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WO2022127847A1 - Pyrimidone derivative and application thereof in drug - Google Patents

Pyrimidone derivative and application thereof in drug Download PDF

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Publication number
WO2022127847A1
WO2022127847A1 PCT/CN2021/138693 CN2021138693W WO2022127847A1 WO 2022127847 A1 WO2022127847 A1 WO 2022127847A1 CN 2021138693 W CN2021138693 W CN 2021138693W WO 2022127847 A1 WO2022127847 A1 WO 2022127847A1
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Prior art keywords
isopropyl
oxo
mmol
chf
och
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French (fr)
Chinese (zh)
Inventor
习宁
李敏雄
吴双
席云龙
廖敏
梁恩
冯学金
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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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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.
  • the KRAS gene encodes a 21kD ras protein, also known as the p21 gene.
  • RAS the ras gene family associated with human tumors
  • KRAS 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 cells to continue growing and stops them 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,
  • X is -LX 1 -, wherein L is a bond or NH, X 1 is a 4-8-membered monocyclic ring, 5-12-membered condensed ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms,
  • the 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spiro ring and 5-12-membered bridged ring can be independently optionally substituted with m R x ;
  • Y is N or CH
  • 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 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
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6 or 7.
  • X is Wherein, the m and R x have the meanings described in the present invention.
  • 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 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 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 is independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 substituted by groups of haloalkyl, C 1-3 alkoxy,
  • 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 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 and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxygen substituted, amino, nitro, cyano, C 1-3 alkyl, C 3-6 cyclo
  • 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
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, or solvate thereof , 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 KRAS G12C mediated diseases 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, bile duct, breast, colon, appendix, small bowel, 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
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
  • C n1-n2 means that the number of carbon atoms contained in the group is n1-n2, both n1 and n2 are natural numbers other than 0, and n2 is greater than n1, and the "n1-n2" includes n1 , n2, and any natural number in between.
  • C 1-6 alkyl group represents an alkyl group containing 1-6 carbon atoms
  • C 1-6 alkoxy group represents an alkoxy group containing 1-6 carbon atoms
  • C 3-6 carbocyclic group represents an alkoxy group containing 3- Carbocyclyl of 6 carbon atoms.
  • 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.
  • the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, denoted as C 1-6 alkyl; in yet other implementations In the scheme, the alkyl group contains 1-4 carbon atoms, denoted as C 1-4 alkyl; also in some embodiments, the alkyl group contains 1-3 carbon atoms, denoted as C 1-3 alkane base.
  • 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.
  • an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms, denoted as C 2-6 alkenyl; in yet another embodiment In the scheme, alkenyl groups contain 2-4 carbon atoms and are denoted as C 2-4 alkenyl.
  • 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, denoted as C 2-6 alkynyl; in still other implementations In the scheme, alkynyl groups contain 2-4 carbon atoms and are denoted as C 2-4 alkenyl.
  • 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, alkoxy groups contain 1-6 carbon atoms, denoted C 1-6 alkoxy; in other embodiments, alkoxy groups contain 1-4 carbon atoms, denoted is C 1-4 alkoxy; in yet other embodiments, the alkoxy group contains 1-3 carbon atoms, denoted as C 1-3 alkoxy.
  • 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
  • haloalkyl or “haloalkoxy” denotes an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl group and the alkoxy group are as specifically defined herein. Such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
  • 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 is 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
  • nitrogen-containing monocyclic ring refers to a monocyclic ring of 4-8 ring atoms containing 1 or 2 nitrogen atoms, the ring may be fully saturated or contain one or more degrees of saturation, but not aromatic.
  • monocyclic rings containing nitrogen atoms include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like.
  • the nitrogen-containing monocyclic ring is optionally substituted with one or more substituents described herein.
  • fused bicyclic means a monovalent or polyvalent saturated or Partially unsaturated ring system
  • the ring system refers to a non-aromatic bicyclic ring system, the two rings in the ring system share two adjacent carbon atoms.
  • Such systems may contain independent or conjugated unsaturated systems, but whose core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may serve as substituents thereon).
  • nitrogen-containing fused ring refers to a fused ring containing 1 or 2 nitrogen atoms, and examples of nitrogen-containing fused rings include, but are not limited to, octahydropyrrolo[3,4-c]pyrrole, and the like .
  • the fused ring is optionally substituted with one or more substituents described herein.
  • spirocyclyl spirocycle
  • spirobicyclyl spirobicyclyl
  • spirobicyclyl spirobicyclyl
  • nitrogen-containing spirocycle refers to a spirocycle containing 1 or 2 nitrogen atoms
  • nitrogen-containing spirocycles include, but are not limited to, 2,7-diazaspiro[3.5]nonane , 2,6-diazaspiro[3.3]heptane and so on.
  • the spiro ring is optionally substituted with one or more substituents described herein.
  • bridged ring or “bridged ring group” refers to a saturated or partially unsaturated bridged ring system, involving a non-aromatic bicyclic ring system, such as shown in formula (b), that is, ring A1 and ring A2 share an alkane chain or A heteroalkane chain wherein each X3 is independently optionally a carbon atom or a heteroatom and j is 1, 2, 3 or 4.
  • Such systems contain 5-12 ring atoms, may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic rings (although aromatics may be used as substituents thereon).
  • nitrogen-containing bridged ring refers to a bridged ring containing 1 or 2 nitrogen atoms
  • nitrogen-containing bridged rings include, But not limited to, (1R,5S)-3,8-diazabicyclo[3.2.1]octane and the like.
  • the bridged ring is optionally substituted with one or more substituents described herein.
  • j-k ring atoms or "j-k membered” are used interchangeably herein to mean that the cyclic group consists of j-k 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 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.
  • aminoalkyl includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups.
  • the aminoalkyl group is a C 1-6 aminoalkyl group substituted with one or more amino groups, such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl , aminobutyl and aminohexyl.
  • the ring system formed by the substituent (R x ) m being attached to the central ring by a bond represents m substituents R x can be carried out at any substitutable position or any reasonable position on the present ring. replace.
  • Formula d represents that the G ring may be substituted with m Rx, and when m is greater than 1 , each Rx 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.
  • linking sites on the substructure of the group X there are two linking sites on the substructure of the group X that can be connected to the rest of the molecule, and the linking modes of the two linking sites can be interchanged.
  • X is When the general formula (I) of the present invention represents that the N connecting end on X 1 is connected to R 1 , and the other C connecting end is connected to the rest of the general formula (I), as shown in formula f; or that the C connecting end on X is connected R 1 , the other N-connected end connecting the rest of formula (I),
  • protecting group refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups.
  • amino protecting 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.
  • Water and Aqueous Solutions Saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, especially for injectable solutions. 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, appendix cancer, small bowel cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, Cancer of the vulva, thyroid, liver, anus, penis, and head and neck.
  • squamous cell carcinoma eg, epithelial squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung
  • 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 act as an inhibitor of KRAS, especially KRAS G12C.
  • 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 X, Y, Z, R 1 , R 2a , R 2b , R 2c , R 2d and R 3 has the meaning described in the present invention.
  • X is -LX 1 -, wherein L is a bond or NH, and X 1 is a nitrogen-containing 4-8 membered monocyclic, 5-12 membered fused ring, 5-12 membered spirocyclic ring, or 5-membered -12-membered bridged rings, the 4-8-membered monocycles, 5-12-membered fused rings, 5-12-membered spiro rings, and 5-12-membered bridged rings can be independently optionally substituted with m Rx ; wherein Rx and m have the meaning described in the present invention.
  • the 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms in the present invention refers to the single ring, fused ring, spiro ring Rings and bridged rings each independently contain 1 or 2 nitrogen atoms.
  • X is wherein Rx and m have the meanings described in the present invention.
  • Y is N or CH.
  • 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 is 1, 2, 3, 4, 5, 6 or 7, and R y has the meaning described herein.
  • 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 Ry is substituted; n is 1, 2, 3, 4, 5, 6 or 7, wherein Ry has the meaning described herein.
  • R3 is Among them, the said independently optionally substituted with n R y ; wherein n is 1, 2, 3, 4, 5, 6 or 7 and R y has the meaning described herein.
  • 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 2-4 alkene group, C 2-4 alkynyl, 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.
  • 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 2-4 alkene group, C 2-4 alkynyl, 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.
  • 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 2-4 alkene group, C 2-4 alkynyl, 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.
  • 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 2-4 alkene group, C 2-4 alkynyl, 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.
  • 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 2-4 alkene group, C 2-4 alkynyl, 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.
  • 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
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6 alkyl, C2-6 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 heterocycle 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, C 3-8 cycloalkyl and 3-8 membered heterocyclyl independently optionally 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
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4 alkyl, C2-4 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 hetero Cyclic 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 group, 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, of oxo, amino, nitro, cyano, C 1-3 alkyl
  • each Rx 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 group, 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 , methyl Amino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl
  • 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, bile duct, breast, colon, appendix, small bowel, 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 carrier) selected according to the form of administration and conventional pharmaceutical practice, which may be an oral tablet, Capsules, elixirs, syrups, and more.
  • a suitable pharmaceutical diluent, excipient, or carrier referred to herein as a pharmaceutical carrier
  • a pharmaceutical carrier selected according to the form of administration and conventional pharmaceutical practice, which may be an oral tablet, Capsules, elixirs, syrups, and more.
  • the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier 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 can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combined, 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, appendix cancer, small bowel 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 ( 15 ) 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 formula ( 11 ) is obtained by reacting with potassium acetate (or cesium carbonate) under the action.
  • the compound represented by formula ( 11 ) is in zinc cyanide, bis(tri-tert-butylphosphine) palladium and tri-tert-butylphosphine (or zinc cyanide and chloro(2-dicyclohexylphosphino-2',4', Under the action of 6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), the reaction obtained by formula ( 12 ) compounds shown.
  • the compound represented by the formula ( 12 ) is de-Boc removed under the action of trifluoroacetic acid to obtain the compound represented by the formula ( 13 ).
  • the compound represented by the formula ( 13 ) and the compound represented by the formula ( 14 ) can obtain the compound represented by the formula ( 15 ) under the action of N,N-diisopropylethylamine.
  • 2,5,6-Trichloropyridine-3-carboxylic acid (5.0g, 22mmol), dichloromethane (60.0mL) and N,N-dimethylformamide (0.05mL, 0.6mmol) were added to the reaction flask, Cool to 0°C, add oxalyl chloride (2.4mL, 28mmol) dropwise, stir at 0°C for 24h, add ammonia solution in isopropanol (17.0mL, 2.0mol/L, 34mmol), continue stirring for 4h, suction filter, filter cake Washed with dichloromethane (50 mL ⁇ 2), and dried to obtain the title compound as a white solid (1.6 g, yield 32.0%).
  • the second step Synthesis of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide
  • 2,5,6-Trichloronicotinamide (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 reaction was stirred at 75°C for 1 h, Cooled to room temperature, concentrated to remove the solvent, cooled to 0 °C, added tetrahydrofuran (5 mL) to dissolve, and then added dropwise a solution of 2-isopropyl-4-methyl-pyridin-3-amine (1.0 g, 6.7 mmol) in tetrahydrofuran (5 mL).
  • 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 eighth step 7 (2-Fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methyl Synthesis of piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step Synthesis of 5-bromo-1,3-lutidine-2(1H)-one
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7-diazepine Synthesis of Spiro[4.4]nonan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fifth step 4-(7-Acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7-diazepine Synthesis of Spiro[3.5]nonan-7-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester
  • the first step the synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate
  • the aqueous phase was extracted with ethyl acetate (50.0 mL).
  • the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure.
  • the filter cake was dried under vacuum at 60° C. for 12 h to obtain the title compound as an off-white solid (7.30 g, yield 81.3%).
  • the seventh step The synthesis of 6-bromo-4-chloro-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazolin-2(1H)-one
  • 6-Bromo-4-chloro-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazolin-2(1H)-one (2.07g) was successively added to the reaction flask , 3.99mmol), acetonitrile (30mL), N,N-diisopropylethylamine (1.03g, 7.97mmol) and (S)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.80g, 3.99 mmol).
  • the reaction system was heated to 80°C for 2h.
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,6-diazepine Synthesis of Spiro[3.3]heptan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step 7 (2-Fluoro-6-methoxyphenyl)-4-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester
  • the third step 5-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester
  • the second step 4-(6-Chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester
  • the third step 4-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester
  • the fourth step 7 (2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-4-(4,7-diazaspiro[ Synthesis of 2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fifth step 4-(7-acryloyl-4,7-diazaspiro[2.5]octan-4-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4 Synthesis of -methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the third step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-4-((S)-2- Synthesis of Methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-2-oxo-4-(4, Synthesis of 7-diazaspiro[2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • 6-Bromo-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (1.00 g, 2.00 mmol), (2-fluoro-5-methylphenyl)boronic acid (0.37 g, 2.40 mmol), sodium carbonate (0.64 g, 6.00 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 g mmol), 1,4-dioxane (15.0 mL) and water (3.5 mL).
  • the reaction system was heated to 100°C under nitrogen protection for overnight reaction. After the reaction was completed, it was cooled to room temperature and filtered.
  • the first step 4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

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Abstract

A Pyrimidone derivative and an application thereof in a drug. Specifically, the present invention relates to a novel Pyrimidone derivative and a pharmaceutical composition containing such a compound. The present invention further relates to a method for preparing the compound and the pharmaceutical composition, a use in preparation of a drug for treating KRAS G12C-mediated diseases and/or symptoms, and in particular a use in preparation of a drug for treating cancers.

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——HRAS、KRAS和NRAS，分别定位在11、12和1号染色体上。KRAS基因编码21kD的ras蛋白又名p21基因。在RAS基因中，KRAS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—HRAS, KRAS, and NRAS, which are located on chromosomes 11, 12, and 1, respectively. The KRAS gene encodes a 21kD ras protein, also known as the p21 gene. Of the RAS genes, KRAS 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 cells to continue growing and stops them 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、WO2019141250、WO2019213516和WO2020050890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, WO2019141250, WO2019213516 and WO2020050890 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 PCTCN2021138693-appb-000001
Figure PCTCN2021138693-appb-000001

其中：in:

X为-L-X 1-，其中，L为键或NH，X 1为含氮原子的4-8元单环、5-12元稠环、5-12元螺环或5-12元桥环，所述4-8元单环、5-12元稠环、5-12元螺环和5-12元桥环可独立任选地被m个R x取代； X is -LX 1 -, wherein L is a bond or NH, X 1 is a 4-8-membered monocyclic ring, 5-12-membered condensed ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms, The 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spiro ring and 5-12-membered bridged ring can be independently optionally substituted with m R x ;

Y为N或CH；Y is N or CH;

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 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、氧代、-C(＝O)OC 1-6烷基、C 1-6烷氨基、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(＝O)OC 1-6烷基、C 1-6烷氨基、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, oxo, -C(=O)OC 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocycle consisting of 3-8 atoms group, C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms; wherein, the -C(=O)OC 1-6 alkyl group, C 1-6 alkylamino group, C 1-6 alkane group base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms Cyclic group, C 6-10 aryl group and heteroaryl group consisting of 5-10 atoms are 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 ;

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.

在一些实施方案中，X为

Figure PCTCN2021138693-appb-000002
Figure PCTCN2021138693-appb-000003
其中，所述m和R x具有本发明所述的含义。 In some embodiments, X is
Figure PCTCN2021138693-appb-000002
Figure PCTCN2021138693-appb-000003
Wherein, the m and R x have the meanings described in the present invention.

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 PCTCN2021138693-appb-000004
Figure PCTCN2021138693-appb-000005
Figure PCTCN2021138693-appb-000006
其中，所述的
Figure PCTCN2021138693-appb-000007
Figure PCTCN2021138693-appb-000008
Figure PCTCN2021138693-appb-000009
独立任选地被n个R y取代。 In some embodiments, R is
Figure PCTCN2021138693-appb-000004
Figure PCTCN2021138693-appb-000005
Figure PCTCN2021138693-appb-000006
Among them, the said
Figure PCTCN2021138693-appb-000007
Figure PCTCN2021138693-appb-000008
Figure PCTCN2021138693-appb-000009
independently optionally substituted with n R ys .

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 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。 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 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 is independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 substituted by groups of haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.

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 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。 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 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 and 3-6 membered heterocyclyl independently optionally 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，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、氧代、-C(＝O)OC 1-4烷基、 C 1-4烷氨基、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(＝O)OC 1-4烷基、C 1-4烷氨基、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, oxo, -C( = O)OC 1-4 alkyl, C 1-4 alkylamino, 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 A heterocyclic group composed of 1 atoms, a C 6-10 aryl group or a heteroaryl group composed of 5-6 atoms; wherein, the -C(=O)OC 1-4 alkyl group, C 1-4 alkylamino group , 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 selected from 1, 2, 3, 4 or 5 atoms 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 substituted with the radical group.

在一些实施方案中，各R y独立地为氘、氟、氯、溴、羟基、氨基、硝基、氰基、氧代、-C(＝O)OCH 3、二甲氨基、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。 In some embodiments, each R is independently deuterium, fluorine, chlorine, bromine, hydroxy, amino, nitro, cyano, oxo, -C( = O) OCH3 , dimethylamino, methyl, ethyl radical, 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 and triazole group independently optionally 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.

一方面，本发明涉及药物组合物，该药物组合物，包含本发明所述的化合物，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 a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, or solvate thereof , 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 KRAS G12C mediated diseases 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、阑尾癌、小肠癌、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, bile duct, breast, colon, appendix, small bowel, 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 should 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 can be found 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 description, 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.

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 .

本发明中，“C n1-n2”表示所述基团含有的碳原子个数为n1-n2，n1和n2均为非0的自然数，且n2大于n1，所述“n1-n2”包括n1、n2和两者之间的任意自然数。如C 1-6烷基表示含有1-6个碳原子的烷基；C 1-6烷氧基表示含有1-6个碳原子的烷氧基；C 3-6碳环基表示含有3-6个碳原子的碳环基。 In the present invention, "C n1-n2 " means that the number of carbon atoms contained in the group is n1-n2, both n1 and n2 are natural numbers other than 0, and n2 is greater than n1, and the "n1-n2" includes n1 , n2, and any natural number in between. For example, C 1-6 alkyl group represents an alkyl group containing 1-6 carbon atoms; C 1-6 alkoxy group represents an alkoxy group containing 1-6 carbon atoms; C 3-6 carbocyclic group represents an alkoxy group containing 3- Carbocyclyl of 6 carbon atoms.

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，表示为C 1-6烷基；在又一些实施方案中，烷基基团含有1-4个碳原子，表示为C 1-4烷基；还在一些实施方案中，烷基基团含有1-3个碳原子，表示为C 1-3烷基。 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, denoted as C 1-6 alkyl; in yet other implementations In the scheme, the alkyl group contains 1-4 carbon atoms, denoted as C 1-4 alkyl; also in some embodiments, the alkyl group contains 1-3 carbon atoms, denoted as C 1-3 alkane base.

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，表示为C 2-6烯基；在又一实施方案中，烯基基团包含2-4个碳原子，表示为C 2-4烯基。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, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms, denoted as C 2-6 alkenyl; in yet another embodiment In the scheme, alkenyl groups contain 2-4 carbon atoms and are denoted as C 2-4 alkenyl. 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，表示为C 2-6炔基；在又一些实施方案中，炔基基团包含2-4个碳原子，表示为C 2-4烯基。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, denoted as C 2-6 alkynyl; in still other implementations In the scheme, alkynyl groups contain 2-4 carbon atoms and are denoted as C 2-4 alkenyl. 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，表示为C 1-6烷氧基；在另一些实施方案中，烷氧基基团含有1-4个碳原子，表示为C 1-4烷氧基；在又一些实施方案中，烷氧基基团含有1-3个碳原子，表示为C 1-3烷氧基。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, alkoxy groups contain 1-6 carbon atoms, denoted C 1-6 alkoxy; in other embodiments, alkoxy groups contain 1-4 carbon atoms, denoted is C 1-4 alkoxy; in yet other embodiments, the alkoxy group contains 1-3 carbon atoms, denoted as C 1-3 alkoxy. 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，其中烷基基团和烷氧基基团具体如本发明所述的定义。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" denotes an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl group and the alkoxy group are as specifically defined herein. Such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

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 is 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 PCTCN2021138693-appb-000010
基，二氮杂
Figure PCTCN2021138693-appb-000011
基，硫氮杂
Figure PCTCN2021138693-appb-000012
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 PCTCN2021138693-appb-000010
base, diazepine
Figure PCTCN2021138693-appb-000011
base, thiazepine
Figure PCTCN2021138693-appb-000012
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“含氮原子的单环”是指包含1或2个氮原子的4-8个环原子的单环，环可以是完全饱和或包含一个或多个饱和度，但没有芳香性。含氮原子的单环实例包括，但并不限于，氮杂环丁烷、吡咯烷、哌啶、哌嗪等。所述的含氮原子的单环任选地被一个或多个本发明所描述的取代基取代。The term "nitrogen-containing monocyclic ring" refers to a monocyclic ring of 4-8 ring atoms containing 1 or 2 nitrogen atoms, the ring may be fully saturated or contain one or more degrees of saturation, but not aromatic. Examples of monocyclic rings containing nitrogen atoms include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like. The nitrogen-containing monocyclic ring is optionally substituted with one or more substituents described herein.

术语“稠合双环”，“稠环”，“稠合双环基”和“稠环基”在此处可交换使用，都是指包含5-12个环原子的，单价或多价的饱和或部分不饱和的并环体系，所述并环体系是指非芳香族的双环体系，该并环体系中的两个环公用两个相邻的碳原子。这样的体系可以包含独立的或共轭的不饱和体系，但其 核心结构不包含芳香环或芳杂环(但是芳香族基团可以作为其上的取代基)。术语“含氮原子的稠环”是指包含1或2个氮原子的稠环，含氮原子的稠环的实例包括，但并不限于，八氢吡咯并[3,4-c]吡咯等。所述稠环任选地被一个或多个本发明所描述的取代基所取代。The terms "fused bicyclic", "fused ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein and all refer to a monovalent or polyvalent saturated or Partially unsaturated ring system, the ring system refers to a non-aromatic bicyclic ring system, the two rings in the ring system share two adjacent carbon atoms. Such systems may contain independent or conjugated unsaturated systems, but whose core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may serve as substituents thereon). The term "nitrogen-containing fused ring" refers to a fused ring containing 1 or 2 nitrogen atoms, and examples of nitrogen-containing fused rings include, but are not limited to, octahydropyrrolo[3,4-c]pyrrole, and the like . The fused ring is optionally substituted with one or more substituents described herein.

术语“螺环基”，“螺环”，“螺双环基”或“螺双环”在此处可交换使用，是指包含5-12个环原子的，单价或多价的饱和或部分不饱和的双环体系，其中一个环起源于另一个环上特定的环碳原子。如式(a)所示，环A和环B在两个饱和的环体系中共享一个碳原子，被称为“螺环”或“螺双环”，而环B和环B’被称为“稠合双环”。螺双环基中的每个环都可以是碳环基或杂环基。术语“含氮原子的螺环”是指包含1或2个氮原子的螺环，含氮原子的螺环的实例包括，但并不限于，2,7-二氮杂螺[3.5]壬烷，2,6-二氮杂螺[3.3]庚烷等。所述螺环任选地被一个或多个本发明所描述的取代基所取代。The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicyclyl" are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated ring containing 5 to 12 ring atoms. A bicyclic ring system in which one ring originates from a specific ring carbon atom in the other. As shown in formula (a), Ring A and Ring B share a carbon atom in two saturated ring systems, referred to as "spiro" or "spirobicyclic", while Ring B and Ring B' are referred to as " fused bicyclic". Each ring in a spirobicyclyl can be carbocyclyl or heterocyclyl. The term "nitrogen-containing spirocycle" refers to a spirocycle containing 1 or 2 nitrogen atoms, examples of nitrogen-containing spirocycles include, but are not limited to, 2,7-diazaspiro[3.5]nonane , 2,6-diazaspiro[3.3]heptane and so on. The spiro ring is optionally substituted with one or more substituents described herein.

Figure PCTCN2021138693-appb-000013
Figure PCTCN2021138693-appb-000013

术语“桥环”或“桥环基”表示饱和或部分不饱和的桥环体系，涉及到非芳香族的双环体系，例如式(b)所示，即环A1与环A2共有一个烷链或一个杂烷链，其中各X 3独立任选地为碳原子或杂原子，j为1、2、3或4。这样的体系包含5-12个环原子，可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳环(但是芳香族可以作为其上的取代基)。其中每一个环，如A1或A2，包含4-7个原子，术语“含氮原子的桥环”是指包含1或2个氮原子的桥环，含氮原子的桥环这样的实例包括，但并不限于，(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷等。所述桥环任选地被一个或多个本发明所描述的取代基所取代。 The term "bridged ring" or "bridged ring group" refers to a saturated or partially unsaturated bridged ring system, involving a non-aromatic bicyclic ring system, such as shown in formula (b), that is, ring A1 and ring A2 share an alkane chain or A heteroalkane chain wherein each X3 is independently optionally a carbon atom or a heteroatom and j is 1, 2, 3 or 4. Such systems contain 5-12 ring atoms, may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic rings (although aromatics may be used as substituents thereon). Wherein each ring, such as A1 or A2, contains 4-7 atoms, the term "nitrogen-containing bridged ring" refers to a bridged ring containing 1 or 2 nitrogen atoms, such examples of nitrogen-containing bridged rings include, But not limited to, (1R,5S)-3,8-diazabicyclo[3.2.1]octane and the like. The bridged ring is optionally substituted with one or more substituents described herein.

Figure PCTCN2021138693-appb-000014
Figure PCTCN2021138693-appb-000014

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 j-k ring atoms" or "j-k membered" are used interchangeably herein to mean that the cyclic group consists of j-k 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 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.

术语“氨基烷基”包括被一个或多个氨基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-6氨基烷基，这样的实例包括，但并不限于，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。 The term "aminoalkyl" includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a C 1-6 aminoalkyl group substituted with one or more amino groups, such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl , aminobutyl and aminohexyl.

如本发明所描述，取代基(R x) m由一个键连接到中心的环上形成的环体系代表m个取代基R x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m个R x取代，当m大于1时，各R x可独立地选自相同或不同的取代基团。 As described in the present invention, the ring system formed by the substituent (R x ) m being attached to the central ring by a bond represents m substituents R x can be carried out at any substitutable position or any reasonable position on the present ring. replace. For example, Formula d represents that the G ring may be substituted with m Rx, and when m is greater than 1 , each Rx may be independently selected from the same or different substituent groups.

Figure PCTCN2021138693-appb-000015
Figure PCTCN2021138693-appb-000015

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 PCTCN2021138693-appb-000016
Figure PCTCN2021138693-appb-000016

如本发明所描述，基团X的子结构上有两个连接位点可与分子其余部分相连，两个连接位点的连接方式可以互换。例如，当X为

Figure PCTCN2021138693-appb-000017
时，本发明通式(I)表示X 1上的N连接端连接R 1，另一个C连接端连接通式(I)其余部分，如式f所示；或表示X上的C连接端连接R 1，另一个N连接端连接通式(I)其余部分， As described in the present invention, there are two linking sites on the substructure of the group X that can be connected to the rest of the molecule, and the linking modes of the two linking sites can be interchanged. For example, when X is
Figure PCTCN2021138693-appb-000017
When the general formula (I) of the present invention represents that the N connecting end on X 1 is connected to R 1 , and the other C connecting end is connected to the rest of the general formula (I), as shown in formula f; or that the C connecting end on X is connected R 1 , the other N-connected end connecting the rest of formula (I),

如式g所示。

Figure PCTCN2021138693-appb-000018
as shown in formula g.
Figure PCTCN2021138693-appb-000018

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, "amino protecting 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，本文所用的术语“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。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。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. Water and Aqueous Solutions Saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, especially for injectable solutions. 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, for example, "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、阑尾癌、小肠癌、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, appendix cancer, small bowel cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, Cancer of the vulva, thyroid, liver, anus, penis, and head and neck.

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特别是KRAS G12C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 act as an inhibitor of KRAS, especially KRAS G12C. 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 PCTCN2021138693-appb-000019
Figure PCTCN2021138693-appb-000019

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

在一些实施方案中，X为-L-X 1-，其中，L为键或NH，X 1为含氮原子的4-8元单环、5-12元稠环、5-12元螺环或5-12元桥环，所述4-8元单环、5-12元稠环、5-12元螺环和5-12元桥环可独立任选地被m个R x取代；其中R x和m具有本发明所述的含义。其中，本发明所述的含氮原子的4-8元单环、5-12元稠环、5-12元螺环或5-12元桥环是指所述的单环、稠环、螺环和桥环各自独立地含有1或2个氮原子。 In some embodiments, X is -LX 1 -, wherein L is a bond or NH, and X 1 is a nitrogen-containing 4-8 membered monocyclic, 5-12 membered fused ring, 5-12 membered spirocyclic ring, or 5-membered -12-membered bridged rings, the 4-8-membered monocycles, 5-12-membered fused rings, 5-12-membered spiro rings, and 5-12-membered bridged rings can be independently optionally substituted with m Rx ; wherein Rx and m have the meaning described in the present invention. Wherein, the 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms in the present invention refers to the single ring, fused ring, spiro ring Rings and bridged rings each independently contain 1 or 2 nitrogen atoms.

在另一些实施方案中，X为

Figure PCTCN2021138693-appb-000020
Figure PCTCN2021138693-appb-000021
其中R x和m具有本发明所述的含义。 In other embodiments, X is
Figure PCTCN2021138693-appb-000020
Figure PCTCN2021138693-appb-000021
wherein Rx and m have the meanings described in the present invention.

在一些实施方案中，Y为N或CH。In some embodiments, Y is N or CH.

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各自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 each have the meaning 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为1、2、3、4、5、6或7，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 is 1, 2, 3, 4, 5, 6 or 7, and R y has the meaning described herein.

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；n为1、2、3、4、5、6或7，其中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 Ry is substituted; n is 1, 2, 3, 4, 5, 6 or 7, wherein Ry has the meaning described herein.

在另一些实施方案中，R 3为

Figure PCTCN2021138693-appb-000022
Figure PCTCN2021138693-appb-000023
Figure PCTCN2021138693-appb-000024
Figure PCTCN2021138693-appb-000025
其中，所述的
Figure PCTCN2021138693-appb-000026
Figure PCTCN2021138693-appb-000027
Figure PCTCN2021138693-appb-000028
独立任选地被n个R y取代；其中n为1、2、3、4、5、6或7，R y具有本发明所述的含义。 In other embodiments, R3 is
Figure PCTCN2021138693-appb-000022
Figure PCTCN2021138693-appb-000023
Figure PCTCN2021138693-appb-000024
Figure PCTCN2021138693-appb-000025
Among them, the said
Figure PCTCN2021138693-appb-000026
Figure PCTCN2021138693-appb-000027
Figure PCTCN2021138693-appb-000028
independently optionally substituted with n R y ; wherein n is 1, 2, 3, 4, 5, 6 or 7 and R y has the meaning described herein.

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 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。 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 2-4 alkene group, C 2-4 alkynyl, 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 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。 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 2-4 alkene group, C 2-4 alkynyl, 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 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。 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 2-4 alkene group, C 2-4 alkynyl, 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 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。 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 2-4 alkene group, C 2-4 alkynyl, 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 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。 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 2-4 alkene group, C 2-4 alkynyl, 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，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。 In some embodiments, each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6 alkyl, C2-6 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 heterocycle 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, C 3-8 cycloalkyl and 3-8 membered heterocyclyl independently optionally 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.

在另一些实施方案中，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 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。 In other embodiments, each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4 alkyl, C2-4 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 hetero Cyclic 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 group, 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, 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，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 other embodiments, each Rx 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 group, 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 , methyl Amino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidine Acridyl, 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 group, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are independently optionally selected from 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.

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、氧代、-C(＝O)OC 1-6烷基、C 1-6烷氨基、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(＝O)OC 1-6烷基、C 1-6烷氨基、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, each R is independently deuterium, halogen, hydroxy, amino, nitro, cyano, oxo, -C( = O)OC 1-6 alkyl, C 1-6 alkylamino, 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 A heterocyclic group consisting of 1 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms; wherein, the -C(=O)OC 1-6 alkyl group, C 1-6 alkylamino group , 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, 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 the radical group.

在另一些实施方案中，各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、氧代、-C(＝O)OC 1-4烷基、C 1-4烷氨基、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(＝O)OC 1-4烷基、C 1-4烷氨基、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, each R is independently deuterium, halogen, hydroxy, amino, nitro, cyano, oxo, -C( = O)OC 1-4 alkyl, C 1-4 alkylamino , 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- A heterocyclic group consisting of 6 atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms; wherein, the -C(=O)OC 1-4 alkyl group, C 1-4 alkane group Amino, 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.

在另一些实施方案中，R y为氘、氟、氯、溴、羟基、氨基、硝基、氰基、氧代、-C(＝O)OCH 3、二甲氨基、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, Ry is deuterium, fluorine, chlorine, bromine, hydroxy, amino, nitro, cyano, oxo, -C(=O) OCH3 , dimethylamino, 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, pyrimidine base, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furanyl or triazolyl; wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoro Methyl, methoxy, ethoxy, isopropoxy, -OCH 2 OH, -OCH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrole Alkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or triazolyl 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, -OCH2OH and -OCH2CH2OH .

在另一些实施方案中，各R y独立地为氘、氟、氯、溴、羟基、氨基、硝基、氰基、氧代、甲基、甲 氧基、-C(＝O)OCH 3、二甲氨基、甲氧基甲基或吡唑基。 In other embodiments, each R is independently deuterium, fluorine, chlorine, bromine, hydroxy, amino, nitro, cyano, oxo, methyl, methoxy, -C( = O) OCH3 , Dimethylamino, methoxymethyl or pyrazolyl.

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 PCTCN2021138693-appb-000029
Figure PCTCN2021138693-appb-000029

Figure PCTCN2021138693-appb-000030
Figure PCTCN2021138693-appb-000030

Figure PCTCN2021138693-appb-000031
Figure PCTCN2021138693-appb-000031

Figure PCTCN2021138693-appb-000032
Figure PCTCN2021138693-appb-000032

Figure PCTCN2021138693-appb-000033
Figure PCTCN2021138693-appb-000033

Figure PCTCN2021138693-appb-000034
Figure PCTCN2021138693-appb-000034

Figure PCTCN2021138693-appb-000035
Figure PCTCN2021138693-appb-000035

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、阑尾癌、小肠癌、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, bile duct, breast, colon, appendix, small bowel, 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.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, synthesizing the contents of this document, 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(在此是指药物载剂)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 carrier) selected according to the form of administration and conventional pharmaceutical practice, which may be an oral tablet, Capsules, elixirs, syrups, and more.

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载剂结合，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载剂结合，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 tablet or capsule form, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier 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 can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combined, 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、阑尾癌、小肠癌、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, appendix cancer, small bowel 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)、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), dt (doublet of triplets, double triplet). 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 250pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm下，用UV检测。Pure compounds were detected by UV at 210 nm/254 nm 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 PCTCN2021138693-appb-000036
Figure PCTCN2021138693-appb-000036

Figure PCTCN2021138693-appb-000037
Figure PCTCN2021138693-appb-000037

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X、Y、Z、R 2a、R 2b、R 2c、R 2d和R 3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 X, Y, Z, R 2a , R 2b , R 2c , R 2d and R 3 has the definitions described herein unless otherwise specified.

反应方案1Reaction scheme 1

Figure PCTCN2021138693-appb-000038
Figure PCTCN2021138693-appb-000038

式( 15)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[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物和醋酸钾(或碳酸铯)的作用下反应得到式( 11)所示的化合物。式( 11)所示的化合物在氰化锌、二(三叔丁基膦)钯和三叔丁基膦(或氰化锌和氯(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))的作用下反应得到式( 12)所示的化合物。式( 12)所示的化合物在三氟乙酸的作用下脱Boc得到式( 13)所示的化合物。式( 13)所示的化合物和式( 14)所示化合物在N,N-二异丙基乙胺的作用下得到式( 15)所示的化合物。 The compound represented by formula ( 15 ) 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 ) in [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex The compound represented by formula ( 11 ) is obtained by reacting with potassium acetate (or cesium carbonate) under the action. The compound represented by formula ( 11 ) is in zinc cyanide, bis(tri-tert-butylphosphine) palladium and tri-tert-butylphosphine (or zinc cyanide and chloro(2-dicyclohexylphosphino-2',4', Under the action of 6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), the reaction obtained by formula ( 12 ) compounds shown. The compound represented by the formula ( 12 ) is de-Boc removed under the action of trifluoroacetic acid to obtain the compound represented by the formula ( 13 ). The compound represented by the formula ( 13 ) and the compound represented by the formula ( 14 ) can obtain the compound represented by the formula ( 15 ) under the action of N,N-diisopropylethylamine.

