步4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The first step 4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1,2 - Synthesis of tert-butyl dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

反应瓶中加入4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(0.21g,0.39mmol)，2-甲氧基苯硼酸(0.21g,1.35mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(34.9mg,0.043mmol)，醋酸钾(52.3mg,0.53mmol)和1,4-二氧六环(10.0mL)，氮气保护，升温至90℃，搅拌10分钟后加入水(0.5mL)，继续搅拌3h。冷却至室温，浓缩除去溶剂，加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(10mL×3)，合并有机相，浓缩，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.19g,81.8％)。4-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2, 3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.21 g, 0.39 mmol), 2-methoxybenzeneboronic acid (0.21 g, 1.35 mmol), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (34.9 mg, 0.043 mmol), potassium acetate (52.3 mg, 0.53 mmol) and 1,4-dioxane (10.0 mL) , under nitrogen protection, the temperature was raised to 90°C, and after stirring for 10 minutes, water (0.5 mL) was added, and stirring was continued for 3h. Cooled to room temperature, concentrated to remove the solvent, added saturated brine (30 mL), stirred for 10 min, extracted with ethyl acetate (10 mL×3), combined the organic phases, concentrated, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=1/1) to give the title compound as a yellow solid (0.19 g, 81.8%).

MS(ESI,pos.ion)m/z:605.2[M+H] +. MS(ESI,pos.ion)m/z:605.2[M+H] + .

第二步4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The second step 4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1 Synthesis of ,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(0.19g,0.32mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(26.5mg,0.034mmol)和环丙基溴化锌(10.0mL,5.0mmol)，升温至66℃，反应7小时。冷却至室温，加入饱和食盐水(10mL)，乙酸乙酯萃取(30mL×3)，合并有机相，浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(96.5mg,50.1％)。MS(ESI,pos.ion)m/z:611.3[M+H] +. Add 4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1 to the reaction flask, 2-Dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.19 g, 0.32 mmol), chloro(2-dicyclohexylphosphino-2', 4',6'-Triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (26.5 mg, 0.034 mmol) and Cyclopropylzinc bromide (10.0 mL, 5.0 mmol) was heated to 66° C. and reacted for 7 hours. It was cooled to room temperature, saturated brine (10 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v )=1/1) to obtain the title compound as a yellow solid (96.5 mg, 50.1%). MS(ESI,pos.ion)m/z:611.3[M+H] + .

第三步6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-4-(哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮 的合成The third step 6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(piperazin-1-yl) ) Synthesis of pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(80.0mg,0.13mmol)，二氯甲烷(5.0mL)，三氟乙酸(2.0mL)，室温下搅拌1h。待原料反应完全后，体系减压浓缩，干燥得到标题化合物棕色固体(66.9mg,100％)，直接用于下一步。Add 4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (80.0 mg, 0.13 mmol), dichloromethane (5.0 mL), trifluoroacetic acid (2.0 mL), stirred at room temperature for 1 h. After the reaction of the raw materials was completed, the system was concentrated under reduced pressure and dried to obtain the title compound as a brown solid (66.9 mg, 100%), which was directly used in the next step.

MS(ESI,pos.ion)m/z:511.2[M+H] +. MS(ESI,pos.ion)m/z:511.2[M+H] + .

第四步4-(4-丙烯酰基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step 4-(4-acryloylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methyl) Synthesis of oxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-4-(哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(66.9mg,0.13mmol)，N,N-二异丙基乙胺(0.1mL，0.6mmol)，二氯甲烷(5.0mL)，置于0℃，缓慢滴加丙烯酰氯(0.05mL,0.6mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10分钟。待原料反应完全后，体系减压旋干，残余物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1-0/1)，得到标题化合物黄色固体(18.0mg,24.3％)。Add 6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(piperazine-1- yl)pyrido[2,3-d]pyrimidin-2(1H)-one (66.9 mg, 0.13 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), dichloromethane (5.0 mL), placed at 0° C., slowly added dropwise a solution of acryloyl chloride (0.05 mL, 0.6 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 minutes. After the reaction of the raw materials was completed, the system was spin-dried under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1-0/1) to obtain the title compound as a yellow solid (18.0 mg, 24.3%).

MS(ESI,pos.ion)m/z:565.2[M+H] +. MS(ESI,pos.ion)m/z:565.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.66(d,J＝4.8Hz,1H),7.65(s,1H),7.38(t,J＝7.4Hz,1H),7.23(d,J＝4.3Hz,1H),7.02–6.91(m,3H),6.65(dd,J＝17.0,10.3Hz,1H),6.43(d,J＝17.9Hz,1H),5.84(d,J＝10.5Hz,1H),3.72(s,3H),2.86–2.81(m,1H),2.12(s,3H),1.78(dd,J＝9.6,4.3Hz,1H),1.31(d,J＝5.3Hz,5H),1.14(d,J＝6.8Hz,4H),0.88(dd,J＝18.9,7.0Hz,7H),0.54(d,J＝4.1Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.66 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.23 (d, J= 4.3Hz, 1H), 7.02–6.91 (m, 3H), 6.65 (dd, J=17.0, 10.3Hz, 1H), 6.43 (d, J=17.9Hz, 1H), 5.84 (d, J=10.5Hz, 1H), 3.72(s, 3H), 2.86–2.81(m, 1H), 2.12(s, 3H), 1.78(dd, J=9.6, 4.3Hz, 1H), 1.31(d, J=5.3Hz, 5H) ),1.14(d,J＝6.8Hz,4H),0.88(dd,J＝18.9,7.0Hz,7H),0.54(d,J＝4.1Hz,2H).

实施例17(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 17(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(1,5-dimethyl-6-oxo-1 ,6-Dihydropyridin-3-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000044
Figure PCTCN2021112919-appb-000044

第一步5-溴-1,3-二甲基吡啶-2(1H)-酮的合成The first step is the synthesis of 5-bromo-1,3-lutidine-2(1H)-one

钢制反应釜中加入5-溴-3-甲基吡啶-2(1H)-酮(0.51g,2.69mmol)，N,N-二甲基甲酰胺(6.0mL)，叔丁醇钾(0.65g,5.79mmol)和碘甲烷(0.5mL,8mmol)，密闭升温至80℃，搅拌过夜。冷却至室温，减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0-1/1)，得到标题化合物黄色 液体(0.41g,75.9％)。In the steel reactor, add 5-bromo-3-methylpyridine-2(1H)-one (0.51g, 2.69mmol), N,N-dimethylformamide (6.0mL), potassium tert-butoxide (0.65g) g, 5.79 mmol) and methyl iodide (0.5 mL, 8 mmol), closed and heated to 80°C, and stirred overnight. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-1/1) to obtain the title compound as a yellow liquid (0.41 g). , 75.9%).

MS(ESI,pos.ion)m/z:202.0[M+H] +. MS(ESI,pos.ion)m/z:202.0[M+H] + .

第二步1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2(1H)-酮的合成The second step 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2(1H)-one Synthesis

反应瓶中加入5-溴-1,3-二甲基吡啶-2(1H)-酮(0.41g,2.04mmol)，乙酸钾(0.71g,7.26mmol)，Pd(dppf)Cl 2(0.18g,0.22mmol)，1,4-二氧六环(15.0mL)，联硼酸频那醇酯(1.30g,5.10mmol)，氮气保护下，升温至85℃，搅拌过夜。冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化后(石油醚/乙酸乙酯(v/v)＝10/1–1/1)，得到标题化合物黄色液体(0.45g,89.2％)。 5-Bromo-1,3-lutidine-2(1H)-one (0.41g, 2.04mmol), potassium acetate (0.71g, 7.26mmol), Pd(dppf)Cl 2 (0.18g) were added to the reaction flask , 0.22 mmol), 1,4-dioxane (15.0 mL), pinacol biboronate (1.30 g, 5.10 mmol), under nitrogen protection, the temperature was raised to 85° C. and stirred overnight. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1-1/1) to obtain the title compound as a yellow liquid (0.45 g, 89.2 %).

MS(ESI,pos.ion)m/z:250.0[M+H] +. MS(ESI,pos.ion)m/z:250.0[M+H] + .

第三步(S)-4-(6-氯-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The third step (S)-4-(6-chloro-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-isopropyl) (yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate Synthesis of tert-butyl acid

反应瓶中加入(S)-4-[6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-吡啶并[2,3-d]嘧啶-4-基]-3-甲基哌嗪-1-羧酸叔丁酯(0.24g,0.44mmol)，1,3-二甲基-5-((4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2(1H)-酮(0.11g,0.44mmol)，Pd(dppf)Cl 2(32.2mg,0.039mmol)，1,4-二氧六环(10.0mL)，碳酸铯(0.33g,1.01mmol)。氮气保护下，升温至85℃，搅拌24h。冷却至室温，加入水(50mL)，用乙酸乙酯(150mL×3)萃取，合并有机相，减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1–0/1)，得到标题化合物黄色固体(70.0mg,25.2％)。 Add (S)-4-[6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-pyrido[2,3- d] pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate tert-butyl ester (0.24g, 0.44mmol), 1,3-dimethyl-5-((4,4,5,5 - Tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2(1H)-one (0.11 g, 0.44 mmol), Pd(dppf)Cl 2 (32.2 mg, 0.039 mmol) , 1,4-dioxane (10.0 mL), cesium carbonate (0.33 g, 1.01 mmol). Under nitrogen protection, the temperature was raised to 85 ° C and stirred for 24 h. Cooled to room temperature, water (50 mL) was added, and ethyl acetate was used. (150 mL×3) extraction, the organic phases were combined, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1-0/1) to obtain the title compound as a yellow solid ( 70.0 mg, 25.2%).

MS(ESI,pos.ion)m/z:634.3[M+H] +. MS(ESI,pos.ion)m/z:634.3[M+H] + .

第四步(S)-4-(6-环丙基-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The fourth step (S)-4-(6-cyclopropyl-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 -Synthesis of tert-butyl carboxylate

反应瓶中加入(S)-4-(6-氯-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.36g,0.59mmol)，1,4-二氧六环(6.0mL)，xphos Pd G2(73.6mg,0.094mmol)，碳酸钠(0.36g,4.32mmol)，置换氮气并保护，快速加入环丙基溴化锌(12.0mL,0.5mol/L,6mmol)。体系升温至100℃，搅拌24h。冷却至室温，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0–0/1)，再经制备分离得到标题化合物黄色固体(85.3mg,23.5％)。Add (S)-4-(6-chloro-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-iso Propyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- tert-Butyl carboxylate (0.36 g, 0.59 mmol), 1,4-dioxane (6.0 mL), xphos Pd G2 (73.6 mg, 0.094 mmol), sodium carbonate (0.36 g, 4.32 mmol), displacing nitrogen and Protection, cyclopropylzinc bromide (12.0 mL, 0.5 mol/L, 6 mmol) was added quickly. The system was heated to 100°C and stirred for 24h. Cooled to room temperature, concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-0/1), and then the title compound was isolated as a yellow solid (85.3 mg, 23.5%).

第五步(S)-6-环丙基-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fifth step (S)-6-cyclopropyl-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(1,5-二甲基-6-氧-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(40.0mg,0.065mmol)，三氟乙酸(0.5mL)和二氯甲烷(4.0mL)。常温搅拌1h。减压浓缩除去溶剂,得到标题化合物棕色固体(33.5mg,100％)。Add (S)-4-(6-cyclopropyl-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- tert-Butyl carboxylate (40.0 mg, 0.065 mmol), trifluoroacetic acid (0.5 mL) and dichloromethane (4.0 mL). Stir at room temperature for 1 h. Concentration under reduced pressure to remove the solvent gave the title compound as a brown solid (33.5 mg, 100%).

第六步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The sixth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(1,5-dimethyl-6-oxo-1 Synthesis of ,6-dihydropyridin-3-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(33.5mg,0.065mmol)和N,N-二异丙基乙基胺(0.2mL)，二氯甲烷(2mL)，降温至0℃，缓慢滴加丙烯酰氯(13.6mg,0.15mmol)的二氯甲烷(2mL)溶液，滴毕，保温搅拌2.5h。待原料反应完全后，减压浓缩，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1–20/1)，再经制备色谱分离得到标题化合物黄色固体(5.6mg,11％)。Add (S)-6-cyclopropyl-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-isopropyl) to the reaction flask yl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (33.5 mg, 0.065 mmol ) and N,N-diisopropylethylamine (0.2 mL), dichloromethane (2 mL), cooled to 0 °C, slowly added dropwise a solution of acryloyl chloride (13.6 mg, 0.15 mmol) in dichloromethane (2 mL) , After dripping, keep stirring for 2.5h. After the reaction of the raw materials was completed, the reaction was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1), and then by preparative chromatography to obtain the title compound in yellow Solid (5.6 mg, 11%).

MS(ESI,pos.ion)m/z:594.4[M+H] +. MS(ESI,pos.ion)m/z:594.4[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.56(d,J＝4.9Hz,1H),7.84–7.58(m,3H),7.14(d,J＝4.9Hz,1H),6.71–6.54(m,1H),6.41(d,J＝16.7Hz,1H),5.81(d,J＝10.4Hz,1H),4.73(dd,J＝18.2,11.0Hz,1H),4.45(dd,J＝12.3,8.3Hz,1H),4.26(dd,J＝10.5,5.1Hz,1H),4.11–3.80(m,2H),3.66(d,J＝1.8Hz,2H),3.49(s,3H),2.14–1.96(m,7H),1.58–1.55(m,1H),1.51–1.44(m,2H),1.29(s,3H),1.22(s,6H),0.84(dd,J＝12.0,5.3Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.56 (d, J=4.9 Hz, 1H), 7.84-7.58 (m, 3H), 7.14 (d, J=4.9 Hz, 1H), 6.71-6.54 ( m, 1H), 6.41 (d, J=16.7Hz, 1H), 5.81 (d, J=10.4Hz, 1H), 4.73 (dd, J=18.2, 11.0Hz, 1H), 4.45 (dd, J=12.3 ,8.3Hz,1H),4.26(dd,J＝10.5,5.1Hz,1H),4.11–3.80(m,2H),3.66(d,J＝1.8Hz,2H),3.49(s,3H),2.14 –1.96(m,7H),1.58-1.55(m,1H),1.51-1.44(m,2H),1.29(s,3H),1.22(s,6H),0.84(dd,J=12.0,5.3Hz , 2H).

实施例18(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 18 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1 -(2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000045
Figure PCTCN2021112919-appb-000045

第一步(S)-4-(6-氯-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并(2,3-d)嘧啶-4-基)3-甲基哌嗪-1-羧酸叔丁酯(0.30g,0.55mmol)，3-氟-2-甲氧基苯硼酸(93.2mg,0.55mmol)，Pd(dppf)Cl 2(44.8mg,0.055mmol)，1,4-二氧六环(10.0mL)，碳酸铯(0.45g,1.37mmol)。氮气保护下，升温至85℃，搅拌24h。冷却至室温，加入水(50mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/1–0/1)，得到标题化合物黄色固体(0.19g,53.2％)。 Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask (2,3-d)pyrimidin-4-yl)3-methylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.55 mmol), 3-fluoro-2-methoxyphenylboronic acid (93.2 mg) , 0.55 mmol), Pd(dppf)Cl 2 (44.8 mg, 0.055 mmol), 1,4-dioxane (10.0 mL), cesium carbonate (0.45 g, 1.37 mmol). Under nitrogen protection, the temperature was raised to 85 °C and stirred for 24 h. Cooled to room temperature, added water (50 mL), extracted with ethyl acetate (100 mL×3), combined the organic phases, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1-0/1) to give the title compound as a yellow solid (0.19 g, 53.2%).

MS(ESI,pos.ion)m/z:637.3[M+H] +. MS(ESI,pos.ion)m/z:637.3[M+H] + .

第二步(S)-4-(6-环丙基-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(3-氟-2-甲氧基-苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并 [2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.10g,0.16mmol)，xphos Pd G2(49.4mg,0.063mmol)，碳酸钠(83.2mg,0.79mmol)和环丙基溴化锌(10.0mL,10mmol)。体系升温至50℃，搅拌过夜。冷却至室温，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/1–0/1)，得到标题化合物黄色固体(53.5mg,53.1％)。Add (S)-4-(6-chloro-7-(3-fluoro-2-methoxy-phenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.10 g, 0.16 mmol) , xphos Pd G2 (49.4 mg, 0.063 mmol), sodium carbonate (83.2 mg, 0.79 mmol) and cyclopropylzinc bromide (10.0 mL, 10 mmol). The system was warmed to 50°C and stirred overnight. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1-0/1) to obtain the title compound as a yellow solid (53.5 mg, 53.1%).

MS(ESI,pos.ion)m/z:643.2[M+H] +. MS(ESI,pos.ion)m/z:643.2[M+H] + .

第三步(S)-6-环丙基-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4 Synthesis of -(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(53.5mg,0.083mmol)，二氯甲烷(4.0mL)和三氟乙酸(2.0mL)。体系常温搅拌2h，减压浓缩除去溶剂，真空干燥，得到标题化合物黄色固体(45.2mg,100％)。Add (S)-4-(6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridine-3- yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (53.5 mg, 0.083 mmol ), dichloromethane (4.0 mL) and trifluoroacetic acid (2.0 mL). The system was stirred at room temperature for 2 h, concentrated under reduced pressure to remove the solvent, and dried in vacuo to obtain the title compound as a yellow solid (45.2 mg, 100%).

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1 Synthesis of -(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-7-(3-氟-2-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(45.2mg,0.083mmol)，二氯甲烷(4mL)和N,N-二异丙基乙胺(0.2mL,1mmol)。体系降温至0℃，缓慢滴加丙烯酰氯(12.1mg,0.13mmol)的二氯甲烷(2mL)溶液，滴毕，保温搅拌2.5h。待原料反应完全后，减压浓缩，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1–20/1)，再经制备色谱分离得到标题化合物(22.9mg,46.1％)。Add (S)-6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 4-(2-Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (45.2 mg, 0.083 mmol), dichloromethane (4 mL) and N,N- Diisopropylethylamine (0.2 mL, 1 mmol). The system was cooled to 0°C, and a solution of acryloyl chloride (12.1 mg, 0.13 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the reaction of the raw materials was completed, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1), and then by preparative chromatography to obtain the title compound (22.9 mg, 46.1%).

MS(ESI,pos.ion)m/z:597.2[M+H] +. MS(ESI,pos.ion)m/z:597.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.47(d,J＝4.8Hz,1H),7.65(s,1H),7.07(tt,J＝12.5,8.3Hz,3H),6.85(d,J＝7.1Hz,1H),6.73–6.55(m,1H),6.43(d,J＝16.3Hz,1H),5.83(d,J＝10.6Hz,1H),4.82–4.70(m,1H),4.52–4.27(m,1H),4.07–3.86(m,1H),3.83–3.64(m,2H),3.56(s,3H),3.39–3.23(m,1H),3.16–2.98(m,1H),2.06(s,3H),1.23(d,J＝6.5Hz,6H),1.04(d,J＝5.3Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.47 (d, J=4.8 Hz, 1H), 7.65 (s, 1H), 7.07 (tt, J=12.5, 8.3 Hz, 3H), 6.85 (d, J=7.1Hz, 1H), 6.73–6.55 (m, 1H), 6.43 (d, J=16.3Hz, 1H), 5.83 (d, J=10.6Hz, 1H), 4.82–4.70 (m, 1H), 4.52–4.27 (m, 1H), 4.07–3.86 (m, 1H), 3.83–3.64 (m, 2H), 3.56 (s, 3H), 3.39–3.23 (m, 1H), 3.16–2.98 (m, 1H) ), 2.06(s, 3H), 1.23(d, J=6.5Hz, 6H), 1.04(d, J=5.3Hz, 3H).

实施例19(R)-4-(4-丙烯酰基-3-(羟甲基)哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 19(R)-4-(4-Acryloyl-3-(hydroxymethyl)piperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine -3-yl)-7-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000046
Figure PCTCN2021112919-appb-000046

实施例20(R)-(1-丙烯酰基-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-羟甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-2-基)甲基乙酸酯Example 20(R)-(1-Acryloyl-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-hydroxymethyl) Phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)methyl acetate

Figure PCTCN2021112919-appb-000047
Figure PCTCN2021112919-appb-000047

第一步(R)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯的合成The first step (R)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido Synthesis of [2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester

反应瓶中加入4,6,7-三氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(1.10g,2.87mmol)，(R)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(0.80g,3.73mmol)，N,N-二异丙基乙胺(2.5mL,15mmol)和乙腈(10mL)。体系升温至50℃，搅拌过夜。冷却至室温，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/0–1/1)，得到标题化合物黄色固体(1.60g,99.0％)。4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one ( 1.10g, 2.87mmol), (R)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (0.80g, 3.73mmol), N,N-diisopropylethylamine (2.5mL, 15 mmol) and acetonitrile (10 mL). The system was warmed to 50°C and stirred overnight. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/0-1/1) to obtain the title compound as a yellow solid (1.60 g, 99.0%).

MS(ESI,pos.ion)m/z:563.2[M+H] +. MS(ESI,pos.ion)m/z:563.2[M+H] + .

第二步(R)-2-(乙酰氧甲基)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The second step (R)-2-(acetoxymethyl)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester

反应瓶中加入(R)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2-(羟甲基)哌嗪-1-羧酸叔丁酯(1.60g,2.84mmol)，三乙胺(4.0mL,28.7mmol)，二氯甲烷(20.0mL)。再缓慢滴加乙酰氯(0.3mL,4mmol)，体系常温搅拌39h。待原料反应完全后，减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/1–0/1)，得到标题化合物黄色固体(0.42g,24.0％)。Add (R)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (1.60 g, 2.84 mmol), triethylamine (4.0 mL, 28.7 mmol) , dichloromethane (20.0 mL). Acetyl chloride (0.3 mL, 4 mmol) was slowly added dropwise, and the system was stirred at room temperature for 39 h. After the reaction of the raw materials was completed, the solvent was concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1-0/1) to obtain the title compound as a yellow solid ( 0.42g, 24.0%).