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)-7-(2-氟-6-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-6-甲腈Example 1 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000039
Figure PCTCN2021138693-appb-000039

第一步 2,5,6-三氯烟酰胺的合成The first step: Synthesis of 2,5,6-trichloronicotinamide

Figure PCTCN2021138693-appb-000040
Figure PCTCN2021138693-appb-000040

反应瓶中加入2,5,6-三氯吡啶-3-羧酸(5.0g,22mmol)、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)，0℃搅拌反应24h，加入氨水的异丙醇溶液(17.0mL,2.0mol/L,34mmol)，继续搅拌4h，抽滤，滤饼用二氯甲烷(50mL×2)洗，干燥后得到标题化合物为白色固体(1.6g,收率32.0％)。2,5,6-Trichloropyridine-3-carboxylic acid (5.0g, 22mmol), dichloromethane (60.0mL) and N,N-dimethylformamide (0.05mL, 0.6mmol) were added to the reaction flask, Cool to 0°C, add oxalyl chloride (2.4mL, 28mmol) dropwise, stir at 0°C for 24h, add ammonia solution in isopropanol (17.0mL, 2.0mol/L, 34mmol), continue stirring for 4h, suction filter, filter cake Washed with dichloromethane (50 mL×2), and dried to obtain the title compound as a white solid (1.6 g, yield 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: Synthesis of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide

Figure PCTCN2021138693-appb-000041
Figure PCTCN2021138693-appb-000041

反应瓶中加入2,5,6-三氯烟酰胺(1.46g,6.48mmol)和四氢呋喃(10mL)，升温至75℃，滴加草酰氯(1.0g,7.9mmol)，75℃搅拌反应1h，降至室温，浓缩除去溶剂，降温至0℃，加入四氢呋喃(5mL)溶解，然后滴加2-异丙基-4-甲基-吡啶-3-胺(1.0g,6.7mmol)的四氢呋喃(5mL)溶液，0℃搅拌反应过夜，加入饱和氯化铵(10mL)淬灭，用乙酸乙酯(50mL×3)萃取三次，合并有机相，浓缩得到标题化合物为黄色固体(1.4g,收率54.0％)。2,5,6-Trichloronicotinamide (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 reaction was stirred at 75°C for 1 h, Cooled to room temperature, concentrated to remove the solvent, cooled to 0 °C, added tetrahydrofuran (5 mL) to dissolve, and then added dropwise a solution of 2-isopropyl-4-methyl-pyridin-3-amine (1.0 g, 6.7 mmol) in tetrahydrofuran (5 mL). ) solution, the reaction was stirred at 0 °C overnight, quenched by adding saturated ammonium chloride (10 mL), extracted three times 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, yield 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

Figure PCTCN2021138693-appb-000042
Figure PCTCN2021138693-appb-000042

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)和四氢 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)，滴完室温搅拌反应过夜，加入饱和氯化铵(5mL)淬灭，乙酸乙酯(50mL)萃取，减压浓缩至干，得到标题化合物为黄色固体(300.6mg,收率24.0％)。2,5,6-Trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (1.4g, 3.5mmol) and tetrahydrofuran (10.0g) were added to the reaction flask. 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), stirred at room temperature overnight after dropping, and added saturated ammonium chloride (5 mL) Quenched, extracted with ethyl acetate (50 mL), and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (300.6 mg, 24.0% yield).

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

Figure PCTCN2021138693-appb-000043
Figure PCTCN2021138693-appb-000043

反应瓶中加入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(200.0mg,0.5476mmol)、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)，升温至回流搅拌反应过夜，减压除去溶剂，得到标题化合物为棕色油状物(210.1mg,收率100％)。6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)- Diketone (200.0 mg, 0.5476 mmol), N,N-diisopropylethylamine (0.6 mL, 4 mmol) and acetonitrile (2.0 mL) were stirred to dissolve, phosphorus oxychloride (0.3 mL, 3 mmol) was added dropwise, and the temperature was increased. The reaction was stirred at reflux overnight, and the solvent was removed under reduced pressure to give the title compound as a brown oil (210.1 mg, 100% yield).

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

Figure PCTCN2021138693-appb-000044
Figure PCTCN2021138693-appb-000044

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-酮(525.0mg,1.368mmol)、(3S)-3-甲基哌嗪-1-羧酸叔丁酯(411.1mg,2.053mmol)、N,N-二异丙基乙胺(1.2mL,7.2mmol)和乙腈(6mL)，升温至80℃搅拌反应过夜，浓缩除去溶剂，然后柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物为黄色固体(455.6mg,收率60.8％)。4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one (525.0mg, 1.368 mmol), (3S)-3-methylpiperazine-1-carboxylate tert-butyl ester (411.1 mg, 2.053 mmol), N,N-diisopropylethylamine (1.2 mL, 7.2 mmol) and acetonitrile ( 6 mL), warmed to 80 °C and stirred the reaction overnight, concentrated to remove the solvent, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (455.6 mg, yield 60.8%).

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-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 sixth step (3S)-4-(6-chloro-7-(2-fluoro-6-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

Figure PCTCN2021138693-appb-000045
Figure PCTCN2021138693-appb-000045

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(500.0mg,0.91mmol)、[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(80.4mg,0.1mmol)、醋酸钾(451.2mg,4.6mmol)和二氧六环(18.0mL)，氮气保护，90℃搅拌反应10min，加入2-氟-6-甲氧基-苯硼酸(175.3mg,1.0mmol)的二氧六环(2.0mL)溶液，再加入两滴水，继续反应7h，过滤，滤液减压蒸干，然后柱层析(二氯甲烷/甲醇(v/v)＝10/1)纯化，得到标题化合物为黄色固体(190.0mg,收率32.7％)。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 (500.0 mg, 0.91 mmol), [1,1′-[1,1′-bis (diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (80.4 mg, 0.1 mmol), potassium acetate (451.2 mg, 4.6 mmol) and dioxane (18.0 mL), under nitrogen, The reaction was stirred at 90°C for 10 min, and a solution of 2-fluoro-6-methoxy-phenylboronic acid (175.3 mg, 1.0 mmol) in dioxane (2.0 mL) was added, two drops of water were added, and the reaction was continued for 7 h, filtered, and the filtrate was reduced. It was evaporated to dryness by autoclaving, followed by purification by column chromatography (dichloromethane/methanol (v/v)=10/1) to give the title compound as a yellow solid (190.0 mg, yield 32.7%).

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

第七步 (3S)-4-(6-氰基-7-(2-氟-6-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 seventh step (3S)-4-(6-cyano-7-(2-fluoro-6-methoxyphenyl)-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

Figure PCTCN2021138693-appb-000046
Figure PCTCN2021138693-appb-000046

微波瓶中依次加入(3S)-4-(6-氯-7-(2-氟-6-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(170.0mg,0.27mmol)、氰化锌(166.7mg,1.42mmol)、N,N-二甲基甲酰胺(5.0mL)、二(三叔丁基膦)钯(160.5mg,0.31mmol)和三叔丁基膦(0.2mL)，吹氮气后转至微波下120℃加热反应16h，反应液过滤，滤液加入乙酸乙酯(200mL)搅拌1min，饱和食盐水(20mL×5)洗涤，有机相减压蒸干后制备，得到标题化合物为白色固体(80.0mg,收率47.8％)。Add (3S)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the microwave bottle in turn )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (170.0 mg, 0.27 mmol) , zinc cyanide (166.7 mg, 1.42 mmol), N,N-dimethylformamide (5.0 mL), bis(tri-tert-butylphosphine)palladium (160.5 mg, 0.31 mmol) and tri-tert-butylphosphine (0.2 mL), after blowing nitrogen, transfer to microwave for heating at 120 °C for 16 h, the reaction solution was filtered, ethyl acetate (200 mL) was added to the filtrate and stirred for 1 min, washed with saturated brine (20 mL×5), and the organic phase was evaporated to dryness under reduced pressure to prepare, The title compound was obtained as a white solid (80.0 mg, 47.8% yield).

MS(ESI,pos.ion)m/z:628.3[M+H] +. MS(ESI,pos.ion)m/z:628.3[M+H] + .

第八步 7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-((S)-2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The eighth step 7-(2-Fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methyl Synthesis of piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000047
Figure PCTCN2021138693-appb-000047

反应瓶中依次加入(3S)-4-(6-氰基-7-(2-氟-6-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(40.0mg,0.06mmol)、二氯甲烷(3.0mL)和三氟乙酸(0.3mL)，室温搅拌反应2h，反应液减压蒸干，得到标题化合物为无色粘稠液体(31.7mg,收率100.0％)。Add (3S)-4-(6-cyano-7-(2-fluoro-6-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 (40.0 mg, 0.06 mmol ), dichloromethane (3.0 mL) and trifluoroacetic acid (0.3 mL), the reaction was stirred at room temperature for 2 h, the reaction solution was evaporated to dryness under reduced pressure to obtain the title compound as a colorless viscous liquid (31.7 mg, yield 100.0%).

第九步 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-氟-6-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-6-甲腈的合成The ninth step 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000048
Figure PCTCN2021138693-appb-000048

-5℃下反应瓶中依次加入7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-((S)-2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(31.7mg,0.06mmol)、二氯甲烷(5.0mL)和三乙胺(25.6mg,0.25mmol)，然后加入丙烯酰氯(10.2mg,0.11mmol)，-5℃搅拌反应20min，加入硅胶粉旋干，然后柱层析(乙酸乙酯)纯化，得到标题化合物为白色固体(18.0mg,收率49.7％)。7-(2-Fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(((S) )-2-methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (31.7 mg, 0.06 mmol), dichloro Methane (5.0 mL) and triethylamine (25.6 mg, 0.25 mmol), then acryloyl chloride (10.2 mg, 0.11 mmol) was added, the reaction was stirred at -5 °C for 20 min, silica gel powder was added, and the mixture was spin-dried, followed by column chromatography (ethyl acetate) ) was purified to give the title compound as a white solid (18.0 mg, 49.7% yield).

MS(ESI,pos.ion)m/z:582.2[M+H] +. MS(ESI,pos.ion)m/z:582.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.52(d,J＝4.9Hz,1H),8.34(d,J＝3.7Hz,1H),7.40(dd,J＝15.0,8.4Hz,1H),7.10(d,J＝4.7Hz,1H),6.79–6.72(m,2H),6.68–6.59(m,1H),6.47–6.38(m,1H),5.85(dd,J＝10.5,1.6Hz,1H),5.23–5.05(m 1H),4.95–4.78(m,1H),4.65–4.50(m,1H),4.39–4.25(m,1H),4.09–3.92(m,1H),3.78(s,3H),3.56(dd,J＝14.4,7.2Hz,1H),2.28(s,3H),2.02(s,3H),1.27(s,2H),1.25(d,J＝6.7Hz,3H),1.06(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.52 (d, J=4.9 Hz, 1H), 8.34 (d, J=3.7 Hz, 1H), 7.40 (dd, J=15.0, 8.4 Hz, 1H) ,7.10(d,J=4.7Hz,1H),6.79-6.72(m,2H),6.68-6.59(m,1H),6.47-6.38(m,1H),5.85(dd,J=10.5,1.6Hz ,1H),5.23–5.05(m 1H),4.95–4.78(m,1H),4.65–4.50(m,1H),4.39–4.25(m,1H),4.09–3.92(m,1H),3.78( s,3H),3.56(dd,J=14.4,7.2Hz,1H),2.28(s,3H),2.02(s,3H),1.27(s,2H),1.25(d,J=6.7Hz,3H ),1.06(s,3H).

实施例2 (S)-4-(4-丙烯酰基-2-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 2 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl) -4-Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000049
Figure PCTCN2021138693-appb-000049

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

Figure PCTCN2021138693-appb-000050
Figure PCTCN2021138693-appb-000050

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(403.1mg,0.7363mmol)、2-氟-5-甲基苯硼酸(426.1mg,2.768mmol)、[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(76.2mg,0.0933mmol)、醋酸钾(118.7mg,1.209mmol)和二氧六环(15.0mL)，90℃搅拌反应3h，冷却至室温，减压蒸干，得到棕色固体，加入饱和食盐水(30mL)，搅拌10min，乙酸乙酯萃取(100mL×3)，合并有机相，减压蒸干，柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物为黄色固体(378.7mg,收率82.8％)。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 (403.1 mg, 0.7363 mmol), 2-fluoro-5-methylphenylboronic acid (426.1 mg) , 2.768mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (76.2mg, 0.0933mmol), potassium acetate (118.7 mg, 1.209 mmol) and dioxane (15.0 mL), stirred at 90°C for 3 h, cooled to room temperature, evaporated to dryness under reduced pressure to obtain a brown solid, added saturated brine (30 mL), stirred for 10 min, and extracted with ethyl acetate ( 100 mL×3), the organic phases were combined, evaporated to dryness under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (378.7 mg, yield 82.8%) ).

MS(ESI,pos.ion)m/z:621.1[M+H] +. MS(ESI,pos.ion)m/z:621.1[M+H] + .

第二步 (S)-4-(6-氰基-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-cyano-7-(2-fluoro-5-methylphenyl)-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

Figure PCTCN2021138693-appb-000051
Figure PCTCN2021138693-appb-000051

微波管中加入(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(101.5mg,0.1634mmol)、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)(25.5mg,0.0324mmol)、氰化锌(190.2mg,1.620mmol)和N,N-二甲基甲酰胺(3.0mL)，置于微波反应器中，升温至130℃反应7小时，加入饱和食盐水(10.0mL)，乙酸乙酯萃取(30.0mL×3)，有机相减压蒸干，柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物为黄色固体(63.4mg,收率63.4％)。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 (101.5 mg, 0.1634 mmol), chlorine (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium (II) (25.5 mg, 0.0324 mmol), zinc cyanide (190.2 mg, 1.620 mmol) and N,N-dimethylformamide (3.0 mL) were placed in a microwave reactor, and the temperature was raised to 130 ° C for reaction 7 After hours, saturated brine (10.0 mL) was added, extracted with ethyl acetate (30.0 mL×3), the organic phase was evaporated to dryness under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) , the title compound was obtained as a yellow solid (63.4 mg, 63.4% yield).

MS(ESI,pos.ion)m/z:612.3[M+H] +. MS(ESI,pos.ion)m/z:612.3[M+H] + .

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperidine) Synthesis of oxazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000052
Figure PCTCN2021138693-appb-000052

反应瓶中加入(S)-4-(6-氰基-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(91.0mg,0.1430mmol)、三氟乙酸(0.5mL,7mmol)和二氯甲烷(5.0mL)，室温搅拌反应1h，减压浓缩至干，真空干燥后得到标题化合物为棕色固体(73.0mg,收率100.0％)。Add (S)-4-(6-cyano-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 (91.0 mg, 0.1430 mmol), Trifluoroacetic acid (0.5 mL, 7 mmol) and dichloromethane (5.0 mL) were stirred at room temperature for 1 h, concentrated to dryness under reduced pressure, and dried in vacuo to obtain the title compound as a brown solid (73.0 mg, yield 100.0%).

第四步 (S)-4-(4-丙烯酰基-2-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000053
Figure PCTCN2021138693-appb-000053

反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(73.0mg,0.1430mmol)、N,N-二异丙基乙胺(33.4mg,0.2584mmol)和二氯甲烷(5mL)，降温至0℃，缓慢滴加丙烯酰氯(15.3mg,0.1690mmol)的二氯甲烷(1mL)溶液，滴完搅拌反应10分钟，减压浓缩至干，柱层析(二氯甲烷/甲醇(v/v)＝20/1)纯化，得到标题化合物为黄色固体(73.9mg,收率91.6％)。Add (S)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) to the reaction flask Piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (73.0 mg, 0.1430 mmol), N,N-diisopropyl Ethylamine (33.4 mg, 0.2584 mmol) and dichloromethane (5 mL) were cooled to 0 °C, and a solution of acryloyl chloride (15.3 mg, 0.1690 mmol) in dichloromethane (1 mL) was slowly added dropwise, and the stirring reaction was completed for 10 minutes. Concentrated to dryness under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a yellow solid (73.9 mg, yield 91.6%).

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)δ8.56(d,J＝4.9Hz,1H),8.36(s,1H),7.28(s,1H),7.14(d,J＝4.9Hz,1H),7.06(dd,J＝15.6,7.2Hz,2H),6.62(s,1H),6.44(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.31(s,1H),4.82(s,1H),4.49(dd,J＝22.0,15.7Hz,1H),4.13(dt,J＝15.5,7.7Hz,1H),3.88(d,J＝19.9Hz,1H),3.67(s,2H),3.21(d,J＝82.9Hz,1H),2.78–2.68(m,1H),2.29(s,3H),2.06(s,4H),1.54(d,J＝18.6Hz,3H),1.37(d,J＝15.3Hz,1H),1.27(dd,J＝15.5,9.4Hz,6H),1.09(dd,J＝6.6,3.3Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, J=4.9 Hz, 1H), 8.36 (s, 1H), 7.28 (s, 1H), 7.14 (d, J=4.9 Hz, 1H), 7.06 (dd,J＝15.6,7.2Hz,2H),6.62(s,1H),6.44(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.31(s,1H) ,4.82(s,1H),4.49(dd,J＝22.0,15.7Hz,1H),4.13(dt,J＝15.5,7.7Hz,1H),3.88(d,J＝19.9Hz,1H),3.67( s, 2H), 3.21(d, J=82.9Hz, 1H), 2.78–2.68(m, 1H), 2.29(s, 3H), 2.06(s, 4H), 1.54(d, J=18.6Hz, 3H) ),1.37(d,J＝15.3Hz,1H),1.27(dd,J＝15.5,9.4Hz,6H),1.09(dd,J＝6.6,3.3Hz,3H).

13C NMR(151MHz,CDCl 3)δ163.7,160.7,158.9,157.2,154.9,154.2,149.4,145.4,140.3,134.3,134.3,133.9,133.8,131.2,131.1,129.8,129.5,128.2,126.5,123.5,123.4,123.3,116.3,116.1,116.0,103.4,77.3,77.0,76.8,60.4,60.1,53.5,49.9,42.1,31.5,31.4,30.5,30.2,30.1,29.7,22.1,21.7,20.6,17.8,17.8. 13 C NMR (151MHz, CDCl 3 )δ163.7,160.7,158.9,157.2,154.9,154.2,149.4,145.4,140.3,134.3,134.3,133.9,133.1,131.2,131.1,129.8,122.5,26.5,129. ,123.3,116.3,116.1,116.0,103.4,77.3,77.0,76.8,60.4,60.1,53.5,49.9,42.1,31.5,31.4,30.5,30.2,30.1,29.7,22.1,21.7,20.6,17.8,17.8.

实施例3 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 3 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000054
Figure PCTCN2021138693-appb-000054

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

Figure PCTCN2021138693-appb-000055
Figure PCTCN2021138693-appb-000055

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(200mg,0.37mmol)、2-甲氧基-4-氟苯硼酸(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(190mg,1.8mmol)和二氧六环(6mL)，升温至90℃搅拌反应3h，冷却至室温，反应液减压蒸干，柱层析(石油醚/乙酸乙酯(v/v)＝2:1)纯化，得到标题化合物为黄色固体(139mg,收率60％)。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 (200 mg, 0.37 mmol), 2-methoxy-4-fluorophenylboronic acid (70 mg, 0.4 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (61 mg, 0.073 mmol), potassium acetate (190 mg, 1.8 mmol) and dioxane (6 mL), the temperature was raised to 90 °C and stirred for 3 h, cooled to room temperature, the reaction solution was evaporated to dryness under reduced pressure, and column chromatography (petroleum ether/ethyl acetate (v/v)=2:1) Purification gave the title compound as a yellow solid (139 mg, 60% yield).

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)8.48(d,J＝4.9Hz,1H),8.03(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,1H),4.21–3.85(m,2H),3.74(s,3H),3.85–3.51(m,1H),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) 8.48 (d, J=4.9 Hz, 1H), 8.03 (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, 1H), 4.21–3.85 (m, 2H), 3.74 (s, 3H), 3.85–3.51 ( m, 1H), 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-氰基-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-cyano-7-(4-fluoro-2-methoxyphenyl)-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

Figure PCTCN2021138693-appb-000056
Figure PCTCN2021138693-appb-000056

微波管中加入(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(139mg,0.22mmol)、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)(45mg,0.056mmol)、氰化锌(261mg,2.2mmol)和N,N-二甲基甲酰胺(2mL)，置于微波反应器中，升温至130℃反应8小时，加入乙酸乙酯(100mL)稀释，用水(5mL)洗涤三次，有机相浓减压浓缩至干，柱层析(石油醚/乙酸乙酯(v/v)＝3/1)纯化，得到标题化合物为黄色固体(103mg,收率75％)。Add (S)-4-(6-chloro-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the microwave tube -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (139 mg, 0.22 mmol), chloro (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium (II) (45 mg, 0.056 mmol), zinc cyanide (261 mg, 2.2 mmol) and N,N-dimethylformamide (2 mL) were placed in a microwave reactor, heated to 130 ° C for 8 hours, added Diluted with ethyl acetate (100 mL), washed three times with water (5 mL), the organic phase was concentrated to dryness under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as Yellow solid (103 mg, 75% yield).

MS(ESI,pos.ion)m/z:628.2[M+H] +. MS(ESI,pos.ion)m/z:628.2[M+H] + .

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) Synthesis of piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000057
Figure PCTCN2021138693-appb-000057

反应瓶中加入(S)-4-(6-氰基-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(103mg,0.16mmol)、三氟乙酸(1mL)和二氯甲烷(2.0mL)，室温搅拌反应2h，减压浓缩至干，得到标题化合物(257mg,收率100％)。Add (S)-4-(6-cyano-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 (103 mg, 0.16 mmol), Trifluoroacetic acid (1 mL) and dichloromethane (2.0 mL) were stirred at room temperature for 2 h, and concentrated to dryness under reduced pressure to obtain the title compound (257 mg, yield 100%).

MS(ESI,pos.ion)m/z:528.7[M+H] +. MS(ESI,pos.ion)m/z:528.7[M+H] + .

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000058
Figure PCTCN2021138693-appb-000058

反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(257mg,0.4mmol)、三乙胺(90mg，0.88)和二氯甲烷(2mL)，降温至0℃，缓慢滴加丙烯酰氯(50mg,0.54mmol)，滴完室温搅拌反应2小时，反应液减压蒸干，然后柱层析(二氯甲烷/甲醇(v/v)＝200/1)纯化，得到标题化合物为黄色固体(30mg,收率13％)。Add (S)-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) into the reaction flask ylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (257 mg, 0.4 mmol), triethylamine (90 mg, 0.88) and dichloromethane (2 mL), cooled to 0 °C, slowly added dropwise acryloyl chloride (50 mg, 0.54 mmol), stirred at room temperature for 2 hours, the reaction solution was evaporated to dryness under reduced pressure, and then column chromatography (dichloromethane/methanol) (v/v)=200/1) and purified to give the title compound as a yellow solid (30 mg, 13% yield).

MS(ESI,pos.ion)m/z:582.1[M+H] +. MS(ESI,pos.ion)m/z:582.1[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.54(d,J＝4.7Hz,1H),8.27(s,1H),7.21-6.99(m,2H),6.84-6.51(m,3H),6.42(d,J＝16.6Hz,1H),5.83(d,J＝10.6Hz,1H),4.99-4.69(m,1H),4.68-4.41(m,1H),4.40-4.21(m,1H),4.18-3.99(m,1H),3.88(s,3H),3.78-3.51(m,1H),3.47-3.20(m,1H),3.20-2.95(m,1H),2.84-2.53(m,1H),2.04(s,3H),1.28-1.13(m,6H),1.06(d,J＝5.9Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.54(d, J=4.7Hz, 1H), 8.27(s, 1H), 7.21-6.99(m, 2H), 6.84-6.51(m, 3H), 6.42(d,J＝16.6Hz,1H),5.83(d,J＝10.6Hz,1H),4.99-4.69(m,1H),4.68-4.41(m,1H),4.40-4.21(m,1H) ,4.18-3.99(m,1H),3.88(s,3H),3.78-3.51(m,1H),3.47-3.20(m,1H),3.20-2.95(m,1H),2.84-2.53(m, 1H), 2.04(s, 3H), 1.28-1.13(m, 6H), 1.06(d, J=5.9Hz, 3H).

实施例4 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 4 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000059
Figure PCTCN2021138693-appb-000059

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

Figure PCTCN2021138693-appb-000060
Figure PCTCN2021138693-appb-000060

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(300mg,0.55mmol)、3-氟-2-甲氧基苯硼酸(93.2mg,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(44.8mg,0.055mmol)、碳酸铯(446.3mg,1.37mmol)和二氧六环(10.0mL)，升温至100℃搅拌过夜，降至室温，反应液减压蒸干，柱层析(石油醚/乙酸乙酯(v/v)＝2/1)纯化，得到标题化合物为黄色固体(185.8mg,收率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 (300 mg, 0.55 mmol), 3-fluoro-2-methoxybenzeneboronic acid (93.2 mg) , 0.55mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (44.8mg, 0.055mmol), cesium carbonate (446.3 mg, 1.37 mmol) and dioxane (10.0 mL), the temperature was raised to 100 °C and stirred overnight, then lowered to room temperature, the reaction solution was evaporated to dryness under reduced pressure, column chromatography (petroleum ether/ethyl acetate (v/v) = 2 /1) Purification to obtain the title compound as a yellow solid (185.8 mg, yield 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-氰基-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-cyano-7-(3-fluoro-2-methoxyphenyl)-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

Figure PCTCN2021138693-appb-000061
Figure PCTCN2021138693-appb-000061

微波管中加入(S)-4-(6-氯-7-(3-氟-2-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(80.6mg,0.127mmol)、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)(19.9mg,0.025mmol)、氰化锌(149.3mg,1.27mmol)和N,N-二甲 基甲酰胺(2mL)，置于微波反应器中，升温至130℃搅拌反应8小时，加入乙酸乙酯(100mL)稀释，水(5mL)洗涤三次，有机相减压蒸干，然后柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物为黄色固体(79.4mg,收率99％)。Add (S)-4-(6-chloro-7-(3-fluoro-2-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 (80.6 mg, 0.127 mmol), chlorine (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium (II) (19.9 mg, 0.025 mmol), zinc cyanide (149.3 mg, 1.27 mmol) and N,N-dimethylformamide (2 mL) were placed in a microwave reactor, and the temperature was raised to 130 ° C and stirred for reaction 8 After 2 hours, ethyl acetate (100 mL) was added to dilute, washed with water (5 mL) three times, the organic phase was evaporated to dryness under reduced pressure, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title The compound was a yellow solid (79.4 mg, 99% yield).

MS(ESI,pos.ion)m/z:628.3[M+H] +. MS(ESI,pos.ion)m/z:628.3[M+H] + .

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) Synthesis of piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000062
Figure PCTCN2021138693-appb-000062

反应瓶中加入(S)-4-(6-氰基-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(79.4mg,0.126mmol)、三氟乙酸(2mL)和二氯甲烷(4.0mL)，室温搅拌反应2h，减压浓缩至干，室温真空干燥过夜得到标题化合物为黄色液体(66.7mg,收率100％)。Add (S)-4-(6-cyano-7-(3-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 (79.4 mg, 0.126 mmol) , trifluoroacetic acid (2 mL) and dichloromethane (4.0 mL), stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, and vacuum dried at room temperature overnight to obtain the title compound as a yellow liquid (66.7 mg, yield 100%).

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000063
Figure PCTCN2021138693-appb-000063

反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(66.7mg,0.126mmol)、DIPEA(200.5mg，1.536mmol)和二氯甲烷(4.0mL)，降温至0℃，缓慢滴加丙烯酰氯(13.6mg,0.15mmol)的二氯甲烷溶液(2.0mL)，滴完室温搅拌反应2小时，反应液减压蒸干，然后柱层析(二氯甲烷:甲醇(v/v)＝20:1)纯化，得到标题化合物为黄色固体(10.0mg,收率13.7％)。Add (S)-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) into the reaction flask ylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (66.7 mg, 0.126 mmol), DIPEA (200.5 mg, 1.536 mmol) ) and dichloromethane (4.0 mL), cooled to 0°C, slowly added dropwise a solution of acryloyl chloride (13.6 mg, 0.15 mmol) in dichloromethane (2.0 mL), stirred at room temperature for 2 hours, and the reaction solution was evaporated under reduced pressure Dried, then purified by column chromatography (dichloromethane:methanol (v/v)=20:1) to give the title compound as a yellow solid (10.0 mg, yield 13.7%).

MS(ESI,pos.ion)m/z:582.2[M+H] +. MS(ESI,pos.ion)m/z:582.2[M+H] + .

1H NMR(400MHz,CDCl 3)δ8.50(d,J＝3.9Hz,1H),8.33(s,1H),7.20(dd,J＝11.2,9.0Hz,1H),7.10(d,J＝3.7Hz,1H),6.99(dd,J＝6.1,3.7Hz,1H),6.95–6.86(m,1H),6.61(dd,J＝14.8,6.3Hz,1H),6.43(d,J＝16.6Hz,1H),5.83(d,J＝10.0Hz,1H),4.91–4.70(m,1H),4.54(dd,J＝12.4,5.3Hz,1H),4.31(dd,J＝12.8,5.7Hz,1H),4.10(dd,J＝19.1,4.7Hz,1H),3.83(s,3H),3.67(dd,J＝8.1,5.5Hz,2H),3.31(dd,J＝11.8,5.2Hz,1H), 3.10(dd,J＝15.2,8.2Hz,1H),2.05(s,3H),1.22(d,J＝5.7Hz,6H),1.04(d,J＝4.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J=3.9 Hz, 1H), 8.33 (s, 1H), 7.20 (dd, J=11.2, 9.0 Hz, 1H), 7.10 (d, J= 3.7Hz, 1H), 6.99 (dd, J=6.1, 3.7Hz, 1H), 6.95–6.86 (m, 1H), 6.61 (dd, J=14.8, 6.3Hz, 1H), 6.43 (d, J=16.6 Hz, 1H), 5.83 (d, J=10.0Hz, 1H), 4.91–4.70 (m, 1H), 4.54 (dd, J=12.4, 5.3Hz, 1H), 4.31 (dd, J=12.8, 5.7Hz) ,1H),4.10(dd,J＝19.1,4.7Hz,1H),3.83(s,3H),3.67(dd,J＝8.1,5.5Hz,2H),3.31(dd,J＝11.8,5.2Hz, 1H), 3.10(dd, J＝15.2, 8.2Hz, 1H), 2.05(s, 3H), 1.22(d, J＝5.7Hz, 6H), 1.04(d, J＝4.6Hz, 3H).

实施例5 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 5 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridine -3-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6- Formonitrile

Figure PCTCN2021138693-appb-000064
Figure PCTCN2021138693-appb-000064

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

Figure PCTCN2021138693-appb-000065
Figure PCTCN2021138693-appb-000065

向钢制反应釜中加入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)。反应釜密封，加热至80℃反应过夜。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色液体(0.41g,收率75.9％)。Add 5-bromo-3-methylpyridine-2(1H)-one (0.51g, 2.69mmol), N,N-dimethylformamide (6.0mL), potassium tert-butoxide ( 0.65 g, 5.79 mmol) and iodomethane (0.5 mL, 8 mmol). The reactor was sealed and heated to 80°C for overnight reaction. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow liquid (0.41 g, yield 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-1,3,2-二氧杂环戊硼-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-dioxaborol-2-yl)pyridine-2(1H)- Synthesis of Ketones

Figure PCTCN2021138693-appb-000066
Figure PCTCN2021138693-appb-000066

向反应瓶中加入5-溴-1,3-二甲基吡啶-2(1H)-酮(0.41g,2.04mmol)，乙酸钾(0.71g,7.26mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.18g,0.22mmol)，二氧六环(15.0mL)和联硼酸频那醇酯(1.30g,5.10mmol)。反应体系在氮气保护下，加热至85℃反应过夜。反应完全后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色液体(0.45g,收率89.2％)。To the reaction flask was added 5-bromo-1,3-lutidine-2(1H)-one (0.41g, 2.04mmol), potassium acetate (0.71g, 7.26mmol), [1,1′-[1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.18 g, 0.22 mmol), dioxane (15.0 mL) and pinacol biboronate (1.30 g, 5.10 mmol). The reaction system was heated to 85°C under nitrogen protection and reacted overnight. After the reaction was completed, it was cooled to room temperature and dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow liquid (0.45 g, yield 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

Figure PCTCN2021138693-appb-000067
Figure PCTCN2021138693-appb-000067

向反应瓶中加入(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(0.24g,0.44mmol)，1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)吡啶-2(1H)-酮(0.11g,0.44mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(32mg,0.039mmol)，二氧六环(10.0mL)和碳酸铯(0.33g,1.01mmol)。反应体系氮气保护下，加热至85℃反应24h。冷却至室温，加入水(50mL)，经乙酸乙酯(150mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝10/1-0/1)纯化，得到标题化合物黄色固体(70.0mg,收率25.2％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.24 g, 0.44 mmol), 1,3-dimethyl-5-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2(1H)-one (0.11g, 0.44mmol), [1,1′- [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (32 mg, 0.039 mmol), dioxane (10.0 mL) and cesium carbonate (0.33 g, 1.01 mmol). The reaction system was heated to 85°C under nitrogen protection for 24h. Cool to room temperature, add water (50 mL), and extract with ethyl acetate (150 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1-0/1) to obtain the title compound as a yellow solid (70.0 mg, yield 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-氰基-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-cyano-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- Synthesis of tert-butyl carboxylate

Figure PCTCN2021138693-appb-000068
Figure PCTCN2021138693-appb-000068

向微波管中加入(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(50mg,0.08mmol)，Xphos Pd G2(12.5mg,0.016mmol)，DMF(2.0mL)和氰化锌(0.10g,0.85mmol)。反应体系置于微波反应仪，在130℃下反应8h。然后冷却至室温，体系减压旋干。残余物中加入水(10mL)和乙酸乙酯(20mL)，分液。水相经乙酸乙酯(50mL)萃取。合并有机相，减压旋干，得到标题化合物为黄色固体(49.6mg,收率99.9％)。Add (S)-4-(6-chloro-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 (50 mg, 0.08 mmol), Xphos Pd G2 (12.5 mg, 0.016 mmol), DMF (2.0 mL) and zinc cyanide (0.10 g, 0.85 mmol). The reaction system was placed in a microwave reactor and reacted at 130 °C for 8 h. Then cooled to room temperature, and the system was spin-dried under reduced pressure. Water (10 mL) and ethyl acetate (20 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined and spin-dried under reduced pressure to obtain the title compound as a yellow solid (49.6 mg, yield 99.9%).

MS(ESI,pos.ion)m/z:525.2[M–Boc+H] +. MS(ESI,pos.ion)m/z:525.2[M–Boc+H] + .

第五步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fifth step (S)-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-isopropyl-4-methylpyridine Synthesis of -3-yl)-4-(2-methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000069
Figure PCTCN2021138693-appb-000069

向反应瓶中加入(S)-4-(6-氰基-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(49.6mg,0.079mmol)，二氯甲烷(4.0mL)和三氟乙酸(2.0mL)。反应体系室温反应2.5h，然后减压旋干，得到标题化合物为黄色固体(42mg,收率100％)。Add (S)-4-(6-cyano-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2 to the reaction flask -Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- tert-Butyl 1-carboxylate (49.6 mg, 0.079 mmol), dichloromethane (4.0 mL) and trifluoroacetic acid (2.0 mL). The reaction system was reacted at room temperature for 2.5 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (42 mg, yield 100%).

第六步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The sixth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridine -3-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6- Synthesis of formonitrile

Figure PCTCN2021138693-appb-000070
Figure PCTCN2021138693-appb-000070

向瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(42mg,0.079mmol)，二氯甲烷(2.0mL)和N,N-二异丙基乙胺(0.2mL,1.15mmol)。反应体系冷却至0℃，缓慢滴加丙烯酰氯(12.5mg,0.14mmol)的二氯甲烷(2mL)溶液。滴加完毕后，体系保温反应2.5h。然后减压旋干，残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物黄色固体(26mg,收率56.1％)。Add (S)-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-isopropyl-4-methyl) to the bottle Pyridin-3-yl)-4-(2-methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (42 mg , 0.079 mmol), dichloromethane (2.0 mL) and N,N-diisopropylethylamine (0.2 mL, 1.15 mmol). The reaction system was cooled to 0°C, and a solution of acryloyl chloride (12.5 mg, 0.14 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the dropwise addition was completed, the system was incubated for 2.5 hours. Then, it was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (26 mg, yield 56.1%).

MS(ESI,pos.ion)m/z:579.3[M+H] +； MS(ESI, pos.ion) m/z: 579.3 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.61(d,J＝4.8Hz,1H),8.28(s,1H),8.04(s,1H),7.65(s,1H),7.19(d,J＝4.7Hz,1H),6.62(dd,J＝24.7,15.7Hz,1H),6.43(d,J＝16.7Hz,1H),5.84(d,J＝10.5Hz,1H),4.77(dd,J＝16.6,9.2Hz,1H),4.66–4.38(m,1H),4.36–4.02(m,1H),4.00–3.58(m,3H),3.53(s,3H),3.36–3.04(m,1H),2.69(dt,J＝20.6,12.5Hz,1H),2.13–2.00(m,6H),1.26(d,J＝5.0Hz,6H),1.04(s,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.61(d, J=4.8Hz, 1H), 8.28(s, 1H), 8.04(s, 1H), 7.65(s, 1H), 7.19(d, J＝4.7Hz, 1H), 6.62(dd, J＝24.7, 15.7Hz, 1H), 6.43(d, J＝16.7Hz, 1H), 5.84(d, J＝10.5Hz, 1H), 4.77(dd, J=16.6,9.2Hz,1H),4.66-4.38(m,1H),4.36-4.02(m,1H),4.00-3.58(m,3H),3.53(s,3H),3.36-3.04(m, 1H), 2.69(dt, J=20.6, 12.5Hz, 1H), 2.13–2.00(m, 6H), 1.26(d, J=5.0Hz, 6H), 1.04(s, 3H).