第三步(R)-2-(乙酰氧甲基)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The third step (R)-2-(acetoxymethyl)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy Synthesis of tert-butyl phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

反应瓶中加入(R)-2-(乙酰氧甲基)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(0.20g,0.33mmol)，2-甲氧基苯硼酸(60.1mg,0.40mmol)，Pd(dppf)Cl 2(26.9mg,0.033mmol)，碳酸铯(0.16g,0.82mmol)和1,4-二氧六环(10.0mL)。体系氮气保护下，升温至100℃，搅拌24h。冷却至室温，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝1/0–10/1)，得到标题化合物黄色固体(0.13g,57.8％)。 Add (R)-2-(acetoxymethyl)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the reaction flask Substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.20 g, 0.33 mmol), 2-methoxybenzeneboronic acid (60.1 mg, 0.40 mmol), Pd(dppf)Cl2 (26.9 mg , 0.033 mmol), cesium carbonate (0.16 g, 0.82 mmol) and 1,4-dioxane (10.0 mL). Under the protection of nitrogen, the temperature of the system was raised to 100 °C and stirred for 24 h. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1/0-10/1) to obtain the title compound as a yellow solid (0.13 g, 57.8 g) %).

MS(ESI,pos.ion)m/z:677.3[M+H] +. MS(ESI,pos.ion)m/z:677.3[M+H] + .

第四步(R)-2-(乙酰氧甲基)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The fourth step (R)-2-(acetoxymethyl)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2- Synthesis of tert-butyl methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

反应瓶中加入(R)-2-(乙酰氧甲基)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(0.13g,0.18mmol)，xphos Pd G2(29.0mg,0.037mmol)，碳酸钠(97.8mg,0.92mmol)和环丙基溴化锌(10.0mL,10.0mmol)。体系升温至50℃，搅拌过夜。冷却至室温，减压浓缩除去溶剂。残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10/1–0/1)，得到标题化合物黄色固体(0.11g,88.2％)。Add (R)-2-(acetoxymethyl)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methyl) into the reaction flask oxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.13 g, 0.18 mmol), xphos Pd G2 (29.0 mg, 0.037 mmol), sodium carbonate (97.8 mg, 0.92 mmol) and cyclopropylzinc bromide (10.0 mL, 10.0 mmol). The system was warmed to 50°C and stirred overnight. It was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1-0/1) to obtain the title compound as a yellow solid (0.11 g, 88.2%).

第五步(R)-(4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-2-基)甲基乙酸酯的合成The fifth step (R)-(4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2 -Synthesis of oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)methyl acetate

反应瓶中加入(R)-2-(乙酰氧甲基)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(0.11g,0.16mmol)，三氟乙酸(2.0mL)和二氯甲烷(4.0mL)。体系常温搅拌3.5h。待原料反应完全后，减压浓缩得到标题化合物棕色液体(94.9mg,100％)。MS(ESI,pos.ion)m/z:583.3[M+H] +. Add (R)-2-(acetoxymethyl)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2 -Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.11 g, 0.16 mmol ), trifluoroacetic acid (2.0 mL) and dichloromethane (4.0 mL). The system was stirred at room temperature for 3.5h. After the reaction of the starting materials was completed, the mixture was concentrated under reduced pressure to obtain the title compound as a brown liquid (94.9 mg, 100%). MS(ESI,pos.ion)m/z:583.3[M+H] + .

第六步(R)-4-(4-丙烯酰基-3-(羟甲基)哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(实施例19)The sixth step (R)-4-(4-acryloyl-3-(hydroxymethyl)piperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine -3-yl)-7-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Example 19)

和and

(R)-(1-丙烯酰基-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-羟甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-2-基)甲基乙酸酯(实施例20)(R)-(1-Acryloyl-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-hydroxymethylphenyl) -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)methyl acetate (Example 20)

反应瓶中加入(R)-(4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-2-基)甲基乙酸酯(94.9mg,0.16mmol)，N,N-二异丙基乙胺(0.12g,0.91mmol)和二氯甲烷(3mL)。体系降温至0℃，缓慢滴加丙烯酰氯(16.2mg,0.18mmol)的二氯甲烷(3mL)溶液，滴毕，保温搅拌2.5h。待原料反应完全后，减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝100/1–20/1)纯化一次，再经制备分离得到标题化合物实施例19黄色固体(4.9mg,5.1％)和标题化合物实施例20黄色固体(4.6mg,4.4％)。Add (R)-(4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)- 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)methyl acetate (94.9 mg, 0.16 mmol), N,N- Diisopropylethylamine (0.12 g, 0.91 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (16.2 mg, 0.18 mmol) in dichloromethane (3 mL) was slowly added dropwise. After the reaction of the raw materials was completed, it was concentrated under reduced pressure, and the residue was purified once by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1), and then the title compound, Example 19, was obtained by preparative separation. A yellow solid (4.9 mg, 5.1%) and the title compound Example 20 as a yellow solid (4.6 mg, 4.4%).

实施例19Example 19

MS(ESI,pos.ion)m/z:595.31[M+H] +. MS(ESI,pos.ion)m/z:595.31[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.48(d,J＝4.8Hz,1H),7.64(s,1H),7.37(t,J＝7.1Hz,1H),7.10–6.90(m,3H),6.69(s,1H),6.51–6.36(m,1H),5.84(d,J＝11.0Hz,1H),5.36(s,1H),4.98(dd,J＝25.7,14.5Hz,1H),4.47(d,J＝13.5Hz,2H),4.28(d,J＝7.1Hz,1H),3.72(s,3H),3.65–3.60(m,1H),2.03(s,3H),1.65(d,J＝0.5Hz,1H),1.23(d,J＝6.7Hz,6H),1.07(d,J＝6.7Hz,2H),0.85(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.48 (d, J=4.8 Hz, 1H), 7.64 (s, 1H), 7.37 (t, J=7.1 Hz, 1H), 7.10-6.90 (m, 3H), 6.69(s, 1H), 6.51–6.36(m, 1H), 5.84(d, J=11.0Hz, 1H), 5.36(s, 1H), 4.98(dd, J=25.7, 14.5Hz, 1H) ), 4.47(d, J＝13.5Hz, 2H), 4.28(d, J＝7.1Hz, 1H), 3.72(s, 3H), 3.65–3.60(m, 1H), 2.03(s, 3H), 1.65 (d, J=0.5Hz, 1H), 1.23 (d, J=6.7Hz, 6H), 1.07 (d, J=6.7Hz, 2H), 0.85 (s, 2H).

实施例20Example 20

MS(ESI,pos.ion)m/z:637.2[M+H] +. MS(ESI,pos.ion)m/z:637.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.71(d,J＝5.2Hz,1H),8.62(dd,J＝6.7,2.3Hz,1H),8.03(s,1H),7.37(s,1H),7.26(d,J＝5.2Hz,1H),6.96–6.90(m,2H),6.48–6.39(m,1H),5.89–5.82(m,1H),5.46(dd,J＝5.0,4.2Hz,1H),5.38–5.35(m,1H),3.91(t,J＝2.6Hz,1H),3.70(s,3H),2.92(dt,J＝13.3,6.6Hz,2H),2.27–2.22(m,2H),2.19(s,3H),2.02(s,3H),1.68(d,J＝4.6Hz,2H),1.47–1.43(m,1H),1.17(d,J＝6.5Hz,6H),1.04(s,1H),0.77–0.67(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.71 (d, J=5.2 Hz, 1H), 8.62 (dd, J=6.7, 2.3 Hz, 1H), 8.03 (s, 1H), 7.37 (s, 1H), 7.26 (d, J=5.2Hz, 1H), 6.96–6.90 (m, 2H), 6.48–6.39 (m, 1H), 5.89–5.82 (m, 1H), 5.46 (dd, J=5.0, 4.2Hz, 1H), 5.38–5.35 (m, 1H), 3.91 (t, J=2.6Hz, 1H), 3.70 (s, 3H), 2.92 (dt, J=13.3, 6.6Hz, 2H), 2.27– 2.22(m, 2H), 2.19(s, 3H), 2.02(s, 3H), 1.68(d, J=4.6Hz, 2H), 1.47–1.43(m, 1H), 1.17(d, J=6.5Hz) ,6H),1.04(s,1H),0.77–0.67(m,4H).

实施例21(S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-4-氟苯甲酸甲酯Example 21(S)-3-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoic acid methyl ester

Figure PCTCN2021112919-appb-000048
Figure PCTCN2021112919-appb-000048

第一步(S)-4-(6-环丙基-7-(2-氟-5-(甲氧羰基)苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-cyclopropyl-7-(2-fluoro-5-(methoxycarbonyl)phenyl)-1-(2-isopropyl-4-methylpyridine-3 -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(2-氟-5-(甲氧羰基)苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.32g,0.47mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(40mg,0.05mmol)，环丙基溴化锌四氢呋喃溶液(10mL,5mmol)和碳酸钠(0.25g,2.4mmol)，氮气保护下，升温至65℃，反应过夜。冷却至室温，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物黄色固体(0.23g,71％)。Add (S)-4-(6-chloro-7-(2-fluoro-5-(methoxycarbonyl)phenyl)-1-(2-isopropyl-4-methylpyridine-3-) to the reaction flask (0.32 g, 0.47 mmol ), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) Benzene)] palladium (II) (40 mg, 0.05 mmol), cyclopropylzinc bromide tetrahydrofuran solution (10 mL, 5 mmol) and sodium carbonate (0.25 g, 2.4 mmol), under nitrogen protection, the temperature was raised to 65 ° C, and the reaction was performed overnight. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow solid (0.23 g, 71%).

MS(ESI,pos.ion)m/z:671.3[M+H] +. MS(ESI,pos.ion)m/z:671.3[M+H] + .

第二步(S)-3-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-4-氟苯甲酸甲酯的合成The second step (S)-3-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl) - Synthesis of methyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoate

反应瓶中加入(S)-4-(6-环丙基-7-(2-氟-5-(甲氧羰基)苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.13g,0.19mmol)，三氟乙酸(2mL)和二氯甲烷(4mL)。体系常温搅拌2h，减压浓缩除去溶剂，真空干燥得到标题化合物黄色固体(0.11g,100％)，直接用于下一步反应。Add (S)-4-(6-cyclopropyl-7-(2-fluoro-5-(methoxycarbonyl)phenyl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.13 g, 0.19 mmol), trifluoroacetic acid (2 mL) and dichloromethane (4 mL). The system was stirred at room temperature for 2 h, concentrated under reduced pressure to remove the solvent, and dried in vacuo to obtain the title compound as a yellow solid (0.11 g, 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:571.3[M+H] +. MS(ESI,pos.ion)m/z:571.3[M+H] + .

第三步(S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-4-氟苯甲酸甲酯的合成The third step (S)-3-(4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine Synthesis of -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoic acid methyl ester

反应瓶中加入(S)-3-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-7-基)-4-氟苯甲酸甲酯(0.11g,0.19mmol)，三乙胺(0.11g，1.1mmol)，二氯甲烷(4mL)。体系降温至0℃，缓慢滴加丙烯酰氯(40mg,0.43mmol)，滴加完毕，室温搅拌2小时。减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝200/1)，得到标题化合物黄色固体(49mg,40.7％)。MS(ESI,pos.ion)m/z:625.3[M+H] +. Add (S)-3-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoic acid methyl ester (0.11 g, 0.19 mmol), triethylamine (0.11 g , 1.1 mmol), dichloromethane (4 mL). The system was cooled to 0° C., acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise, the dropwise addition was completed, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=200/1) to obtain the title compound as a yellow solid (49 mg, 40.7%). MS(ESI,pos.ion)m/z:625.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.49(d,J＝4.9Hz,1H),8.12–8.01(m,1H),7.92(dd,J＝6.8,1.8Hz,1H),7.70(s,1H),7.15(t,J＝9.0Hz,1H),7.09(d,J＝4.8Hz,1H),6.74–6.53(m,1H),6.41(d,J＝16.6Hz,1H),5.82(dd,J＝10.6,1.2Hz,1H),4.86–4.67(m,1H),4.67–4.42(m,1H),4.31(s,1H),4.10–3.96(m,1H),3.89(s,3H),3.76–3.45(m,2H),3.35–2.98(m,1H),2.90–2.58(m,1H),2.02–1.95(m,1H),1.88–1.77(m,1H),1.64–1.44(m,4H),1.28–1.17(m,6H),1.09(dd,J＝6.7,2.1Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.49 (d, J=4.9 Hz, 1H), 8.12-8.01 (m, 1H), 7.92 (dd, J=6.8, 1.8 Hz, 1H), 7.70 ( s, 1H), 7.15 (t, J=9.0Hz, 1H), 7.09 (d, J=4.8Hz, 1H), 6.74–6.53 (m, 1H), 6.41 (d, J=16.6Hz, 1H), 5.82(dd,J=10.6,1.2Hz,1H),4.86-4.67(m,1H),4.67-4.42(m,1H),4.31(s,1H),4.10-3.96(m,1H),3.89( s, 3H), 3.76–3.45 (m, 2H), 3.35–2.98 (m, 1H), 2.90–2.58 (m, 1H), 2.02–1.95 (m, 1H), 1.88–1.77 (m, 1H), 1.64–1.44 (m, 4H), 1.28–1.17 (m, 6H), 1.09 (dd, J=6.7, 2.1Hz, 3H).

实施例22(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 22(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2 -Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000049
Figure PCTCN2021112919-appb-000049

第一步(S)-4-(6-氯-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of tert-butyl substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

室温下，向反应瓶中依次加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.50g，0.91mmol)，2,5-二氟苯硼酸(0.19g，1.20mmol)，醋酸钾(0.14g，1.40mmol)，PdCl 2(dppf)DCM(0.08g,0.10mmol)，氮气保护下，加入1,4-二氧六环(10mL)，再次氮气换气，置于90℃油浴锅中搅拌反应14h。降温至室温，减压浓缩，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物黄色固体产物(0.52g,91.6％)。 At room temperature, add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 in sequence to the reaction flask, 2-Dipyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), 2,5-difluorophenylboronic acid ( 0.19 g, 1.20 mmol), potassium acetate (0.14 g, 1.40 mmol), PdCl 2 (dppf) DCM (0.08 g, 0.10 mmol), under nitrogen, add 1,4-dioxane (10 mL), and nitrogen again After ventilation, the reaction was stirred for 14 h in a 90°C oil bath. It was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a yellow solid product (0.52 g, 91.6%).

MS(ESI,pos.ion)m/z:625.2[M+H] +. MS(ESI,pos.ion)m/z:625.2[M+H] + .

第二步(S)-4-(6-环丙基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氯吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Synthesis of tert-butyl oxo-1,2-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

室温下，依次向反应瓶中加入(S)-4-(6-氯-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.15g，0.24mmol)，碳酸钠(0.13g，1.22mmol)，xphos Pd G2(0.04g，0.05mmol)和环丙基溴化锌(8mL，4mmol，0.5mol/L in THF)，氮气保护下，置于65℃反应17h，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.15g,99.1％)。At room temperature, add (S)-4-(6-chloro-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridine-3- yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.15 g, 0.24 mmol ), sodium carbonate (0.13g, 1.22mmol), xphos Pd G2 (0.04g, 0.05mmol) and cyclopropyl zinc bromide (8mL, 4mmol, 0.5mol/L in THF), under nitrogen protection, placed at 65°C The reaction was carried out for 17 h, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (0.15 g, 99.1%).

MS(ESI,pos.ion)m/z:631.3[M+H] +. MS(ESI,pos.ion)m/z:631.3[M+H] + .

第三步(S)-6-环丙基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2 Synthesis of -Methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

室温下，向反应瓶中依次加入(S)-4-(6-环丙基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氯吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.14g，0.22mmol)和二氯甲烷(3mL)，然后加入三氟乙酸(1mL)，室温搅拌反应30min。反应完后，减压蒸馏，得到标题化合物棕色油状物(0.12g,100％)，直接用于下一步反应。At room temperature, add (S)-4-(6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.14 g, 0.22 mmol) and dichloromethane (3 mL), then trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 30 min. After the completion of the reaction, distillation under reduced pressure gave the title compound as a brown oil (0.12 g, 100%), which was directly used in the next reaction.

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2 Synthesis of -isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

0℃下，向反应瓶中加入(S)-6-环丙基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.12g,0.22mmol)，二氯甲烷(3mL)和N,N-二异丙基乙胺(0.1mL,0.43mmol)，然后搅拌下滴加入丙烯酰氯(0.03g,0.33mmol)，滴加完毕，转移至室温搅拌反应1h。减压蒸馏，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)，得到标题化合物米黄色固体产物(62.0mg,48.8％)。Add (S)-6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl to the reaction flask at 0°C )-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.12 g, 0.22 mmol), dichloromethane (3 mL) and N, N-diisopropylethylamine (0.1 mL, 0.43 mmol), then acryloyl chloride (0.03 g, 0.33 mmol) was added dropwise with stirring, the dropwise addition was completed, and the mixture was transferred to room temperature and stirred for 1 h. It was distilled under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound as a beige solid product (62.0 mg, 48.8%).

MS(ESI,pos.ion)m/z:585.3[M+H] +. MS(ESI,pos.ion)m/z:585.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.51(d,J＝4.9Hz,1H),7.70(s,1H),7.14–7.00(m,3H),6.91–6.81(m,1H),6.68-6.59(m,1H),6.43(d,J＝16.4Hz,1H),5.83(d,J＝10.5Hz,1H),5.23–5.04(m,1H),4.82–4.25(m,3H),4.07–3.51(m,3H),3.35-3.01(m,1H),2.84–2.61(m,1H),2.02(d,J＝15.1Hz,3H),1.93–1.83(m,1H),1.72(s,3H),1.24(d,J＝6.7Hz,3H),1.06(d,J＝6.3Hz,3H),1.00–0.83(m,4H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.51(d, J=4.9Hz, 1H), 7.70(s, 1H), 7.14-7.00(m, 3H), 6.91-6.81(m, 1H), 6.68-6.59(m,1H),6.43(d,J=16.4Hz,1H),5.83(d,J=10.5Hz,1H),5.23-5.04(m,1H),4.82-4.25(m,3H) ,4.07-3.51(m,3H),3.35-3.01(m,1H),2.84-2.61(m,1H),2.02(d,J=15.1Hz,3H),1.93-1.83(m,1H),1.72 (s, 3H), 1.24 (d, J=6.7Hz, 3H), 1.06 (d, J=6.3Hz, 3H), 1.00–0.83 (m, 4H).

实施例23(S)-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(喹啉-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 23 (S)-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3 -yl)-7-(quinolin-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000050
Figure PCTCN2021112919-appb-000050

第一步(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(喹啉-8-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-Chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(quinolin-8-yl)- Synthesis of 1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并(2,3-d)嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.20g,0.37mmol)，8-喹啉硼酸(72mg,0.4mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(60mg,0.073mmol)，醋酸钾(0.19g,1.8mmol)和二氧六环(6mL)，氮气保护下，升温至90℃，搅拌反应过夜。冷却至室温，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物黄色固体(0.11g,46％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido (2,3-d)pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.37 mmol), 8-quinolineboronic acid (72 mg, 0.4 mmol), [1 ,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (60mg, 0.073mmol), potassium acetate (0.19g, 1.8mmol) and dioxygen Hexacyclic (6 mL) was heated to 90°C under nitrogen protection, and the reaction was stirred overnight. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow solid (0.11 g, 46%).

MS(ESI,pos.ion)m/z:640.4[M+H] +. MS(ESI,pos.ion)m/z:640.4[M+H] + .

第二步(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(喹啉-8-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(quinolin-8-yl) )-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

反应瓶中加入(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(喹啉-8-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.10g,0.16mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(15mg,0.019mmol)，环丙基溴化锌四氢呋喃溶液(4mL,2mmol)和碳酸钠(90mg,0.85mmol)，氮气保护下，升温至65℃，反应过夜。冷却至室温，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物黄色固体(51mg,49％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(quinolin-8-yl) to the reaction flask -1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.10 g, 0.16 mmol), chloro (2-di Cyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15 mg, 0.019 mmol), cyclopropylzinc bromide tetrahydrofuran solution (4 mL, 2 mmol) and sodium carbonate (90 mg, 0.85 mmol), under nitrogen protection, warmed to 65° C. and reacted overnight. It was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow solid (51 mg, 49%).

MS(ESI,pos.ion)m/z:646.4[M+H] +. MS(ESI,pos.ion)m/z:646.4[M+H] + .

第三步(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-(喹啉-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7- Synthesis of (quinolin-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(喹啉-8-基)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(51mg,0.079mmol)，三氟乙酸(1mL)和二氯甲烷(2mL)，常温搅拌2h。减压浓缩除去溶剂，得到标题化合物黄色半固体(43.1mg,100％)，直接用于下一步反应。Add (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(quinoline-8- ( 1 mL) and dichloromethane (2 mL), stirred at room temperature for 2 h. Concentration under reduced pressure to remove the solvent gave the title compound as a yellow semisolid (43.1 mg, 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:546.3[M+H] +. MS(ESI,pos.ion)m/z:546.3[M+H] + .

第四步(S)-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(喹啉-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮The fourth step (S)-(4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3 -yl)-7-(quinolin-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

单口瓶中加入(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-(喹啉-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(43.1mg,0.079mmol)，三乙胺(80mg，0.78mmol)，二氯甲烷(3mL)，降温至0℃，缓慢滴加丙烯酰氯(20mg,0.22mmol)，滴加完毕，室温搅拌2小时。浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝200/1)，得到标题化合物黄色固体(13mg,27.4％)。Add (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7 to the single-necked bottle -(quinolin-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (43.1 mg, 0.079 mmol), triethylamine (80 mg, 0.78 mmol), dichloromethane (3 mL) , the temperature was lowered to 0° C., acryloyl chloride (20 mg, 0.22 mmol) was slowly added dropwise, the dropwise addition was completed, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=200/1) to obtain the title compound as a yellow solid (13 mg, 27.4%).