实施例6 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 6 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2,5-difluorophenyl)-1-(2-isopropyl-4 -Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000071
Figure PCTCN2021138693-appb-000071

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-oxygen Synthesis of tert-butyl substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000072
Figure PCTCN2021138693-appb-000072

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)，(2,5-二氟苯基)硼酸(0.19g，1.20mmol)，醋酸钾(0.14g，1.40mmol)，Pd(dppf)Cl 2-DCM(0.08g,0.10mmol)。氮气保护下，加入二氧六环(10mL)，再次氮气换气，加热至90℃反应14h。降温至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物黄色固体产物(0.52g,收率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-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), (2,5-difluorobenzene (0.19 g, 1.20 mmol), potassium acetate (0.14 g, 1.40 mmol), Pd(dppf)Cl2 - DCM (0.08 g, 0.10 mmol). Under nitrogen protection, dioxane (10 mL) was added, and the mixture was purged with nitrogen again, and heated to 90° C. to react for 14 h. Cool to room temperature and spin dry under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a yellow solid product (0.52 g, yield 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-氰基-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-cyano-7-(2,5-difluorophenyl)-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

Figure PCTCN2021138693-appb-000073
Figure PCTCN2021138693-appb-000073

向微波管中加入将(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)，Xphos Pd G2(0.04g，0.05mmol)，氰化锌(0.29g，2.46mmol)和无水N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，在136℃下反应8h。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/2)纯化，得到标题化合物黄色固体(27mg,收率18.3％)。Add (S)-4-(6-chloro-7-(2,5-difluorophenyl)-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 (0.15 g, 0.24 mmol), Xphos Pd G2 (0.04 g, 0.05 mmol), zinc cyanide (0.29 g, 2.46 mmol) and anhydrous N,N-dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor and reacted at 136 °C for 8 h. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to obtain the title compound as a yellow solid (27 mg, yield 18.3%).

MS(ESI,pos.ion)m/z:616.3[M+H] +； MS(ESI, pos.ion) m/z: 616.3[M+H] + ;

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈三氟乙酸盐的合成The third step (S)-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine- Synthesis of 1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate

Figure PCTCN2021138693-appb-000074
Figure PCTCN2021138693-appb-000074

向反应瓶中加入(S)-4-(6-氰基-7-(2,5-二氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(27mg，0.044mmol)，二氯甲烷(2mL)和三氟乙酸(1mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物黄色油状物(28mg,收率100％)，直接用于下一步反应。Add (S)-4-(6-cyano-7-(2,5-difluorophenyl)-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 (27 mg, 0.044 mmol), dichloro Methane (2 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow oil (28 mg, yield 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)-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2,5-difluorophenyl)-1-(2-isopropyl-4 Synthesis of -methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000075
Figure PCTCN2021138693-appb-000075

向反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈三氟乙酸盐(28mg，0.044mmol)，二氯甲烷(2mL)和N,N-二异丙基乙胺(0.1mL,0.56mmol).体系冷却时0℃，滴加丙烯酰氯(26mg,0.29mmol)。滴加完毕，反应体系室温下反应0.5h，随后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物米黄色固体(20mg,收率80.1％)。Add (S)-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperidine) to the reaction flask Azin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile trifluoroacetate (28 mg, 0.044 mmol), dichloromethane (2 mL) ) and N,N-diisopropylethylamine (0.1 mL, 0.56 mmol). When the system was cooled at 0°C, acryloyl chloride (26 mg, 0.29 mmol) was added dropwise. After the dropwise addition was completed, the reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a beige solid (20 mg, yield 80.1%).

MS(ESI,pos.ion)m/z:570.2[M+H] +； MS(ESI, pos.ion) m/z: 570.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.55(d,J＝4.8Hz,1H),8.36(s,1H),7.21-7.06(m,3H),6.94-6.91(m,1H), 6.65-6.55(m,1H),6.42(d,J＝16.4Hz,1H),5.83(d,J＝10.4Hz,1H),4.92-4.22(m,3H),4.14-3.55(m,4H),2.77-2.57(m,1H),2.03(s,3H),1.28-1.22(m,6H),1.05(d,J＝6.3Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.55(d, J=4.8Hz, 1H), 8.36(s, 1H), 7.21-7.06(m, 3H), 6.94-6.91(m, 1H), 6.65-6.55(m, 1H), 6.42(d, J=16.4Hz, 1H), 5.83(d, J=10.4Hz, 1H), 4.92-4.22(m, 3H), 4.14-3.55(m, 4H) ,2.77-2.57(m,1H),2.03(s,3H),1.28-1.22(m,6H),1.05(d,J=6.3Hz,3H).

实施例7 (S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氰基-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 7 (S)-3-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyano-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoic acid methyl ester

Figure PCTCN2021138693-appb-000076
Figure PCTCN2021138693-appb-000076

第一步 (S)-4-(6-氯-7-(2-氟-5-(甲氧基羰基)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-chloro-7-(2-fluoro-5-(methoxycarbonyl)phenyl)-1-(2-isopropyl-4-methylpyridine-3- Synthesis of tert-butyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000077
Figure PCTCN2021138693-appb-000077

向反应瓶中加入(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-(甲氧基羰基)苯基)硼酸(0.12g,0.6mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(91mg,0.11mmol)，醋酸钾(283mg,2.7mmol)和二氧六环(8mL)。反应体系加热至90℃反应3h。然后冷却至室温，浓缩旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物黄色固体(0.32g,收率86％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.55 mmol), (2-fluoro-5-(methoxycarbonyl) ) phenyl) boronic acid (0.12 g, 0.6 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (91 mg, 0.11 mmol), potassium acetate (283 mg, 2.7 mmol) and dioxane (8 mL). The reaction system was heated to 90°C for 3h. It was then cooled to room temperature, concentrated and spin-dried. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.32 g, yield 86%).

MS(ESI,pos.ion)m/z:665.2[M+H] +； MS(ESI, pos.ion) m/z: 665.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.49(d,J＝4.8Hz,1H),8.20-8.03(m,2H),7.92(dd,J＝6.7,1.8Hz,1H),7.16(t,J＝9.0Hz,1H),7.09(d,J＝4.7Hz,1H),4.92(s,1H),4.32(s,2H),4.00(s,1H),3.89(s,3H),3.70(s,1H),3.43-3.05(m,2H),2.83-2.66(m,1H),2.04(d,J＝6.3Hz,3H),1.52(s,9H),1.32-1.16(m,6H),1.10(dd,J＝6.5,3.4Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.49 (d, J=4.8 Hz, 1H), 8.20-8.03 (m, 2H), 7.92 (dd, J=6.7, 1.8 Hz, 1H), 7.16 ( t, J=9.0Hz, 1H), 7.09(d, J=4.7Hz, 1H), 4.92(s, 1H), 4.32(s, 2H), 4.00(s, 1H), 3.89(s, 3H), 3.70(s, 1H), 3.43-3.05(m, 2H), 2.83-2.66(m, 1H), 2.04(d, J=6.3Hz, 3H), 1.52(s, 9H), 1.32-1.16(m, 6H),1.10(dd,J=6.5,3.4Hz,3H).

第二步 (S)-4-(6-氰基-7-(2-氟-5-(甲氧基羰基)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 second step (S)-4-(6-cyano-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

Figure PCTCN2021138693-appb-000078
Figure PCTCN2021138693-appb-000078

向微波瓶依次加入(S)-4-(6-氯-7-(2-氟-5-(甲氧基羰基)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(0.25g,0.38mmol)，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)(0.10g,0.13mmol)，氰化锌(0.45g,3.8mmol)和超干N,N-二甲基甲酰胺(2mL)。反应体系置于微波反应仪中，升温至130℃反应8h。然后冷却至室温，加入乙酸乙酯(20mL)，经水(5mL×3)洗涤。有机相减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物黄色固体(80mg,收率32％)。Add (S)-4-(6-chloro-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 (0.25g, 0.38mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1' - biphenyl)] palladium(II) (0.10 g, 0.13 mmol), zinc cyanide (0.45 g, 3.8 mmol) and ultra-dry N,N-dimethylformamide (2 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 130 °C for 8 h. It was then cooled to room temperature, ethyl acetate (20 mL) was added, washed with water (5 mL x 3). The organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (80 mg, yield 32%).

MS(ESI,pos.ion)m/z:656.3[M+H] +； MS(ESI, pos.ion) m/z: 656.3[M+H] + ;

第三步 (S)-3-(6-氰基-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-氟苯甲酸甲酯三氟乙酸盐的合成The third step (S)-3-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoic acid methyl ester trifluoroacetate

Figure PCTCN2021138693-appb-000079
Figure PCTCN2021138693-appb-000079

向反应瓶中加入(S)-4-(6-氰基-7-(2-氟-5-(甲氧基羰基)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(80mg,0.12mmol)，三氟乙酸(2mL)和二氯甲烷(4mL)。反应体系室温反应2h，然后减压旋干，得到标题化合物为黄色粘稠状半固体(82mg,收率100％)。MS(ESI,pos.ion)m/z:556.2[M+H] +； Add (S)-4-(6-cyano-7-(2-fluoro-5-(methoxycarbonyl)phenyl)-1-(2-isopropyl-4-methylpyridine) to the reaction flask -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (80 mg, 0.12 mmol), trifluoroacetic acid (2 mL) and dichloromethane (4 mL). The reaction system was reacted at room temperature for 2 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow viscous semi-solid (82 mg, yield 100%). MS(ESI, pos.ion) m/z: 556.2[M+H] + ;

第四步 (S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氰基-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 fourth step (S)-3-(4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyano-1-(2-isopropyl-4-methylpyridine- Synthesis of methyl 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-fluorobenzoate

Figure PCTCN2021138693-appb-000080
Figure PCTCN2021138693-appb-000080

向反应瓶中加入(S)-3-(6-氰基-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-氟苯甲酸甲酯三氟乙酸盐(82mg,0.12mmol)，三乙胺(0.14g，1.38mmol)和二氯甲烷(4.0mL).体系冷却至0℃，缓慢滴加丙烯酰氯(40mg,0.43mmol)。滴加完毕，反应体系室温反应2h，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物黄色固体(7mg,收率9.4％)。Add (S)-3-(6-cyano-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 trifluoroacetate (82 mg, 0.12 mmol), triethyl Amine (0.14 g, 1.38 mmol) and dichloromethane (4.0 mL). The system was cooled to 0°C and acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction system was reacted at room temperature for 2 hours, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to obtain the title compound as a yellow solid (7 mg, yield 9.4%).

MS(ESI,pos.ion)m/z:610.3[M+H] +； MS(ESI, pos.ion) m/z: 610.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.55(d,J＝4.7Hz,1H),8.37(s,1H),8.24-8.11(m,1H),8.01(d,J＝6.7Hz,1H),7.26(d,J＝6.4Hz,1H),7.14(d,J＝4.1Hz,1H),6.75-6.53(m,1H),6.43(d,J＝16.6Hz,1H),5.84(d,J＝10.0Hz,1H),4.82(s,1H),4.54(s,1H),4.31(s,1H),4.09(s,1H),3.90(s,3H),3.68(s,1H),3.39-3.21(m,1H),3.09(s,1H),2.68-2.60(m,1H),2.04(s,3H),1.27(d,J＝12.4Hz,6H),1.10(d,J＝6.5Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.55(d, J=4.7Hz, 1H), 8.37(s, 1H), 8.24-8.11(m, 1H), 8.01(d, J=6.7Hz, 1H), 7.26(d, J＝6.4Hz, 1H), 7.14(d, J＝4.1Hz, 1H), 6.75-6.53(m, 1H), 6.43(d, J＝16.6Hz, 1H), 5.84( d, J=10.0Hz, 1H), 4.82(s, 1H), 4.54(s, 1H), 4.31(s, 1H), 4.09(s, 1H), 3.90(s, 3H), 3.68(s, 1H) ), 3.39-3.21(m, 1H), 3.09(s, 1H), 2.68-2.60(m, 1H), 2.04(s, 3H), 1.27(d, J＝12.4Hz, 6H), 1.10(d, J=6.5Hz, 3H).

实施例8 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 8 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( 2-Methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000081
Figure PCTCN2021138693-appb-000081

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

Figure PCTCN2021138693-appb-000082
Figure PCTCN2021138693-appb-000082

向瓶中加入(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-甲基苯基)硼酸(0.42g,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(81mg,0.10mmol)，醋酸钾(0.12g,1.21mmol)和二氧六环(15.0mL)。反应体系氮气保护下加热至90℃反应3h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(30mL)，搅拌10min，经乙酸乙酯(30mL×3)萃取，合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(0.51mg,收率90.3％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridine to the bottle [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), (2-hydroxy-3-methylphenyl)boronic acid (0.42 g, 2.77 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (81 mg, 0.10 mmol), potassium acetate (0.12 g, 1.21 mmol) and dioxane (15.0 mL). The reaction system was heated to 90°C under nitrogen protection for 3h. It was then cooled to room temperature and spin-dried under reduced pressure. 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 spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.51 mg, yield 90.3%).

MS(ESI,pos.ion)m/z:620.1[M+H] +. MS(ESI,pos.ion)m/z:620.1[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

Figure PCTCN2021138693-appb-000083
Figure PCTCN2021138693-appb-000083

向反应瓶中加入(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(0.40g,0.64mmol)，氢氧化钾(0.19g,3.39mmol)和碘甲烷(0.3mL,5.0mmol)。反应体系室温下反应3小时。然后加入饱和食盐水(10.0mL)，经乙酸乙酯(30mL×3)萃取。合并有机相，减压旋干。有机相浓缩除去溶剂，得到棕色固体。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(0.36g,收率86.8％)。Add (S)-4-(6-chloro-7-(2-hydroxy-3-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 (0.40 g, 0.64 mmol), Potassium hydroxide (0.19 g, 3.39 mmol) and iodomethane (0.3 mL, 5.0 mmol). The reaction system was reacted at room temperature for 3 hours. Then, saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and spun dry under reduced pressure. The organic phase was concentrated to remove the solvent to give a brown solid. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.36 g, yield 86.8%).

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

第三步 (S)-4-(6-氰基-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-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000084
Figure PCTCN2021138693-appb-000084

向微波管中加入(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)(41mg,0.05mmol)，氰化锌(0.20g,1.71mmol)和超干DMF(2.0mL)。反应体系置于微博反应器内，升温至130℃，反应7小时。冷却至室温，加入饱和食盐水(10.0mL)，经乙酸乙酯(30.0mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(46mg,收率45.8％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylbenzene) to the microwave tube (0.10 g, 0.16 mmol) ), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) benzene)] palladium(II) (41 mg, 0.05 mmol), zinc cyanide (0.20 g, 1.71 mmol) and ultra-dry DMF (2.0 mL). The reaction system was placed in a microblogging reactor, heated to 130° C., and reacted for 7 hours. It was cooled to room temperature, saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (46 mg, yield 45.8%).

MS(ESI,pos.ion)m/z:624.3[M+H] +； MS(ESI, pos.ion) m/z: 624.3[M+H] + ;

第四步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-4-(2-methyl) Synthesis of Piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000085
Figure PCTCN2021138693-appb-000085

向反应瓶中加入(S)-4-(6-氰基-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(46mg,0.07mmol)，三氟乙酸(0.1mL,1mmol)和二氯甲烷(3.0mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(38.4mg,收率100％)，直接用于下一步。Add (S)-4-(6-cyano-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 (46 mg, 0.07 mmol ), trifluoroacetic acid (0.1 mL, 1 mmol) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (38.4 mg, yield 100%), which was directly used in the next step.

MS(ESI,pos.ion)m/z:524.3[M+H] +； MS(ESI, pos.ion) m/z: 524.3[M+H] + ;

第五步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The fifth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( Synthesis of 2-methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000086
Figure PCTCN2021138693-appb-000086

向反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(38.4mg,0.07mmol)，N,N-二异丙基乙胺(0.1mL，0.56mmol)和二氯甲烷(3.0mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(0.1mL,0.6mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10分钟，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物黄色固体(40mg,收率95.6％)。Add (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-4-(2 to the reaction flask -Methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (38.4 mg, 0.07 mmol), N,N-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile Isopropylethylamine (0.1 mL, 0.56 mmol) and dichloromethane (3.0 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (0.1 mL, 0.6 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition was completed, the reaction system was incubated for 10 minutes, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (40 mg, yield 95.6%).

MS(ESI,pos.ion)m/z:578.2[M+H] +； MS(ESI, pos.ion) m/z: 578.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.53(d,J＝4.4Hz,1H),8.35(s,1H),7.32(d,J＝7.0Hz,1H),7.17-6.95(m,3H),6.74-6.55(m,1H),6.44(d,J＝16.5Hz,1H),5.85(d,J＝10.4Hz,1H),5.24-5.04(m,0.5H),4.96-4.72(m,1H),4.66-4.44(m,1H),4.40-4.26(m,0.5H),4.25-4.01(m,1H),4.01-3.82(m,1H),3.77-3.57(m,2H),3.31(s,3H),2.80-2.65(m,1H),2.34(s,3H),2.07(s,3H),1.30-1.20(m,6H),1.12-0.99(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.53 (d, J=4.4Hz, 1H), 8.35 (s, 1H), 7.32 (d, J=7.0Hz, 1H), 7.17-6.95 (m, 3H), 6.74-6.55(m, 1H), 6.44(d, J=16.5Hz, 1H), 5.85(d, J=10.4Hz, 1H), 5.24-5.04(m, 0.5H), 4.96-4.72( m,1H),4.66-4.44(m,1H),4.40-4.26(m,0.5H),4.25-4.01(m,1H),4.01-3.82(m,1H),3.77-3.57(m,2H) ,3.31(s,3H),2.80-2.65(m,1H),2.34(s,3H),2.07(s,3H),1.30-1.20(m,6H),1.12-0.99(m,3H).

实施例9 (S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氰基-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-(二甲基氨基)苯甲酸甲酯Example 9 (S)-3-(4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-cyano-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-(dimethylamino)benzoic acid methyl ester

Figure PCTCN2021138693-appb-000087
Figure PCTCN2021138693-appb-000087

第一步 (S)-4-(6-氰基-7-(2-(二甲基氨基)-5-(甲氧基羰基)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-cyano-7-(2-(dimethylamino)-5-(methoxycarbonyl)phenyl)-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 Synthesis

Figure PCTCN2021138693-appb-000088
Figure PCTCN2021138693-appb-000088

向微波管中加入(S)-4-(6-氯-7-(2-氟-5-(甲氧基羰基)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(0.25g,0.38mmol)，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)(100mg,0.13mmol)，氰化锌(454mg,3.8mmol)和超干N,N-二甲基甲酰胺(2mL)。反应体系置于微波反应器中，升温至130℃，反应8小时。然后冷却至室温，加入乙酸乙酯(100mL)，用水(5mL×3)洗涤。有机相减压旋干，残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物黄色固体(0.16g,收率63％)。Add (S)-4-(6-chloro-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 (0.25g, 0.38mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1' -biphenyl)] palladium(II) (100 mg, 0.13 mmol), zinc cyanide (454 mg, 3.8 mmol) and ultra-dry N,N-dimethylformamide (2 mL). The reaction system was placed in a microwave reactor, heated to 130° C., and reacted for 8 hours. It was then cooled to room temperature, ethyl acetate (100 mL) was added, and washed with water (5 mL x 3). The organic phase was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.16 g, yield 63%).

MS(ESI,pos.ion)m/z:681.4[M+H] +. MS(ESI,pos.ion)m/z:681.4[M+H] + .

第二步 (S)-3-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-7-基)-4-(二甲基氨基)苯甲酸甲酯的合成The second step (S)-3-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)- Synthesis of methyl 2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-7-yl)-4-(dimethylamino)benzoate

Figure PCTCN2021138693-appb-000089
Figure PCTCN2021138693-appb-000089

向反应瓶中加入(S)-4-(6-氰基-7-(2-(二甲基氨基)-5-(甲氧基羰基)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(85mg,0.12mmol)，三氟乙酸(1mL)和二氯甲烷(2mL)。反应体系室温反应2h，然后减压旋干，得到标题化合物为黄色固体(73mg,收率100％)，直接用于下一步反应。Add (S)-4-(6-cyano-7-(2-(dimethylamino)-5-(methoxycarbonyl)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. Butyl ester (85 mg, 0.12 mmol), trifluoroacetic acid (1 mL) and dichloromethane (2 mL). The reaction system was reacted at room temperature for 2 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (73 mg, yield 100%), which was directly used in the next reaction.

第三步 (S)-3-(4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氰基-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-(二甲基氨基)苯甲酸甲酯的合成The third step (S)-3-(4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyano-1-(2-isopropyl-4-methylpyridine- Synthesis of methyl 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-4-(dimethylamino)benzoate

Figure PCTCN2021138693-appb-000090
Figure PCTCN2021138693-appb-000090

向反应瓶中加入(S)-3-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-7-基)-4-(二甲基氨基)苯甲酸甲酯(73mg,0.12mmol)，三乙胺(0.15g，1.48mmol)和二氯甲烷(4.0mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(40mg,0.43mmol)。滴加完毕后，反应体系室温下反应2h，然后减压旋干，残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物黄色固体(11mg,收率13.8％)。Add (S)-3-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl) to the reaction flask )-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-7-yl)-4-(dimethylamino)benzoic acid methyl ester (73 mg, 0.12 mmol), triethyl Amine (0.15 g, 1.48 mmol) and dichloromethane (4.0 mL). The system was cooled to 0°C, and acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 2 h, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to obtain the title compound as a yellow solid (11 mg, yield). rate 13.8%).

MS(ESI,pos.ion)m/z:635.3[M+H] +； MS(ESI, pos.ion) m/z: 635.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.60-8.48(m,1H),8.28(d,J＝3.6Hz,1H),8.00(d,J＝7.9Hz,1H),7.70(s,1H),7.14(d,J＝3.5Hz,1H),7.03(d,J＝8.6Hz,1H),6.72-6.53(m,1H),6.43(d,J＝16.7Hz,1H),5.84(d,J＝10.5Hz,1H),4.79(d,J＝12.2Hz,1H),4.49(s,1H),4.39-4.16(m,1H),4.07(s,1H),3.84(s,3H),3.68(s,1H),3.33(s,1H),3.10(s,1H),2.74(s,1H),2.69(s,6H),2.05(s,3H),1.28-1.23(m,6H),1.13(d,J＝6.2Hz,3H) 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.60-8.48(m, 1H), 8.28(d, J=3.6Hz, 1H), 8.00(d, J=7.9Hz, 1H), 7.70(s, 1H), 7.14(d, J＝3.5Hz, 1H), 7.03(d, J＝8.6Hz, 1H), 6.72-6.53(m, 1H), 6.43(d, J＝16.7Hz, 1H), 5.84( d, J＝10.5Hz, 1H), 4.79(d, J＝12.2Hz, 1H), 4.49(s, 1H), 4.39-4.16(m, 1H), 4.07(s, 1H), 3.84(s, 3H) ), 3.68(s, 1H), 3.33(s, 1H), 3.10(s, 1H), 2.74(s, 1H), 2.69(s, 6H), 2.05(s, 3H), 1.28-1.23(m, 6H),1.13(d,J＝6.2Hz,3H)

实施例10 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 10 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( 8-Methylnaphthalen-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000091
Figure PCTCN2021138693-appb-000091

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

Figure PCTCN2021138693-appb-000092
Figure PCTCN2021138693-appb-000092

向反应瓶中加入(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-甲基萘-1-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,0.09mmol)，碳酸钠(0.13g,1.23mmol)和二氧六环(10.0mL)。反应体系加热至90℃反应3h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(30mL)，搅拌10min，经乙酸乙酯(100mL×3)萃取。合并有机相，减压旋干，残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(0.40g,收率65.2％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.51 g, 0.93 mmol), (8-methylnaphthalen-1-yl)boronic acid (0.26 g, 1.40 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (77.1 mg, 0.09 mmol), carbonic acid Sodium (0.13 g, 1.23 mmol) and dioxane (10.0 mL). The reaction system was heated to 90°C for 3h. It was then cooled to room temperature and spin-dried under reduced pressure. Saturated brine (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.40 g, yield 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-氰基-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-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalene-1-yl)-2 -Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000093
Figure PCTCN2021138693-appb-000093

向微波管中加入(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(0.11mg,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)(0.12g,0.16mmol)，氰化锌(0.20g,1.71mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至130℃，反应7h。然后冷却至室温，加入饱和食盐水(10.0mL)，经乙酸乙酯(30.0mL×3)萃取。合并有机相，减压旋干，残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(46mg,收率44.3％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalen-1-yl)- 2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.11 mg, 0.16 mmol), chloro (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium(II) (0.12 g, 0.16 mmol), zinc cyanide (0.20 g, 1.71 mmol) and ultra-dry N,N-dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 130 °C, and reacted for 7 h. Then, it was cooled to room temperature, saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL×3). The organic phases were combined, spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (46 mg, yield 44.3%).

MS(ESI,pos.ion)m/z:644.3[M+H] +； MS(ESI, pos.ion) m/z: 644.3[M+H] + ;

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalene-1-yl)-4-(2-methylpiperazine) Synthesis of -1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000094
Figure PCTCN2021138693-appb-000094

向反应瓶中加入(S)-4-(6-氰基-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(62mg,0.10mmol)，三氟乙酸(0.1mL)和二氯甲烷(5.0mL)。反应体系常温反应1h，然后减压旋干，得到标题化合物棕色固体(52mg,收率100％)。Add (S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalen-1-yl) to the reaction flask -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (62 mg, 0.10 mmol), tris Fluoroacetic acid (0.1 mL) and dichloromethane (5.0 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a brown solid (52 mg, yield 100%).

MS(ESI,pos.ion)m/z:544.3[M+H] +； MS(ESI, pos.ion) m/z: 544.3 [M+H] + ;

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( Synthesis of 8-methylnaphthalen-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000095
Figure PCTCN2021138693-appb-000095

向反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(52mg,0.10mmol)，N,N-二异丙基乙胺(0.3mL，1.68mmol)和二氯甲烷(5mL)。体系降温至0℃，缓慢滴加丙烯酰氯(0.1mL,0.1mmol)的二氯甲烷(1mL)溶液。滴加完毕后，体系保温反应10min，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)，得到标题化合物黄色固体(50mg,收率87.0％)。Add (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthalen-1-yl)-4-(2-methyl) to the reaction flask Piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (52 mg, 0.10 mmol), N,N-diisopropylethyl Amine (0.3 mL, 1.68 mmol) and dichloromethane (5 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (0.1 mL, 0.1 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the system was incubated for 10 minutes, and then spin-dried under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (50 mg, yield 87.0%).

MS(ESI,pos.ion)m/z:598.3[M+H] +； MS(ESI, pos.ion) m/z: 598.3 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.46(t,J＝4.5Hz,1H),8.35(d,J＝7.7Hz,1H),7.96(d,J＝7.5Hz,1H),7.79(d,J＝8.0Hz,1H),7.44(dt,J＝15.0,7.4Hz,2H),7.30(s,1H),7.17(d,J＝6.6Hz,1H),7.06(dd,J＝13.5,4.5Hz,1H),6.61(s,1H),6.47-6.39(m,1H),5.84(t,J＝9.0Hz,1H),3.67(s,2H),2.76(dd,J＝33.9,27.8Hz, 2H),2.07(d,J＝10.1Hz,2H),1.99(d,J＝4.6Hz,3H),1.52(s,3H),1.34-1.20(m,8H),1.07(d,J＝4.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.46 (t, J=4.5Hz, 1H), 8.35 (d, J=7.7Hz, 1H), 7.96 (d, J=7.5Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.44 (dt, J=15.0, 7.4Hz, 2H), 7.30 (s, 1H), 7.17 (d, J=6.6Hz, 1H), 7.06 (dd, J= 13.5,4.5Hz,1H),6.61(s,1H),6.47-6.39(m,1H),5.84(t,J=9.0Hz,1H),3.67(s,2H),2.76(dd,J=33.9 , 27.8Hz, 2H), 2.07(d, J＝10.1Hz, 2H), 1.99(d, J＝4.6Hz, 3H), 1.52(s, 3H), 1.34-1.20(m, 8H), 1.07(d ,J=4.6Hz,3H).

实施例11 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 11 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( 2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000096
Figure PCTCN2021138693-appb-000096

第一步 (S)-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)-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-(2-methoxyphenyl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000097
Figure PCTCN2021138693-appb-000097

向反应瓶中加入(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-甲氧基苯基)硼酸(0.15g,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(75mg,0.09mmol)，碳酸钾(0.43g,4.30mmol)和二氧六环(10.0mL)。反应体系加热至100℃反应24h。然后冷却至室温，减压旋干。残余物中加入水(30mL)，搅拌10min，经乙酸乙酯(100mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/0-0/1)纯化，得到标题化合物为黄色固体(0.42g,收率74.4％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.91 mmol), (2-methoxyphenyl)boronic acid (0.15 g, 1.01 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (75 mg, 0.09 mmol), potassium carbonate (0.43 g, 4.30 mmol) and dioxane (10.0 mL). The reaction system was heated to 100°C for 24h. It was then cooled to room temperature and spin-dried under reduced pressure. Water (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (100 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/0-0/1) to give the title compound as a yellow solid (0.42 g, yield 74.4%).

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-氰基-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)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxygen Synthesis of tert-butyl substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000098
Figure PCTCN2021138693-appb-000098

向微波管中加入(S)-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)-3-甲基哌嗪-1-羧酸叔丁酯(0.17g,0.27mmol)，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)(54mg,0.067mm ol)，氰化锌(0.32g,2.7mmol)和超干N,N-二甲基甲酰胺(2mL)。反应体系置于微波反应器中，升温至130℃，反应8h。反应结束后，冷却至室温，加入乙酸乙酯(100mL)稀释，经水(5mL×3)洗涤。有机相减压旋干，残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(74mg,收率45％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2- Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.17 g, 0.27 mmol), chloro (2 -Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium ( II) (54 mg, 0.067 mmol), zinc cyanide (0.32 g, 2.7 mmol) and ultra-dry N,N-dimethylformamide (2 mL). The reaction system was placed in a microwave reactor, heated to 130 °C, and reacted for 8 h. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (5 mL×3). The organic phase was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (74 mg, yield 45%).

MS(ESI,pos.ion)m/z:610.3[M+H] +； MS(ESI, pos.ion) m/z: 610.3[M+H] + ;

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(2-methylpiperazine-1 -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000099
Figure PCTCN2021138693-appb-000099

向反应瓶中加入(S)-4-(6-氰基-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)-3-甲基哌嗪-1-羧酸叔丁酯(80mg,0.13mmol)，三氟乙酸(1mL)和二氯甲烷(2mL)。反应体系室温反应1.5h，然后减压旋干，得到标题化合物为棕色固体(67mg,收率100％)，直接用于下一步反应。Add (S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2 to the reaction flask -Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (80 mg, 0.13 mmol), trifluoroacetic acid (1 mL) and dichloromethane (2 mL). The reaction system was reacted at room temperature for 1.5 h, and then spin-dried under reduced pressure to obtain the title compound as a brown solid (67 mg, yield 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:510.2[M+H] +； MS(ESI, pos.ion) m/z: 510.2[M+H] + ;

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( Synthesis of 2-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000100
Figure PCTCN2021138693-appb-000100

向反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(67mg,0.13mmol)，三乙胺(0.12g,1.2mmol)和二氯甲烷(2mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(40mg,0.43mmol)。滴加完毕后，反应体系室温反应3h。待反应完全后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物为黄色固体(25mg,收率33.7％)。Add (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(2-methylpiperazine) to the reaction flask -1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (67 mg, 0.13 mmol), triethylamine (0.12 g, 1.2 mmol) and Dichloromethane (2 mL). The system was cooled to 0°C, and acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 3 hours. After the reaction was completed, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to obtain the title compound as a yellow solid (25 mg, yield 33.7%).

MS(ESI,pos.ion)m/z:564.3[M+H] +； MS(ESI, pos.ion) m/z: 564.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.54(d,J＝4.9Hz,1H),8.28(s,1H),7.50-7.39(m,1H),7.19-7.05(m,2H),7.05-6.91(m,2H),6.71-6.53(m,1H),6.42(d,J＝16.7Hz,1H),5.83(dd,J＝10.4,1.3Hz,1H),4.95-4.71(m,1H),4.65-4.44(m,1H),4.40-4.24(m,1H),4.17-3.99(m,1H),3.88(s,3H),3.74-3.55(m,1H),3.37-3.20(m,1H),3.17-2.98(m,1H),2.83-2.54(m,1H),2.05(s,3H),1.33-1.17(m,6H),1.08(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.54(d, J=4.9Hz, 1H), 8.28(s, 1H), 7.50-7.39(m, 1H), 7.19-7.05(m, 2H), 7.05-6.91(m, 2H), 6.71-6.53(m, 1H), 6.42(d, J=16.7Hz, 1H), 5.83(dd, J=10.4, 1.3Hz, 1H), 4.95-4.71(m, 1H), 4.65-4.44(m, 1H), 4.40-4.24(m, 1H), 4.17-3.99(m, 1H), 3.88(s, 3H), 3.74-3.55(m, 1H), 3.37-3.20( m, 1H), 3.17-2.98(m, 1H), 2.83-2.54(m, 1H), 2.05(s, 3H), 1.33-1.17(m, 6H), 1.08(d, J=6.6Hz, 3H) .

实施例12 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈Example 12 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methyl) Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000101
Figure PCTCN2021138693-appb-000101

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

Figure PCTCN2021138693-appb-000102
Figure PCTCN2021138693-appb-000102

向反应瓶中加入(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-氟苯基)硼酸(0.15g,1.10mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(30.3mg,0.04mmol)，醋酸钾(71.4mg,0.73mmol)和二氧六环(10.0mL)。反应体系氮气保护下，加入至90℃反应3h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(30mL)，搅拌10min，经乙酸乙酯(30mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(0.22g,收率99.6％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.37 mmol), (2-fluorophenyl)boronic acid (0.15 g, 1.10mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30.3mg, 0.04mmol), potassium acetate (71.4mg , 0.73 mmol) and dioxane (10.0 mL). Under the protection of nitrogen, the reaction system was added to 90°C and reacted for 3h. It was then cooled to room temperature and spin-dried under reduced pressure. Saturated brine (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (30 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.22 g, yield 99.6%).

MS(ESI,pos.ion)m/z:608.3[M+H] +； MS(ESI, pos.ion) m/z: 608.3[M+H] + ;

第二步 (S)-4-(6-氰基-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-cyano-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-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000103
Figure PCTCN2021138693-appb-000103

向微波管中加入(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(0.10mg,0.17mmol)，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)(72.3mg,0.10mmol)，氰化锌(0.20g,1.71mmol)和无水DMF(2.0mL)。反应体系置于微波反应器内，升温至130℃反应7h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(10.0mL)，经乙酸乙酯(30.0mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(54mg,收率54.5％)。Add (S)-4-(6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo to the microwave tube -1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.10 mg, 0.17 mmol), chloro (2-di Cyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (72.3 mg, 0.10 mmol), zinc cyanide (0.20 g, 1.71 mmol) and anhydrous DMF (2.0 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 130 °C for 7 h. It was then cooled to room temperature and spin-dried under reduced pressure. Saturated brine (10.0 mL) was added to the residue, followed by extraction with ethyl acetate (30.0 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (54 mg, yield 54.5%).

MS(ESI,pos.ion)m/z:598.3[M+H] +. MS(ESI,pos.ion)m/z:598.3[M+H] + .

第三步 (S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000104
Figure PCTCN2021138693-appb-000104

向反应瓶中加入(S)-4-(6-氰基-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(54mg,0.09mmol)，三氟乙酸(0.1mL)和二氯甲烷(3.0mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物黄色固体(45mg,收率100％)，直接用于下一步。Add (S)-4-(6-cyano-7-(2-fluorophenyl)-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 (54 mg, 0.09 mmol), trifluoroacetic acid (0.1 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (45 mg, yield 100%), which was directly used in the next step.

MS(ESI,pos.ion)m/z:498.2[M+H] +； MS(ESI, pos.ion) m/z: 498.2[M+H] + ;

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methyl) Synthesis of Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000105
Figure PCTCN2021138693-appb-000105

向反应瓶中加入(S)-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(45mg,0.09mmol)，N,N-二异丙基乙胺(34mg，0.26mmol)和二氯甲烷(3.0mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(16.7mg,0.19mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10min，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝40/1)纯化，得到标题化合物黄色固体(31mg,收率61.7％)。Add (S)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine-1 to the reaction flask -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (45 mg, 0.09 mmol), N,N-diisopropylethylamine (34 mg, 0.26 mmol) and dichloromethane (3.0 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (16.7 mg, 0.19 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 10 min, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a yellow solid (31 mg, yield 61.7%).

MS(ESI,pos.ion)m/z:552.2[M+H] +； MS(ESI, pos.ion) m/z: 552.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.57(d,J＝4.5Hz,1H),8.38(s,1H),7.54-7.47(m,1H),7.27(d,J＝10.1Hz,1H),7.23-7.13(m,3H),6.62(s,1H),6.44(d,J＝16.5Hz,1H),5.85(d,J＝10.2Hz,1H),3.74-3.62(m,2H),3.11(dd,J＝15.5,10.0Hz,1H),2.77-2.72(m,1H),2.05(s,3H),1.54(d,J＝22.7Hz,3H),1.26(dd,J＝ 15.9,9.1Hz,7H),1.07(d,J＝4.0Hz,3H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.57 (d, J=4.5 Hz, 1H), 8.38 (s, 1H), 7.54-7.47 (m, 1H), 7.27 (d, J=10.1 Hz, 1H), 7.23-7.13(m, 3H), 6.62(s, 1H), 6.44(d, J=16.5Hz, 1H), 5.85(d, J=10.2Hz, 1H), 3.74-3.62(m, 2H) ),3.11(dd,J＝15.5,10.0Hz,1H),2.77-2.72(m,1H),2.05(s,3H),1.54(d,J＝22.7Hz,3H),1.26(dd,J＝ 15.9,9.1Hz,7H),1.07(d,J=4.0Hz,3H);

19F NMR(376MHz,CDCl 3)δ(ppm)-112.48(s). 19 F NMR (376MHz, CDCl 3 ) δ(ppm)-112.48(s).

实施例13 4-(7-丙烯酰基-2,7-二氮杂螺[4.4]壬烷-2-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-6-甲腈Example 13 4-(7-Acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000106
Figure PCTCN2021138693-appb-000106

第一步 7-(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)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯的合成The first step 7-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000107
Figure PCTCN2021138693-appb-000107

向反应瓶中依次加入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(0.53g,1.37mmol)，2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(0.31g,1.37mmol)，无水乙腈(10mL)和N,N-二异丙基乙胺(1.1mL,6.32mmol)。反应体系氮气保护下，加热至55℃反应3.5h。待原料反应完，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物黄色固体(0.60g,收率76.1％)。MS(ESI,pos.ion)m/z:573.2[M+H] +； 4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Ketone (0.53 g, 1.37 mmol), tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (0.31 g, 1.37 mmol), anhydrous acetonitrile (10 mL) and N,N-di Isopropylethylamine (1.1 mL, 6.32 mmol). The reaction system was heated to 55°C under nitrogen protection for 3.5h. After the reaction of the raw materials was completed, it was cooled to room temperature, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.60 g, yield 76.1%). MS(ESI, pos.ion) m/z: 573.2[M+H] + ;

第二步 7-(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)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯的合成The second step 7-(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)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Figure PCTCN2021138693-appb-000108
Figure PCTCN2021138693-appb-000108

向反应瓶中依次加入7-(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)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(0.15g，0.26mmol)，(2-甲氧基苯基)硼酸(48mg，0.32mmol)，1,4-二氧六环(5mL)和醋酸钾(39mg，0.40mmol)。体系氮气保护下，加入[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(25mg，0.03mmol)。反应体系加热至90℃反应过夜，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物黄色固体(0.16g,收率94.8％)。7-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[ 2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate tert-butyl ester (0.15 g, 0.26 mmol), (2-methoxyphenyl ) boronic acid (48 mg, 0.32 mmol), 1,4-dioxane (5 mL) and potassium acetate (39 mg, 0.40 mmol). Under nitrogen protection of the system, [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) was added. The reaction system was heated to 90°C for overnight reaction, then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow solid (0.16 g, yield 94.8%).

MS(ESI,pos.ion)m/z:645.3[M+H] +； MS(ESI, pos.ion) m/z: 645.3[M+H] + ;

第三步 7-(6-氰基-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)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯的合成The third step 7-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1, Synthesis of 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000109
Figure PCTCN2021138693-appb-000109

向微波管中依次加入7-(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)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(0.10g，0.16mmol)，二(三叔丁基磷)钯(42mg，0.08mmol)，氰化锌(56mg，0.47mmol)，三叔丁基磷(96mg，0.47mmol，10％的正己烷溶液)和无水N,N-二甲基甲酰胺(5mL)。反应体系氮气保护后，置于微波反应器中，升温至138℃反应1h，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物白色固体(34mg,收率33.8％)。7-(6-Chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate tert-butyl ester (0.10 g, 0.16 mmol) , bis(tri-tert-butylphosphorus)palladium (42mg, 0.08mmol), zinc cyanide (56mg, 0.47mmol), tri-tert-butylphosphorus (96mg, 0.47mmol, 10% in hexane) and anhydrous N, N-Dimethylformamide (5 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, heated to 138° C. for 1 h, then cooled to room temperature, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a white solid (34 mg, yield 33.8%).

MS(ESI,pos.ion)m/z:636.3[M+H] +； MS(ESI, pos.ion) m/z: 636.3[M+H] + ;

第四步 1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-4-(2,7-二氮杂螺[4.4]壬烷-2-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7-diazepine Synthesis of Spiro[4.4]nonan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000110
Figure PCTCN2021138693-appb-000110

向反应瓶中加入7-(6-氰基-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)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(34mg，0.05mmol)，二氯甲烷(2mL)和三氟乙酸(1mL)。反应体系室温反应30min，然后减压旋干，得到标题化合物黄色油状物(29mg,收率100％)，直接用于下一步反应。Add 7-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate tert-butyl ester (34 mg, 0.05 mmol), Dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 30 min, and then spin-dried under reduced pressure to obtain the title compound as a yellow oil (29 mg, yield 100%), which was directly used in the next reaction.

第五步 4-(7-丙烯酰基-2,7-二氮杂螺[4.4]壬烷-2-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-6-甲腈The fifth step 4-(7-Acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000111
Figure PCTCN2021138693-appb-000111

向反应瓶中依次加入1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-4-(2,7-二氮杂螺[4.4]壬烷-2-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(35mg，0.05mmol)，二氯甲烷(3mL)和N,N-二异丙基乙胺(0.1mL，0.57mmol)。体系冷却至0℃，然后滴加丙烯酰氯(30mg，0.33mmol)。滴加完毕，反应体系室温下反应1h，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝60/1)纯化，得到标题化合物(27mg,收率85.6％)。Add 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7- Diazaspiro[4.4]nonan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (35 mg, 0.05 mmol), dichloromethane (3 mL) and N,N-Diisopropylethylamine (0.1 mL, 0.57 mmol). The system was cooled to 0°C, and then acryloyl chloride (30 mg, 0.33 mmol) was added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=60/1) to obtain the title compound (27 mg, yield 85.6%).

MS(ESI,pos.ion)m/z:590.2[M+H] +； MS(ESI, pos.ion) m/z: 590.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.58(s,1H),8.52(d,J＝4.8Hz,1H),7.44(t,J＝7.9Hz,1H),7.15-7.05(m,2H),6.97(dd,J＝16.6,8.4Hz,2H),6.53-6.39(m,2H),5.78-5.74(m 1H),4.15-3.93(m,3H),3.86(s,3H),3.83-3.55(m,5H),2.86-2.67(m,1H),2.04(s,3H),1.54-1.40(m,4H),1.24(d,J＝6.7Hz,3H),1.07(d,J＝6.7Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.58 (s, 1H), 8.52 (d, J=4.8Hz, 1H), 7.44 (t, J=7.9Hz, 1H), 7.15-7.05 (m, 2H), 6.97(dd, J=16.6, 8.4Hz, 2H), 6.53-6.39(m, 2H), 5.78-5.74(m 1H), 4.15-3.93(m, 3H), 3.86(s, 3H), 3.83-3.55(m, 5H), 2.86-2.67(m, 1H), 2.04(s, 3H), 1.54-1.40(m, 4H), 1.24(d, J=6.7Hz, 3H), 1.07(d, J=6.7Hz, 3H).

实施例14 4-(2-丙烯酰基-2,7-二氮杂螺[3.5]壬烷-7-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-6-甲腈Example 14 4-(2-Acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000112
Figure PCTCN2021138693-appb-000112

第一步 7-(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)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯的合成The first step 7-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000113
Figure PCTCN2021138693-appb-000113

向反应瓶中依次加入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(0.21g，0.55mmol)，2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.13g，0.55mmol)，无水乙腈(10mL)和N,N-二异丙基乙胺(0.5mL,3mmol)。反应体系氮气保护下加热至55℃反应过夜。待原料反应完，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物黄色固体(0.25g,收率78.4％)。4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Ketone (0.21 g, 0.55 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.13 g, 0.55 mmol), anhydrous acetonitrile (10 mL) and N,N-dicarboxylate Isopropylethylamine (0.5 mL, 3 mmol). The reaction system was heated to 55°C under nitrogen protection and reacted overnight. After the reaction of the raw materials was completed, the mixture was cooled to room temperature, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow solid (0.25 g, yield 78.4%).

MS(ESI,pos.ion)m/z:573.2[M+H] +； MS(ESI, pos.ion) m/z: 573.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.55(d,J＝4.9Hz,1H),8.04(s,1H),7.13(d,J＝4.9Hz,1H),3.87-3.78(m,4H),3.77(s,3H),2.68-2.54(m,1H),2.11-1.93(m,8H),1.46(s,9H),1.20(d,J＝6.7Hz,3H),1.11(d,J＝6.7Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.55 (d, J=4.9 Hz, 1H), 8.04 (s, 1H), 7.13 (d, J=4.9 Hz, 1H), 3.87-3.78 (m, 4H), 3.77(s, 3H), 2.68-2.54(m, 1H), 2.11-1.93(m, 8H), 1.46(s, 9H), 1.20(d, J＝6.7Hz, 3H), 1.11(d ,J=6.7Hz,3H).

第二步 7-(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)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯的合成The second step 7-(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)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Figure PCTCN2021138693-appb-000114
Figure PCTCN2021138693-appb-000114

向反应瓶中依次加入7-(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)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.10g，0.17mmol)，(2-甲氧基苯基)硼酸(32mg，0.21mmol)，1,4-二氧六环(5mL)和醋酸钾(27mg，0.28mmol)。体系氮气保护下，加入[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(16mg，0.02mmol)。反应体系加热至90℃反应7.5h，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物黄色固体(0.11g,收率产率98.7％)。7-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[ 2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (0.10 g, 0.17 mmol), (2-methoxyphenyl ) boronic acid (32 mg, 0.21 mmol), 1,4-dioxane (5 mL) and potassium acetate (27 mg, 0.28 mmol). Under nitrogen protection of the system, [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (16 mg, 0.02 mmol) was added. The reaction system was heated to 90° C. for 7.5 hours, then cooled to room temperature, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow solid (0.11 g, yield 98.7%).

MS(ESI,pos.ion)m/z:645.4[M+H] +； MS(ESI, pos.ion) m/z: 645.4[M+H] + ;

第三步 7-(6-氰基-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)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯的合成The third step 7-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1, Synthesis of 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000115
Figure PCTCN2021138693-appb-000115

向微波管中依次加入7-(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)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(74mg，0.11mmol)，二(三叔丁基磷)钯(59mg，0.12mmol)，氰化锌(67mg，0.58mmol)，三叔丁基磷(0.69g，0.34mmol，10％的正己烷溶液)和无水N,N-二甲基甲酰胺(4mL)。反应体系氮气保护后，置于微波反应器中，升温至130℃反应4h，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物白色固体(45mg,收率61.7％)。7-(6-Chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (74 mg, 0.11 mmol), Bis(tri-tert-butylphosphorus)palladium (59 mg, 0.12 mmol), zinc cyanide (67 mg, 0.58 mmol), tri-tert-butylphosphorus (0.69 g, 0.34 mmol, 10% in n-hexane) and anhydrous N, N-Dimethylformamide (4 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, heated to 130° C. for 4 h, then cooled to room temperature, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a white solid (45 mg, yield 61.7%).

MS(ESI,pos.ion)m/z:636.3[M+H] +. MS(ESI,pos.ion)m/z:636.3[M+H] + .

第四步 1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7-diazepine Synthesis of Spiro[3.5]nonan-7-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000116
Figure PCTCN2021138693-appb-000116

向反应瓶中加入7-(6-氰基-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)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(45mg，0.07mmol)，二氯甲烷(2mL)和三氟乙酸(1mL)。反应体系室温反应45min，然后减压旋干，得到标题化合物黄色油状物(29mg,100％)，直接用于下一步反应。室温搅拌反应约45min，减压蒸馏，得到黄色油状物(38mg,收率100％)，直接用于下一步反应。Add 7-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (45 mg, 0.07 mmol), Dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 45 min, and then spin-dried under reduced pressure to obtain the title compound as a yellow oil (29 mg, 100%), which was directly used in the next reaction. The reaction was stirred at room temperature for about 45 min, and distilled under reduced pressure to obtain a yellow oil (38 mg, yield 100%), which was directly used in the next reaction.

第五步 4-(2-丙烯酰基-2,7-二氮杂螺[3.5]壬烷-7-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-6-甲腈的合成The fifth step 4-(2-Acryloyl-2,7-diazaspiro[3.5]nonan-7-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 7-(2-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000117
Figure PCTCN2021138693-appb-000117

向反应瓶中依次加入1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(38mg，0.07mmol)，二氯甲烷(3mL)和N,N-二异丙基乙胺(0.1mL，0.57mmol)。体系冷却至0℃，缓慢滴加丙烯酰氯(32mg，0.35mmol)。滴加完毕后，反应体系转移至室温反应1.5h，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝60/1)纯化，得到标题化合物白色固体(27mg,收率64.7％)。Add 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7- Diazaspiro[3.5]nonan-7-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (38 mg, 0.07 mmol), dichloromethane (3 mL) and N,N-Diisopropylethylamine (0.1 mL, 0.57 mmol). The system was cooled to 0°C, and acryloyl chloride (32 mg, 0.35 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was transferred to room temperature for 1.5 h, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=60/1) to obtain the title compound as a white solid (27 mg, yield 64.7%).

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

1H NMR(400MHz,CDCl 3)δ(ppm)8.53(d,J＝4.8Hz,1H),8.28(s,1H),7.48-7.39(m,1H),7.15-7.05(m,2H),7.01-6.91(m,2H),6.99-6.93(m,1H),6.27-6.20(m,1H),5.73(d,J＝10.6Hz,1H),4.06(s,2H),4.03-3.91(m,4H),3.87(s,3H),3.84(dd,J＝7.0,3.2Hz,2H),2.77-2.65(m,1H),2.03(s,3H),1.47(d,J＝7.1Hz,2H),1.41(d,J＝6.7Hz,2H),1.23(d,J＝6.7Hz,3H),1.06(d,J＝6.7Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.53(d, J=4.8Hz, 1H), 8.28(s, 1H), 7.48-7.39(m, 1H), 7.15-7.05(m, 2H), 7.01-6.91(m, 2H), 6.99-6.93(m, 1H), 6.27-6.20(m, 1H), 5.73(d, J=10.6Hz, 1H), 4.06(s, 2H), 4.03-3.91( m, 4H), 3.87(s, 3H), 3.84(dd, J=7.0, 3.2Hz, 2H), 2.77-2.65(m, 1H), 2.03(s, 3H), 1.47(d, J=7.1Hz ,2H),1.41(d,J＝6.7Hz,2H),1.23(d,J＝6.7Hz,3H),1.06(d,J＝6.7Hz,3H).

实施例15 4-(5-丙烯酰基六氢吡咯并[3,4-c]吡咯-2(1H)-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-6-甲腈Example 15 4-(5-Acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(2-isopropyl-4-methylpyridin-3-yl) -7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000118
Figure PCTCN2021138693-appb-000118

第一步 5-(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)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯的合成The first step 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000119
Figure PCTCN2021138693-appb-000119

向反应瓶中依次加入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(0.32g,0.82mmol)，六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(0.18g,0.83mmol)，无水乙腈(10mL)和N,N-二异丙基乙胺(0.7mL,4.02mmol)。反应体系氮气保护下，加热至55℃反应4h。待原料反应完，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物黄色固体(0.28g,收率61.8％)。4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Ketone (0.32 g, 0.82 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.18 g, 0.83 mmol), anhydrous acetonitrile (10 mL) and N,N - Diisopropylethylamine (0.7 mL, 4.02 mmol). The reaction system was heated to 55°C under nitrogen protection for 4h. After the reaction of the raw materials was completed, the mixture was cooled to room temperature, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow solid (0.28 g, yield 61.8%).

MS(ESI,pos.ion)m/z:559.2[M+H] +； MS(ESI, pos.ion) m/z: 559.2 [M+H] + ;

第二步 5-(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)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯的合成The second step 5-(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)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Figure PCTCN2021138693-appb-000120
Figure PCTCN2021138693-appb-000120

向反应瓶中依次加入5-(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)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(0.10g，0.18mmol)，(2-甲氧基苯基)硼酸(35mg，0.23mmol)， 1,4-二氧六环(5mL)和醋酸钾(30mg，0.31mmol)。体系氮气保护下，加入[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(17mg，0.02mmol)。反应体系加热至90℃反应过夜，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物黄色固体(0.11g,收率97.5％)。MS(ESI,pos.ion)m/z:631.3[M+H] +； 5-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[ 2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (0.10 g, 0.18 mmol), (2-methoxybenzene yl)boronic acid (35 mg, 0.23 mmol), 1,4-dioxane (5 mL) and potassium acetate (30 mg, 0.31 mmol). Under nitrogen protection of the system, [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) was added. The reaction system was heated to 90°C for overnight reaction, then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow solid (0.11 g, yield 97.5%). MS(ESI, pos.ion) m/z: 631.3[M+H] + ;

第三步 5-(6-氰基-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)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯的合成The third step 5-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1, Synthesis of 2-dihydropyrido[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000121
Figure PCTCN2021138693-appb-000121

向微波管中依次加入5-(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)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(0.11g，0.18mmol)，二(三叔丁基磷)钯(46mg，0.09mmol)，氰化锌(66mg，0.56mmol)，三叔丁基磷(0.17g，0.08mmol，10％的正己烷溶液)和无水N,N-二甲基甲酰胺(4mL)。反应体系氮气保护后，置于微波反应器中，升温至140℃反应3h，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物黄色固体(94mg,收率86.8％)。5-(6-Chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (0.11 g, 0.18 mmol ), bis(tri-tert-butylphosphorus)palladium (46 mg, 0.09 mmol), zinc cyanide (66 mg, 0.56 mmol), tri-tert-butylphosphorus (0.17 g, 0.08 mmol, 10% in hexane) and anhydrous N,N-Dimethylformamide (4 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, heated to 140° C. for 3 hours, then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow solid (94 mg, yield 86.8%).

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

第四步 4-(六氢吡咯并[3,4-c]吡咯-2(1H)-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-6-甲腈的合成The fourth step 4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( Synthesis of 2-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000122
Figure PCTCN2021138693-appb-000122

向反应瓶中加入5-(6-氰基-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)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(94mg,0.15mmol)，二氯甲烷(2mL)和三氟乙酸(1mL)。反应体系室温反应30min，然后减压蒸馏，得到标题化合物黄色油状物(79mg,收率99.9％)，直接用于下一步反应。Add 5-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (94 mg, 0.15 mmol) , dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 30 min, and then distilled under reduced pressure to obtain the title compound as a yellow oil (79 mg, yield 99.9%), which was directly used in the next reaction.

第五步 4-(5-丙烯酰基六氢吡咯并[3,4-c]吡咯-2(1H)-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-6-甲腈的合成The fifth step 4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(2-isopropyl-4-methylpyridin-3-yl) Synthesis of -7-(2-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000123
Figure PCTCN2021138693-appb-000123

向反应瓶中依次加入4-(六氢吡咯并[3,4-c]吡咯-2(1H)-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-6-甲腈(79mg，0.15mmol)，二氯甲烷(3mL)和N,N-二异丙基乙胺(0.1mL，0.57mmol)。体系冷却至0℃，缓慢滴加丙烯酰氯(30mg，0.33mmol)。滴加完毕后，反应体系转移至室温反应1.5h，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物类白色固体(25mg,收率28.8％)。4-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (79 mg, 0.15 mmol), dichloromethane (3 mL) ) and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol). The system was cooled to 0°C, and acryloyl chloride (30 mg, 0.33 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was transferred to room temperature for 1.5 h, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as an off-white solid (25 mg, yield 28.8%).

MS(ESI,pos.ion)m/z:576.3[M+H] +； MS(ESI, pos.ion) m/z: 576.3 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.59(s,1H),8.54(d,J＝3.5Hz,1H),7.43(t,J＝7.6Hz,1H),7.14(d,J＝3.7Hz,1H),7.06(d,J＝6.6Hz,1H),6.96(dd,J＝15.6,8.3Hz,2H),6.44(d,J＝5.7Hz,2H),5.83-5.71(m,1H),4.41-4.28(m,2H),4.11-4.01(m,2H),3.86(s,3H),3.70-3.63(m,2H),3.31-3.15(m,2H),2.79-2.72(m,1H),2.37-2.33(m,1H),2.26-2.20(m,1H),2.06(s,3H),1.26(s,3H),1.08(d,J＝5.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.59 (s, 1H), 8.54 (d, J=3.5 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.14 (d, J= 3.7Hz, 1H), 7.06(d, J＝6.6Hz, 1H), 6.96(dd, J＝15.6, 8.3Hz, 2H), 6.44(d, J＝5.7Hz, 2H), 5.83-5.71(m, 1H), 4.41-4.28(m, 2H), 4.11-4.01(m, 2H), 3.86(s, 3H), 3.70-3.63(m, 2H), 3.31-3.15(m, 2H), 2.79-2.72( m, 1H), 2.37-2.33(m, 1H), 2.26-2.20(m, 1H), 2.06(s, 3H), 1.26(s, 3H), 1.08(d, J=5.6Hz, 3H).

实施例16 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-6-甲腈Example 16 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methyl) Pyridin-3-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile

Figure PCTCN2021138693-appb-000124
Figure PCTCN2021138693-appb-000124

第一步 4-氨基-5-溴-2-氟苯甲酸甲酯的合成The first step: the synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate

Figure PCTCN2021138693-appb-000125
Figure PCTCN2021138693-appb-000125

向反应瓶中加入4-氨基-2-氟苯甲酸甲酯(5.00g,29.60mmol)和氯仿(90mL)。体系冷却至0℃，向其中分批加入N-溴代丁二酰亚胺(5.26g,29.60mmol)。加完后，反应体系转移至室温反应过夜。待原料完全后，加入乙酸乙酯(100mL)，经水(50mL×3)洗涤。有机相无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝10/1)纯化，得到标题化合物为白色固体(4.00g,收率54.6％)。To the reaction flask was added methyl 4-amino-2-fluorobenzoate (5.00 g, 29.60 mmol) and chloroform (90 mL). The system was cooled to 0°C, and N-bromosuccinimide (5.26 g, 29.60 mmol) was added thereto in portions. After the addition, the reaction system was transferred to room temperature for overnight reaction. After the raw materials were completed, ethyl acetate (100 mL) was added and washed with water (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to obtain the title compound as a white solid (4.00 g, yield 54.6%).

MS(ESI,pos.ion)m/z:248.0[M+H] +； MS(ESI, pos.ion) m/z: 248.0 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.03(d,J＝7.4Hz,1H),6.45(d,J＝12.2Hz,1H),4.63(s,2H),3.87(s,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.03(d, J=7.4Hz, 1H), 6.45(d, J=12.2Hz, 1H), 4.63(s, 2H), 3.87(s, 3H) .

第二步 5-溴-2-氟-4-碘苯甲酸甲酯的合成The synthesis of the second step 5-bromo-2-fluoro-4-iodobenzoic acid methyl ester

Figure PCTCN2021138693-appb-000126
Figure PCTCN2021138693-appb-000126

向反应瓶中加入4-氨基-5-溴-2-氟苯甲酸甲酯(0.23g,0.93mmol)和丙酮(5mL)。体系冷却至0℃，向其中滴入盐酸(1.5mL,9.0mmol,6.00mol/L)，保温搅拌10min后，再缓慢滴加亚硝酸钠水溶液(0.4mL,1.4mmol,3.5mol/L)。滴完后，反应体系保温反应1h。再向上述体系中缓慢滴加碘化钾水溶液(0.5mL,1.75mmol,3.5mol/L)。滴完后反应体系保温反应2h。待原料反应完全后，加入饱和硫代硫酸钠(30mL)，经乙酸乙酯(30mL×2)萃取。合并有机相，饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝20/1)纯化，得到标题化合物为白色固体(0.24g,收率73.6％)。To the reaction flask was added methyl 4-amino-5-bromo-2-fluorobenzoate (0.23 g, 0.93 mmol) and acetone (5 mL). The system was cooled to 0°C, hydrochloric acid (1.5 mL, 9.0 mmol, 6.00 mol/L) was added dropwise to it, and after stirring for 10 min, an aqueous solution of sodium nitrite (0.4 mL, 1.4 mmol, 3.5 mol/L) was slowly added dropwise. After dripping, the reaction system was incubated for 1 h. To the above system, potassium iodide aqueous solution (0.5 mL, 1.75 mmol, 3.5 mol/L) was slowly added dropwise. After dripping, the reaction system was incubated for 2h. After the reaction of the raw materials was completed, saturated sodium thiosulfate (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) to obtain the title compound as a white solid (0.24 g, yield 73.6%).

MS(ESI,pos.ion)m/z:358.8[M+H] +； MS(ESI, pos.ion) m/z: 358.8[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.13(d,J＝6.9Hz,1H),7.68(d,J＝9.6Hz,1H),3.93(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.13 (d, J=6.9 Hz, 1H), 7.68 (d, J=9.6 Hz, 1H), 3.93 (s, 3H).

第三步 5-溴-2-氟-4-碘苯甲酸的合成The synthesis of the third step 5-bromo-2-fluoro-4-iodobenzoic acid

Figure PCTCN2021138693-appb-000127
Figure PCTCN2021138693-appb-000127

向反应瓶中依次加入5-溴-2-氟-4-碘苯甲酸甲酯(9.37g,26.1mmol)，四氢呋喃(20mL)，甲醇(100mL)，水(20mL)和氢氧化锂一水合物(4.45g,0.11mol)。反应体系室温反应30min。待原料反应完全后，减压旋干。残余物中加入水(100mL)，用柠檬酸固体调节体系至pH＝4，搅拌30min后，过滤。滤饼经水(100mL)洗涤，60℃真空干燥12h，得到标题化合物为白色固体(9.00g,收率100％)。To the reaction flask were sequentially added methyl 5-bromo-2-fluoro-4-iodobenzoate (9.37 g, 26.1 mmol), tetrahydrofuran (20 mL), methanol (100 mL), water (20 mL) and lithium hydroxide monohydrate (4.45 g, 0.11 mol). The reaction system was reacted at room temperature for 30 min. After the reaction of the raw materials is complete, spin dry under reduced pressure. Water (100 mL) was added to the residue, and the system was adjusted to pH=4 with solid citric acid, stirred for 30 min, and filtered. The filter cake was washed with water (100 mL) and dried under vacuum at 60° C. for 12 h to obtain the title compound as a white solid (9.00 g, yield 100%).

MS(ESI,pos.ion)m/z:344.8[M+H] +； MS(ESI, pos.ion) m/z: 344.8[M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ(ppm)8.02(d,J＝7.0Hz,1H),7.96(d,J＝10.0Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 8.02 (d, J=7.0 Hz, 1H), 7.96 (d, J=10.0 Hz, 1H).

第四步 5-溴-2-氟-4-碘苯甲酰胺的合成The synthesis of the 4th step 5-bromo-2-fluoro-4-iodobenzamide

Figure PCTCN2021138693-appb-000128
Figure PCTCN2021138693-appb-000128

向反应瓶中加入5-溴-2-氟-4-碘苯甲酸(9.00g,26.1mmol)和二氯亚砜(50.0mL)。反应体系加热至80℃反应4h，然后冷却至室温，减压旋干。残余物中加入无水二氧六环(50mL)。向上述混合物中缓慢滴加氨水(5.0mL,28％)。滴加完毕后，体系室温反应20min，然后加入水(50.0mL)和乙酸乙酯(50.0mL)，分液。水相经乙酸乙酯(50.0mL)萃取。合并有机相，经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物中加入乙酸乙酯和石油醚的混合液(120mL,v/v＝1/10)，室温搅拌1h，过滤。滤饼60℃真空干燥12h，得到标题化合物为米白色固体(7.30g,收率81.3％)。To the reaction flask was added 5-bromo-2-fluoro-4-iodobenzoic acid (9.00 g, 26.1 mmol) and thionyl chloride (50.0 mL). The reaction system was heated to 80° C. for 4 h, then cooled to room temperature and dried under reduced pressure. To the residue was added anhydrous dioxane (50 mL). Aqueous ammonia (5.0 mL, 28%) was slowly added dropwise to the above mixture. After the dropwise addition, the system was reacted at room temperature for 20 min, and then water (50.0 mL) and ethyl acetate (50.0 mL) were added to separate the layers. The aqueous phase was extracted with ethyl acetate (50.0 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. A mixture of ethyl acetate and petroleum ether (120 mL, v/v=1/10) was added to the residue, stirred at room temperature for 1 h, and filtered. The filter cake was dried under vacuum at 60° C. for 12 h to obtain the title compound as an off-white solid (7.30 g, yield 81.3%).

MS(ESI,pos.ion)m/z:343.8[M+H] +； MS(ESI, pos.ion) m/z: 343.8[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.30(d,J＝7.5Hz,1H),7.67(d,J＝10.6Hz,1H),6.59(s,1H),6.25(s,1H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.30(d, J=7.5Hz, 1H), 7.67(d, J=10.6Hz, 1H), 6.59(s, 1H), 6.25(s, 1H) .

第五步 5-溴-2-氟-4-碘-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰基)苯甲酰胺的合成Synthesis of the fifth step 5-bromo-2-fluoro-4-iodo-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)benzamide

Figure PCTCN2021138693-appb-000129
Figure PCTCN2021138693-appb-000129

向反应瓶中加入5-溴-2-氟-4-碘苯甲酰胺(6.98g,20.30mmol)，四氢呋喃(50mL)和草酰氯(4.38g,34.51mmol)。反应体系加热至75℃反应3h，然后冷却至室温，减压旋干。残余物中加入四氢呋喃(40mL)，向其中滴加2-异丙基-4-甲基吡啶-3-胺(3.20g,21.32mmol)。加完后，反应体系室温反应30min，过滤。滤液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为白色固体(7.84g,收率74.3％)。To the reaction flask was added 5-bromo-2-fluoro-4-iodobenzamide (6.98 g, 20.30 mmol), tetrahydrofuran (50 mL) and oxalyl chloride (4.38 g, 34.51 mmol). The reaction system was heated to 75°C for 3 hours, then cooled to room temperature, and dried under reduced pressure. To the residue was added tetrahydrofuran (40 mL), and thereto was added dropwise 2-isopropyl-4-methylpyridin-3-amine (3.20 g, 21.32 mmol). After the addition, the reaction system was reacted at room temperature for 30 min, and filtered. The filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a white solid (7.84 g, yield 74.3%).

MS(ESI,pos.ion)m/z:519.9[M+H] +； MS(ESI, pos.ion) m/z: 519.9 [M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ(ppm)11.17(s,1H),9.74(s,1H),8.35(d,J＝4.7Hz,1H),8.04(dd,J＝7.8,4.4Hz,2H),7.20(s,1H),3.31-3.26(m,1H),2.23(s,3H),1.17(d,J＝6.7Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 11.17 (s, 1H), 9.74 (s, 1H), 8.35 (d, J=4.7 Hz, 1H), 8.04 (dd, J=7.8, 4.4 Hz, 2H), 7.20(s, 1H), 3.31-3.26(m, 1H), 2.23(s, 3H), 1.17(d, J=6.7Hz, 6H).

第六步 6-溴-7-碘-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2,4(1H,3H)-二酮的合成The sixth step Synthesis of 6-bromo-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione

Figure PCTCN2021138693-appb-000130
Figure PCTCN2021138693-appb-000130

向反应瓶中加入5-溴-2-氟-4-碘-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰基)苯甲酰胺(7.84g,15.10mmol)和四氢呋喃(110mL)。体系冷却至-20℃，缓慢滴加KHMDS(33.2mL,33.2mmol,1.0M)。滴加完毕 后，反应体系转移至室温反应5h。再次冷却至-20℃，向其中补加KHMDS(4.5mL,4.5mmol,1.0M)。滴加完毕后，反应体系转移至室温反应过夜。反应结束后，加入水(50mL)，10％柠檬酸水溶液(50mL)淬灭反应，经乙酸乙酯(120mL×3)萃取。合并有机相，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压旋干，得到标题化合物白色固体(6.83g,收率90.6％)，直接用于下一步。5-Bromo-2-fluoro-4-iodo-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)benzamide (7.84g, 15.10mmol) was added to the reaction flask ) and tetrahydrofuran (110 mL). The system was cooled to -20°C, and KHMDS (33.2 mL, 33.2 mmol, 1.0 M) was slowly added dropwise. After the dropwise addition, the reaction system was transferred to room temperature for 5h. Cooled again to -20°C, and to it additional KHMDS (4.5 mL, 4.5 mmol, 1.0 M) was added. After the dropwise addition, the reaction system was transferred to room temperature to react overnight. After the reaction, water (50 mL) was added, 10% aqueous citric acid solution (50 mL) was used to quench the reaction, and the reaction was extracted with ethyl acetate (120 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the title compound as a white solid (6.83 g, yield 90.6%), which was directly used in the next step.

MS(ESI,pos.ion)m/z:499.9[M+H] +； MS(ESI, pos.ion) m/z: 499.9 [M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ(ppm)12.10(s,1H),8.61(d,J＝4.8Hz,1H),8.18(s,1H),7.38(d,J＝4.8Hz,1H),6.75(s,1H),2.82(dt,J＝13.2,6.6Hz,1H),2.05(s,3H),1.05(dd,J＝16.7,6.6Hz,6H). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm) 12.10(s, 1H), 8.61(d, J=4.8Hz, 1H), 8.18(s, 1H), 7.38(d, J=4.8Hz, 1H), 6.75(s, 1H), 2.82(dt, J=13.2, 6.6Hz, 1H), 2.05(s, 3H), 1.05(dd, J=16.7, 6.6Hz, 6H).

第七步 6-溴-4-氯-7-碘-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2(1H)-酮的合成The seventh step The synthesis of 6-bromo-4-chloro-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazolin-2(1H)-one

Figure PCTCN2021138693-appb-000131
Figure PCTCN2021138693-appb-000131

向反应瓶中依次加入6-溴-7-碘-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2,4(1H,3H)-二酮(2.00g,4.00mmol)，乙腈(30mL)，N,N-二异丙基乙胺(2.8mL,16.00mmol)和三氯氧磷(2.45g,16.00mmol)。反应体系加热至80℃反应5h，然后冷却至室温，减压旋干，得到标题化合物为黄色固体(2.07g,收率100％)，直接用于下一步反应。6-Bromo-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (2.00 g, 4.00 mmol), acetonitrile (30 mL), N,N-diisopropylethylamine (2.8 mL, 16.00 mmol) and phosphorus oxychloride (2.45 g, 16.00 mmol). The reaction system was heated to 80° C. for 5 h, then cooled to room temperature and spin-dried under reduced pressure to obtain the title compound as a yellow solid (2.07 g, yield 100%), which was directly used in the next reaction.

第八步 (S)-4-(6-溴-7-碘-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The eighth step (S)-4-(6-bromo-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline Synthesis of oxazolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000132
Figure PCTCN2021138693-appb-000132

向反应瓶中依次加入6-溴-4-氯-7-碘-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2(1H)-酮(2.07g,3.99mmol)，乙腈(30mL)，N,N-二异丙基乙胺(1.03g,7.97mmol)和(S)-3-甲基哌嗪-1-羧酸叔丁酯(0.80g,3.99mmol)。反应体系加热至80℃反应2h。待原料反应完全后，冷却至室温，向其中加入乙酸乙酯(50mL)和水(50mL)，分液。水相经乙酸乙酯(100mL×2)萃取。合并所有有机相，经饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(1.84g,收率67.6％)。6-Bromo-4-chloro-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazolin-2(1H)-one (2.07g) was successively added to the reaction flask , 3.99mmol), acetonitrile (30mL), N,N-diisopropylethylamine (1.03g, 7.97mmol) and (S)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.80g, 3.99 mmol). The reaction system was heated to 80°C for 2h. After the reaction of the raw materials was completed, the mixture was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added thereto, and the solution was separated. The aqueous phase was extracted with ethyl acetate (100 mL×2). All organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (1.84 g, yield 67.6%).

MS(ESI,pos.ion)m/z:682.1[M+H] +； MS(ESI, pos.ion) m/z: 682.1[M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ(ppm)8.58(d,J＝4.8Hz,1H),8.03(d,J＝4.8Hz,1H),7.36(d,J＝4.9Hz,1H),6.78(s,1H),4.76(s,1H),4.17-4.06(m,1H),4.06-3.99(m,1H),3.96(s,1H),3.86-3.75(m,1H),3.67-3.52(m,1H),3.07(s,1H),2.64-2.54(m,1H),1.95(d,J＝2.4Hz,3H),1.44(s,9H),1.34-1.27(m,3H),1.07-0.99(m,6H). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm) 8.58(d,J=4.8Hz,1H),8.03(d,J=4.8Hz,1H),7.36(d,J=4.9Hz,1H) ,6.78(s,1H),4.76(s,1H),4.17-4.06(m,1H),4.06-3.99(m,1H),3.96(s,1H),3.86-3.75(m,1H),3.67 -3.52(m, 1H), 3.07(s, 1H), 2.64-2.54(m, 1H), 1.95(d, J=2.4Hz, 3H), 1.44(s, 9H), 1.34-1.27(m, 3H) ),1.07-0.99(m,6H).

第九步 (S)-4-(6-溴-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The ninth step (S)-4-(6-bromo-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 Synthesis of ,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000133
Figure PCTCN2021138693-appb-000133

向反应瓶中依次加入(S)-4-(6-溴-7-碘-1-(4-异丙基-2-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.80g,1.17mmol)，(2-氟苯基)硼酸(0.16g,1.17mmol)，四(三苯基膦)钯(67mg,0.06mmol)，碳酸钠水溶液(2.5mL,5.0mmol,2.0M)和1,4-二氧六环(16mL)。反应体系氮气保护下，加热至60℃反应过夜。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/2)纯化，得到标题化合物为淡黄色固体(0.40g,收率52.4％)。Add (S)-4-(6-bromo-7-iodo-1-(4-isopropyl-2-methylpyridin-3-yl)-2-oxo-1,2- Dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.80 g, 1.17 mmol), (2-fluorophenyl)boronic acid (0.16 g, 1.17 mmol), tetrakis (Triphenylphosphine)palladium (67 mg, 0.06 mmol), aqueous sodium carbonate (2.5 mL, 5.0 mmol, 2.0 M) and 1,4-dioxane (16 mL). The reaction system was heated to 60°C under nitrogen protection for overnight reaction. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the title compound as a pale yellow solid (0.40 g, yield 52.4%).