MS(ESI,pos.ion)m/z:600.3[M+H] +. MS(ESI,pos.ion)m/z:600.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.81(s,1H),8.42(d,J＝3.3Hz,1H),8.19(d,J＝8.6Hz,1H),7.88(d,J＝8.2Hz,1H),7.72(s,1H),7.62–7.51(m,1H),7.46–7.36(m,2H),7.18–7.01(m,1H),6.76–6.53(m,1H),6.42(d,J＝16.8Hz,1H),5.82(d,J＝10.0Hz,1H),4.88–4.66(m,1H),4.51(s,1H),4.02(s,1H),3.97–3.81(m,1H),3.66(s,2H),2.78(d,J＝7.8Hz,1H),2.07(s,3H),1.55–1.49(m,6H),1.27(d,J＝11.6Hz,6H),0.94–0.81(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.81 (s, 1H), 8.42 (d, J=3.3 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.88 (d, J= 8.2Hz, 1H), 7.72 (s, 1H), 7.62–7.51 (m, 1H), 7.46–7.36 (m, 2H), 7.18–7.01 (m, 1H), 6.76–6.53 (m, 1H), 6.42 (d, J=16.8Hz, 1H), 5.82 (d, J=10.0Hz, 1H), 4.88–4.66 (m, 1H), 4.51 (s, 1H), 4.02 (s, 1H), 3.97–3.81 ( m, 1H), 3.66(s, 2H), 2.78(d, J=7.8Hz, 1H), 2.07(s, 3H), 1.55–1.49(m, 6H), 1.27(d, J=11.6Hz, 6H) ),0.94–0.81(m,3H).

实施例24(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(5-氯-2-氟苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 24 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(5-chloro-2-fluorophenyl)-6-cyclopropyl-1-( 2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000051
Figure PCTCN2021112919-appb-000051

第一步(S)-4-(6-氯-7-(5-氯-2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(5-chloro-2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.50g,0.91mmol)，5-氯-2-氟-苯硼酸(0.48g,2.75mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(77.3mg,0.095mmol)，醋酸钾(0.12g,1.20mmol)和1,4-二氧六环(15.0mL)，氮气保护下，升温至90℃，搅拌3h。冷却至室温，减压浓缩除去溶剂。所得残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.53g,90.0％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), 5-chloro-2-fluoro-phenylboronic acid (0.48 g , 2.75 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (77.3 mg, 0.095 mmol), potassium acetate (0.12 g, 1.20 mmol) and 1,4-dioxane (15.0 mL), under nitrogen protection, the temperature was raised to 90 °C and stirred for 3 h. It was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Saturated brine (30 mL) was added to the obtained residue, stirred for 10 min, extracted with ethyl acetate (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=1/1) to obtain the title compound as a yellow solid (0.53 g, 90.0%).

MS(ESI,pos.ion)m/z:641.3[M+H] +. MS(ESI,pos.ion)m/z:641.3[M+H] + .

第二步(S)-4-(7-(5-氯-2-氟苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成Second step (S)-4-(7-(5-Chloro-2-fluorophenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-氯-7-(5-氯-2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d] 嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.10g,0.16mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(15.3mg,0.019mmol)，环丙基溴化锌(8.0mL,8.0mmol)，升温至66℃，反应7h。冷却至室温，加入饱和食盐水(10.0mL)，用乙酸乙酯萃取(30.0mL×3)，合并有机相，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(67.3mg,66.1％)。Add (S)-4-(6-chloro-7-(5-chloro-2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the reaction flask - tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.10 g, 0.16 mmol), chloro ( 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II) (15.3 mg, 0.019 mmol), cyclopropylzinc bromide (8.0 mL, 8.0 mmol), the temperature was raised to 66° C. and reacted for 7 h. Cooled to room temperature, added saturated brine (10.0 mL), extracted with ethyl acetate (30.0 mL×3), combined the organic phases, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) Ester (v/v)=1/1) to give the title compound as a yellow solid (67.3 mg, 66.1%).

MS(ESI,pos.ion)m/z:647.4[M+H] +. MS(ESI,pos.ion)m/z:647.4[M+H] + .

第三步(S)-7-(5-氯-2-氟-苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-7-(5-chloro-2-fluoro-phenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4- Synthesis of (2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(7-(5-氯-2-氟苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(67.3mg,0.10mmol)，三氟乙酸(0.5mL)和二氯甲烷(3.0mL)，体系常温搅拌1h。原料反应完全后，减压旋干，得到标题化合物棕色固体(56.9mg,100.0％)，直接用于下一步。Add (S)-4-(7-(5-chloro-2-fluorophenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (67.3 mg, 0.10 mmol), Trifluoroacetic acid (0.5 mL) and dichloromethane (3.0 mL) were stirred at room temperature for 1 h. After the reaction of the starting material was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (56.9 mg, 100.0%), which was directly used in the next step.

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(5-氯-2-氟-苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-chloro-2-fluoro-phenyl)-6-cyclopropyl-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-7-(5-氯-2-氟苯基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮(67.3mg,0.12mmol)，N,N-二异丙基乙胺(0.1mL，1.0mmol)，二氯甲烷(3.0mL)，降温至0℃，缓慢滴加丙烯酰氯(0.1mL,0.6mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10min。减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1-20/1)，得到标题化合物黄色固体(50.9mg,68.8％)。Add (S)-7-(5-chloro-2-fluorophenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4- (2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (67.3 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 mL, 1.0 mmol), dichloromethane (3.0 mL), cooled to 0 °C, slowly added dropwise a solution of acryloyl chloride (0.1 mL, 0.6 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 min. The solvent was removed by concentration under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (50.9 mg, 68.8%).

MS(ESI,pos.ion)m/z:601.3[M+H] +. MS(ESI,pos.ion)m/z:601.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.53(d,J＝4.9Hz,1H),7.69(s,1H),7.36–7.31(m,1H),7.13(dd,J＝9.9,3.8Hz,2H),7.04(t,J＝9.0Hz,1H),6.62(dd,J＝26.5,11.6Hz,1H),6.42(d,J＝17.2Hz,1H),5.83(d,J＝11.8Hz,1H),3.33–3.02(m,2H),2.74(t,J＝6.4Hz,1H),2.07–1.99(m,4H),1.83(dd,J＝11.3,5.6Hz,1H),1.53(d,J＝32.8Hz,3H),1.34(s,1H),1.30–1.23(m,6H),1.07(d,J＝6.1Hz,3H),0.94(d,J＝7.6Hz,2H),0.57(s,2H) 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.53 (d, J=4.9 Hz, 1H), 7.69 (s, 1H), 7.36-7.31 (m, 1H), 7.13 (dd, J=9.9, 3.8 Hz, 2H), 7.04 (t, J=9.0Hz, 1H), 6.62 (dd, J=26.5, 11.6Hz, 1H), 6.42 (d, J=17.2Hz, 1H), 5.83 (d, J=11.8 Hz, 1H), 3.33–3.02 (m, 2H), 2.74 (t, J=6.4Hz, 1H), 2.07–1.99 (m, 4H), 1.83 (dd, J=11.3, 5.6Hz, 1H), 1.53 (d,J＝32.8Hz,3H),1.34(s,1H),1.30-1.23(m,6H),1.07(d,J＝6.1Hz,3H),0.94(d,J＝7.6Hz,2H) ,0.57(s,2H)

实施例25(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 25 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- yl)-7-(2-methoxy-3-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000052
Figure PCTCN2021112919-appb-000052

第一步(S)-4-(6-氯-7-(2-羟基-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-7-(2-hydroxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.50g,0.91mmol)，2-羟基-3-甲基苯硼酸(0.43g,2.77mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(80.6mg,0.099mmol)，醋酸钾(0.12g,1.21mmol)和1,4-二氧六环(15.0mL)，氮气保护下，升温至90℃，搅拌3h。冷却至室温，浓缩除去溶剂，残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.51g,90.3％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), 2-hydroxy-3-methylphenylboronic acid (0.43 g , 2.77mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (80.6mg, 0.099mmol), potassium acetate (0.12 g, 1.21 mmol) and 1,4-dioxane (15.0 mL), under nitrogen protection, the temperature was raised to 90 °C and stirred for 3 h. It was cooled to room temperature, concentrated to remove the solvent, saturated brine (30 mL) was added to the residue, stirred for 10 min, extracted with ethyl acetate (30 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (0.51 g, 90.3%).

MS(ESI,pos.ion)m/z:619.3[M+H] +. MS(ESI,pos.ion)m/z:619.3[M+H] + .

第二步(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl) -Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6-氯-7-(2-羟基-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.40mg,0.64mmol)，氢氧化钾(0.19g,3.39mmol)，碘甲烷(0.3mL,5.0mmol)。体系室温下搅拌3小时。加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30.0mL×3)，合并有机相，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.35g,86.8％)。Add (S)-4-(6-chloro-7-(2-hydroxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.40 mg, 0.64 mmol), hydrogen Potassium oxide (0.19 g, 3.39 mmol), iodomethane (0.3 mL, 5.0 mmol). The system was stirred at room temperature for 3 hours. Saturated brine (10.0 mL) was added, extracted with ethyl acetate (30.0 mL×3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v )=1/1) to obtain the title compound as a yellow solid (0.35 g, 86.8%).

MS(ESI,pos.ion)m/z:633.3[M+H] +. MS(ESI,pos.ion)m/z:633.3[M+H] + .

第三步(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The third step (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylbenzene) Synthesis of tert-butyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.10g,0.16mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(15.3mg,0.019mmol)，环丙基溴化锌(8.0mL,8.0mmol)。体系升温至66℃，反应7小时。冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30.0mL×3)，合并有机相浓，减压缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄 色固体(86.8mg,85.5％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.10 g, 0.16 mmol) , chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl )] palladium(II) (15.3 mg, 0.019 mmol), cyclopropylzinc bromide (8.0 mL, 8.0 mmol). The temperature of the system was raised to 66°C, and the reaction was carried out for 7 hours. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (30.0 mL×3), combine the organic phases and concentrate, remove the solvent under reduced pressure, and separate and purify the residue by silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=1/1) to obtain the title compound as a yellow solid (86.8 mg, 85.5%).

MS(ESI,pos.ion)m/z:639.4[M+H] +. MS(ESI,pos.ion)m/z:639.4[M+H] + .

第四步(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)- Synthesis of 4-(2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(86.7mg,0.14mmol)，三氟乙酸(0.5mL)和二氯甲烷(3.0mL)。体系常温搅拌1h，减压浓缩除去溶剂，干燥得到标题化合物(73.1mg,100.0％)，直接用于下一步。Add (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methyl) to the reaction flask Phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (86.7 mg, 0.14 mmol), trifluoroacetic acid (0.5 mL) and dichloromethane (3.0 mL). The system was stirred at room temperature for 1 h, concentrated under reduced pressure to remove the solvent, and dried to obtain the title compound (73.1 mg, 100.0%), which was directly used in the next step.

第五步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fifth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- yl)-7-(2-methoxy-3-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基-3-甲基苯基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮(73.1mg,0.14mmol)，N,N-二异丙基乙胺(0.1mL,1.0mmol)，二氯甲烷(3.0mL)，降温至0℃，缓慢滴加丙烯酰氯(0.1mL,0.6mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10分钟。减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1-20/1)，得到标题化合物黄色固体(32.9mg,40.9％)。Add (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl) to the reaction flask -4-(2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (73.1 mg, 0.14 mmol), N,N-diisopropylethylamine ( 0.1 mL, 1.0 mmol), dichloromethane (3.0 mL), cooled to 0°C, slowly added dropwise a solution of acryloyl chloride (0.1 mL, 0.6 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 minutes. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (32.9 mg, 40.9%).

MS(ESI,pos.ion)m/z:593.3[M+H] +. MS(ESI,pos.ion)m/z:593.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.50(d,J＝4.9Hz,1H),7.63(s,1H),7.21(d,J＝7.4Hz,1H),7.07(d,J＝4.8Hz,1H),7.01(t,J＝7.5Hz,1H),6.87(d,J＝7.3Hz,1H),6.63(dd,J＝24.0,13.4Hz,1H),6.42(d,J＝17.0Hz,1H),5.82(d,J＝10.5Hz,1H),3.74–3.67(m,1H),3.28(s,3H),2.29(s,3H),2.05(s,3H),1.58(dd,J＝13.4,4.9Hz,2H),1.49(dd,J＝10.4,5.7Hz,2H),1.34(s,2H),1.29(s,3H),1.23(d,J＝6.7Hz,3H),1.05(s,3H),0.86(dd,J＝11.1,8.3Hz,4H),0.51(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.50 (d, J=4.9 Hz, 1H), 7.63 (s, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.07 (d, J= 4.8Hz, 1H), 7.01 (t, J=7.5Hz, 1H), 6.87 (d, J=7.3Hz, 1H), 6.63 (dd, J=24.0, 13.4Hz, 1H), 6.42 (d, J= 17.0Hz, 1H), 5.82(d, J=10.5Hz, 1H), 3.74-3.67(m, 1H), 3.28(s, 3H), 2.29(s, 3H), 2.05(s, 3H), 1.58( dd,J＝13.4,4.9Hz,2H),1.49(dd,J＝10.4,5.7Hz,2H),1.34(s,2H),1.29(s,3H),1.23(d,J＝6.7Hz,3H ),1.05(s,3H),0.86(dd,J=11.1,8.3Hz,4H),0.51(s,2H).

实施例26(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 26 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- yl)-7-(8-methylnaphthalen-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000053
Figure PCTCN2021112919-appb-000053

第一步(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4- 基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalen-1-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

反应瓶中加入(S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.51g,0.93mmol)，8-甲基-1-萘基硼酸(0.26g,1.40mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(77.1mg,0.094mmol)，碳酸钠(0.13g,1.23mmol)和1,4-二氧六环(10.0mL)，氮气保护，升温至90℃，搅拌10min后加入水(0.5mL)，继续搅拌3h。冷却至室温，减压浓缩除去溶剂，残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.40g,65.2％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.51 g, 0.93 mmol), 8-methyl-1-naphthylboronic acid (0.26 g , 1.40 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (77.1 mg, 0.094 mmol), sodium carbonate (0.13 g, 1.23 mmol) and 1,4-dioxane (10.0 mL), under nitrogen protection, heated to 90° C., stirred for 10 min, added water (0.5 mL), and continued to stir for 3 h. Cooled to room temperature, concentrated under reduced pressure to remove the solvent, added saturated brine (30 mL) to the residue, stirred for 10 min, extracted with ethyl acetate (30 mL×3), combined the organic phases, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (petroleum ether/ethyl acetate (v/v)=1/1) gave the title compound as a yellow solid (0.40 g, 65.2%).

MS(ESI,pos.ion)m/z:653.4[M+H] +. MS(ESI,pos.ion)m/z:653.4[M+H] + .

第二步(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalen-1-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

反应瓶中加入(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.11g,0.18mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(70.3mg,0.089mmol)，环丙基溴化锌(10.0mL,5.0mmol)，升温至66℃，反应7h。冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30.0mL×3)，合并有机相，减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(84.7mg,73.2％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalene-1-yl)-2 to the reaction flask -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.11 g, 0.18 mmol), chloro ( 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II) (70.3 mg, 0.089 mmol), cyclopropylzinc bromide (10.0 mL, 5.0 mmol), the temperature was raised to 66° C. and reacted for 7 h. Cooled to room temperature, saturated brine (10.0 mL) was added, extracted with ethyl acetate (30.0 mL×3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=1/1) to obtain the title compound as a yellow solid (84.7 mg, 73.2%).

MS(ESI,pos.ion)m/z:659.4[M+H] +. MS(ESI,pos.ion)m/z:659.4[M+H] + .

第三步(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮的合成The third step (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalene-1-yl)-4-( Synthesis of 2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-4-(6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(84.7mg,0.13mmol)，三氟乙酸(0.2mL)和二氯甲烷(3.0mL)，常温搅拌1h。减压浓缩除去溶剂，干燥得到标题化合物黄色固体(71.8mg,100.0％)，直接用于下一步。Add (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalene-1-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (84.7 mg, 0.13 mmol), Trifluoroacetic acid (0.2 mL) and dichloromethane (3.0 mL) were stirred at room temperature for 1 h. Concentration under reduced pressure to remove the solvent and drying gave the title compound as a yellow solid (71.8 mg, 100.0%), which was used directly in the next step.

MS(ESI,pos.ion)m/z:559.4[M+H] +. MS(ESI,pos.ion)m/z:559.4[M+H] + .

第四步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridine-3- yl)-7-(8-methylnaphthalen-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(S)-6-环丙基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(8-甲基萘-1-基)-4-(2-甲基哌嗪-1-基)吡啶[2,3-d]嘧啶-2(1H)-酮(71.8mg,0.13mmol)，N,N-二异丙基乙胺(25.6mg，0.20mmol)，二氯甲烷(3.0mL)，降温至0℃，缓慢滴加丙烯酰氯(15.3mg,0.17mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10min。减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1-40/1)，得到标题化合物黄 色固体(36.7mg,46.6％)。Add (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalene-1-yl)-4- (2-Methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (71.8 mg, 0.13 mmol), N,N-diisopropylethylamine (25.6 mg, 0.20 mmol), dichloromethane (3.0 mL), cooled to 0°C, slowly added dropwise a solution of acryloyl chloride (15.3 mg, 0.17 mmol) in dichloromethane (1 mL), the dropwise addition was completed, and stirred for 10 min. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1-40/1) to obtain the title compound as a yellow solid (36.7 mg, 46.6%).

MS(ESI,pos.ion)m/z:613.4[M+H] +. MS(ESI,pos.ion)m/z:613.4[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.41(s,1H),7.88(d,J＝7.6Hz,1H),7.76(d,J＝7.7Hz,1H),7.54(d,J＝5.8Hz,1H),7.47–7.41(m,1H),7.37(t,J＝7.3Hz,1H),7.22(d,J＝6.1Hz,1H),7.11–6.99(m,2H),6.73–6.58(m,1H),6.43(d,J＝16.7Hz,1H),5.83(d,J＝10.0Hz,1H),3.85(dd,J＝55.9,20.4Hz,2H),2.07–1.96(m,6H),1.55(d,J＝31.4Hz,3H),1.37(d,J＝15.2Hz,2H),1.28(t,J＝10.7Hz,9H),1.12(s,2H),1.05(d,J＝6.0Hz,2H),0.89(d,J＝6.8Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.41 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54 (d, J= 5.8Hz, 1H), 7.47–7.41 (m, 1H), 7.37 (t, J=7.3Hz, 1H), 7.22 (d, J=6.1Hz, 1H), 7.11–6.99 (m, 2H), 6.73– 6.58(m,1H),6.43(d,J=16.7Hz,1H),5.83(d,J=10.0Hz,1H),3.85(dd,J=55.9,20.4Hz,2H),2.07–1.96(m ,6H),1.55(d,J＝31.4Hz,3H),1.37(d,J＝15.2Hz,2H),1.28(t,J＝10.7Hz,9H),1.12(s,2H),1.05(d , J=6.0Hz, 2H), 0.89(d, J=6.8Hz, 2H).

实施例27 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基))-6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮Example 27 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl))-6-cyclopropyl-7-(2-fluoro-5-methyl Phenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Figure PCTCN2021112919-appb-000054
Figure PCTCN2021112919-appb-000054

第一步(2R,5S)-4-(6-氯-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) -Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.37g,0.66mmol)，2-氟-5-甲基苯硼酸(0.30g,1.98mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.11g,0.13mmol)，醋酸钾(0.13g,1.32mmol)和1,4-二氧六环(10.0mL)，氮气保护，升温至90℃，搅拌3h。冷却至室温，浓缩除去溶剂，得到的残余物中加入饱和食盐水(10mL)，搅拌10min，用乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.34g,80.6％)。Add (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.37 g, 0.66 mmol), 2-fluoro-5-methyl Phenylboronic acid (0.30 g, 1.98 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.11 g, 0.13 mmol) , potassium acetate (0.13 g, 1.32 mmol) and 1,4-dioxane (10.0 mL), under nitrogen protection, the temperature was raised to 90 °C and stirred for 3 h. It was cooled to room temperature, concentrated to remove the solvent, saturated brine (10 mL) was added to the obtained residue, stirred for 10 min, extracted with ethyl acetate (10 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separation and purification (petroleum ether/ethyl acetate (v/v)=1/1) gave the title compound as a yellow solid (0.34 g, 80.6%).

MS(ESI,pos.ion)m/z:635.4[M+H] +. MS(ESI,pos.ion)m/z:635.4[M+H] + .

第二步(2R,5S)-4-(6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3- Synthesis of tert-butyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

反应瓶中加入(2R,5S)-4-(6-氯-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.12g,0.19mmol)，氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)(74.3mg,0.094mmol)，环丙基溴化锌(10.0mL,5.0mmol)，升温至66℃，反应7小时。冷却至室温，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(15.0mL×3)，合并有 机相，减压浓缩除去溶剂，所得残余物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物黄色固体(0.11g,92.0％)。Add (2R,5S)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.12g, 0.19mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1' -biphenyl)] palladium (II) (74.3 mg, 0.094 mmol), cyclopropyl zinc bromide (10.0 mL, 5.0 mmol), the temperature was raised to 66° C., and the reaction was carried out for 7 hours. Cooled to room temperature, saturated brine (10.0 mL) was added, extracted with ethyl acetate (15.0 mL×3), the organic phases were combined, concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) Ester (v/v)=1/1) to give the title compound as a yellow solid (0.11 g, 92.0%).

MS(ESI,pos.ion)m/z:641.3[M+H] +. MS(ESI,pos.ion)m/z:641.3[M+H] + .

第三步6-环丙基-4-((2S,5R)-2,5-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The third step 6-cyclopropyl-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入(2R,5S)-4-(6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.11g,0.17mmol)，三氟乙酸(0.2mL)和二氯甲烷(3.0mL)，常温搅拌1h。减压浓缩除去溶剂，真空干燥得到标题化合物黄色固体(92.8mg,100％)，直接用于下一步。Add (2R,5S)-4-(6-cyclopropyl-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3 to the reaction flask) -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.11 g, 0.17 mmol), trifluoroacetic acid (0.2 mL) and dichloromethane (3.0 mL), and stirred at room temperature for 1 h. Concentration under reduced pressure to remove the solvent and drying in vacuo gave the title compound as a yellow solid (92.8 mg, 100%), which was used directly in the next step.

MS(ESI,pos.ion)m/z:541.3[M+H] +. MS(ESI,pos.ion)m/z:541.3[M+H] + .