MS(ESI,pos.ion)m/z:650.2[M+H] +； MS(ESI, pos.ion) m/z: 650.2[M+H] + ;

第十步 (S)-4-(6-氰基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The tenth step (S)-4-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo- Synthesis of 1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000134
Figure PCTCN2021138693-appb-000134

向微波管中依次加入(S)-4-(6-溴-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(0.30g,0.46mmol)，氰化锌(0.54g,4.61mmol)，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)(72mg,0.09mmol)，N,N-二甲基甲酰胺(3mL)。反应体 系氮气保护下，置于微波反应器中，升温至120℃反应7h。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为浅棕色固体(90mg,收率32.7％)。Add (S)-4-(6-bromo-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen into the microwave tube in turn tert-butyl-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (0.30 g, 0.46 mmol), zinc cyanide (0.54 g, 4.61 mmol), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ] Palladium(II) (72 mg, 0.09 mmol), N,N-dimethylformamide (3 mL). The reaction system was placed in a microwave reactor under the protection of nitrogen, and the temperature was raised to 120 °C for 7 h. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a light brown solid (90 mg, yield 32.7%).

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

第十一步 (S)-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)-2-氧代-1,2-二氢喹唑啉-6-甲腈的合成The eleventh step (S)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine-1- Synthesis of )-2-oxo-1,2-dihydroquinazoline-6-carbonitrile

Figure PCTCN2021138693-appb-000135
Figure PCTCN2021138693-appb-000135

向反应瓶中依次加入(S)-4-(6-氰基-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(90mg,0.15mmol)，DCM(3mL)和三氟乙酸(1mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(75mg,收率100％)，直接用于下一步。Add (S)-4-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- tert-butyl oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (90 mg, 0.15 mmol), DCM (3 mL) and trifluoroacetic acid (1 mL) . The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (75 mg, yield 100%), which was directly used in the next step.

MS(ESI,pos.ion)m/z:497.2[M+H] +； MS(ESI, pos.ion) m/z: 497.2 [M+H] + ;

第十二步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-6-甲腈的合成The twelfth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methyl) Synthesis of pyridin-3-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile

Figure PCTCN2021138693-appb-000136
Figure PCTCN2021138693-appb-000136

向反应瓶中加入(S)-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)-2-氧代-1,2-二氢喹唑啉-6-甲腈(75mg,0.15mmol)，二氯甲烷(3mL)和三乙胺(45mg,0.44mmol)。体系冷却-10℃，缓慢滴加丙烯酰氯(20mg,0.22mmol)。滴加完毕后，反应体系保温反应30min，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为灰白色固体(41mg,收率49.2％)。Add (S)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine-1 to the reaction flask -yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile (75 mg, 0.15 mmol), dichloromethane (3 mL) and triethylamine (45 mg, 0.44 mmol). The system was cooled to -10°C, and acryloyl chloride (20 mg, 0.22 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 30 min, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as an off-white solid (41 mg, yield 49.2%).

MS(ESI,pos.ion)m/z:551.3[M+H] +； MS(ESI, pos.ion) m/z: 551.3 [M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ(ppm)8.60-8.44(m,2H),7.60-7.47(m,1H),7.42-7.26(m,4H),6.94-6.79(m,1H),6.39(s,1H),6.27-6.14(m,1H),5.81-5.70(m,1H),4.94(s,1H),4.50-3.94(m,3H),3.86-3.55(m, 2H),3.18-2.98(m,1H),2.76-2.60(m,1H),2.04-1.89(m,3H),1.38-1.27(m,3H),1.13-0.94(m,6H)； 1 H NMR (400MHz, DMSO-d 6 )δ(ppm) 8.60-8.44(m, 2H), 7.60-7.47(m, 1H), 7.42-7.26(m, 4H), 6.94-6.79(m, 1H) ,6.39(s,1H),6.27-6.14(m,1H),5.81-5.70(m,1H),4.94(s,1H),4.50-3.94(m,3H),3.86-3.55(m,2H) ,3.18-2.98(m,1H),2.76-2.60(m,1H),2.04-1.89(m,3H),1.38-1.27(m,3H),1.13-0.94(m,6H);

19F NMR(376MHz,DMSO-d 6)δ(ppm)-115.65(s),-115.72(s). 19 F NMR (376MHz, DMSO-d 6 )δ(ppm)-115.65(s),-115.72(s).

实施例17 4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈阻转异构体1和Example 17 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile atropisomer 1 and

实施例18 4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈阻转异构体2Example 18 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile atropisomer 2

Figure PCTCN2021138693-appb-000137
Figure PCTCN2021138693-appb-000137

第一步 (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-羧酸叔丁酯的合成The first step (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro Synthesis of pyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000138
Figure PCTCN2021138693-appb-000138

向反应瓶中加入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(1.05g,2.88mmol)，(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.62g,2.90mmol)，乙腈(30mL)和DIPEA(1.81g,14.00mmol)。反应体系加热至55℃反应2h。反应结束后，冷却至室温，减压旋干。残余物中加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(1.51g,收率98.3％)。Add 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one to the reaction flask (1.05 g, 2.88 mmol), (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (0.62 g, 2.90 mmol), acetonitrile (30 mL) and DIPEA (1.81 g, 14.00 mmol). The reaction system was heated to 55°C for 2h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Water (50 mL) was added to the residue, which was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (1.51 g, yield 98.3%).

MS(ESI,pos.ion)m/z:561.3[M+H] +； MS(ESI, pos.ion) m/z: 561.3[M+H] + ;

第二步 (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 second 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

Figure PCTCN2021138693-appb-000139
Figure PCTCN2021138693-appb-000139

向反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧基-1,2-二氢吡啶[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-甲基苯基)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(0.13mg,1.32mmol)和二氧六环(10.0mL)。反应体系加热至90℃反应3h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(30mL)，搅拌10min，用乙酸乙酯(100mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.34g,收率80.6％)。To the reaction flask was added (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxy-1,2- Dihydropyridin[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.37 g, 0.66 mmol), (2-fluoro-5-methyl) phenyl)boronic 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 mg, 1.32 mmol) and dioxane (10.0 mL). The reaction system was heated to 90°C for 3h. It was then cooled to room temperature and spin-dried under reduced pressure. Saturated brine (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (100 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a yellow solid (0.34 g, yield 80.6%).

MS(ESI,pos.ion)m/z:635.3[M+H] +. MS(ESI,pos.ion)m/z:635.3[M+H] + .

第三步 (2R,5S)-4-(6-氰基-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 third step (2R,5S)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000140
Figure PCTCN2021138693-appb-000140

向微波管中加入(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(0.13g,0.20mmol)，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)(80mg,0.10mmol)，氰化锌(0.25g,2.13mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至130℃，反应7h。然后冷却至室温，加入饱和食盐水(10.0mL)，经乙酸乙酯(30.0mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(76mg,收率61.4％)。Add (2R,5S)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3-) to the microwave tube (0.13 g) , 0.20 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) (80 mg, 0.10 mmol), zinc cyanide (0.25 g, 2.13 mmol) and ultra-dry N,N-dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 130 °C, and reacted for 7 h. Then, it was cooled to room temperature, saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (76 mg, yield 61.4%).

MS(ESI,pos.ion)m/z:626.4[M+H] +. MS(ESI,pos.ion)m/z:626.4[M+H] + .

第四步 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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000141
Figure PCTCN2021138693-appb-000141

向反应瓶中加入(2R,5S)-4-(6-氰基-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(49.5mg,0.08mmol)，三氟乙酸(0.1mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。待原料反应完全后，减压旋干，得到标题化合物为棕色固体(42mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-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 (49.5 mg, 0.08 mmol), trifluoroacetic acid (0.1 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, spin-dried under reduced pressure to obtain the title compound as a brown solid (42 mg, yield 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:526.3[M+H] +； MS(ESI, pos.ion) m/z: 526.3[M+H] + ;

第五步 4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fifth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000142
Figure PCTCN2021138693-appb-000142

向反应瓶中加入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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(42mg,0.08mmol)，N,N-二异丙基乙胺(16mg，0.13mmol)和二氯甲烷(3mL)，体系冷却至0℃，缓慢滴加丙烯酰氯(8.3mg,0.09mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10min，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(24mg,收率53.4％)。To the reaction flask was added 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-iso Propyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (42 mg, 0.08 mmol), N,N - Diisopropylethylamine (16 mg, 0.13 mmol) and dichloromethane (3 mL), the system was cooled to 0°C, and a solution of acryloyl chloride (8.3 mg, 0.09 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 10 min, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (24 mg, yield 53.4%).

MS(ESI,pos.ion)m/z:580.3[M+H] +； MS(ESI, pos.ion) m/z: 580.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.56(d,J＝4.9Hz,1H),8.36(s,1H),7.30-7.27(m,1H),7.14(d,J＝4.9 Hz,1H),7.12-7.01(m,2H),6.73-6.54(m,1H),6.49-6.39(m,1H),5.88-5.81(m,1H),5.22-5.06(m,1H),4.94-4.72(m,1H),4.64-4.44(m,1H),4.40-4.25(m,1H),4.17-4.03(m,1H),3.99-3.78(m,1H),3.78-3.55(m,2H),3.40-2.99(m,1H),2.82-2.58(m,1H),2.32-2.24(m,3H),2.10-2.02(m,3H),1.31-1.20(m,6H),1.09(dd,J＝6.6,3.3Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.56(d, J=4.9Hz, 1H), 8.36(s, 1H), 7.30-7.27(m, 1H), 7.14(d, J=4.9 Hz, 1H), 7.12-7.01(m, 2H), 6.73-6.54(m, 1H), 6.49-6.39(m, 1H), 5.88-5.81(m, 1H), 5.22-5.06(m, 1H), 4.94- 4.72(m, 1H), 4.64-4.44(m, 1H), 4.40-4.25(m, 1H), 4.17-4.03(m, 1H), 3.99-3.78(m, 1H), 3.78-3.55(m, 2H ),3.40-2.99(m,1H),2.82-2.58(m,1H),2.32-2.24(m,3H),2.10-2.02(m,3H),1.31-1.20(m,6H),1.09(dd ,J=6.6,3.3Hz,3H).

19F NMR(376MHz,CDCl 3)δ(ppm)-117.88. 19 F NMR (376MHz, CDCl 3 ) δ (ppm)-117.88.

第六步 4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(阻转异构体1)The sixth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (atropisomer 1 )

Figure PCTCN2021138693-appb-000143
和4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(阻转异构体2)的合成
Figure PCTCN2021138693-appb-000143
and 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (atropisomer 2) synthesis

Figure PCTCN2021138693-appb-000144
Figure PCTCN2021138693-appb-000144

将4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(1.0g,1.7mmol)用手性柱拆分(大赛璐AD-H手性柱,10mm×250mm,5μm,20％异丙醇/CO 2,8mL/min)，分离得到目标化合物阻转异构体1为黄色固体(0.30g,收率30％)和目标化合物阻转异构体2为黄色固体(0.17g,收率17％)。 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (1.0 g, 1.7 mmol) was prepared by hand Column separation (Daicel AD-H chiral column, 10mm×250mm, 5μm, 20% isopropanol/CO 2 , 8mL/min), the target compound atropisomer 1 was isolated as a yellow solid (0.30g , yield 30%) and the target compound atropisomer 2 was a yellow solid (0.17 g, yield 17%).

实施例17 阻转异构体1：Example 17 Atropisomer 1:

MS(ESI,pos.ion)m/z:580.5[M+H] +； MS(ESI, pos.ion) m/z: 580.5[M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ8.86(d,J＝6.3Hz,1H),8.45(d,J＝4.8Hz,1H),7.45-7.33(m,1H),7.33- 7.19(m,2H),7.10(d,J＝6.5Hz,1H),6.94-6.77(m,1H),6.20(d,J＝16.7Hz,1H),5.85-5.70(m,1H),5.02-4.84(m,1H),4.79(s,0.5H),4.49(s,0.5H),4.30-4.10(m,1.5H),4.02-3.76(m,2H),3.52(dd,J＝13.7,3.4Hz,0.5H),2.79-2.64(m,1H),2.25(s,3H),1.95(s,3H),1.34(t,J＝6.4Hz,3H),1.21(dd,J＝29.0,6.8Hz,3H),1.07(d,J＝6.7Hz,3H),1.00(d,J＝6.6Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.86 (d, J=6.3 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.45-7.33 (m, 1H), 7.33-7.19 ( m, 2H), 7.10(d, J=6.5Hz, 1H), 6.94-6.77(m, 1H), 6.20(d, J=16.7Hz, 1H), 5.85-5.70(m, 1H), 5.02-4.84 (m,1H),4.79(s,0.5H),4.49(s,0.5H),4.30-4.10(m,1.5H),4.02-3.76(m,2H),3.52(dd,J=13.7,3.4 Hz,0.5H),2.79-2.64(m,1H),2.25(s,3H),1.95(s,3H),1.34(t,J=6.4Hz,3H),1.21(dd,J=29.0,6.8 Hz,3H),1.07(d,J＝6.7Hz,3H),1.00(d,J＝6.6Hz,3H).

实施例18 阻转异构体2：Example 18 Atropisomer 2:

MS(ESI,pos.ion)m/z:580.5[M+H] +； MS(ESI, pos.ion) m/z: 580.5[M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ8.86(d,J＝7.2Hz,1H),8.44(d,J＝4.9Hz,1H),7.42-7.33(m,1H),7.30-7.22(m,2H),7.10(d,J＝5.5Hz,1H),6.93-6.72(m,1H),6.20(d,J＝16.7Hz,1H),5.76(d,J＝10.1Hz,1H),4.91(s,1H),4.78(s,0.5H),4.48(s,0.5H),4.30-4.09(m,1.5H),3.98-3.79(m,2H),3.51(dd,J＝13.8,3.4Hz,0.5H),2.77-2.65(m,1H),2.26(s,3H),1.96(s,3H),1.38-1.31(m,3H),1.20(dd,J＝30.7,5.5Hz,3H),1.07(d,J＝6.8Hz,3H),0.97(d,J＝6.6Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.86 (d, J=7.2 Hz, 1H), 8.44 (d, J=4.9 Hz, 1H), 7.42-7.33 (m, 1H), 7.30-7.22 ( m,2H),7.10(d,J＝5.5Hz,1H),6.93-6.72(m,1H),6.20(d,J＝16.7Hz,1H),5.76(d,J＝10.1Hz,1H), 4.91(s, 1H), 4.78(s, 0.5H), 4.48(s, 0.5H), 4.30-4.09(m, 1.5H), 3.98-3.79(m, 2H), 3.51(dd, J=13.8, 3.4Hz, 0.5H), 2.77-2.65(m, 1H), 2.26(s, 3H), 1.96(s, 3H), 1.38-1.31(m, 3H), 1.20(dd, J=30.7, 5.5Hz, 3H), 1.07(d, J=6.8Hz, 3H), 0.97(d, J=6.6Hz, 3H).

实施例19 4-(6-丙烯酰基-2,6-二氮杂螺[3.3]庚烷-2-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-6-甲腈Example 19 4-(6-Acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000145
Figure PCTCN2021138693-appb-000145

第一步 6-(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)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成The first step 6-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000146
Figure PCTCN2021138693-appb-000146

向反应瓶中依次加入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(0.21g，0.55mmol)，2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(0.11g，0.56mmol)，无水乙腈(5.0mL)和N,N-二异丙基乙胺(0.5mL,2.87mmol)。反应体系加热至55℃反应4.5h，然后冷却至室温，减压旋干。残余物经硅胶柱 层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为黄色固体(0.11g,收率36.8％)。4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Ketone (0.21 g, 0.55 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.11 g, 0.56 mmol), anhydrous acetonitrile (5.0 mL) and N,N- Diisopropylethylamine (0.5 mL, 2.87 mmol). The reaction system was heated to 55° C. for 4.5 hours, then cooled to room temperature, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to obtain the title compound as a yellow solid (0.11 g, yield 36.8%).

MS(ESI,pos.ion)m/z:545.2[M+H] +； MS(ESI, pos.ion) m/z: 545.2 [M+H] + ;

第二步 6-(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)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成The second step 6-(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)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Figure PCTCN2021138693-appb-000147
Figure PCTCN2021138693-appb-000147

向反应瓶中依次加入6-(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)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(0.11g，0.20mmol)，(2-甲氧基苯基)硼酸(36mg，0.24mmol)，1,4-二氧六环(5.0mL)和醋酸钾(32mg，0.33mmol)。体系氮气保护下，加入[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(19mg，0.02mmol)。反应体系加热至90℃反应5h，然后冷却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄色固体(96mg,收率77.2％)。6-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[ 2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (0.11 g, 0.20 mmol), (2-methoxyphenyl ) boronic acid (36 mg, 0.24 mmol), 1,4-dioxane (5.0 mL) and potassium acetate (32 mg, 0.33 mmol). Under nitrogen protection of the system, [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (19 mg, 0.02 mmol) was added. The reaction system was heated to 90 °C for 5 h, then cooled to room temperature, and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow solid (96 mg, yield 77.2%).

MS(ESI,pos.ion)m/z:617.2[M+H] +； MS(ESI, pos.ion) m/z: 617.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.45(d,J＝4.9Hz,1H),8.00(s,1H),7.42-7.34(m,1H),7.05(d,J＝4.9Hz,1H),7.00(dd,J＝7.4,1.4Hz,1H),6.94(dd,J＝13.7,7.8Hz,2H),4.81(s,4H),4.23(s,4H),3.73(s,3H),2.78-2.71(m,1H),2.04(s,3H),1.48(s,9H),1.22(d,J＝6.7Hz,3H),1.05(d,J＝6.7Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.45(d, J=4.9Hz, 1H), 8.00(s, 1H), 7.42-7.34(m, 1H), 7.05(d, J=4.9Hz, 1H), 7.00(dd, J＝7.4, 1.4Hz, 1H), 6.94(dd, J＝13.7, 7.8Hz, 2H), 4.81(s, 4H), 4.23(s, 4H), 3.73(s, 3H ), 2.78-2.71(m, 1H), 2.04(s, 3H), 1.48(s, 9H), 1.22(d, J=6.7Hz, 3H), 1.05(d, J=6.7Hz, 3H).

第三步 6-(6-氰基-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)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成The third step 6-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1, Synthesis of 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000148
Figure PCTCN2021138693-appb-000148

向微波管中依次加入6-(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)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(96mg,0.16mmol)，二(三叔丁基磷)钯(86mg,0.17mmol)，氰化锌(92mg,0.78mmol)，三叔丁基磷(0.45g，0.22mmol，10％的正己烷溶液)和无水N,N-二甲基甲酰胺(4mL)。反应体系氮气置换后，置于微波反应器中，升温至130℃反应5h。反应结束后，冷 却至室温，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为白色固体(31mg,收率32.8％)。6-(6-Chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (96 mg, 0.16 mmol), Bis(tri-tert-butylphosphorus)palladium (86 mg, 0.17 mmol), zinc cyanide (92 mg, 0.78 mmol), tri-tert-butylphosphorus (0.45 g, 0.22 mmol, 10% in hexane) and anhydrous N, N-Dimethylformamide (4 mL). After the reaction system was replaced with nitrogen, it was placed in a microwave reactor, and the temperature was raised to 130 °C for 5 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a white solid (31 mg, yield 32.8%).

MS(ESI,pos.ion)m/z:608.3[M+H] +； MS(ESI, pos.ion) m/z: 608.3[M+H] + ;

第四步 1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-4-(2,6-二氮杂螺[3.3]庚烷-2-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,6-diazepine Synthesis of Spiro[3.3]heptan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000149
Figure PCTCN2021138693-appb-000149

向反应瓶中加入6-(6-氰基-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)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(31mg，0.05mmol)，二氯甲烷(2mL)和三氟乙酸(1mL)。反应体系室温反应45min。原料反应完全后，减压旋干，得到标题化合物为黄色油状物(26mg,收率100％)，直接用于下一步反应。Add 6-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (31 mg, 0.05 mmol), Dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 45 min. After the reaction of the raw materials was completed, spin-dried under reduced pressure to obtain the title compound as a yellow oil (26 mg, yield 100%), which was directly used in the next reaction.

第五步 4-(6-丙烯酰基-2,6-二氮杂螺[3.3]庚烷-2-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-6-甲腈的合成The fifth step 4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 7-(2-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000150
Figure PCTCN2021138693-appb-000150

向反应瓶中依次加入1-(2-异丙基-4-甲基吡啶-3-基)-7-(2-甲氧基苯基)-2-氧代-4-(2,6-二氮杂螺[3.3]庚烷-2-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(26mg,0.05mmol)，二氯甲烷(3mL)和N,N-二异丙基乙胺(0.1mL,0.57mmol)。体系冷却至0℃，缓慢滴加丙烯酰氯(26mg,0.28mmol)。滴加完毕后，反应体系转移至室温反应1h，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝60/1)纯化，得到标题化合物为类白色固体(17mg,收率59.3％)。Add 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,6- Diazaspiro[3.3]heptan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (26 mg, 0.05 mmol), dichloromethane (3 mL) and N,N-Diisopropylethylamine (0.1 mL, 0.57 mmol). The system was cooled to 0°C, and acryloyl chloride (26 mg, 0.28 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was transferred to room temperature for 1 h, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=60/1) to obtain the title compound as an off-white solid (17 mg, yield 59.3%).

MS(ESI,pos.ion)m/z:562.2[M+H] +； MS(ESI, pos.ion) m/z: 562.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.51(d,J＝4.6Hz,1H),8.23(s,1H),7.44(t,J＝7.4Hz,1H),7.16-6.90(m,4H),6.41(d,J＝16.8Hz,1H),6.22(dd,J＝16.9,10.3Hz,1H),5.78(d,J＝10.4Hz,1H),4.88(s,2H),4.54(s,2H),4.40(s,2H),3.86(s,3H),3.76(s,2H),2.76-2.69(m 1H),2.05(s,3H),1.23(d,J＝6.5Hz,3H),1.07(d,J＝6.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.51 (d, J=4.6 Hz, 1H), 8.23 (s, 1H), 7.44 (t, J=7.4 Hz, 1H), 7.16-6.90 (m, 4H), 6.41(d, J＝16.8Hz, 1H), 6.22(dd, J＝16.9, 10.3Hz, 1H), 5.78(d, J＝10.4Hz, 1H), 4.88(s, 2H), 4.54( s, 2H), 4.40(s, 2H), 3.86(s, 3H), 3.76(s, 2H), 2.76-2.69(m 1H), 2.05(s, 3H), 1.23(d, J=6.5Hz, 3H),1.07(d,J=6.6Hz,3H).

实施例20 7-(2-氟-6-甲氧基苯基)-4-((S)-4-(2-氟丙烯酰基)-2-甲基哌嗪-1-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-6-甲腈Example 20 7-(2-Fluoro-6-methoxyphenyl)-4-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-1- (2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000151
Figure PCTCN2021138693-appb-000151

第一步 7-(2-氟-6-甲氧基苯基)-4-((S)-4-(2-氟丙烯酰基)-2-甲基哌嗪-1-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-6-甲腈的合成The first step 7-(2-Fluoro-6-methoxyphenyl)-4-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000152
Figure PCTCN2021138693-appb-000152

向反应瓶中加入7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-((S)-2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(0.16g,0.30mmol)，2-氟丙烯酸(60mg,0.65mmol)，HATU(0.24g,0.61mmol)，三乙胺(0.10g,0.61mmol)和超干N,N-二甲基甲酰胺(3mL)。反应体系室温反应过夜。反应结束后，反应混合物中加入乙酸乙酯(100mL)稀释，经水(5mL)洗涤。有机相减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物为黄色固体(9mg,收率5％)。7-(2-Fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2- Methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.16g, 0.30mmol), 2-fluoroacrylic acid (60mg , 0.65 mmol), HATU (0.24 g, 0.61 mmol), triethylamine (0.10 g, 0.61 mmol) and ultra-dry N,N-dimethylformamide (3 mL). The reaction system was allowed to react overnight at room temperature. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (5 mL). The organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to give the title compound as a yellow solid (9 mg, yield 5%).

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

实施例21 4-(5-丙烯酰基-2,5-二氮杂二环[2.2.2]辛烷-2-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-6-甲腈Example 21 4-(5-Acryloyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(2-fluoro-5-methylphenyl)-1- (2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000153
Figure PCTCN2021138693-appb-000153

第一步 5-(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)-2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯的合成The first step 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000154
Figure PCTCN2021138693-appb-000154

向反应瓶中加入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(0.53g,1.38mmol)，2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯(0.29g,1.38mmol)，乙腈(15.0mL)和N,N-二异丙基乙胺(0.8mL,4.59mmol)。反应体系加热至55℃反应1.5h。原料反应完全后，冷却至室温，加入饱和食盐水(30mL)，经乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为橙色固体(0.33g,收率43.2％)。Add 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one to the reaction flask (0.53 g, 1.38 mmol), tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.29 g, 1.38 mmol), acetonitrile (15.0 mL) and N,N- Diisopropylethylamine (0.8 mL, 4.59 mmol). The reaction system was heated to 55°C for 1.5h. After the reaction of the raw materials was completed, it was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as an orange solid (0.33 g, yield 43.2%).

MS(ESI,pos.ion)m/z:559.2[M+H] +. MS(ESI,pos.ion)m/z:559.2[M+H] + .

第二步 5-(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)-2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯的合成The second step 5-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo- Synthesis of 1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000155
Figure PCTCN2021138693-appb-000155

向反应瓶中加入5-(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)-2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯(0.33g,0.60mmol)，(2-氟-5-甲基苯基)硼酸(0.28g,1.79 mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.10g,0.12mmol)，醋酸钾(0.11g,1.20mmol)和二氧六环(10.0mL)。反应体系加热至90℃反应3h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.32g,收率84.6％)。To the reaction flask was added 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2 ,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate tert-butyl ester (0.33 g, 0.60 mmol), (2-fluoro-5 -methylphenyl)boronic acid (0.28 g, 1.79 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.10 g, 0.12 mmol), potassium acetate (0.11 g, 1.20 mmol) and dioxane (10.0 mL). The reaction system was heated to 90°C for 3h. It was then cooled to room temperature and spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.32 g, yield 84.6%).

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

第三步 5-(6-氰基-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)-2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯的合成The third step 5-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000156
Figure PCTCN2021138693-appb-000156

向微波管中加入5-(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)-2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯(0.20g,0.31mmol)，二(三叔丁基膦)钯(0.16g,0.32mmol)，三叔丁基膦(2.4mL,1.0mmol)，氰化锌(0.37g,3.20mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10.0mL)，经乙酸乙酯(30.0mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(80mg,收率40.9％)。Add 5-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the microwave tube Substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (0.20 g, 0.31 mmol), bis(tri-tert-butylphosphine)palladium (0.16 g, 0.32 mmol), tri-tert-butylphosphine (2.4 mL, 1.0 mmol), zinc cyanide (0.37 g, 3.20 mmol) and ultradry N , N-dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (80 mg, yield 40.9%).

MS(ESI,pos.ion)m/z:624.3[M+H] +. MS(ESI,pos.ion)m/z:624.3[M+H] + .

第四步 4-(2,5-二氮杂二环[2.2.2]辛烷-2-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-6-甲腈的合成The fourth step 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000157
Figure PCTCN2021138693-appb-000157

向反应瓶中加入5-(6-氰基-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)-2,5-二氮杂二环[2.2.2]辛烷-2-羧酸叔丁酯(80mg,0.13mmol)，三氟乙酸(0.1mL,1.0 mmol)和二氯甲烷(3.0mL)。反应体系室温下反应1h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(70mg,收率100％)。Add 5-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- tert-Butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate ( 80 mg, 0.13 mmol), trifluoroacetic acid (0.1 mL, 1.0 mmol) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (70 mg, yield 100%).

MS(ESI,pos.ion)m/z:524.3[M+H] +. MS(ESI,pos.ion)m/z:524.3[M+H] + .

第五步 4-(5-丙烯酰基-2,5-二氮杂二环[2.2.2]辛烷-2-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-6-甲腈的合成The fifth step 4-(5-acryloyl-2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(2-fluoro-5-methylphenyl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000158
Figure PCTCN2021138693-appb-000158

向反应瓶中加入4-(2,5-二氮杂二环[2.2.2]辛烷-2-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-6-甲腈(70mg,0.13mmol)，N,N-二异丙基乙胺(25.3mg，0.20mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(12.2mg,0.14mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10min。然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(72mg,收率97.3％)。Add 4-(2,5-diazabicyclo[2.2.2]octan-2-yl)-7-(2-fluoro-5-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (70 mg, 0.13 mmol), N, N-Diisopropylethylamine (25.3 mg, 0.20 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (12.2 mg, 0.14 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 10 min. Then spin dry under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (72 mg, yield 97.3%).

MS(ESI,pos.ion)m/z:578.3[M+H] +； MS(ESI, pos.ion) m/z: 578.3 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.61(s,1H),8.55(d,J＝4.9Hz,1H),7.28-7.23(m,1H),7.13(d,J＝4.9Hz,1H),7.03(dd,J＝18.5,8.5Hz,2H),6.48(dd,J＝5.3,2.0Hz,1H),5.85-5.80(m,1H),5.48(s,1H),3.72-3.66(m,2H),3.15-3.09(m,2H),2.72(dd,J＝14.8,6.8Hz,1H),2.28(s,3H),2.07-2.03(m,4H),1.50(d,J＝7.4Hz,3H),1.27(s,2H),1.24(dd,J＝4.7,1.8Hz,3H),1.09-1.06(m,3H)； 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.61(s, 1H), 8.55(d, J=4.9Hz, 1H), 7.28-7.23(m, 1H), 7.13(d, J=4.9Hz, 1H), 7.03(dd, J＝18.5, 8.5Hz, 2H), 6.48(dd, J＝5.3, 2.0Hz, 1H), 5.85-5.80(m, 1H), 5.48(s, 1H), 3.72-3.66 (m,2H),3.15-3.09(m,2H),2.72(dd,J=14.8,6.8Hz,1H),2.28(s,3H),2.07-2.03(m,4H),1.50(d,J =7.4Hz,3H),1.27(s,2H),1.24(dd,J=4.7,1.8Hz,3H),1.09-1.06(m,3H);

13C NMR(151MHz,CDCl 3)δ(ppm)165.2,163.6,158.8,157.2,154.8,153.9,149.1,140.7,134.2,133.7,133.7,131.1,130.1,129.8,126.7,126.5,123.6,123.5,116.2,116.1,116.0,103.2,53.6,42.7,41.9,30.4,29.7,26.4,24.6,22.2,21.6,20.6,11.9； 13 C NMR (151MHz, CDCl 3 )δ(ppm) 165.2, 163.6, 158.8, 157.2, 154.8, 153.9, 149.1, 140.7, 134.2, 133.7, 133.7, 131.1, 130.1, 129.8, 126.7, 126.5, 116.6, 12 ,116.1,116.0,103.2,53.6,42.7,41.9,30.4,29.7,26.4,24.6,22.2,21.6,20.6,11.9;

19F NMR(376MHz,CDCl 3)δ(ppm)-75.60. 19 F NMR (376MHz, CDCl 3 ) δ (ppm)-75.60.

实施例22 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(2,3,4-三氟苯基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 22 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Substituted-7-(2,3,4-trifluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000159
Figure PCTCN2021138693-appb-000159

第一步 (S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(2,3,4-三氟苯基)-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-(2,3,4-trifluoro) Synthesis of phenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000160
Figure PCTCN2021138693-appb-000160

向反应瓶中加入(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)，(2,3,4-三氟苯基)硼酸(0.15g,0.84mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(91mg,0.11mmol)，醋酸钾(0.29g,2.8mmol)和二氧六环(8mL)。反应体系加入至90℃反应4h。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.30g,收率85％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.55 mmol), (2,3,4-trifluorophenyl) Boronic acid (0.15 g, 0.84 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (91 mg, 0.11 mmol), acetic acid Potassium (0.29 g, 2.8 mmol) and dioxane (8 mL). The reaction system was added to 90°C and reacted for 4h. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (0.30 g, yield 85%).

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

1H NMR(400MHz,CDCl 3)δ(ppm)8.51(d,J＝4.9Hz,1H),8.11(s,1H),7.10(d,J＝4.8Hz,1H),7.03-6.94(m,1H),6.94-6.85(m,1H),5.12-4.71(m,1H),4.54-4.21(m,2H),4.10-3.88(m,1H),3.84-3.54(m,1H),3.47-2.97(m,2H),2.86-2.59(m,1H),2.03(d,J＝6.8Hz,3H),1.52(s,9H),1.27-1.18(m,6H),1.09-1.01(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.51 (d, J=4.9 Hz, 1H), 8.11 (s, 1H), 7.10 (d, J=4.8 Hz, 1H), 7.03-6.94 (m, 1H), 6.94-6.85(m, 1H), 5.12-4.71(m, 1H), 4.54-4.21(m, 2H), 4.10-3.88(m, 1H), 3.84-3.54(m, 1H), 3.47- 2.97(m, 2H), 2.86-2.59(m, 1H), 2.03(d, J=6.8Hz, 3H), 1.52(s, 9H), 1.27-1.18(m, 6H), 1.09-1.01(m, 3H).

第二步 (S)-4-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(2,3,4-三氟苯基)-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-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(2,3,4-tri Synthesis of fluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000161
Figure PCTCN2021138693-appb-000161

向微波管中加入(S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(2,3,4-三氟苯基)-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(0.29g,0.45mmol)，二(三叔丁基膦)钯(0.12g,0.23mmol)，10％的三叔丁基膦正己烷溶液(0.92g,0.45mmol)，氰化锌(542mg,4.5mmol)和超干二甲基亚砜(6mL)。反应体系置于微波反应器中，升温至130℃，反应8h。反应结束后，加入乙酸乙酯(100mL)稀释，经水(12mL×5)洗涤。有机相减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.17g,收率60％)。Add (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(2,3,4- trifluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.29 g, 0.45 mmol), Bis(tri-tert-butylphosphine)palladium (0.12 g, 0.23 mmol), 10% tri-tert-butylphosphine in n-hexane (0.92 g, 0.45 mmol), zinc cyanide (542 mg, 4.5 mmol) and ultra-dry dimethyl sulfoxide (6 mL). The reaction system was placed in a microwave reactor, heated to 130 °C, and reacted for 8 h. After the reaction was completed, ethyl acetate (100 mL) was added to dilute and washed with water (12 mL×5). The organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (0.17 g, yield 60%).

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

第三步 (S)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-7-(2,3,4-三氟苯基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-2-oxo-7-( Synthesis of 2,3,4-Trifluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000162
Figure PCTCN2021138693-appb-000162

向反应瓶中加入(S)-4-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(2,3,4-三氟苯基)-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(0.17g,0.27mmol)，三氟乙酸(3mL)和二氯甲烷(6mL)。反应体系常温反应2h。然后减压旋干，得到标题化合物为黄色半固体(0.14g,收率97.8％)，直接用于下一步反应。Add (S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(2,3,4) to the reaction flask -Trifluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.17 g, 0.27 mmol) , trifluoroacetic acid (3 mL) and dichloromethane (6 mL). The reaction system was reacted at room temperature for 2h. Then spin-dried under reduced pressure to obtain the title compound as a yellow semisolid (0.14 g, yield 97.8%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:534.2[M+H] +； MS(ESI, pos.ion) m/z: 534.2[M+H] + ;

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(2,3,4-三氟苯基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen Synthesis of substituted-7-(2,3,4-trifluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000163
Figure PCTCN2021138693-appb-000163

向反应瓶中加入(S)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-2-氧代-7-(2,3,4-三氟苯基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(0.14g,0.26mmol)，三乙胺(0.28g，2.77mmol)和二氯甲烷(6mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(80mg,0.87mmol)。滴加完毕后，反应体系室温反应3h，然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物为黄色固体(6mg,收率3.9％)。MS(ESI,pos.ion)m/z:588.2[M+H] +； Add (S)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-2-oxo-7 to the reaction flask -(2,3,4-Trifluorophenyl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.14g, 0.26mmol), triethylamine (0.28g, 2.77 mmol) and dichloromethane (6 mL). The system was cooled to 0°C, and acryloyl chloride (80 mg, 0.87 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 3 hours, and then spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to obtain the title compound as a yellow solid (6 mg, yield 3.9%). MS(ESI, pos.ion) m/z: 588.2[M+H] + ;

实施例23 4-(3-丙烯酰基-3,8-二氮杂二环[3.2.1]辛烷-8-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-6-甲腈Example 23 4-(3-Acryloyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(2-fluorophenyl)-1-(2-isopropyl) yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000164
Figure PCTCN2021138693-appb-000164

第一步 8-(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)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯的合成The first step 8-(6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000165
Figure PCTCN2021138693-appb-000165

向反应瓶中加入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(0.52g,1.37 mmol)，3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯(0.29g,1.37mmol)，乙腈(20.0mL)和N,N-二异丙基乙胺(0.7mL,4.02mmol)。反应体系加热至55℃反应1.5h。原料反应完全后，冷却至室温，加入饱和食盐水(30mL)，经乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为橙色固体(0.58g,收率75.4％)。Add 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one to the reaction flask (0.52 g, 1.37 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.29 g, 1.37 mmol), acetonitrile (20.0 mL) and N,N- Diisopropylethylamine (0.7 mL, 4.02 mmol). The reaction system was heated to 55°C for 1.5h. After the reaction of the raw materials was completed, it was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as an orange solid (0.58 g, yield 75.4%).

MS(ESI,pos.ion)m/z:559.2[M+H] +. MS(ESI,pos.ion)m/z:559.2[M+H] + .

第二步 8-(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)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯的合成The second step 8-(6-Chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000166
Figure PCTCN2021138693-appb-000166

向反应瓶中加入8-(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)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯(0.58g,1.03mmol)，(2-氟苯基)硼酸(0.55g,3.93mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.17g,0.21mmol)，醋酸钾(0.41g,4.20mmol)和二氧六环(10.0mL)。反应体系加热至90℃反应3h。然后冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.56g,收率88.0％)。To the reaction flask was added 8-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester (0.58 g, 1.03 mmol), (2-fluorophenyl ) boric acid (0.55g, 3.93mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.17g, 0.21mmol) , potassium acetate (0.41 g, 4.20 mmol) and dioxane (10.0 mL). The reaction system was heated to 90°C for 3h. It was then cooled to room temperature and spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a yellow solid (0.56 g, yield 88.0%).

MS(ESI,pos.ion)m/z:620.2[M+H] +； MS(ESI, pos.ion) m/z: 620.2[M+H] + ;

第三步 8-(6-氰基-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)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯的合成The third step 8-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Synthesis of tert-butyl dihydropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Figure PCTCN2021138693-appb-000167
Figure PCTCN2021138693-appb-000167

向微波管中加入8-(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)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯(0.11g,0.18mmol)，二(三叔丁基膦)钯(0.11g,0.22mmol)，三叔丁基膦(0.36g,0.18mmol,10％)，氰化锌(0.25g,2.15mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应4h。反应结束后，冷却至室温，加入饱和食盐水(10.0mL)，经乙酸乙酯(15.0mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(83mg,收率74.9％)。Add 8-(6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to the microwave tube - Dihydropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester (0.11 g, 0.18 mmol) , bis(tri-tert-butylphosphine)palladium (0.11 g, 0.22 mmol), tri-tert-butylphosphine (0.36 g, 0.18 mmol, 10%), zinc cyanide (0.25 g, 2.15 mmol) and ultradry N,N - Dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 4 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (15.0 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (83 mg, yield 74.9%).

MS(ESI,pos.ion)m/z:610.3[M+H] +； MS(ESI, pos.ion) m/z: 610.3[M+H] + ;

第四步 4-(3,8-二氮杂二环[3.2.1]辛烷-8-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-6-甲腈的合成The fourth step 4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4-methyl) Synthesis of pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000168
Figure PCTCN2021138693-appb-000168

向反应瓶中加入8-(6-氰基-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)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯(83mg,0.14mmol)，三氟乙酸(0.2mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(70mg,收率100％)。Add 8-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1 to the reaction flask, 2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester (83 mg, 0.14 mmol) , trifluoroacetic acid (0.2 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (70 mg, yield 100%).

MS(ESI,pos.ion)m/z:510.3[M+H] +. MS(ESI,pos.ion)m/z:510.3[M+H] + .

第五步 4-(3-丙烯酰基-3,8-二氮杂二环[3.2.1]辛烷-8-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-6-甲腈的合成The fifth step 4-(3-acryloyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(2-fluorophenyl)-1-(2-isopropyl) Synthesis of yl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000169
Figure PCTCN2021138693-appb-000169

向反应瓶中加入4-(3,8-二氮杂二环[3.2.1]辛烷-8-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-6-甲腈(70mg,0.14mmol)，N,N-二异丙基乙胺(55.6mg，0.43mmol)和二氯甲烷(3mL)。反应体系冷却至0℃，缓慢滴加丙烯酰氯(26mg,0.29mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10min。然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝40/1)纯化，得到标题化合物为黄色固体(48mg,收率63.0％)。Add 4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4 to the reaction flask -Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (70 mg, 0.14 mmol), N,N-diisopropyl Ethylamine (55.6 mg, 0.43 mmol) and dichloromethane (3 mL). The reaction system was cooled to 0°C, and a solution of acryloyl chloride (26 mg, 0.29 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 10 min. Then spin dry under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a yellow solid (48 mg, yield 63.0%).

MS(ESI,pos.ion)m/z:564.2[M+H] +； MS(ESI, pos.ion) m/z: 564.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.54(d,J＝4.9Hz,1H),8.47(s,1H),7.50(dd,J＝13.2,6.0Hz,1H),7.29-7.25(m,1H),7.22-7.15(m,2H),7.12(d,J＝4.8Hz,1H),6.60(dd,J＝16.7,10.5Hz,1H),6.41(d,J＝16.7Hz,1H),5.83(d,J＝11.7Hz,1H),4.73(d,J＝13.0Hz,1H),3.96(d,J＝12.1Hz,1H),3.79(d,J＝12.7Hz,1H),3.26(d,J＝13.0Hz,1H),2.70(dt,J＝13.3,6.5Hz,1H),2.19(s,2H),2.05(s,3H),1.90(d,J＝9.2Hz,2H),1.27(s,2H),1.23(d,J＝6.7Hz,3H),1.06(d,J＝6.7Hz,3H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.54 (d, J=4.9 Hz, 1H), 8.47 (s, 1H), 7.50 (dd, J=13.2, 6.0 Hz, 1H), 7.29-7.25 ( m, 1H), 7.22-7.15 (m, 2H), 7.12 (d, J=4.8Hz, 1H), 6.60 (dd, J=16.7, 10.5Hz, 1H), 6.41 (d, J=16.7Hz, 1H) ),5.83(d,J＝11.7Hz,1H),4.73(d,J＝13.0Hz,1H),3.96(d,J＝12.1Hz,1H),3.79(d,J＝12.7Hz,1H), 3.26(d,J＝13.0Hz,1H),2.70(dt,J＝13.3,6.5Hz,1H),2.19(s,2H),2.05(s,3H),1.90(d,J＝9.2Hz,2H ), 1.27(s, 2H), 1.23(d, J=6.7Hz, 3H), 1.06(d, J=6.7Hz, 3H);

19F NMR(376MHz,CDCl 3)δ(ppm)-112.5. 19 F NMR (376MHz, CDCl 3 ) δ (ppm)-112.5.

实施例24 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(3-氟-2-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-6-甲腈Example 24 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-fluoro-2-methylphenyl)-1-(2-isopropyl) -4-Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000170
Figure PCTCN2021138693-appb-000170

第一步 (S)-4-(6-氯-7-(3-氟-2-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-(3-fluoro-2-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

Figure PCTCN2021138693-appb-000171
Figure PCTCN2021138693-appb-000171

向反应瓶中加入(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)，(3-氟-2-甲基苯基)硼酸(0.11g,0.74mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(60mg,0.08mmol)，乙酸钾(90mg,0.89mmol)，1,4-二氧六环(10mL)和水(0.2mL)。反应体系氮气保护下，加热至95℃反应6h。反应结束后，冷却至室温，减压旋干。残余物中加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄绿色固体(0.23g,收率100％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.37 mmol), (3-fluoro-2-methylphenyl) Boronic acid (0.11 g, 0.74 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (60 mg, 0.08 mmol), acetic acid Potassium (90 mg, 0.89 mmol), 1,4-dioxane (10 mL) and water (0.2 mL). The reaction system was heated to 95°C under nitrogen protection for 6h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Water (50 mL) was added to the residue, which was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow-green solid (0.23 g, yield 100%).

MS(ESI,pos.ion)m/z:621.3[M+H] +. MS(ESI,pos.ion)m/z:621.3[M+H] + .

第二步 (S)-4-(6-氰基-7-(3-氟-2-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-cyano-7-(3-fluoro-2-methylphenyl)-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

Figure PCTCN2021138693-appb-000172
Figure PCTCN2021138693-appb-000172

向微波管中加入(S)-4-(6-氯-7-(3-氟-2-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(0.23g,0.37mmol)，氰化锌(0.42g,3.63mmol)，二(三叔丁基膦)钯(0.74g,0.36mmol)，三叔丁基膦的正己烷溶液(10％,0.5mL)和超干N,N-二甲基甲酰胺(2.0mL)。反应体系置于微波反应器中，升温至135℃反应7h。反应结束后，冷却至室温，过滤除去不溶物。滤液减压旋干。残余物经(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(90mg,收率39.9％)。Add (S)-4-(6-chloro-7-(3-fluoro-2-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the microwave tube -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.23 g, 0.37 mmol), Zinc cyanide (0.42 g, 3.63 mmol), bis(tri-tert-butylphosphine)palladium (0.74 g, 0.36 mmol), tri-tert-butylphosphine in n-hexane (10%, 0.5 mL) and ultradry N,N - Dimethylformamide (2.0 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 135 °C for 7 h. After the reaction was completed, the mixture was cooled to room temperature, and the insoluble matter was removed by filtration. The filtrate was spin-dried under reduced pressure. The residue was purified by (PE/EtOAc (v/v)=1/1) to give the title compound as a yellow solid (90 mg, yield 39.9%).

MS(ESI,pos.ion)m/z:612.3[M+H] +. MS(ESI,pos.ion)m/z:612.3[M+H] + .

第三步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(3-氟-2-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-6-甲腈的合成The third step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(3-fluoro-2-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000173
Figure PCTCN2021138693-appb-000173

向反应瓶中加入(S)-4-(6-氰基-7-(3-氟-2-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(90mg,0.15mmol)和二氯甲烷(15mL)。室温下向其中滴加三氟乙酸(0.11mL,1.50mmol)。滴加完毕后，反应体系室温下反应3h，然后减压旋干。残余物中加入二氯甲烷(15mL)和DIPEA(30mg,0.23mmol)。体系冷却至0℃，缓慢滴加丙烯酰氯(20mg，0.19mmol)。加完后，反应体系室室温反应2h。反应结束后，体系经水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(25mg,收率31.3％)。Add (S)-4-(6-cyano-7-(3-fluoro-2-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 (90 mg, 0.15 mmol) and Dichloromethane (15 mL). To this was added dropwise trifluoroacetic acid (0.11 mL, 1.50 mmol) at room temperature. After the dropwise addition, the reaction system was reacted at room temperature for 3 hours, and then spin-dried under reduced pressure. To the residue was added dichloromethane (15 mL) and DIPEA (30 mg, 0.23 mmol). The system was cooled to 0°C, and acryloyl chloride (20 mg, 0.19 mmol) was slowly added dropwise. After the addition, the reaction system was allowed to react at room temperature for 2h. After the reaction, the system was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as a yellow solid (25 mg, yield 31.3%).

MS(ESI,pos.ion)m/z:566.2[M+H] +； MS(ESI, pos.ion) m/z: 566.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.53(d,J＝3.8Hz,1H),8.46-8.33(m,1H),7.25(d,J＝5.7Hz,1H),7.19-7.02(m,3H),6.62(s,1H),6.51-6.36(m,1H),5.97-5.75(m,1H),5.30-4.59(m,2H),4.55-4.24(m,1H),4.07-3.61(m,3H),3.43-3.02(m,1H),2.71(s,1H),2.03(s,3H),1.92(s,3H),1.38-1.15(m,6H),1.02(d,J＝4.5Hz,3H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.53 (d, J=3.8 Hz, 1H), 8.46-8.33 (m, 1H), 7.25 (d, J=5.7 Hz, 1H), 7.19-7.02 ( m,3H),6.62(s,1H),6.51-6.36(m,1H),5.97-5.75(m,1H),5.30-4.59(m,2H),4.55-4.24(m,1H),4.07- 3.61(m, 3H), 3.43-3.02(m, 1H), 2.71(s, 1H), 2.03(s, 3H), 1.92(s, 3H), 1.38-1.15(m, 6H), 1.02(d, J=4.5Hz, 3H);

19F NMR(376MHz,CDCl 3)δ-114.21,-115.65. 19 F NMR (376MHz, CDCl 3 ) δ-114.21,-115.65.

实施例25 4-(7-丙烯酰基-4,7-二氮杂螺[2.5]辛烷-4-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-6-甲腈Example 25 4-(7-Acryloyl-4,7-diazaspiro[2.5]octan-4-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4 -Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000174
Figure PCTCN2021138693-appb-000174

第一步 (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)-4,7-二氮杂 螺[2.5]辛烷-7-羧酸叔丁酯的合成The first 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)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000175
Figure PCTCN2021138693-appb-000175

向反应瓶中加入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(0.32g,0.84mmol)，4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(0.18g,0.86mmol)，乙腈(20.0mL)和N,N-二异丙基乙胺(0.4mL,2.30mmol)。反应体系加热至55℃反应1.5h。原料反应完全后，冷却至室温，加入饱和食盐水(30mL)，经乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为橙色固体(0.45g,收率95.3％)。Add 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one to the reaction flask (0.32 g, 0.84 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (0.18 g, 0.86 mmol), acetonitrile (20.0 mL) and N,N-diisopropyl Ethylamine (0.4 mL, 2.30 mmol). The reaction system was heated to 55°C for 1.5h. After the reaction of the raw materials was completed, it was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as an orange solid (0.45 g, yield 95.3%).

MS(ESI,pos.ion)m/z:559.2[M+H] +. MS(ESI,pos.ion)m/z:559.2[M+H] + .

第二步 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)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯的合成The second step 4-(6-Chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000176
Figure PCTCN2021138693-appb-000176

向反应瓶中加入(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)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(0.25g,0.45mmol)，(2-氟苯基)硼酸(0.19g,1.35mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(75mg,0.09mmol)，碳酸钾(0.19g,1.34mmol)和二氧六环(10.0mL)。反应体系加热至100℃，10min后向其中加入水(0.1mL)和二氧六环(0.5mL)的混合溶液，体系保温继续反应3h。反应结束后，冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(96mg,收率34.8％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (0.25 g, 0.45 mmol), (2-fluorobenzene base)boronic acid (0.19g, 1.35mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (75mg, 0.09mmol) , potassium carbonate (0.19 g, 1.34 mmol) and dioxane (10.0 mL). The reaction system was heated to 100°C, and a mixed solution of water (0.1 mL) and dioxane (0.5 mL) was added to it after 10 min, and the system was kept warm for 3 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (96 mg, yield 34.8%).

MS(ESI,pos.ion)m/z:620.1[M+H] +. MS(ESI,pos.ion)m/z:620.1[M+H] + .

第三步 4-(6-氰基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)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯的合成The third step 4-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000177
Figure PCTCN2021138693-appb-000177

向微波管中加入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)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(96mg,0.16mmol)，二(三叔丁基膦)钯(0.24g,0.47mmol)，三叔丁基膦(0.33g，0.16mmol,10％)，氰化锌(0.19g,1.58mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(79mg,收率83.0％)。Add 4-(6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to the microwave tube - Dihydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (96 mg, 0.16 mmol), bis(tris tert-butylphosphine) palladium (0.24 g, 0.47 mmol), tri-tert-butylphosphine (0.33 g, 0.16 mmol, 10%), zinc cyanide (0.19 g, 1.58 mmol) and ultra-dry N,N-dimethyl Formamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (79 mg, yield 83.0%).

MS(ESI,pos.ion)m/z:610.3[M+H] +； MS(ESI, pos.ion) m/z: 610.3[M+H] + ;

第四步 7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-4-(4,7-二氮杂螺[2.5]辛烷-4-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-4-(4,7-diazaspiro[ Synthesis of 2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000178
Figure PCTCN2021138693-appb-000178

向反应瓶中加入4-(6-氰基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)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(79mg,0.13mmol)，三氟乙酸(0.1mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(66mg,收率100％)。MS(ESI,pos.ion)m/z:510.3[M+H] +. Add 4-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to the reaction flask -dihydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (79 mg, 0.13 mmol), trifluoroacetic acid (0.1 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (66 mg, yield 100%). MS(ESI,pos.ion)m/z:510.3[M+H] + .

第五步 4-(7-丙烯酰基-4,7-二氮杂螺[2.5]辛烷-4-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-6-甲腈的合成The fifth step 4-(7-acryloyl-4,7-diazaspiro[2.5]octan-4-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4 Synthesis of -methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000179
Figure PCTCN2021138693-appb-000179

向反应瓶中加入7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-4-(4,7-二氮杂螺[2.5]辛烷-4-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(66mg,0.13mmol)，N,N-二异丙基乙胺(47mg，0.36mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(13.6mg,0.13mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系室温反应10min。反应结束后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(46mg,收率63.6％)。Add 7-(2-Fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-4-(4,7-diazepine to the reaction flask Spiro[2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (66 mg, 0.13 mmol), N,N-diisopropylethylamine (47 mg, 0.36 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (13.6 mg, 0.13 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 10 min. After the reaction, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (46 mg, yield 63.6%).

MS(ESI,pos.ion)m/z:564.3[M+H] +； MS(ESI, pos.ion) m/z: 564.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.81-8.43(m,2H),7.60-7.43(m,1H),7.34-7.27(m,2H),7.25-7.11(m,2H),6.77-6.32(m,2H),5.95-5.72(m,1H),4.12-3.94(m,2H),3.77-3.59(m,2H),3.23-3.04(m,2H),2.85-2.67(m,1H),2.11(s,3H),1.41(d,J＝4.7Hz,6H),1.13(d,J＝5.7Hz,4H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.81-8.43 (m, 2H), 7.60-7.43 (m, 1H), 7.34-7.27 (m, 2H), 7.25-7.11 (m, 2H), 6.77 -6.32(m, 2H), 5.95-5.72(m, 1H), 4.12-3.94(m, 2H), 3.77-3.59(m, 2H), 3.23-3.04(m, 2H), 2.85-2.67(m, 1H), 2.11(s, 3H), 1.41(d, J=4.7Hz, 6H), 1.13(d, J=5.7Hz, 4H);

19F NMR(376MHz,CDCl 3)δ-112.48，-75.65. 19 F NMR (376MHz, CDCl 3 ) δ-112.48, -75.65.

实施例26 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2,6-二氟苯基)-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-6-甲腈Example 26 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2,6-difluorophenyl)-1-(2-isopropyl-4 -Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000180
Figure PCTCN2021138693-appb-000180

第一步 (S)-4-(6-氯-7-(2,6-二氟苯基)-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-(2,6-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen Synthesis of tert-butyl substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000181
Figure PCTCN2021138693-appb-000181

向反应瓶中加入(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(0.10g,0.18mmol)，(2,6-二氟苯基)硼酸(0.13g,0.83mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(48mg,0.05mmol)，醋酸钾(77mg,0.79mmol)和二氧六环(10.0mL)。反应体系加热至100℃，10min后向其中加入水(0.1mL)和二氧六环(0.5mL)的混合溶液，体系保温继续反应3h。反应结束后，冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(45mg,收率39.6％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.10 g, 0.18 mmol), (2,6-difluorophenyl)boronic acid ( 0.13g, 0.83mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (48mg, 0.05mmol), potassium acetate ( 77 mg, 0.79 mmol) and dioxane (10.0 mL). The reaction system was heated to 100°C, and a mixed solution of water (0.1 mL) and dioxane (0.5 mL) was added to it after 10 min, and the system was kept warm for 3 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (45 mg, yield 39.6%).

MS(ESI,pos.ion)m/z:626.2[M+H] +. MS(ESI,pos.ion)m/z:626.2[M+H] + .

第二步 (S)-4-(6-氰基-7-(2,6-二氟苯基)-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 second step (S)-4-(6-cyano-7-(2,6-difluorophenyl)-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

Figure PCTCN2021138693-appb-000182
Figure PCTCN2021138693-appb-000182

向微波管中加入(S)-4-(6-氯-7-(2,6-二氟苯基)-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(45mg,0.07mmol)，二(三叔丁基膦)钯(0.12g,0.24mmol)，三叔丁基膦(0.14g，0.07mmol,10％)，氰化锌(92mg,0.79mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析 (PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(40mg,收率90.1％)。Add (S)-4-(6-chloro-7-(2,6-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the microwave tube -Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (45mg, 0.07mmol), bis(tris tert-butylphosphine) palladium (0.12 g, 0.24 mmol), tri-tert-butylphosphine (0.14 g, 0.07 mmol, 10%), zinc cyanide (92 mg, 0.79 mmol) and ultra-dry N,N-dimethylmethane amide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a yellow solid (40 mg, yield 90.1%).

MS(ESI,pos.ion)m/z:616.2[M+H] +. MS(ESI,pos.ion)m/z:616.2[M+H] + .

第三步 (S)-7-(2,6-二氟苯基)-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-6-甲腈的合成The third step (S)-7-(2,6-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazine- Synthesis of 1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000183
Figure PCTCN2021138693-appb-000183

向反应瓶中加入(S)-4-(6-氰基-7-(2,6-二氟苯基)-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(45mg,0.07mmol)，三氟乙酸(0.1mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。反应结束后，减压旋干，得到标题化合物为棕色固体(34mg,收率100％)。MS(ESI,pos.ion)m/z:516.4[M+H] +. Add (S)-4-(6-cyano-7-(2,6-difluorophenyl)-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 (45 mg, 0.07 mmol), trifluoro Acetic acid (0.1 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (34 mg, yield 100%). MS(ESI,pos.ion)m/z:516.4[M+H] + .

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2,6-二氟苯基)-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2,6-difluorophenyl)-1-(2-isopropyl-4 Synthesis of -methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000184
Figure PCTCN2021138693-appb-000184

向反应瓶中加入(S)-7-(2,6-二氟苯基)-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-6-甲腈(34mg,0.07mmol)，N,N-二异丙基乙胺(27mg，0.21mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(10.3mg,0.11mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系室温反应10min。反应结束后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(12mg,收率32.5％)。Add (S)-7-(2,6-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperidine) to the reaction flask Azin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (34 mg, 0.07 mmol), N,N-diisopropylethylamine (27 mg, 0.21 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (10.3 mg, 0.11 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 10 min. After the reaction, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (12 mg, yield 32.5%).

MS(ESI,pos.ion)m/z:570.2[M+H] +； MS(ESI, pos.ion) m/z: 570.2 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.54(d,J＝4.9Hz,1H),8.38(d,J＝4.5Hz,1H),7.47(dt,J＝14.8,7.4Hz,1H),7.12(d,J＝4.9Hz,1H),7.01(t,J＝8.5Hz,2H),6.64(s,1H),6.48-6.41(m,1H),5.86(d,J＝10.4Hz,1H), 3.70(m,J＝18.6Hz,1H),2.75(m,J＝6.2Hz,1H),2.02(s,3H),1.53(d,J＝16.7Hz,4H),1.27(dd,J＝17.3,9.2Hz,8H),1.07(d,J＝6.1Hz,3H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.54 (d, J=4.9 Hz, 1H), 8.38 (d, J=4.5 Hz, 1H), 7.47 (dt, J=14.8, 7.4 Hz, 1H) ,7.12(d,J＝4.9Hz,1H),7.01(t,J＝8.5Hz,2H),6.64(s,1H),6.48-6.41(m,1H),5.86(d,J＝10.4Hz, 1H), 3.70(m, J=18.6Hz, 1H), 2.75(m, J=6.2Hz, 1H), 2.02(s, 3H), 1.53(d, J=16.7Hz, 4H), 1.27(dd, J=17.3, 9.2Hz, 8H), 1.07 (d, J=6.1Hz, 3H);

19F NMR(376MHz,CDCl 3)δ(ppm)-112.48，-112.57. 19 F NMR (376 MHz, CDCl 3 ) δ (ppm) -112.48, -112.57.

实施例27 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 27 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( 5-Methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000185
Figure PCTCN2021138693-appb-000185

第一步 (3S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-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 (3S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000186
Figure PCTCN2021138693-appb-000186

向反应瓶中加入(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)，(5-甲基-1H-吲唑-4-基)硼酸(0.65g,3.68mmol)，[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,0.18mmol)，碳酸钠(0.39g，3.68mmol)和二氧六环(15.0mL)。反应体系加热至90℃，反应10min后向其中加入水(0.1mL)和二氧六环(0.5mL)的混合溶液，体系保温继续反应3h。反应结束后，冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.11g,收率19.3％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.50 g, 0.92 mmol), (5-methyl-1H-indazole-4 -yl)boronic acid (0.65g, 3.68mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.15g, 0.18 mmol), sodium carbonate (0.39 g, 3.68 mmol) and dioxane (15.0 mL). The reaction system was heated to 90°C, and after 10 min of reaction, a mixed solution of water (0.1 mL) and dioxane (0.5 mL) was added, and the system was kept warm for 3 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.11 g, yield 19.3%).

MS(ESI,pos.ion)m/z:626.2[M+H] +. MS(ESI,pos.ion)m/z:626.2[M+H] + .

第二步 (3S)-4-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-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 (3S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazole-4- Synthesis of tert-butyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000187
Figure PCTCN2021138693-appb-000187

向微波管中加入(3S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-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(93mg,0.15mmol)，二(三叔丁基膦)钯(76mg,0.15mmol)，三叔丁基膦(0.34g，0.17mmol，10％)，氰化锌(0.17g,1.47mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(77mg,收率83.5％)。Add (3S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazole-4 to the microwave tube) -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (93 mg, 0.15 mmol ), bis(tri-tert-butylphosphine)palladium (76 mg, 0.15 mmol), tri-tert-butylphosphine (0.34 g, 0.17 mmol, 10%), zinc cyanide (0.17 g, 1.47 mmol) and ultradry N,N - Dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (77 mg, yield 83.5%).

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

第三步 1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)-4-((S)-2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-4-((S)-2- Synthesis of Methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000188
Figure PCTCN2021138693-appb-000188

向反应瓶中加入(3S)-4-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-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(77mg,0.12mmol)，三氟乙酸(0.1mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。反应结束后，减压旋干，得到标题化合物为棕色固体(65mg,收率100％)。MS(ESI,pos.ion)m/z:534.3[M+H] +. Add (3S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazole- 4-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (77 mg, 0.12 mmol), trifluoroacetic acid (0.1 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (65 mg, yield 100%). MS(ESI,pos.ion)m/z:534.3[M+H] + .

第四步 4-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)-2-氧代--1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( Synthesis of 5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000189
Figure PCTCN2021138693-appb-000189

向反应瓶中加入1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)-4-((S)-2-甲基哌嗪-1-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(65mg,0.12mmol)，N,N-二异丙基乙胺(25.3mg，0.20mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(11.2mg,0.12mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10min。反应结束后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝40/1)纯化，得到标题化合物为淡黄色油状液体(51mg,收率71.8％)。Add 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-4-(((S)- 2-Methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (65 mg, 0.12 mmol), N,N-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile Isopropylethylamine (25.3 mg, 0.20 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (11.2 mg, 0.12 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 10 min. After the reaction, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a pale yellow oily liquid (51 mg, yield 71.8%).

MS(ESI,pos.ion)m/z:588.3[M+H] +. MS(ESI,pos.ion)m/z:588.3[M+H] + .

实施例28 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-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-6-甲腈Example 28 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl )-7-(2-methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000190
Figure PCTCN2021138693-appb-000190

第一步 (2R,5S)-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)-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-hydroxy-3-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

Figure PCTCN2021138693-appb-000191
Figure PCTCN2021138693-appb-000191

向反应瓶中加入(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(0.30g,0.53mmol)，(2-羟基-3-甲基苯基)硼酸(0.13g,0.81mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(90mg,0.11mmol)，醋酸钾(0.28g,2.7mmol)和二氧六环(8mL)。反应体系加热至90℃反应5h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为黄色固体(0.24g,收率69％)。Add (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.53 mmol), (2-hydroxy-3- Methylphenyl)boronic acid (0.13g, 0.81mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (90mg, 0.11 mmol), potassium acetate (0.28 g, 2.7 mmol) and dioxane (8 mL). The reaction system was heated to 90°C for 5h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a yellow solid (0.24 g, yield 69%).

MS(ESI,pos.ion)m/z:633.2[M+H] +； MS(ESI, pos.ion) m/z: 633.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)9.97(d,J＝10.5Hz,1H),8.62(dd,J＝4.6,3.0Hz,1H),8.17(d,J＝11.6Hz,1H),7.89(d,J＝8.0Hz,1H),7.24-7.12(m,2H),6.78(t,J＝7.7Hz,1H),5.12-4.85(m,1H),4.69-4.51(m,1H),4.49-4.33(m,1H),4.04-3.73(m,2H),3.68-3.39(m,1H),2.85-2.65(m,1H),2.10(d,J＝1.8Hz,3H),2.08(d,J＝7.6Hz,3H),1.52(s,9H),1.48-1.39(m,3H),1.29-1.19(m,6H),1.10-0.99(m,3H) 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.97 (d, J=10.5 Hz, 1H), 8.62 (dd, J=4.6, 3.0 Hz, 1H), 8.17 (d, J=11.6 Hz, 1H) ,7.89(d,J＝8.0Hz,1H),7.24-7.12(m,2H),6.78(t,J＝7.7Hz,1H),5.12-4.85(m,1H),4.69-4.51(m,1H) ), 4.49-4.33(m, 1H), 4.04-3.73(m, 2H), 3.68-3.39(m, 1H), 2.85-2.65(m, 1H), 2.10(d, J=1.8Hz, 3H), 2.08(d, J＝7.6Hz, 3H), 1.52(s, 9H), 1.48-1.39(m, 3H), 1.29-1.19(m, 6H), 1.10-0.99(m, 3H)

第二步 (2R,5S)-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-chloro-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)-2,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000192
Figure PCTCN2021138693-appb-000192

向反应瓶中加入(2R,5S)-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.22g,0.34mmol)，碘甲烷(0.25g,1.7mmol)，氢氧化钾(0.11g,1.7mmol)和二氯甲烷(6mL)。反应体系室温反应4h。待反应完全后，加入二氯甲烷(100mL)稀释，经饱和食盐水(5mL)洗涤。有机相减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为黄色固体(0.15g,收率66％)。Add (2R,5S)-4-(6-chloro-7-(2-hydroxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3-) to the reaction flask (0.22 g) , 0.34 mmol), iodomethane (0.25 g, 1.7 mmol), potassium hydroxide (0.11 g, 1.7 mmol) and dichloromethane (6 mL). The reaction system was reacted at room temperature for 4 h. After the reaction was completed, dichloromethane (100 mL) was added to dilute, and the mixture was washed with saturated brine (5 mL). The organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a yellow solid (0.15 g, yield 66%).

MS(ESI,pos.ion)m/z:647.2[M+H] +. MS(ESI,pos.ion)m/z:647.2[M+H] + .

第三步 (2R,5S)-4-(6-氰基-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The third step (2R,5S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methyl) Synthesis of phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000193
Figure PCTCN2021138693-appb-000193

向微波管中加入(2R,5S)-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.16g,0.24mmol)，二(三叔丁基膦)钯(0.13g,0.25mmol)，10％的三叔丁基膦正己烷溶液(0.5g,0.25mmol)，氰化锌(0.30g,2.5mmol)和超干N,N-二甲基甲酰胺(4mL)。反应体系置于微波反应器中，升温至140℃，反应8h。反应结束后，冷却至室温，加入乙酸乙酯(100mL)稀释，经水(8mL×4)洗涤。有机相减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(65mg,收率43％)。Add (2R,5S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methyl) to the microwave tube ( 0.16g, 0.24mmol), bis(tri-tert-butylphosphine)palladium (0.13g, 0.25mmol), 10% solution of tri-tert-butylphosphine in n-hexane (0.5g, 0.25mmol), zinc cyanide (0.30g, 2.5 mmol) and ultra-dry N,N-dimethylformamide (4 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 8 h. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (8 mL×4). The organic phase was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (65 mg, yield 43%).

MS(ESI,pos.ion)m/z:638.3[M+H] +. MS(ESI,pos.ion)m/z:638.3[M+H] + .

第四步 4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈的合成The fourth step 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7-( Synthesis of 2-methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000194
Figure PCTCN2021138693-appb-000194

向反应瓶中加入(2R,5S)-4-(6-氰基-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(65mg,0.10mmol)，三氟乙酸(2mL)和二氯甲烷(4mL)。反应体系常温反应2h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(55mg,收率100％)，直接用于下一步反应。To the reaction flask was added (2R,5S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3- Methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (65 mg, 0.10 mmol), trifluoroacetic acid (2 mL) and dichloromethane (4 mL). The reaction system was reacted at room temperature for 2h. After the reaction of the raw materials was completed, spin-dried under reduced pressure to obtain the title compound as a brown solid (55 mg, yield 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:538.3[M+H] +； MS(ESI, pos.ion) m/z: 538.3[M+H] + ;

第五步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-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-6-甲腈的合成The fifth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl )-7-(2-methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000195
Figure PCTCN2021138693-appb-000195

向反应瓶中加入4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈(55mg,0.10mmol)，三乙胺(0.15g，1.48mmol)和二氯甲 烷(4mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(40mg,0.43mmol)。滴加完毕后，反应体系室温反应3h。反应结束后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物为黄色固体(25mg,收率41.3％)。Add 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-7 to the reaction flask -(2-Methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (55 mg, 0.10 mmol), tris Ethylamine (0.15 g, 1.48 mmol) and dichloromethane (4 mL). The system was cooled to 0°C, and acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 3 hours. After the reaction, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to obtain the title compound as a yellow solid (25 mg, yield 41.3%).

MS(ESI,pos.ion)m/z:592.3[M+H] +； MS(ESI, pos.ion) m/z: 592.3 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.51(d,J＝4.5Hz,1H),8.34(s,1H),7.31(d,J＝7.2Hz,1H),7.20-6.95(m,3H),6.72-6.50(m,1H),6.41(t,J＝15.5Hz,1H),5.82(t,J＝8.8Hz,1H),5.23-5.03(m,1H),4.54-4.26(m,1H),4.10-3.97(m,1H),3.97-3.81(m,1H),3.81-3.70(m,1H),3.59-3.38(m,1H),3.29(s,3H),2.60-2.52(m,1H),2.32(s,3H),2.06(d,J＝2.9Hz,3H),1.35-1.28(m,3H),1.28-1.16(m,6H),1.04(d,J＝4.7Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.51 (d, J=4.5 Hz, 1H), 8.34 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.20-6.95 (m, 3H), 6.72-6.50(m, 1H), 6.41(t, J=15.5Hz, 1H), 5.82(t, J=8.8Hz, 1H), 5.23-5.03(m, 1H), 4.54-4.26(m ,1H),4.10-3.97(m,1H),3.97-3.81(m,1H),3.81-3.70(m,1H),3.59-3.38(m,1H),3.29(s,3H),2.60-2.52 (m, 1H), 2.32(s, 3H), 2.06(d, J=2.9Hz, 3H), 1.35-1.28(m, 3H), 1.28-1.16(m, 6H), 1.04(d, J=4.7 Hz, 3H).

实施例29 4-(7-丙烯酰基-4,7-二氮杂螺[2.5]辛烷-4-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-6-甲腈Example 29 4-(7-Acryloyl-4,7-diazaspiro[2.5]octan-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000196
Figure PCTCN2021138693-appb-000196

第一步 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-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯的合成The first step 4-(6-chloro-7-(2-hydroxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo- Synthesis of 1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000197
Figure PCTCN2021138693-appb-000197

向反应瓶中加入(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)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(0.20g,0.36mmol)，(2-羟基-3甲基苯基)硼酸(0.22g,1.44mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(62.6mg,0.08mmol)，醋酸钾(0.15g,1.49mmol) 和二氧六环(10.0mL)。反应体系加热至100℃，反应10min后向其中加入水(0.1mL)和二氧六环(0.5mL)的混合溶液，体系保温继续反应3h。反应结束后，冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(96mg,收率34.8％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (0.20 g, 0.36 mmol), (2-hydroxy- 3 methylphenyl)boronic acid (0.22 g, 1.44 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (62.6 mg, 0.08 mmol), potassium acetate (0.15 g, 1.49 mmol) and dioxane (10.0 mL). The reaction system was heated to 100°C, and after 10 min of reaction, a mixed solution of water (0.1 mL) and dioxane (0.5 mL) was added, and the system was kept warm for 3 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (96 mg, yield 34.8%).

MS(ESI,pos.ion)m/z:631.2[M+H] +. MS(ESI,pos.ion)m/z:631.2[M+H] + .

第二步 4-(6-氯-7-(2-甲氧基-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯的合成The second step 4-(6-Chloro-7-(2-methoxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen Synthesis of tert-butyl substituted-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate

Figure PCTCN2021138693-appb-000198
Figure PCTCN2021138693-appb-000198

向反应瓶中加入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-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(0.18g，0.29mmol)、氢氧化钾(80.3mg，1.43mmol)、二氯甲烷(8.0mL)和碘甲烷(0.1mL，2.0mmol)。反应体系室温反应3h。原料反应完全后，向体系加入饱和食盐水(10.0mL)，经乙酸乙酯(10.0mL×3)萃取。合并有机相，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.18g,收率95.8％)。Add 4-(6-chloro-7-(2-hydroxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the reaction flask Substituted-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (0.18 g, 0.29 mmol), potassium hydroxide (80.3 mg, 1.43 mmol), dichloromethane (8.0 mL) and iodomethane (0.1 mL, 2.0 mmol). The reaction system was reacted at room temperature for 3h. After the reaction of the raw materials was completed, saturated brine (10.0 mL) was added to the system, followed by extraction with ethyl acetate (10.0 mL×3). The organic phases were combined and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.18 g, yield 95.8%).

MS(ESI,pos.ion)m/z:645.3[M+H] +. MS(ESI,pos.ion)m/z:645.3[M+H] + .

第三步 4-(6-氰基-7-(2-甲氧基-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯的合成The third step 4-(6-cyano-7-(2-methoxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate

Figure PCTCN2021138693-appb-000199
Figure PCTCN2021138693-appb-000199

向微波管中加入4-(6-氯-7-(2-甲氧基-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(0.18g,0.27mmol)，二(三叔丁基膦)钯(0.14g,0.28mmol)，三叔丁基膦(0.55g，0.28mmol，10％)，氰化锌(0.33g,2.82mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.13g,收率73.2％)。Add 4-(6-chloro-7-(2-methoxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 to the microwave tube -Oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (0.18g , 0.27mmol), bis(tri-tert-butylphosphine)palladium (0.14g, 0.28mmol), tri-tert-butylphosphine (0.55g, 0.28mmol, 10%), zinc cyanide (0.33g, 2.82mmol) and ultra Dry N,N-dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (0.13 g, yield 73.2%).