第四步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-6-环丙基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The fourth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-5-methylbenzene yl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

反应瓶中加入6-环丙基-4-((2S,5R)-2,5-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(92.8mg,0.17mmol)，N,N-二异丙基乙胺(0.3mL，2.0mmol)，二氯甲烷(3.0mL)，降温至0℃，缓慢滴加丙烯酰氯(0.1mL,1.0mmol)的二氯甲烷(1mL)溶液，滴加完毕，搅拌10min。减压浓缩除去溶剂，残余物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1-20/1)，得到标题化合物黄色固体(74.4mg,72.3％)。Add 6-cyclopropyl-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1 to the reaction flask -(2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (92.8 mg, 0.17 mmol), N,N-diisopropyl Ethylethylamine (0.3 mL, 2.0 mmol), dichloromethane (3.0 mL), cooled to 0 °C, slowly added dropwise a solution of acryloyl chloride (0.1 mL, 1.0 mmol) in dichloromethane (1 mL), the dropwise addition was completed, stirring 10min. The solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1-20/1) to obtain the title compound as a yellow solid (74.4 mg, 72.3%).

MS(ESI,pos.ion)m/z:595.3[M+H] +. MS(ESI,pos.ion)m/z:595.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ8.49(d,J＝3.9Hz,1H),7.68–7.62(m,1H),7.17(d,J＝5.7Hz,1H),7.09(dd,J＝4.5,2.4Hz,1H),6.97(t,J＝8.9Hz,2H),6.63(ddd,J＝34.7,16.8,10.5Hz,1H),6.41(t,J＝15.1Hz,1H),5.81(t,J＝8.7Hz,1H),3.97–3.90(m,1H),2.75(dt,J＝13.1,6.6Hz,1H),2.29(s,3H),2.06–2.02(m,3H),1.88(dd,J＝12.6,6.2Hz,1H),1.51–1.39(m,5H),1.34(d,J＝6.6Hz,2H),1.26(dd,J＝18.9,9.2Hz,6H),1.08(dd,J＝15.5,6.7Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (d, J=3.9 Hz, 1H), 7.68-7.62 (m, 1H), 7.17 (d, J=5.7 Hz, 1H), 7.09 (dd, J= 4.5,2.4Hz,1H),6.97(t,J＝8.9Hz,2H),6.63(ddd,J＝34.7,16.8,10.5Hz,1H),6.41(t,J＝15.1Hz,1H),5.81( t, J=8.7Hz, 1H), 3.97–3.90 (m, 1H), 2.75 (dt, J=13.1, 6.6Hz, 1H), 2.29 (s, 3H), 2.06–2.02 (m, 3H), 1.88 (dd, J=12.6, 6.2Hz, 1H), 1.51–1.39 (m, 5H), 1.34 (d, J=6.6Hz, 2H), 1.26 (dd, J=18.9, 9.2Hz, 6H), 1.08 ( dd,J=15.5,6.7Hz,3H).

生物试验biological test

实施例A：CTG方法检测化合物对H358(KRAS G12C)细胞增殖的抑制活性实验Example A: CTG method to detect the inhibitory activity of compounds on H358 (KRAS G12C) cell proliferation

细胞实验条件如表A所示：The cell experimental conditions are shown in Table A:

表ATable A

细胞名称cell name 细胞(个)/孔Cell(s)/well 孵化时间(h)Incubation time (h) 完全培养基complete medium H358H358 10001000 7272 RPMI1640+10％FBSRPMI1640+10%FBS

1)细胞培养1) Cell culture

采用合适的培养基培养细胞，置于37℃、5％二氧化碳培养箱中培养。每日使用倒置显微镜观察细胞1次，隔2-4天换培养液一次。收集细胞离心1200rpm离心5min，弃上清液，以1:3-1:8比例转移至新的无菌培养皿中培养。The cells were cultured in a suitable medium and placed in a 37°C, 5% carbon dioxide incubator. The cells were observed with an inverted microscope once a day, and the culture medium was changed every 2-4 days. The cells were collected and centrifuged at 1200 rpm for 5 min, the supernatant was discarded, and the cells were transferred to a new sterile culture dish at a ratio of 1:3-1:8.

2)细胞铺板2) Cell plating

收集处于指数生长期的细胞，并用细胞计数仪进行细胞计数。用相应培养基重悬细胞并调整到适当的浓度。每孔加入90μL细胞悬液于96孔细胞培养板中。置于37℃、5％二氧化碳培养箱中过夜培养。Cells in exponential growth phase were collected and counted with a cell counter. Resuspend the cells in the appropriate medium and adjust to the appropriate concentration. Add 90 μL of cell suspension to each well in a 96-well cell culture plate. Incubate overnight in a 37°C, 5% carbon dioxide incubator.

3)化合物配制及加药处理3) Compound preparation and dosing treatment

a母液配制：用DMSO溶解待测化合物，配置10mM的母液。a. Preparation of stock solution: Dissolve the test compound with DMSO to prepare a 10 mM stock solution.

b用时用DMSO将化合物3倍稀释，得到9个浓度梯度的化合物，用完全培养基将上述梯度稀释后的化合物进行20倍稀释，并混合均匀得到10×浓度的药物工作液。b. The compound was diluted 3 times with DMSO to obtain 9 concentration gradient compounds. The above gradient diluted compounds were diluted 20 times with complete medium, and mixed evenly to obtain a 10× concentration drug working solution.

c加药：取出细胞培养板，将10μL/孔的上述10×浓度的药物工作液加入到细胞培养板的相应孔中，在37℃培养箱中孵育72h。c Dosing: Take out the cell culture plate, add 10 μL/well of the above 10× concentration drug working solution to the corresponding well of the cell culture plate, and incubate in a 37°C incubator for 72h.

4)读板检测4) plate reading detection

a化合物处理72h后，在倒置显微镜下观察细胞形态，DMSO对照孔中的细胞生长状态正常，未见有污染现象，各孔是否有化合物析出现象。a After the compound was treated for 72 hours, the cell morphology was observed under an inverted microscope. The cells in the DMSO control wells grew normally, and there was no contamination. Whether there was compound precipitation in each well.

b将配制好的CTG溶液放置室温平衡10-20min。b Put the prepared CTG solution at room temperature to equilibrate for 10-20min.

c按照CTG操作说明加入50μL/孔的CTG溶液，置于摇床上避光振荡20min。c Add 50 μL/well of CTG solution according to the CTG operating instructions, and place it on a shaker to shake for 20 min in the dark.

d使用酶标仪测定荧光信号值。d Measure the fluorescence signal value using a microplate reader.

5)数据分析5) Data analysis

生长抑制率％＝(V 阴性组-V 实验组)/(V 阴性组-V 空白组)×100％，其中V 阴性组为溶剂对照组的平均值，V 实验组为药物处理组的读数，V 空白组为无细胞无药物处理组的读数。应用GraphPad Prism 5.0软件对数据进行分析并计数得到IC 50值。结果参见表1，表1为本发明实施例提供的化合物对H358细胞增殖抑制实验结果。 Growth inhibition rate %=(V negative group- V experimental group )/(V negative group- V blank group )×100%, where V negative group is the average value of solvent control group, V experimental group is the reading of drug treatment group, The V blank group is the reading of the cell-free and drug-free group. Data were analyzed using GraphPad Prism 5.0 software and counted to obtain IC50 values. The results are shown in Table 1, and Table 1 is the results of the experiments of inhibiting the proliferation of H358 cells by the compounds provided in the examples of the present invention.

表1本发明实施例提供的化合物对H358细胞增殖抑制实验结果Table 1 Results of the compounds provided in the examples of the present invention to inhibit the proliferation of H358 cells

实施例号Example number IC 50(nM) IC50 (nM) 实施例1Example 1 185.7185.7 实施例3Example 3 358.3358.3 实施例5Example 5 131.65131.65 实施例7Example 7 247.53247.53 实施例8Example 8 230.62230.62 实施例9Example 9 206.91206.91 实施例10Example 10 105.07105.07 实施例13Example 13 314.0314.0 实施例18Example 18 403.6403.6 实施例21Example 21 454.3454.3 实施例23Example 23 414.2414.2 实施例24Example 24 313.7313.7 实施例25Example 25 290.9290.9 实施例26Example 26 294.1294.1 实施例27Example 27 150.89150.89

Figure PCTCN2021112919-appb-000055
Figure PCTCN2021112919-appb-000055

实验结果显示，在对H358细胞增殖的抑制活性测试中，本发明化合物对H358细胞增殖有较强的抑制活性，且活性优于阳性对照品ARS1620。The experimental results show that in the test of inhibitory activity on H358 cell proliferation, the compound of the present invention has a strong inhibitory activity on H358 cell proliferation, and the activity is better than that of the positive control substance ARS1620.

实施例B：LC-MS法检测化合物与KRAS G12C蛋白的结合情况实验Example B: LC-MS method to detect the binding of compounds to KRAS G12C protein

实验步骤：Experimental steps:

1)实验缓冲液准备如表B所示1) The experimental buffer preparation is shown in Table B

表BForm B

Figure PCTCN2021112919-appb-000056
Figure PCTCN2021112919-appb-000056

2)将GDP载入KRAS G12C蛋白2) Load GDP into KRAS G12C protein

将KRAS G12C蛋白储备液(11.13mg/mL,550μM)用低Mg 2+缓冲液5倍稀释至110μM。取1mL 110μM的KRAS G12C蛋白并加入1mL的2×GDP载入缓冲液，轻轻混匀，室温孵育1.5h后，分装成40μL/管，迅速冷冻保存于-80℃冰箱中。 The KRAS G12C protein stock solution (11.13 mg/mL, 550 μM) was diluted 5-fold to 110 μM with low Mg 2+ buffer. Take 1 mL of 110 μM KRAS G12C protein and add 1 mL of 2×GDP loading buffer, mix gently, incubate at room temperature for 1.5 h, divide into 40 μL/tube, quickly freeze and store in -80 °C refrigerator.

3)KRAS G12C结合试验3) KRAS G12C binding assay

用10×孵育缓冲液将GDP载入的KRAS G12C稀释至20μM，按下表C将各试剂混合。The GDP-loaded KRAS G12C was diluted to 20 μM with 10× incubation buffer and the reagents were mixed as shown in Table C below.

表CForm C

试剂reagent 加入体积add volume GDP载入的KRAS G12C(20μM)GDP-loaded KRAS G12C (20 μM) 5μL5μL 化合物(10％的DMSO溶液)Compound (10% in DMSO) 5μL5μL 10×孵育缓冲液10x Incubation Buffer 5μL5μL 超纯水Ultra-pure water 35μL35μL 共计total 50μL50μL

注：各试剂用量可根据需要按一定比例变化。Note: The dosage of each reagent can be changed in a certain proportion as needed.

4)常温下分别孵育5min及1h4) Incubate at room temperature for 5min and 1h respectively

5)加入5μL的5％甲酸终止反应(注：根据孵育溶液体积按10％比例加入5％甲酸溶液)5) Add 5 μL of 5% formic acid to stop the reaction (Note: add 5% formic acid solution at a ratio of 10% according to the volume of the incubation solution)

6)LC-MS检测6) LC-MS detection

孵育液混匀后转移至进样小瓶，进行LC-MS分析检测。分析条件如下：The incubation solution was mixed and transferred to the injection vial for LC-MS analysis and detection. The analysis conditions are as follows:

Figure PCTCN2021112919-appb-000057
Figure PCTCN2021112919-appb-000057

Figure PCTCN2021112919-appb-000058
Figure PCTCN2021112919-appb-000058

7)计算KRAS G12C结合率％7) Calculate the KRAS G12C binding rate %

KRAS G12C结合率％＝复合物峰面积/(复合物峰面积+未与KRAS G12C结合峰面积)×100KRAS G12C binding rate % = complex peak area / (complex peak area + peak area not bound to KRAS G12C) × 100

结果参见表2，表2为本发明实施例提供的化合物与KRAS G12C蛋白结合1h的实验结果。The results are shown in Table 2, and Table 2 is the experimental result that the compound provided in the embodiment of the present invention binds to the KRAS G12C protein for 1 h.

表2本发明实施例提供的化合物与KRAS G12C蛋白结合的实验结果Table 2 The experimental results of the combination of the compounds provided in the embodiments of the present invention with KRAS G12C protein

Figure PCTCN2021112919-appb-000059
Figure PCTCN2021112919-appb-000059

实验结果显示，本发明化合物与KRAS-4B-G12C蛋白结合率较高。The experimental results show that the compound of the present invention has a high binding rate to KRAS-4B-G12C protein.

实施例C：小鼠在静脉注射和口服定量本发明化合物后的药代动力学评价Example C: Pharmacokinetic Evaluation of Compounds of the Invention Following Intravenous and Oral Quantification in Mice

取18-22g雄性ICR小鼠，随机分为两组，一组静脉注射待测化合物，剂量为2.0mg/kg，另一组口服给予待测化合物，剂量为5mg/kg；静脉注射给药后按时间点0.083、0.25、0.5、1、2、4、6、8和24小时尾静脉采血；口服给药后按时间点0.25、0.5、1、2、4、6、8和24小时尾静脉采血。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下测定血浆样品中待测化合物的浓度。根据药物浓度-时间曲线，采用WinNonLin 6.3软件非房室模型法计算药代动力学参数。18-22g male ICR mice were taken and randomly divided into two groups. One group was intravenously injected with the test compound at a dose of 2.0 mg/kg, and the other group was orally administered the test compound at a dose of 5 mg/kg; Tail vein blood was collected at time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours; tail vein at time points 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration Blood collection. Establish a standard curve with an appropriate range according to the sample concentration, and use AB SCIEX API4000 LC-MS/MS to determine the concentration of the test compound in the plasma sample in MRM mode. According to the drug concentration-time curve, the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters.

结果显示，将本发明提供的化合物静脉注射给药或口服给药时，本发明所述化合物表现出好的药代动力学性质，包括较好的吸收和较好的口服生物利用度。The results show that when the compounds provided by the present invention are administered intravenously or orally, the compounds of the present invention exhibit good pharmacokinetic properties, including better absorption and better oral bioavailability.

在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (12)

一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，A compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I) product, a pharmaceutically acceptable salt or a prodrug thereof,
Figure PCTCN2021112919-appb-100001
Figure PCTCN2021112919-appb-100001
 其中：in: Z为N或CR 2e； Z is N or CR 2e ; R 1为-C(＝O)-CR a＝CR b-R c、-C(＝O)-C≡C-R c、-S(＝O) 2-CR a＝CR b-R c或-S(＝O) 2-C≡C-R c； R 1 is -C(=O)-CR a =CR b -R c , -C(=O)-C≡CR c , -S(=O) 2 -CR a =CR b -R c or -S (=O) 2 -C≡CR c ; R a和R b各自独立地为氢、氘、卤原子、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基，其中，所述的C 1-3烷基、C 1-3卤代烷基和C 1-3烷氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； R a and R b are each independently hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups; R c为氢、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、5-6元杂芳基、C 3-6碳环基或3-6元杂环基，其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、5-6元杂芳基、C 3-6碳环基和3-6元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟基烷氧基和3-6元杂环基的基团所取代； R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, 5-6-membered heteroaryl, C 3-6 carbocyclic or 3-6-membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C1 -3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkoxy and 3-6 membered heterocyclic groups; R 3为C 6-12芳基或5-10元杂芳基，其中，所述的C 6-12芳基和5-10元杂芳基独立任选地被n个R y取代； R 3 is C 6-12 aryl or 5-10-membered heteroaryl, wherein the C 6-12 aryl and 5-10-membered heteroaryl are independently optionally substituted by n R y ; R 4为氢、氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-3羟基烷氧基； R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 1-3 hydroxyalkoxy; R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally selected from 1, 2, 3, 4 or 5 independently selected from Deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1 -3 hydroxyalkoxy groups are substituted; R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6烷氨基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； R 2a , R 2b , R 2c , R 2d and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1- 3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups; 各R x独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环基；其中，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 3-8环烷基和3-8元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、 C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy Amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups; 各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟基烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基；其中，所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟基烷氧基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； Each R y is independently deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocyclic group composed of 3-8 atoms, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms; C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, 3 -Heterocyclic groups consisting of 8 atoms, C 6-10 aryl groups and heteroaryl groups consisting of 5-10 atoms are independently optionally selected from 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen atoms , hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy substituted with an oxy group; m为0、1、2、3、4、5、6、7或8；m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; n为1、2、3、4、5、6或7；n is 1, 2, 3, 4, 5, 6 or 7; p为0、1、2、3、4或5。p is 0, 1, 2, 3, 4 or 5. 根据权利要求1所述的化合物，其中R a和R b各自独立地为氢、氘、卤原子、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基，其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代； The compound of claim 1, wherein R a and R b are each independently hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, Methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independent optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, substituted with groups of trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH; R c为氢、氘、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、-OCH 2OH、-OCH 2CH 2OH、异丙氧基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基的基团所取代。 R c is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, - CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclo Butenyl, cyclopentenyl, cyclohexenyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, tris Azazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; wherein the methyl, ethyl, n-propyl , isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methyl Oxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, di- methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidine, pyrrolidinyl, Tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl , pyrimidinyl, pyrazinyl and pyridazinyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl , ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, isopropyl oxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups . 根据权利要求1或2所述的化合物，其中R 3为C 6-10芳基或5-10元杂芳基，其中，所述的C 6-10芳基和5-10元杂芳基独立任选地被n个R y取代。 The compound according to claim 1 or 2, wherein R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independent Optionally substituted with n R y . 根据权利要求1-3任意一项所述的化合物，其中R 3为
Figure PCTCN2021112919-appb-100002
Figure PCTCN2021112919-appb-100003
Figure PCTCN2021112919-appb-100004
其中，所述的
Figure PCTCN2021112919-appb-100005
Figure PCTCN2021112919-appb-100006
Figure PCTCN2021112919-appb-100007
独立任选地被n个R y取代。 The compound of any one of claims 1-3, wherein R is
Figure PCTCN2021112919-appb-100002
Figure PCTCN2021112919-appb-100003
Figure PCTCN2021112919-appb-100004
Among them, the said
Figure PCTCN2021112919-appb-100005
Figure PCTCN2021112919-appb-100006
Figure PCTCN2021112919-appb-100007
independently optionally substituted with n R ys . 根据权利要求1-4任意一项所述的化合物，其中R 4为氢、氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH或-OCH 2CH 2OH； The compound according to any one of claims 1-4, wherein R 4 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n- propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH or -OCH 2 CH 2 OH; R 5为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 R 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, Propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, Isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino; wherein, The methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino and ethylamino are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups. 根据权利要求1-5任意一项所述的化合物，其中R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 1-4烷氨基；其中，所述的C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 1-4烷氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； The compound of any one of claims 1-5, wherein R 2a , R 2b , R 2c , R 2d and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro group, cyano group, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 Alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1- 4 haloalkoxy and C 1-4 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1 -3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups; 各R x独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基或3-6元杂环基；其中，所述的C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 3-6环烷基和3-6元杂环基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代； Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclic group; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy Amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups; 各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟基烷氧基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基；其中，所述的C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟基烷氧基、C 3-6环烷基、 3-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基和C 1-3羟基烷氧基的基团所取代。 Each R y is independently deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy , C 1-4 hydroxyalkoxy, C 3-6 cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms; C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 3-6 cycloalkyl, 3 -Heterocyclic groups consisting of 6 atoms, C 6-10 aryl groups and heteroaryl groups consisting of 5-6 atoms are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atoms , hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy substituted with an oxy group. 根据权利要求1-6任意一项所述的化合物，其中R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基或乙氨基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基和乙氨基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代； The compound of any one of claims 1-6, wherein R 2a , R 2b , R 2c , R 2d and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, allyl group, propenyl group, propargyl group, propynyl group, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl , propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n- Propyloxy , isopropyloxy , -OCHF2 , -OCHFCH2F , -OCF2CHF2 , -OCH2CF3 , -OCH2CF2CHF2 , methylamino , dimethylamino and ethylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, substituted with groups of trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH; 各R x独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF 2、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代； Each R is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n- Propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethyl amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or Morpholinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl , thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl , oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl fluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups; 各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH、-OCH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三唑基；其中，所述的甲基、乙基、正丙基、异丙基、叔丁基、二氟甲基、甲氧基、乙氧基、异丙氧基、-OCH 2OH、-OCH 2CH 2OH、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基和三唑基独立任选地被1、2、3、4或5个独立地选自氘、卤原子、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH 2OH和-OCH 2CH 2OH的基团所取代。 Each R y is independently deuterium, halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methyl Oxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine , pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl or triazole group; wherein, the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl , pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl and triazolyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, Trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups. 一种化合物，包含以下其中之一的化合物或以下其中之一的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：A compound comprising one of the following compounds or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:
Figure PCTCN2021112919-appb-100008
Figure PCTCN2021112919-appb-100008
Figure PCTCN2021112919-appb-100009
Figure PCTCN2021112919-appb-100009
Figure PCTCN2021112919-appb-100010
Figure PCTCN2021112919-appb-100010
Figure PCTCN2021112919-appb-100011
Figure PCTCN2021112919-appb-100011
Figure PCTCN2021112919-appb-100012
Figure PCTCN2021112919-appb-100012
 一种药物组合物，包含权利要求1-8任意一项所述的化合物；和所述药物组合物任选地包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。A pharmaceutical composition comprising the compound of any one of claims 1-8; and the pharmaceutical composition optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof. 权利要求1-8任意一项所述的化合物或者权利要求9所述的药物组合物在制备用于预防、治疗或减轻患者KRAS G12C介导的疾病的药物中的用途。Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament for preventing, treating or alleviating a KRAS G12C-mediated disease in a patient. 根据权利要求10所述的用途，其中，所述的KRAS G12C介导的疾病为癌症。The use according to claim 10, wherein the disease mediated by KRAS G12C is cancer. 根据权利要求11所述的用途，其中所述的癌症为肺癌、淋巴癌、食管癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、白血病或黑色素瘤。The use according to claim 11, wherein the cancer is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, intrauterine cancer Membranous cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia or melanoma.
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