MS(ESI,pos.ion)m/z:636.4[M+H] +. MS(ESI,pos.ion)m/z:636.4[M+H] + .

第四步 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-4-(4,7-二氮杂螺[2.5]辛烷-4-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-2-oxo-4-(4, Synthesis of 7-diazaspiro[2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000200
Figure PCTCN2021138693-appb-000200

向反应瓶中加入4-(6-氰基-7-(2-甲氧基-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-7-羧酸叔丁酯(0.13g,0.20mmol)，三氟乙酸(0.2mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(0.11g,收率100％)。Add 4-(6-cyano-7-(2-methoxy-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 2-Oxo-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate tert-butyl ester (0.13 g, 0.20 mmol), trifluoroacetic acid (0.2 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (0.11 g, yield 100%).

MS(ESI,pos.ion)m/z:536.3[M+H] +. MS(ESI,pos.ion)m/z:536.3[M+H] + .

第五步 4-(7-丙烯酰基-4,7-二氮杂螺[2.5]辛烷-4-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-6-甲腈的合成The fifth step 4-(7-Acryloyl-4,7-diazaspiro[2.5]octan-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 7-(2-Methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000201
Figure PCTCN2021138693-appb-000201

向反应瓶中加入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-4-(4,7-二氮杂螺[2.5]辛 烷-4-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(0.11g,0.20mmol)，N,N-二异丙基乙胺(72mg，0.55mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(22mg,0.24mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系室温反应10min。反应结束后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝40/1)纯化，得到标题化合物为黄色固体(22mg,收率18.8％)。Add 1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-2-oxo-4-( 4,7-Diazaspiro[2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.11 g, 0.20 mmol), N, N-diisopropylethylamine (72 mg, 0.55 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (22 mg, 0.24 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 10 min. After the reaction, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a yellow solid (22 mg, yield 18.8%).

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

1H NMR(400MHz,CDCl 3)δ(ppm)8.64-8.42(m,2H),7.32(d,J＝7.3Hz,1H),7.12(d,J＝4.9Hz,1H),7.07(t,J＝7.6Hz,1H),7.01(d,J＝7.5Hz,1H),6.65-6.54(m,1H),6.47-6.38(m,1H),5.82(d,J＝8.1Hz,1H),3.30(s,3H),2.33(s,3H),2.07(s,3H),1.31-1.21(m,11H),1.05(d,J＝6.7Hz,3H),0.91-0.84(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.64-8.42 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 7.12 (d, J=4.9 Hz, 1H), 7.07 (t, J=7.6Hz, 1H), 7.01(d, J=7.5Hz, 1H), 6.65-6.54(m, 1H), 6.47-6.38(m, 1H), 5.82(d, J=8.1Hz, 1H), 3.30(s, 3H), 2.33(s, 3H), 2.07(s, 3H), 1.31-1.21(m, 11H), 1.05(d, J=6.7Hz, 3H), 0.91-0.84(m, 2H) .

实施例30 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈Example 30 (S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl) -4-Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000202
Figure PCTCN2021138693-appb-000202

第一步 (S)-4-(6-氯-7-(2-氟-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-fluoro-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

Figure PCTCN2021138693-appb-000203
Figure PCTCN2021138693-appb-000203

向反应瓶中加入(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(0.21g,0.38mmol)，(2-氟-3-甲基苯基)硼酸(0.18g,1.17mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.06g,0.08mmol)，乙酸钾(0.12g,1.25mmol)，1,4-二氧六环(10mL)和水(0.2mL)。反应体系氮气保护下加热至95℃反应6h。待反应结束后，冷却至室温，减压 旋干。残余物中加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄绿色固体(0.23g,收率95.1％)。Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.21 g, 0.38 mmol), (2-fluoro-3-methylphenyl) Boronic acid (0.18 g, 1.17 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.06 g, 0.08 mmol), Potassium acetate (0.12 g, 1.25 mmol), 1,4-dioxane (10 mL) and water (0.2 mL). The reaction system was heated to 95°C under nitrogen protection for 6h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Water (50 mL) was added to the residue, which was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow-green solid (0.23 g, yield 95.1%).

MS(ESI,pos.ion)m/z:621.3[M+H] +. MS(ESI,pos.ion)m/z:621.3[M+H] + .

第二步 (S)-4-(6-氰基-7-(2-氟-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 second step (S)-4-(6-cyano-7-(2-fluoro-3-methylphenyl)-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

Figure PCTCN2021138693-appb-000204
Figure PCTCN2021138693-appb-000204

向微波管中加入(S)-4-(6-氯-7-(2-氟-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(0.20g,0.32mmol)，二(三叔丁基膦)钯(0.33g,0.65mmol)，三叔丁基膦(0.33g，0.16mmol，10％)，氰化锌(0.38g,3.25mmol)和超干N,N-二甲基甲酰胺(3.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(96mg,收率48.6％)。Add (S)-4-(6-chloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) to the microwave tube -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.32 mmol), Bis(tri-tert-butylphosphine)palladium (0.33 g, 0.65 mmol), tri-tert-butylphosphine (0.33 g, 0.16 mmol, 10%), zinc cyanide (0.38 g, 3.25 mmol) and ultra-dry N,N- Dimethylformamide (3.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a yellow solid (96 mg, yield 48.6%).

MS(ESI,pos.ion)m/z:612.3[M+H] +. MS(ESI,pos.ion)m/z:612.3[M+H] + .

第三步 (S)-7-(2-氟-3-甲基苯基)-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-6-甲腈的合成The third step (S)-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperidine) Synthesis of oxazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000205
Figure PCTCN2021138693-appb-000205

向反应瓶中加入(S)-4-(6-氰基-7-(2-氟-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(0.12g,0.20mmol)，三氟乙酸(0.2mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(0.10g,收率100％)。MS(ESI,pos.ion)m/z:512.3[M+H] +. Add (S)-4-(6-cyano-7-(2-fluoro-3-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 (0.12g, 0.20mmol) , trifluoroacetic acid (0.2 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, the mixture was spin-dried under reduced pressure to obtain the title compound as a brown solid (0.10 g, yield 100%). MS(ESI,pos.ion)m/z:512.3[M+H] + .

第四步 (S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈的合成The fourth step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000206
Figure PCTCN2021138693-appb-000206

向反应瓶中加入(S)-7-(2-氟-3-甲基苯基)-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-6-甲腈(0.10g,0.20mmol)，N,N-二异丙基乙胺(67mg，0.46mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(23.6mg,0.31mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系室温反应10min。反应结束后，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝40/1)纯化，得到标题化合物为黄色固体(53mg,收率52.3％)。Add (S)-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl) to the reaction flask ylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.10 g, 0.20 mmol), N,N-diisopropyl Ethylamine (67 mg, 0.46 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (23.6 mg, 0.31 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 10 min. After the reaction, it was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a yellow solid (53 mg, yield 52.3%).

MS(ESI,pos.ion)m/z:566.3[M+H] +； MS(ESI, pos.ion) m/z: 566.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.72(d,J＝5.1Hz,1H),8.38(s,1H),7.36(dd,J＝10.1,4.2Hz,1H),7.28(s,1H),7.13-7.04(m,2H),6.69-6.56(m,1H),6.45(d,J＝16.8Hz,1H),5.86(d,J＝10.4Hz,1H),4.14(dd,J＝14.3,7.1Hz,1H),3.97-3.85(m,1H),3.70(d,J＝11.1Hz,1H),2.85-2.72(m,1H),2.34(s,3H),2.11(d,J＝8.8Hz,3H),1.62-1.52(m,2H),1.46-1.38(m,3H),1.34-1.24(m,5H),1.16-1.11(m,3H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.72 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 7.36 (dd, J=10.1, 4.2 Hz, 1H), 7.28 (s, 1H),7.13-7.04(m,2H),6.69-6.56(m,1H),6.45(d,J=16.8Hz,1H),5.86(d,J=10.4Hz,1H),4.14(dd,J =14.3,7.1Hz,1H),3.97-3.85(m,1H),3.70(d,J=11.1Hz,1H),2.85-2.72(m,1H),2.34(s,3H),2.11(d, J=8.8Hz, 3H), 1.62-1.52 (m, 2H), 1.46-1.38 (m, 3H), 1.34-1.24 (m, 5H), 1.16-1.11 (m, 3H);

19F NMR(376MHz,CDCl 3)δ(ppm)-112.48，-75.62. 19 F NMR (376MHz, CDCl 3 ) δ (ppm) -112.48, -75.62.

实施例31 4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢喹唑啉-6-甲腈Example 31 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile

Figure PCTCN2021138693-appb-000207
Figure PCTCN2021138693-appb-000207

第一步 6-溴-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2,4(1H,3H)-二酮的合成The first step 6-bromo-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2,4(1H Synthesis of ,3H)-dione

Figure PCTCN2021138693-appb-000208
Figure PCTCN2021138693-appb-000208

向反应瓶中依次加入6-溴-7-碘-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2,4(1H,3H)-二酮(1.00g,2.00mmol)，(2-氟-5-甲基苯基)硼酸(0.37g,2.40mmol)，碳酸钠(0.64g,6.00mmol)，四(三苯基膦)钯(0.12g,0.10mmol)，1,4-二氧六环(15.0mL)和水(3.5mL)。反应体系氮气保护下加热至100℃反应过夜。反应结束后，冷却至室温，过滤。过滤的母液减压旋干，残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到目标产物为淡黄色固体(0.96g,收率100％)。6-Bromo-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (1.00 g, 2.00 mmol), (2-fluoro-5-methylphenyl)boronic acid (0.37 g, 2.40 mmol), sodium carbonate (0.64 g, 6.00 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 g mmol), 1,4-dioxane (15.0 mL) and water (3.5 mL). The reaction system was heated to 100°C under nitrogen protection for overnight reaction. After the reaction was completed, it was cooled to room temperature and filtered. The filtered mother liquor was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the target product as a pale yellow solid (0.96 g, yield 100%).

MS(ESI,pos.ion)m/z:482.1[M+H] +. MS(ESI,pos.ion)m/z:482.1[M+H] + .

第二步 6-溴-4-氯-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2(1H)-酮的合成The second step 6-bromo-4-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2 Synthesis of (1H)-ketones

Figure PCTCN2021138693-appb-000209
Figure PCTCN2021138693-appb-000209

向反应瓶中依次加入6-溴-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2,4(1H,3H)-二酮(0.98g,2.03mmol)，乙腈(20.0mL)和N,N-二异丙基乙胺(1.05g,8.13mmol)。体系搅拌下，滴入三氯氧磷(1.25g,8.15mmol)。反应体系加热至90℃反应过夜。反应结束后，冷却至室温，减压旋干，得到标题化合物为棕色半固体(1.02g,收率100％)，直接用于下一步反应。To the reaction flask, add 6-bromo-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2 successively, 4(1H,3H)-dione (0.98 g, 2.03 mmol), acetonitrile (20.0 mL) and N,N-diisopropylethylamine (1.05 g, 8.13 mmol). While the system was stirring, phosphorus oxychloride (1.25 g, 8.15 mmol) was added dropwise. The reaction system was heated to 90°C for overnight reaction. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure to obtain the title compound as a brown semi-solid (1.02 g, yield 100%), which was directly used in the next reaction.

第三步 (2R,5S)-4-(6-溴-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The third step (2R,5S)-4-(6-bromo-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) -Synthesis of tert-butyl 2-oxo-1,2-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000210
Figure PCTCN2021138693-appb-000210

向反应瓶中加入6-溴-4-氯-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)喹唑啉-2(1H)-酮(1.02g,2.03mmol)，N,N-二甲基甲酰胺(12.0mL)，(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.44g,2.03mmol)和N,N二异丙基乙胺(0.5mL,2.87mmol)。反应体系加热至60℃反应过夜。待反应完全后，冷却至室温，将体系倾倒入碎冰(50g)中，经乙酸乙酯(50mL×2)萃取。合并有机相，经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(0.65g,收率48％)。Add 6-bromo-4-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline to the reaction flask -2(1H)-one (1.02 g, 2.03 mmol), N,N-dimethylformamide (12.0 mL), (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert. Butyl ester (0.44 g, 2.03 mmol) and N,N diisopropylethylamine (0.5 mL, 2.87 mmol). The reaction system was heated to 60°C for overnight reaction. After the reaction was completed, it was cooled to room temperature, the system was poured into crushed ice (50 g), and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a pale yellow solid (0.65 g, yield 48%).

MS(ESI,pos.ion)m/z:678.2[M+H] +. MS(ESI,pos.ion)m/z:678.2[M+H] + .

第四步 (2R,5S)-4-(6-氰基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The fourth step (2R,5S)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl Synthesis of )-2-oxo-1,2-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000211
Figure PCTCN2021138693-appb-000211

向微波管中依次加入(2R,5S)-4-(6-溴-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.40g,0.59mmol)，氰化锌(0.62g,5.30mmol)，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)(92mg,0.12mmol)和N,N-二甲基甲酰胺(4.0mL)。反应体系氮气保护后，置于微波反应器置于微波反应器中，升温至125℃反应8h。冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为无色透明液体(0.19g,收率51％)。Add (2R,5S)-4-(6-bromo-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3) to the microwave tube in turn -yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.40 g, 0.59 mmol), cyanide Zinc chloride (0.62 g, 5.30 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'- Amino-1,1'-biphenyl)]palladium(II) (92 mg, 0.12 mmol) and N,N-dimethylformamide (4.0 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor and placed in a microwave reactor, and the temperature was raised to 125 °C for 8 h. Cool to room temperature and spin dry under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a colorless transparent liquid (0.19 g, yield 51%).

MS(ESI,pos.ion)m/z:625.3[M+H] +. MS(ESI,pos.ion)m/z:625.3[M+H] + .

第五步 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)-2-氧代-1,2-二氢喹唑啉-6-甲腈的合成The fifth step 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile

Figure PCTCN2021138693-appb-000212
Figure PCTCN2021138693-appb-000212

向反应瓶中依次加入(2R,5S)-4-(6-氰基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.19g,0.30mmol)，二氯甲烷(2.5mL)和三氟乙酸(1mL)。反应体系室温反应30min，然后减压旋干，得到标题化合物为黄色固体(0.16g,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.19 g, 0.30 mmol), Dichloromethane (2.5 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 30 min, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (0.16 g, yield 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:525.3[M+H] +. MS(ESI,pos.ion)m/z:525.3[M+H] + .

第六步 4-((2S,5R)-4-丙烯酰基-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)-2-氧代-1,2-二氢喹唑啉-6-甲腈的合成The sixth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile

Figure PCTCN2021138693-appb-000213
Figure PCTCN2021138693-appb-000213

向反应瓶中依次加入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)-2-氧代-1,2-二氢喹唑啉-6-甲腈(0.16g,0.30mmol)，二氯甲烷(4.0mL)和N,N二异丙基乙胺(0.19g,1.46mmol)、体系冷却至-10℃，缓慢滴加丙烯酰氯(49mg,0.54mmol)。滴加完毕后，反应体系保温反应30min。反应完全后，向体系中加入水(20mL)淬灭反应，经二氯甲烷(20mL×2)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物为白色固体(90.0mg,收率51％)。Add 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile (0.16 g, 0.30 mmol), dichloromethane (4.0 mL) and N,N diisopropylethylamine (0.19 g, 1.46 mmol), the system was cooled to -10°C, and acryloyl chloride (49 mg, 0.54 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 30 min. After the reaction was completed, water (20 mL) was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a white solid (90.0 mg, yield 51%).

MS(ESI,pos.ion)m/z:579.3[M+H] +； MS(ESI, pos.ion) m/z: 579.3 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.64-8.51(m,1H),8.18-8.05(m,1H),7.29-7.11(m,3H),7.12-6.99(m,2H),6.71-6.53(m,1H),6.45-6.32(m,1H),5.85-5.73(m,1H),5.20-4.87(m,2H),4.50-4.31(m,1H),4.28-3.81(m,2H),3.77-3.47(m,1H),2.80-2.62(m,1H),2.34(s,3H),2.06(s,3H),1.47-1.35(m,3H),1.30-1.17(m,6H),1.16-1.06(m,3H)； 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.64-8.51 (m, 1H), 8.18-8.05 (m, 1H), 7.29-7.11 (m, 3H), 7.12-6.99 (m, 2H), 6.71 -6.53(m,1H),6.45-6.32(m,1H),5.85-5.73(m,1H),5.20-4.87(m,2H),4.50-4.31(m,1H),4.28-3.81(m, 2H), 3.77-3.47(m, 1H), 2.80-2.62(m, 1H), 2.34(s, 3H), 2.06(s, 3H), 1.47-1.35(m, 3H), 1.30-1.17(m, 6H), 1.16-1.06(m, 3H);

19F NMR(376MHz,CDCl 3)δ(ppm)-120.20,-120.26,-120.48,-120.55. 19 F NMR (376MHz, CDCl 3 )δ(ppm)-120.20,-120.26,-120.48,-120.55.

实施例32 4-((2S,6R)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 32 4-((2S,6R)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000214
Figure PCTCN2021138693-appb-000214

第一步 (3S,5R)-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (3S,5R)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro Synthesis of pyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000215
Figure PCTCN2021138693-appb-000215

向反应瓶中加入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(0.55g,1.43mmol)，(3S,5R)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.32g,1.50mmol)，乙腈(15.0mL)和N,N-二异丙基乙胺(0.7mL,4.02mmol)。反应体系加热至55℃反应1.5h。原料反应完全后，冷却至室温，加入饱和食盐水(30mL)，经乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为橙色固体(0.40g,收率50.6％)。Add 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one to the reaction flask (0.55 g, 1.43 mmol), (3S,5R)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (0.32 g, 1.50 mmol), acetonitrile (15.0 mL) and N,N-dicarboxylate Isopropylethylamine (0.7 mL, 4.02 mmol). The reaction system was heated to 55°C for 1.5h. After the reaction of the raw materials was completed, it was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as an orange solid (0.40 g, yield 50.6%).

MS(ESI,pos.ion)m/z:561.3[M+H] +. MS(ESI,pos.ion)m/z:561.3[M+H] + .

第二步 (3S,5R)-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (3S,5R)-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)-3,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000216
Figure PCTCN2021138693-appb-000216

向反应瓶中加入(3S,5R)-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.40g,0.72mmol)，(2-氟-5-甲基苯基)硼酸(0.33g,2.17mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.12g,0.15mmol)，醋酸钾(0.22g,2.20mmol)和二氧六环(10.0mL)。反应体系加热至95℃，反应10min后向其中加入水(0.1mL)和二氧六环(0.5mL)的混合溶液，体系保温继续反应3h。反应结束后，冷却至室温，减压旋干。残余物中加入饱和食盐水(10mL)，经乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.37g,收率81.3％)。Add (3S,5R)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.40 g, 0.72 mmol), (2-fluoro-5- Methylphenyl)boronic acid (0.33g, 2.17mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.12g , 0.15 mmol), potassium acetate (0.22 g, 2.20 mmol) and dioxane (10.0 mL). The reaction system was heated to 95°C, and after 10 min of reaction, a mixed solution of water (0.1 mL) and dioxane (0.5 mL) was added, and the system was kept warm for 3 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Saturated brine (10 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a yellow solid (0.37 g, yield 81.3%).

MS(ESI,pos.ion)m/z:636.3[M+H] +. MS(ESI,pos.ion)m/z:636.3[M+H] + .

第三步 (3S,5R)-4-(6-氰基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The third step (3S,5R)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000217
Figure PCTCN2021138693-appb-000217

向微波管中加入(3S,5R)-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.15g,0.24mmol)，二(三叔丁基膦)钯(0.24g,0.48mmol)，三叔丁基膦(0.50g,1.03mmol,10％)，氰化锌(0.28g,2.41mmol)和超干N,N-二甲基甲酰胺(4.0mL)。反应体系置于微波反应器中，升温至140℃，反应7h。反应结束后，冷却至室温，加入饱和食盐水(10mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱 层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为黄色固体(0.11g,收率76.3％)。Add (3S,5R)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3-) to the microwave tube (0.15 g) , 0.24mmol), bis(tri-tert-butylphosphine)palladium (0.24g, 0.48mmol), tri-tert-butylphosphine (0.50g, 1.03mmol, 10%), zinc cyanide (0.28g, 2.41mmol) and ultra Dry N,N-dimethylformamide (4.0 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 7 h. After the reaction was completed, it was cooled to room temperature, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (0.11 g, yield 76.3%).

MS(ESI,pos.ion)m/z:626.4[M+H] +. MS(ESI,pos.ion)m/z:626.4[M+H] + .

第四步 4-((2S,6R)-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 4-((2S,6R)-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000218
Figure PCTCN2021138693-appb-000218

向反应瓶中加入(3S,5R)-4-(6-氰基-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶基[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.11g,0.18mmol)，三氟乙酸(0.2mL)和二氯甲烷(3.0mL)。反应体系室温反应1h。反应结束后，减压旋干，得到标题化合物为棕色固体(96mg,收率100％)。Add (3S,5R)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3 to the reaction flask) -yl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.11 g, 0.18 mmol), trifluoroacetic acid (0.2 mL) and dichloromethane (3.0 mL). The reaction system was reacted at room temperature for 1 h. After the completion of the reaction, it was spin-dried under reduced pressure to obtain the title compound as a brown solid (96 mg, yield 100%).

第五步 4-((2S,6R)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fifth step 4-((2S,6R)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000219
Figure PCTCN2021138693-appb-000219

向反应瓶中加入4-((2S,6R)-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(96mg,0.18mmol)，N,N-二异丙基乙胺(0.1mL，0.57mmol)和二氯甲烷(3mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(26.7mg,0.30mmol)的二氯甲烷(1mL)溶液。滴加完毕后，反应体系保温反应10min。反应结束后，减压旋干，残余物经硅胶柱层析(DCM/MeOH(v/v)＝40/1)纯化，得到标题化合物为黄色固体(51mg,收率47.8％)。To the reaction flask was added 4-((2S,6R)-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-iso Propyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (96 mg, 0.18 mmol), N,N - Diisopropylethylamine (0.1 mL, 0.57 mmol) and dichloromethane (3 mL). The system was cooled to 0°C, and a solution of acryloyl chloride (26.7 mg, 0.30 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 10 min. After the reaction was completed, it was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain the title compound as a yellow solid (51 mg, yield 47.8%).

MS(ESI,pos.ion)m/z:580.3[M+H] +. MS(ESI,pos.ion)m/z:580.3[M+H] + .

1H NMR(400MHz,CDCl 3)δ(ppm)8.44(s,1H),7.28(d,J＝6.6Hz,1H),7.13(d,J＝4.7Hz,1H),7.09-7.01(m,2H),6.71-6.60(m,1H),6.55-6.39(m,1H),5.91-5.82(m,1H),5.39-5.27(m,1H),3.98-3.89(m,1H), 3.65(d,J＝9.4Hz,1H),3.19(d,J＝7.8Hz,1H),2.28(s,3H),2.10-1.99(m,4H),1.69(s,3H),1.61(s,3H),1.29-1.22(m,6H),1.08(d,J＝6.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.44 (s, 1H), 7.28 (d, J=6.6 Hz, 1H), 7.13 (d, J=4.7 Hz, 1H), 7.09-7.01 (m, 2H), 6.71-6.60(m, 1H), 6.55-6.39(m, 1H), 5.91-5.82(m, 1H), 5.39-5.27(m, 1H), 3.98-3.89(m, 1H), 3.65( d, J=9.4Hz, 1H), 3.19(d, J=7.8Hz, 1H), 2.28(s, 3H), 2.10-1.99(m, 4H), 1.69(s, 3H), 1.61(s, 3H) ),1.29-1.22(m,6H),1.08(d,J=6.6Hz,3H).

19F NMR(376MHz,CDCl 3)δ(ppm)-117.83. 19 F NMR (376MHz, CDCl 3 ) δ (ppm)-117.83.

实施例33 4-(4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 33 4-(4-Acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl- 4-Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000220
Figure PCTCN2021138693-appb-000220

第一步 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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step 4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000221
Figure PCTCN2021138693-appb-000221

向反应瓶中加入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(1.05g,2.7mmol)，3,5-二甲基哌嗪-1-羧酸叔丁酯(0.68g,3.0mmol)，N,N-二异丙基乙胺(2.5mL,15mmol)和乙腈(15mL)。反应体系加热至60℃反应4h。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.51g,收率33％)。Add 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one to the reaction flask (1.05 g, 2.7 mmol), tert-butyl 3,5-dimethylpiperazine-1-carboxylate (0.68 g, 3.0 mmol), N,N-diisopropylethylamine (2.5 mL, 15 mmol) and Acetonitrile (15 mL). The reaction system was heated to 60°C for 4h. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (0.51 g, yield 33%).

MS(ESI,pos.ion)m/z:561.3[M+H] +； MS(ESI, pos.ion) m/z: 561.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.56(d,J＝4.9Hz,1H),8.17(s,1H),7.14(d,J＝4.8Hz,1H),5.03(s,1H),4.84(s,1H),4.10-3.80(m,2H),3.40-3.08(m,2H),2.73-2.52(m,1H),2.04(s,3H),1.62(s,6H),1.52(s,9H),1.22(d,J＝6.7Hz,3H),1.12(d,J＝6.7Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.56 (d, J=4.9 Hz, 1H), 8.17 (s, 1H), 7.14 (d, J=4.8 Hz, 1H), 5.03 (s, 1H) ,4.84(s,1H),4.10-3.80(m,2H),3.40-3.08(m,2H),2.73-2.52(m,1H),2.04(s,3H),1.62(s,6H),1.52 (s,9H),1.22(d,J=6.7Hz,3H),1.12(d,J=6.7Hz,3H).

第二步 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)-3,5-二甲基哌嗪-1-羧酸叔丁酯The second step 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)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000222
Figure PCTCN2021138693-appb-000222

向反应瓶中加入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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.30g,0.53mmol)，(2-氟-5-甲基苯基)硼酸(0.13g,0.80mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(90mg,0.11mmol)，醋酸钾(0.28g,2.7mmol)和二氧六环(8mL)。反应体系加热至90℃反应5h。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.31g,收率90％)。To the reaction flask was added 4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2 ,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.53 mmol), (2-fluoro-5-methylphenyl)boronic acid (0.13 g, 0.80 mmol), [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (90 mg, 0.11 mmol), potassium acetate (0.28 g, 2.7 mmol) and dioxane (8 mL). The reaction system was heated to 90°C for 5h. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a yellow solid (0.31 g, yield 90%).

MS(ESI,pos.ion)m/z:635.3[M+H] +； MS(ESI, pos.ion) m/z: 635.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.49(d,J＝4.9Hz,1H),8.20(s,1H),7.23-7.15(m,1H),7.09(d,J＝4.9Hz,1H),7.02-6.94(m,1H),6.92(dd,J＝6.6,1.3Hz,1H),5.24-5.02(m,1H),5.01-4.80(m,1H),4.16-4.01(m,1H),4.00-3.82(m,1H),3.33-3.21(m,2H),2.86-2.66(m,1H),2.27(s,3H),2.04(d,J＝3.4Hz,3H),1.63(s,6H),1.53(s,9H),1.24(d,J＝6.7Hz,3H),1.08(d,J＝6.7Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.49(d, J=4.9Hz, 1H), 8.20(s, 1H), 7.23-7.15(m, 1H), 7.09(d, J=4.9Hz, 1H), 7.02-6.94(m, 1H), 6.92(dd, J=6.6, 1.3Hz, 1H), 5.24-5.02(m, 1H), 5.01-4.80(m, 1H), 4.16-4.01(m, 1H), 4.00-3.82(m, 1H), 3.33-3.21(m, 2H), 2.86-2.66(m, 1H), 2.27(s, 3H), 2.04(d, J=3.4Hz, 3H), 1.63 (s, 6H), 1.53(s, 9H), 1.24(d, J=6.7Hz, 3H), 1.08(d, J=6.7Hz, 3H).

第三步 4-(6-氰基-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The third step 4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

Figure PCTCN2021138693-appb-000223
Figure PCTCN2021138693-appb-000223

向微波管中加入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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.30g,0.46mmol)，二(三叔丁基膦)钯(0.37g,0.70mmol)，10％的三叔丁基膦正己烷溶液(0.94g,0.46mmol)，氰化锌(0.56g,4.7mmol)和超干N,N-二甲基甲酰胺(5mL)。反应体系置于微波反应器中，升温至140℃，反应8h。反应结束后，冷却至室温，加入乙酸乙酯(100mL)稀释，经水(8mL×4)洗涤。有机相无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为黄色固体(0.26g,收率91％)。Add 4-(6-Chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen to the microwave tube Substituted-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.46 mmol), bis (tri-tert-butylphosphine)palladium (0.37 g, 0.70 mmol), 10% tri-tert-butylphosphine in n-hexane (0.94 g, 0.46 mmol), zinc cyanide (0.56 g, 4.7 mmol) and ultradry N, N-Dimethylformamide (5 mL). The reaction system was placed in a microwave reactor, heated to 140 °C, and reacted for 8 h. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (8 mL×4). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a yellow solid (0.26 g, yield 91%).

MS(ESI,pos.ion)m/z:626.3[M+H] +； MS(ESI, pos.ion) m/z: 626.3[M+H] + ;

第四步 4-(2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 4-(2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine Synthesis of -3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000224
Figure PCTCN2021138693-appb-000224

向反应瓶中加入4-(6-氰基-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.25g,0.40mmol)，三氟乙酸(3mL)和二氯甲烷(6mL)。反应体系常温反应2h。然后减压旋干，得到标题化合物为棕色固体(0.21g,收率100％)，直接用于下一步反应。Add 4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2- tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (0.25 g, 0.40 mmol), Trifluoroacetic acid (3 mL) and dichloromethane (6 mL). The reaction system was reacted at room temperature for 2h. Then spin-dried under reduced pressure to obtain the title compound as a brown solid (0.21 g, yield 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:526.1[M+H] +. MS(ESI,pos.ion)m/z:526.1[M+H] + .

第五步 4-(4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fifth step 4-(4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl- Synthesis of 4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000225
Figure PCTCN2021138693-appb-000225

向反应瓶中加入4-(2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(0.21g,0.40mmol)，三乙胺(0.58g,5.7mmol)和二氯甲烷(6mL)。体系冷却至0℃，缓慢滴加丙烯酰氯(0.16g,1.7mmol)。滴加完毕后，反应体系室温反应3h。然后减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝200/1)纯化，得到标题化合物为黄色固体(0.13g,收率56.1％)。Add 4-(2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methyl) to the reaction flask pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.21 g, 0.40 mmol), triethylamine (0.58 g, 5.7 mmol) and dichloromethane (6 mL). The system was cooled to 0°C, and acryloyl chloride (0.16 g, 1.7 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 3 hours. Then spin dry under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=200/1) to obtain the title compound as a yellow solid (0.13 g, yield 56.1%).

MS(ESI,pos.ion)m/z:580.5[M+H] +； MS(ESI, pos.ion) m/z: 580.5[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.55(d,J＝4.9Hz,1H),8.42(s,1H),7.32-7.23(m,1H),7.13(d,J＝4.8Hz,1H),7.10-6.98(m,2H),6.73-6.61(m,1H),6.52-6.44(m,1H),5.86(d,J＝10.6Hz,1H),5.42-5.24(m,1H),5.00-4.78(m,1H),4.70-4.51(m,1H),4.02-3.85(m,1H),3.71-3.54(m,1H),3.26-3.09(m,1H),2.83- 2.70(m,1H),2.28(s,3H),2.06-1.92(m,3H),1.77-1.53(m,6H),1.24(d,J＝6.9Hz,3H),1.07(d,J＝6.6Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.55(d, J=4.9Hz, 1H), 8.42(s, 1H), 7.32-7.23(m, 1H), 7.13(d, J=4.8Hz, 1H), 7.10-6.98(m, 2H), 6.73-6.61(m, 1H), 6.52-6.44(m, 1H), 5.86(d, J=10.6Hz, 1H), 5.42-5.24(m, 1H) ,5.00-4.78(m,1H),4.70-4.51(m,1H),4.02-3.85(m,1H),3.71-3.54(m,1H),3.26-3.09(m,1H),2.83-2.70( m,1H),2.28(s,3H),2.06-1.92(m,3H),1.77-1.53(m,6H),1.24(d,J=6.9Hz,3H),1.07(d,J=6.6Hz , 3H).

实施例34 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(1,3-二甲基-1H-吡唑-4-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-6-甲腈Example 34 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(1,3-dimethyl-1H-pyrazole-4- yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000226
Figure PCTCN2021138693-appb-000226

第一步 (2R,5S)-4-(6-氯-7-(1,3-二甲基-1H-吡唑-4-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-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-isopropyl-4-methyl) Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl Synthesis of Esters

Figure PCTCN2021138693-appb-000227
Figure PCTCN2021138693-appb-000227

向反应瓶中加入(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(0.20g,0.36mmol)，1,3-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)-1H-吡唑(0.12g,0.54mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(70mg,0.09mmol)，乙酸钾(0.15g,1.58mmol)，1,4-二氧六环(15mL)和水(0.2mL)。反应体系氮气保护下，加热至95℃反应10h。反应结束后，冷却至室温，减压旋干。残余物中加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为黄绿色固体(0.12g,收率53.8％)。Add (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.20 g, 0.36 mmol), 1,3-dimethyl -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (0.12g, 0.54mmol), [1,1 '-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (70 mg, 0.09 mmol), potassium acetate (0.15 g, 1.58 mmol), 1,4- Dioxane (15 mL) and water (0.2 mL). The reaction system was heated to 95°C under nitrogen protection for 10h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Water (50 mL) was added to the residue, which was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow-green solid (0.12 g, yield 53.8%).

MS(ESI,pos.ion)m/z:621.0[M+H] +. MS(ESI,pos.ion)m/z:621.0[M+H] + .

第二步 (2R,5S)-4-(6-氰基-7-(1,3-二甲基-1H-吡唑-4-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-cyano-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-isopropyl-4-methyl) pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert. Synthesis of Butyl Ester

Figure PCTCN2021138693-appb-000228
Figure PCTCN2021138693-appb-000228

向微波管中加入(2R,5S)-4-(6-氯-7-(1,3-二甲基-1H-吡唑-4-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)，氰化锌(0.24g,2.05mmol)，二(三叔丁基膦)钯(0.30g,0.60mmol)，三叔丁基膦的正己烷溶液(10％,0.5mL)和超干N,N-二甲基甲酰胺(2.0mL)。反应体系置于微波反应器中，升温至135℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为黄色固体(0.12g,收率100％)。MS(ESI,pos.ion)m/z:612.5[M+H] +. Add (2R,5S)-4-(6-chloro-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-isopropyl-4-yl) to the microwave tube Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-Butyl ester (0.12 g, 0.19 mmol), zinc cyanide (0.24 g, 2.05 mmol), bis(tri-tert-butylphosphine)palladium (0.30 g, 0.60 mmol), tri-tert-butylphosphine in n-hexane (10 %, 0.5 mL) and ultra-dry N,N-dimethylformamide (2.0 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 135 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow solid (0.12 g, yield 100%). MS(ESI,pos.ion)m/z:612.5[M+H] + .

第三步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(1,3-二甲基-1H-吡唑-4-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-6-甲腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(1,3-dimethyl-1H-pyrazole-4- yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile synthesis

Figure PCTCN2021138693-appb-000229
Figure PCTCN2021138693-appb-000229

向反应瓶中加入(2R,5S)-4-(6-氰基-7-(1,3-二甲基-1H-吡唑-4-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,0.20mmol)，二氯甲烷(10mL)和三氟乙酸(0.20mL)。反应体系室温反应3h。待原料反应完全后，减压旋干。残余物中加入二氯甲烷(10mL)和DIPEA(0.04g,0.35mmol)。体系冷却至0℃，缓慢滴加丙烯酰氯(0.02g，0.20mmol)。滴加完毕后，体系室温反应2h。反应结束后，体系中加入水(20mL)，分液。有机相用无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(83mg,收率75.1％)。MS(ESI,pos.ion)m/z:566.3[M+H] +； Add (2R,5S)-4-(6-cyano-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-isopropyl-4 to the reaction flask) -Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxy tert-Butyl acid (0.12 g, 0.20 mmol), dichloromethane (10 mL) and trifluoroacetic acid (0.20 mL). The reaction system was reacted at room temperature for 3h. After the reaction of the raw materials is complete, spin dry under reduced pressure. To the residue was added dichloromethane (10 mL) and DIPEA (0.04 g, 0.35 mmol). The system was cooled to 0°C, and acryloyl chloride (0.02 g, 0.20 mmol) was slowly added dropwise. After the dropwise addition, the system was reacted at room temperature for 2h. After the reaction was completed, water (20 mL) was added to the system, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (83 mg, yield 75.1%). MS(ESI, pos.ion) m/z: 566.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.62-8.54(m,1H),8.48(d,J＝5.1Hz,1H),8.24(d,J＝5.5Hz,1H),7.16(t,J＝9.0Hz,1H),6.72-6.51(m,1H),6.48-6.35(m,1H),5.82(t,J＝8.7Hz,1H),4.06-3.94(m,1H),3.88(s, 3H),3.78-3.64(m,1H),2.82-2.61(m,1H),2.11-2.01(m,4H),1.66-1.58(m,3H),1.47-1.40(m,3H),1.30-1.23(m,9H),1.10-0.99(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.62-8.54 (m, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.24 (d, J=5.5 Hz, 1H), 7.16 (t, J=9.0Hz, 1H), 6.72-6.51(m, 1H), 6.48-6.35(m, 1H), 5.82(t, J=8.7Hz, 1H), 4.06-3.94(m, 1H), 3.88(s , 3H),3.78-3.64(m,1H),2.82-2.61(m,1H),2.11-2.01(m,4H),1.66-1.58(m,3H),1.47-1.40(m,3H),1.30 -1.23(m,9H),1.10-0.99(m,3H).

实施例35 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氨基吡啶-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-6-甲腈Example 35 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-aminopyridin-3-yl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000230
Figure PCTCN2021138693-appb-000230

第一步 (2R,5S)-4-(7-(2-氨基吡啶-3-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(7-(2-aminopyridin-3-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000231
Figure PCTCN2021138693-appb-000231

向反应瓶中加入(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(0.44g,0.18mmol)，3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)吡啶-2-胺(0.26g,1.18mmol)，[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.14g,0.17mmol)，乙酸钾(0.37g,3.76mmol)，1,4-二氧六环(30mL)和水(0.2mL)。反应体系氮气保护下，加热至95℃反应6h。反应结束后，冷却至室温，减压旋干。残余物中加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为黄绿色固体(0.32g,收率65.3％)。Add (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.44 g, 0.18 mmol), 3-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-amine (0.26g, 1.18mmol), [1,1′-[1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.14 g, 0.17 mmol), potassium acetate (0.37 g, 3.76 mmol), 1,4-dioxane (30 mL) and water (0.2 mL). The reaction system was heated to 95°C under nitrogen protection for 6h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. Water (50 mL) was added to the residue, which was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow-green solid (0.32 g, yield 65.3%).

MS(ESI,pos.ion)m/z:619.2[M+H] +. MS(ESI,pos.ion)m/z:619.2[M+H] + .

第二步 (2R,5S)-4-(7-(2-氨基吡啶-3-基)-6-氰基-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-(7-(2-aminopyridin-3-yl)-6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000232
Figure PCTCN2021138693-appb-000232

向微波管中加入(2R,5S)-4-(7-(2-氨基吡啶-3-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.25g,0.40mmol)，氰化锌(0.48g,4.06mmol)，二(三叔丁基膦)钯(0.65g,1.28mmol)，三叔丁基膦的正己烷溶液(10％,0.5mL)和超干N,N-二甲基甲酰胺(2.0mL)。反应体系置于微波反应器中，升温至135℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为黄色固体(0.15g,收率60.9％)。Add (2R,5S)-4-(7-(2-aminopyridin-3-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl) to the microwave tube -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.25 g, 0.40 mmol), zinc cyanide (0.48 g, 4.06 mmol), bis(tri-tert-butylphosphine)palladium (0.65 g, 1.28 mmol), tri-tert-butylphosphine in n-hexane (10%, 0.5 mL) and ultra-dry N,N-Dimethylformamide (2.0 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 135 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow solid (0.15 g, yield 60.9%).

MS(ESI,pos.ion)m/z:610.2[M+H] +. MS(ESI,pos.ion)m/z:610.2[M+H] + .

第三步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氨基吡啶-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-6-甲腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-aminopyridin-3-yl)-1-(2- Synthesis of isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000233
Figure PCTCN2021138693-appb-000233

向反应瓶中加入(2R,5S)-4-(7-(2-氨基吡啶-3-基)-6-氰基-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(0.20g,0.32mmol)，二氯甲烷(10mL)和三氟乙酸(0.20mL)。反应体系室温反应3h。待原料反应完全后，减压旋干。残余物中加入二氯甲烷(10mL)和DIPEA(70mg,0.54mmol)。体系冷却至0℃，缓慢滴加丙烯酰氯(30mg，0.37mmol)。滴加完毕后，体系室温反应2h。反应结束后，体系中加入水(20mL)，分液。有机相用无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(25mg,收率14.0％)。Add (2R,5S)-4-(7-(2-aminopyridin-3-yl)-6-cyano-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 (0.20 g, 0.32 mmol), dichloromethane (10 mL) and trifluoroacetic acid (0.20 mL). The reaction system was reacted at room temperature for 3h. After the reaction of the raw materials is complete, spin dry under reduced pressure. To the residue was added dichloromethane (10 mL) and DIPEA (70 mg, 0.54 mmol). The system was cooled to 0°C, and acryloyl chloride (30 mg, 0.37 mmol) was slowly added dropwise. After the dropwise addition, the system was reacted at room temperature for 2h. After the reaction was completed, water (20 mL) was added to the system, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (25 mg, yield 14.0%).

MS(ESI,pos.ion)m/z:564.2[M+H] +. MS(ESI,pos.ion)m/z:564.2[M+H] + .

1H NMR(400MHz,CDCl3)δ(ppm)9.27(s,1H),8.86(s,1H),8.66(s,1H),8.31(s,1H),7.22(s,2H),6.73-6.49(m,1H),6.47-6.24(m,1H),5.87-5.70(m,1H),5.41(s,1H),5.01(s,1H),4.49-4.22(m,2H),4.18-3.90 (m,2H),3.78-3.62(m,1H),2.91(s,1H),2.58(s,1H),1.99(s,3H),1.33-1.18(m,9H),1.00-0.81(m,3H).1H NMR(400MHz, CDCl3)δ(ppm)9.27(s,1H),8.86(s,1H),8.66(s,1H),8.31(s,1H),7.22(s,2H),6.73-6.49( m,1H),6.47-6.24(m,1H),5.87-5.70(m,1H),5.41(s,1H),5.01(s,1H),4.49-4.22(m,2H),4.18-3.90 ( m,2H),3.78-3.62(m,1H),2.91(s,1H),2.58(s,1H),1.99(s,3H),1.33-1.18(m,9H),1.00-0.81(m, 3H).

实施例36 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈Example 36 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000234
Figure PCTCN2021138693-appb-000234

第一步 6-氯-7-(2-氟-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成The first step 6-chloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d] Synthesis of Pyrimidine-2,4(1H,3H)-Dione

Figure PCTCN2021138693-appb-000235
Figure PCTCN2021138693-appb-000235

向反应瓶中依次加入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(0.91g,2.49mmol)，(2-氟-3-甲基苯基)硼酸(0.77g,4.98mmol，乙酸钾(0.73g,7.47mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(60mg,0.07mmol)，1,4-二氧六环(20.0mL)和水(3.0mL)。反应体系氮气保护下，加热之回流反应过夜。待原料反应完全后，冷却至室温，过滤。过滤母液中加入乙酸乙酯(30mL)和水(30mL)，分液。水相经乙酸乙酯(30mL)萃取。合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.64g,收率59％)。6,7-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (0.91 g, 2.49 mmol), (2-fluoro-3-methylphenyl)boronic acid (0.77 g, 4.98 mmol, potassium acetate (0.73 g, 7.47 mmol), [1,1'-bis (diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (60mg, 0.07mmol), 1,4-dioxane (20.0mL) and water (3.0mL). The reaction system was under nitrogen protection The reflux reaction of heating was overnight. After the reaction of the raw materials was completed, it was cooled to room temperature and filtered. Ethyl acetate (30 mL) and water (30 mL) were added to the filtration mother liquor, and the liquid was separated. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title The compound was a pale yellow solid (0.64 g, 59% yield).

MS(ESI,pos.ion)m/z:439.1[M+H] +. MS(ESI,pos.ion)m/z:439.1[M+H] + .

第二步 4,6-二氯-7-(2-氟-3-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 second step 4,6-dichloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3 Synthesis of -d]pyrimidin-2(1H)-one

Figure PCTCN2021138693-appb-000236
Figure PCTCN2021138693-appb-000236

向反应瓶中依次加入6-氯-7-(2-氟-3-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶 -2,4(1H,3H)-二酮(0.60g,1.37mmol)，乙腈(7.0mL)，N,N-二异丙基乙胺(0.71g,5.48mmol)，三氯氧磷(0.84g,5.48mmol)。反应体系加热至回流反应6h。待反应完全后，冷却至室温，减压旋干，得到标题化合物为黄色固体(0.62g,收率100％)，直接用于下一步反应。6-Chloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3 -d]pyrimidine-2,4(1H,3H)-dione (0.60 g, 1.37 mmol), acetonitrile (7.0 mL), N,N-diisopropylethylamine (0.71 g, 5.48 mmol), trichloro Phosphorus oxide (0.84 g, 5.48 mmol). The reaction system was heated to reflux for 6h. After the reaction was completed, it was cooled to room temperature and spin-dried under reduced pressure to obtain the title compound as a yellow solid (0.62 g, yield 100%), which was directly used in the next reaction.

第三步 (2R,5S)-4-(6-氯-7-(2-氟-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The third step (2R,5S)-4-(6-chloro-7-(2-fluoro-3-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

Figure PCTCN2021138693-appb-000237
Figure PCTCN2021138693-appb-000237

向反应瓶中加入4,6-二氯-7-(2-氟-3-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(0.62g,1.36mmol)，(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.31g,1.45mmol)，N,N-二异丙基乙胺(0.36g,2.76mmol)和N,N-二甲基甲酰胺(10.0mL)。反应体系加热至80℃反应4h。待反应结束后，冷却至室温，向其中依次加入水(30mL)，经乙酸乙酯(30mL×2)萃取。合并有机相，经饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为淡黄色固体(0.43g,收率49％)。To the reaction flask was added 4,6-dichloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2 ,3-d]pyrimidin-2(1H)-one (0.62g, 1.36mmol), (2R,5S)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.31g, 1.45mmol) ), N,N-diisopropylethylamine (0.36 g, 2.76 mmol) and N,N-dimethylformamide (10.0 mL). The reaction system was heated to 80°C for 4h. After the reaction was completed, it was cooled to room temperature, and water (30 mL) was added to it, followed by extraction with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a pale yellow solid (0.43 g, yield 49%).

MS(ESI,pos.ion)m/z:635.3[M+H] +. MS(ESI,pos.ion)m/z:635.3[M+H] + .

第四步 (2R,5S)-4-(6-氰基-7-(2-氟-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The fourth step (2R,5S)-4-(6-cyano-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000238
Figure PCTCN2021138693-appb-000238

向微波管中依次加入(2R,5S)-4-(6-氯-7-(2-氟-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.27g,0.42mmol)，氰化锌(0.49g,4.2mmol)，二(三叔丁基膦)钯(0.64g,1.26mmol)和N,N-二甲基甲酰胺(4.0mL)。反应体系置于微波反应器中，升温至140℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化， 得到标题化合物为白色固体(90mg,收率34％)。Add (2R,5S)-4-(6-chloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3) to the microwave tube in turn -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.27 g, 0.42 mmol), zinc cyanide (0.49 g, 4.2 mmol), bis(tri-tert-butylphosphine)palladium (0.64 g, 1.26 mmol) and N,N-dimethylformamide (4.0 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 140 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a white solid (90 mg, yield 34%).

MS(ESI,pos.ion)m/z:626.2[M+H] +； MS(ESI, pos.ion) m/z: 626.2[M+H] + ;

第五步 4-((2S,5R)-2,5-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈的合成The fifth step 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000239
Figure PCTCN2021138693-appb-000239

向反应瓶中依次加入(2R,5S)-4-(6-氰基-7-(2-氟-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(90mg,0.14mmol)，二氯甲烷(2.0mL)和三氟乙酸(0.77g,6.71mmol)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(76mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester ( 90 mg, 0.14 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (0.77 g, 6.71 mmol). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (76 mg, yield 100%), which was directly used in the next reaction.

第六步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈的合成The sixth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000240
Figure PCTCN2021138693-appb-000240

向反应瓶中依次加入4-((2S,5R)-2,5-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈(76mg,0.14mmol)，二氯甲烷(2.0mL)和三乙胺(32mg,0.32mmol)。体系冷却至-20℃，缓慢滴加丙烯酰氯(17mg,0.19mmol)的二氯甲烷(1.0mL)溶液。滴加完毕后，反应体系保温反应30min。待反应完全后，加入水(10mL)，经二氯甲烷(10mL×2)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物为淡黄色固体(45mg,收率53.7％)。Add 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (76 mg, 0.14 mmol), dichloro Methane (2.0 mL) and triethylamine (32 mg, 0.32 mmol). The system was cooled to -20°C, and a solution of acryloyl chloride (17 mg, 0.19 mmol) in dichloromethane (1.0 mL) was slowly added dropwise. After the dropwise addition, the reaction system was incubated for 30 min. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a pale yellow solid (45 mg, yield 53.7%).

MS(ESI,pos.ion)m/z:580.3[M+H] +； MS(ESI, pos.ion) m/z: 580.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.57-8.48(m,1H),8.35(s,1H),7.36-7.28(m,1H),7.16-7.01(m,3H), 6.69-6.49(m,1H),6.45-6.33(m,1H),5.85-5.75(m,1H),5.17-4.99(m,2H),4.53-4.24(m,1H),4.07-3.81(m,2H),3.75-3.41(m,1H),2.75-2.58(m,1H),2.30(s,3H),2.06-1.97(m,3H),1.51-1.17(m,9H),1.10-1.00(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.57-8.48 (m, 1H), 8.35 (s, 1H), 7.36-7.28 (m, 1H), 7.16-7.01 (m, 3H), 6.69-6.49 (m,1H),6.45-6.33(m,1H),5.85-5.75(m,1H),5.17-4.99(m,2H),4.53-4.24(m,1H),4.07-3.81(m,2H) ,3.75-3.41(m,1H),2.75-2.58(m,1H),2.30(s,3H),2.06-1.97(m,3H),1.51-1.17(m,9H),1.10-1.00(m, 3H).

实施例37 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(环己-1-烯-1-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-6-甲腈Example 37 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(cyclohex-1-en-1-yl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000241
Figure PCTCN2021138693-appb-000241

第一步 (2R,5S)-4-(6-氯-7-(环己-1-烯-1-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-(cyclohex-1-en-1-yl)-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

Figure PCTCN2021138693-appb-000242
Figure PCTCN2021138693-appb-000242

向反应瓶中依次加入(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(0.17g,0.30mmol)，2-(环己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.12g,0.60mmol)，乙酸钾(0.09g,0.90mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.02g,0.03mmol)，1,4-二氧六环(4mL)和水(1mL)。反应体系加热至回流反应过夜。然后冷却至室温，加入水(10mL)，经乙酸乙酯(10mL×2)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.10g,收率55％)。Add (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to the reaction flask in turn - Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.17 g, 0.30 mmol), 2-(cyclohexyl- 1-En-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.12g, 0.60mmol), potassium acetate (0.09g, 0.90mmol) ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.02 g, 0.03 mmol), 1,4-dioxane (4 mL) and water (1 mL). The reaction system was heated to reflux overnight. It was then cooled to room temperature, water (10 mL) was added, and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.10 g, yield 55%).

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

第二步 (2R,5S)-4-(6-氰基-7-(环己-1-烯-1-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-cyano-7-(cyclohex-1-en-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000243
Figure PCTCN2021138693-appb-000243

向微波管中依次加入(2R,5S)-4-(6-氯-7-(环己-1-烯-1-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(0.18g,0.30mmol)，氰化锌(0.18g,1.5mmol)，二(三叔丁基膦)钯(0.15g,0.30mmol)和N,N-二甲基甲酰胺(3mL)。反应体系置于微波反应器中，升温至140℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为淡黄色固体(0.14g,收率78％)。Add (2R,5S)-4-(6-chloro-7-(cyclohex-1-en-1-yl)-1-(2-isopropyl-4-methylpyridine-3) to the microwave tube in turn -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.18 g, 0.30 mmol), zinc cyanide (0.18 g, 1.5 mmol), bis(tri-tert-butylphosphine)palladium (0.15 g, 0.30 mmol) and N,N-dimethylformamide (3 mL). The reaction system was placed in a microwave reactor, and the temperature was raised to 140 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a pale yellow solid (0.14 g, yield 78%).

MS(ESI,pos.ion)m/z:598.3[M+H] +. MS(ESI,pos.ion)m/z:598.3[M+H] + .

第三步 7-(环己-1-烯-1-基)-4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈的合成The third step 7-(cyclohex-1-en-1-yl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000244
Figure PCTCN2021138693-appb-000244

向瓶中依次加入(2R,5S)-4-(6-氰基-7-(环己-1-烯-1-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(80mg,0.13mmol)，二氯甲烷(2mL)和三氟乙酸(0.5mL)。反应体系室温反应2h，然后减压旋干，得到标题化合物为黄色固体(67mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-7-(cyclohex-1-en-1-yl)-1-(2-isopropyl-4-methylpyridine-3) to the bottle sequentially -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (80 mg , 0.13 mmol), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 2 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (67 mg, yield 100%), which was directly used in the next reaction.

第四步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(环己-1-烯-1-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-6-甲腈的合成The fourth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(cyclohex-1-en-1-yl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000245
Figure PCTCN2021138693-appb-000245

向反应瓶中依次加入7-(环己-1-烯-1-基)-4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈(60mg,0.12mmol)，二氯甲烷(2.0mL)和N,N-二异丙基乙胺(50mg,0.39mmol)。体系冷却至-20℃，缓慢滴加丙烯酰氯(10mg,0.12mmol)。滴加完毕后，反应体系室温反应1h。待反应完全后，加入水(20mL)，经二氯甲烷(20mL×2)萃取。合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经厚制备板(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(15.1mg,收率23％)。Add 7-(cyclohex-1-en-1-yl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (60 mg, 0.12 mmol), dichloro Methane (2.0 mL) and N,N-diisopropylethylamine (50 mg, 0.39 mmol). The system was cooled to -20°C, and acryloyl chloride (10 mg, 0.12 mmol) was slowly added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 1 h. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by thick prep plate (DCM/MeOH (v/v)=30/1) to give the title compound as a pale yellow solid (15.1 mg, 23% yield).

MS(ESI,pos.ion)m/z:552.3[M+H] +； MS(ESI, pos.ion) m/z: 552.3[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.58-8.50(m,1H),8.25-8.18(m,1H),7.17-7.09(m,1H),6.88(s,1H),6.67-6.49(m,1H),6.44-6.32(m,1H),5.84-5.75(m,1H),5.19-4.82(m,2H),4.49-4.31(m,1H),4.04-3.76(m,2H),3.74-3.39(m,1H),2.74-2.53(m,1H),2.06-1.91(m,6H),1.49-1.34(m,5H),1.34-1.15(m,9H),1.08-0.99(m,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.58-8.50(m,1H), 8.25-8.18(m,1H), 7.17-7.09(m,1H), 6.88(s,1H), 6.67-6.49 (m,1H),6.44-6.32(m,1H),5.84-5.75(m,1H),5.19-4.82(m,2H),4.49-4.31(m,1H),4.04-3.76(m,2H) ,3.74-3.39(m,1H),2.74-2.53(m,1H),2.06-1.91(m,6H),1.49-1.34(m,5H),1.34-1.15(m,9H),1.08-0.99( m,3H).

实施例38 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-环己基-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-6-甲腈Example 38 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-cyclohexyl-1-(2-isopropyl-4-methyl Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000246
Figure PCTCN2021138693-appb-000246

第一步 (2R,5S)-4-(6-氰基-7-环己基-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-cyano-7-cyclohexyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 - Synthesis of tert-butyl dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000247
Figure PCTCN2021138693-appb-000247

向反应瓶中依次加入(2R,5S)-4-(6-氰基-7-(环己-1-烯-1-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(60mg,0.10mmol)，乙酸乙酯(4.0mL)，10％钯炭(10mg)。反应体系氢气氛围下室温反应4h。待原料反应完全后，过滤。过滤的母液减压旋干，得到标 题化合物为棕色固体(60mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-7-(cyclohex-1-en-1-yl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester ( 60 mg, 0.10 mmol), ethyl acetate (4.0 mL), 10% palladium on carbon (10 mg). The reaction system was reacted at room temperature for 4h under a hydrogen atmosphere. After the reaction of the raw materials is complete, filter. The filtered mother liquor was spin-dried under reduced pressure to obtain the title compound as a brown solid (60 mg, yield 100%), which was directly used in the next reaction.

MS(ESI,pos.ion)m/z:600.4[M+H] +. MS(ESI,pos.ion)m/z:600.4[M+H] + .

第二步 7-环己基-4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈的合成The second step 7-cyclohexyl-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000248
Figure PCTCN2021138693-appb-000248

向反应瓶中依次加入(2R,5S)-4-(6-氰基-7-环己基-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(35mg,0.06mmol)，二氯甲烷(2.0mL)和三氟乙酸(0.5mL)。反应体系室温反应1h。原料反应完全后，减压旋干，得到标题化合物为棕色固体(29mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-7-cyclohexyl-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (35 mg, 0.06 mmol), dichloromethane ( 2.0 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials was completed, spin-dried under reduced pressure to obtain the title compound as a brown solid (29 mg, yield 100%), which was directly used in the next reaction.

第三步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-环己基-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-6-甲腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-cyclohexyl-1-(2-isopropyl-4-methyl Synthesis of Pyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000249
Figure PCTCN2021138693-appb-000249

向反应瓶中依次加入7-环己基-4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈(29mg,0.06mmol)，二氯甲烷(2mL)和N,N-二异丙基乙胺(20mg,0.15mmol)。体系冷却至-20℃，缓慢滴加丙烯酰氯(10mg,0.11mmol)。反应体系室温下反应1h。反应结束后，向上述混合物中加入水(20mL)，经二氯甲烷(20mL×2)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经厚制备板(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(10.0mg,收率31％)。Add 7-cyclohexyl-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (29 mg, 0.06 mmol), dichloromethane (2 mL) and N,N-dichloromethane Isopropylethylamine (20 mg, 0.15 mmol). The system was cooled to -20°C, and acryloyl chloride (10 mg, 0.11 mmol) was slowly added dropwise. The reaction system was reacted at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the above mixture, and the mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by thick prep plate (DCM/MeOH (v/v)=30/1) to give the title compound as a pale yellow solid (10.0 mg, 31% yield).

MS(ESI,pos.ion)m/z:554.5[M+H] +； MS(ESI, pos.ion) m/z: 554.5[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.59-8.54(m,1H),8.21-8.16(m,1H),7.18-7.12(m,1H),6.67-6.48(m, 1H),6.44-6.33(m,1H),5.84-5.75(m,1H),5.17-4.98(m,1H),4.48-4.31(m,1H),4.03-3.80(m,2H),3.73-3.62(m,1H),3.58-3.38(m,1H),3.08-2.97(m,1H),2.75-2.59(m,1H),1.99-1.91(m,3H),1.74-1.60(m,5H),1.48-1.37(m,4H),1.32-1.28(m,2H),1.24-1.21(m,5H),1.15-1.01(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.59-8.54 (m, 1H), 8.21-8.16 (m, 1H), 7.18-7.12 (m, 1H), 6.67-6.48 (m, 1H), 6.44 -6.33(m, 1H), 5.84-5.75(m, 1H), 5.17-4.98(m, 1H), 4.48-4.31(m, 1H), 4.03-3.80(m, 2H), 3.73-3.62(m, 1H), 3.58-3.38(m, 1H), 3.08-2.97(m, 1H), 2.75-2.59(m, 1H), 1.99-1.91(m, 3H), 1.74-1.60(m, 5H), 1.48- 1.37(m,4H),1.32-1.28(m,2H),1.24-1.21(m,5H),1.15-1.01(m,6H).

实施例39 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)--1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 39 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl )-2-oxo-7-(piperidin-1-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000250
Figure PCTCN2021138693-appb-000250

第一步 (2R,5S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-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-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(piperidin-1-yl) )-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000251
Figure PCTCN2021138693-appb-000251

向反应瓶中依次加入(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(0.30g,0.53mmol)，N,N-二异丙基乙胺(0.14g,1.06mmol)，哌啶(0.14g,1.59mmol)和N,N-二甲基甲酰胺(5.0ml)。反应体系加热至90℃反应1h。然后冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.25g,收率77％)。Add (2R,5S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2 to the reaction flask in turn - Dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.30 g, 0.53 mmol), N,N-diiso Propylethylamine (0.14 g, 1.06 mmol), piperidine (0.14 g, 1.59 mmol) and N,N-dimethylformamide (5.0 ml). The reaction system was heated to 90 °C for 1 h. It was then cooled to room temperature and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.25 g, yield 77%).

MS(ESI,pos.ion)m/z:610.3[M+H] +. MS(ESI,pos.ion)m/z:610.3[M+H] + .

第二步 (2R,5S)-4-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-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-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(piperidine-1- Synthesis of tert-butyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000252
Figure PCTCN2021138693-appb-000252

向微波管中依次加入(2R,5S)-4-(6-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-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(0.15g,0.25mmol)，氰化锌(0.23g,2.00mmol)，二(三叔丁基膦)钯(0.06g,0.13mmol)，三叔丁基膦四氟硼酸盐(0.01g,0.05mmol)和N,N-二甲基甲酰胺(3mL)。反应体系氮气保护后，置于微波反应器中，升温至140℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.14g,收率95％)。Add (2R,5S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(piperidine- 1-yl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.15 g, 0.25 mmol ), zinc cyanide (0.23 g, 2.00 mmol), bis(tri-tert-butylphosphine)palladium (0.06 g, 0.13 mmol), tri-tert-butylphosphine tetrafluoroborate (0.01 g, 0.05 mmol) and N, N-Dimethylformamide (3 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, and the temperature was raised to 140 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.14 g, yield 95%).

MS(ESI,pos.ion)m/z:601.5[M+H] +. MS(ESI,pos.ion)m/z:601.5[M+H] + .

第三步 4-((2S,5R)-2,5-二甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxygen Synthesis of Geno-7-(piperidin-1-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000253
Figure PCTCN2021138693-appb-000253

向反应瓶中依次加入(2R,5S)-4-(6-氰基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-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(50mg,0.08mmol)，二氯甲烷(2mL)和三氟乙酸(0.5mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(42mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(6-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(piperidine) to the reaction flask in turn -1-yl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (50 mg, 0.08 mmol ), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (42 mg, yield 100%), which was directly used in the next reaction.

第四步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl )-2-oxo-7-(piperidin-1-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000254
Figure PCTCN2021138693-appb-000254

向反应瓶中依次加入4-((2S,5R)-2,5-二甲基哌嗪-1-基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-7-(哌啶-1-基)-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(42mg,0.08mmol)，二氯甲烷(2.0mL)和N,N-二异丙基乙胺(20mg,0.15mmol)。体系冷却至-20℃，缓慢滴加丙烯酰氯(0.01g,0.17mmol)。反应体系室温下反应1h。反应结束后，向上述混合物中加入水(20mL)，经二氯甲烷(20mL×2)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经厚制备板(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(24mg,收率52％)。Add 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 2-oxo-7-(piperidin-1-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (42 mg, 0.08 mmol), dichloromethane (2.0 mL) ) and N,N-diisopropylethylamine (20 mg, 0.15 mmol). The system was cooled to -20°C, and acryloyl chloride (0.01 g, 0.17 mmol) was slowly added dropwise. The reaction system was reacted at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the above mixture, and the mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by thick prep plate (DCM/MeOH (v/v)=30/1) to give the title compound as a pale yellow solid (24 mg, 52% yield).

MS(ESI,pos.ion)m/z:555.5[M+H] +； MS(ESI, pos.ion) m/z: 555.5 [M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.55-8.43(m,1H),8.03-7.93(m,1H),7.14-7.03(m,1H),6.66-6.45(m,1H),6.42-6.28(m,1H),5.84-5.67(m,1H),5.13-4.93(m,1H),4.44-4.14(m,1H),3.92-3.60(m,3H),3.53(s,4H),3.48-3.29(m,1H),2.80-2.58(m,1H),2.05-1.95(m,3H),1.64-1.55(m,2H),1.53-1.44(m,4H),1.41-1.32(m,4H),1.28-1.17(m,6H),1.09-1.03(m,2H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.55-8.43(m,1H), 8.03-7.93(m,1H), 7.14-7.03(m,1H), 6.66-6.45(m,1H), 6.42 -6.28(m,1H),5.84-5.67(m,1H),5.13-4.93(m,1H),4.44-4.14(m,1H),3.92-3.60(m,3H),3.53(s,4H) ,3.48-3.29(m,1H),2.80-2.58(m,1H),2.05-1.95(m,3H),1.64-1.55(m,2H),1.53-1.44(m,4H),1.41-1.32( m,4H),1.28-1.17(m,6H),1.09-1.03(m,2H).

实施例40 4-((2S,6R)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈Example 40 4-((2S,6R)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000255
Figure PCTCN2021138693-appb-000255

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

Figure PCTCN2021138693-appb-000256
Figure PCTCN2021138693-appb-000256

向反应瓶中依次加入4,6-二氯-7-(2-氟-3-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(0.60g,1.31mmol)，(3R,5S)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.29g,1.38mmol)，N,N-二异丙基乙胺(0.34g,2.63mmol)和N,N-二甲基甲酰胺(10.0mL)。反应体系加热至85℃反应过夜。氮气置换后混合物升温至85℃搅拌过夜。然后冷却至室温，加入水(30mL)，经乙酸乙酯(30mL×2)萃取。合并有机相，经饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为白色固体(0.10g,收率12％)。4,6-Dichloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[ 2,3-d]pyrimidin-2(1H)-one (0.60 g, 1.31 mmol), (3R,5S)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.29 g, 1.38 mmol), N,N-diisopropylethylamine (0.34 g, 2.63 mmol) and N,N-dimethylformamide (10.0 mL). The reaction system was heated to 85°C for overnight reaction. After nitrogen replacement, the mixture was warmed to 85°C and stirred overnight. It was then cooled to room temperature, water (30 mL) was added, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a white solid (0.10 g, yield 12%).

MS(ESI,pos.ion)m/z:635.3[M+H] +. MS(ESI,pos.ion)m/z:635.3[M+H] + .

第二步 (3R,5S)-4-(6-氰基-7-(2-氟-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (3R,5S)-4-(6-cyano-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000257
Figure PCTCN2021138693-appb-000257

向微波管中依次加入(3R,5S)-4-(6-氯-7-(2-氟-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(66mg,0.10mmol)，氰化锌(59mg,0.50mmol)，二(三叔丁基膦)钯(5.8mg,0.02mmol)和N,N-二甲基甲酰胺(2.0mL)。反应体系氮气保护后，置于微波反应器中，升温至140℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为无色透明固体(35mg,收率56％)。Add (3R,5S)-4-(6-chloro-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3) to the microwave tube in turn -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (66 mg , 0.10 mmol), zinc cyanide (59 mg, 0.50 mmol), bis(tri-tert-butylphosphine)palladium (5.8 mg, 0.02 mmol) and N,N-dimethylformamide (2.0 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, and the temperature was raised to 140 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a colorless transparent solid (35 mg, yield 56%).

MS(ESI,pos.ion)m/z:626.5[M+H] +. MS(ESI,pos.ion)m/z:626.5[M+H] + .

第三步 4-((2R,6S)-2,6-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈的合成The third step 4-((2R,6S)-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000258
Figure PCTCN2021138693-appb-000258

向反应瓶中依次加入(3R,5S)-4-(6-氰基-7-(2-氟-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(35mg,0.06mmol)，二氯甲烷(2.0mL)和三氟乙酸(0.5mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(30mg,收率100％)，直接用于下一步反应。Add (3R,5S)-4-(6-cyano-7-(2-fluoro-3-methylphenyl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester ( 35 mg, 0.06 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (30 mg, yield 100%), which was directly used in the next reaction.

第四步 4-((2S,6R)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈的合成The fourth step 4-((2S,6R)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000259
Figure PCTCN2021138693-appb-000259

向反应瓶中依次加入4-((2R,6S)-2,6-二甲基哌嗪-1-基)-7-(2-氟-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-6-甲腈(30mg,0.06mmol)，二氯甲烷(2.0mL)和三乙胺(29.0mg,0.29mmol)。体系冷却至-20℃，缓慢滴加，缓慢滴加丙烯酰氯(10mg,0.11mmol)的二氯甲烷(1mL)溶液。反应体系室温下反应1h。反应结束后，向上述混合物中加入水(10mL)，经二氯甲烷(10mL×2)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝50/1)纯化，得到标题化合物为淡黄色固体(16mg,收率48％)。Add 4-((2R,6S)-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-3-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (30 mg, 0.06 mmol), dichloro Methane (2.0 mL) and triethylamine (29.0 mg, 0.29 mmol). The system was cooled to -20°C, slowly added dropwise, and a solution of acryloyl chloride (10 mg, 0.11 mmol) in dichloromethane (1 mL) was slowly added dropwise. The reaction system was reacted at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to the above mixture, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to obtain the title compound as a pale yellow solid (16 mg, yield 48%).

MS(ESI,pos.ion)m/z:580.2[M+H] +； MS(ESI, pos.ion) m/z: 580.2[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.52(d,J＝4.9Hz,1H),8.42(s,1H),7.34-7.28(m,1H),7.11(d,J＝4.9Hz,1H),7.07-7.00(m,2H),6.70-6.60(m,1H),6.50-6.42(m,1H),5.87-5.81(m,1H),5.41-5.22(m,1H),4.96-4.51(m,2H),4.00-3.84(m,1H),3.64(s,1H),3.24-3.12(m,1H),2.81-2.57(m,1H),2.33-2.26(m,3H),2.08-1.96(m,3H),1.75-1.54(m,6H),1.24-1.20(m,3H),1.08-1.02(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.52 (d, J=4.9 Hz, 1H), 8.42 (s, 1H), 7.34-7.28 (m, 1H), 7.11 (d, J=4.9 Hz, 1H), 7.07-7.00(m, 2H), 6.70-6.60(m, 1H), 6.50-6.42(m, 1H), 5.87-5.81(m, 1H), 5.41-5.22(m, 1H), 4.96- 4.51(m,2H),4.00-3.84(m,1H),3.64(s,1H),3.24-3.12(m,1H),2.81-2.57(m,1H),2.33-2.26(m,3H), 2.08-1.96(m,3H),1.75-1.54(m,6H),1.24-1.20(m,3H),1.08-1.02(m,3H).

实施例41 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氨基-3-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-6-甲腈Example 41 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-3-fluorophenyl)-1-(2 -Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000260
Figure PCTCN2021138693-appb-000260

第一步 (2R,5S)-4-(7-(2-氨基-3-氟苯基)-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)- Synthesis of 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000261
Figure PCTCN2021138693-appb-000261

向反应瓶总依次加入(2R,5S)-4-(6-氯-7-(1,3-二甲基-1H-吡唑-4-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(0.30g,0.53mmol)，2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂环硼-2-基)苯胺(0.25g,1.06mmol)，乙酸钾(0.16g,0.59mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.02g,0.03mmol)，1,4-二氧六环(6mL)和水(0.5mL)。反应体系氮气保护下，加热至回流反应过夜。反应结束后，冷却至室温，向其中加入水(30mL)，经乙酸乙酯(30mL×2)萃取。合并有机相，经饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.28g,收率83％)。To the reaction flask, add (2R,5S)-4-(6-chloro-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-isopropyl-4 -Methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxy tert-Butyl acid (0.30 g, 0.53 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)aniline (0.25 g, 1.06 mmol), potassium acetate (0.16 g, 0.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.02 g, 0.03 mmol) , 1,4-dioxane (6 mL) and water (0.5 mL). The reaction system was heated to reflux overnight under nitrogen protection. After the reaction was completed, it was cooled to room temperature, water (30 mL) was added thereto, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.28 g, yield 83%).

MS(ESI,pos.ion)m/z:636.3[M+H] +； MS(ESI, pos.ion) m/z: 636.3[M+H] + ;

第二步 (2R,5S)-4-(7-(2-氨基-3-氟苯基)-6-氰基-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-(7-(2-amino-3-fluorophenyl)-6-cyano-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

Figure PCTCN2021138693-appb-000262
Figure PCTCN2021138693-appb-000262

向微波管中依次加入(2R,5S)-4-(7-(2-氨基-3-氟苯基)-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)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.18g,0.28mmol)，氰化锌(0.16g,1.4mmol)，二(三叔丁基膦)钯(0.14g,0.28mmol)，三叔丁基膦四氟硼酸盐(0.01g,0.03mmol)和N,N-二甲基甲酰胺(1.0mL)。反应体系氮气保护后，置于微波反应器中，升温至140℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.10g,收率57％)。Add (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridine-3- (0.18 g) , 0.28mmol), zinc cyanide (0.16g, 1.4mmol), bis(tri-tert-butylphosphine)palladium (0.14g, 0.28mmol), tri-tert-butylphosphine tetrafluoroborate (0.01g, 0.03mmol) and N,N-dimethylformamide (1.0 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, and the temperature was raised to 140 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.10 g, yield 57%).

MS(ESI,pos.ion)m/z:627.3[M+H] +. MS(ESI,pos.ion)m/z:627.3[M+H] + .

第三步 7-(2-氨基-3-氟苯基)-4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈的合成The third step 7-(2-amino-3-fluorophenyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl- Synthesis of 4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000263
Figure PCTCN2021138693-appb-000263

向反应瓶中依次加入(2R,5S)-4-(7-(2-氨基-3-氟苯基)-6-氰基-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(0.10g,0.16mmol)，二氯甲烷(4mL)和三氟乙酸(1mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(80mg,收率100％)，直接用于下一步反应。Add (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-cyano-1-(2-isopropyl-4-methylpyridine-3 to the reaction flask in turn -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.10 g, 0.16 mmol), dichloromethane (4 mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (80 mg, yield 100%), which was directly used in the next reaction.

第四步 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氨基-3-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-6-甲腈的合成The fourth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-3-fluorophenyl)-1-(2 Synthesis of -isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000264
Figure PCTCN2021138693-appb-000264

向反应瓶中依次加入7-(2-氨基-3-氟苯基)-4-((2S,5R)-2,5-二甲基哌嗪-1-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-6-甲腈(0.08g,0.16mmol)，二氯甲烷(2.0mL)和N,N-二异丙基乙胺(80mg,0.62mmol)。体系冷却至-20℃，缓慢滴加丙烯酰氯(0.02g,0.18mmol)。反应体系室温下反应1h。反应结束后，向上述混合物中加入水(200mL)，经二氯甲烷(20mL×2)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经厚制备板(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(56mg,收率60％)。Add 7-(2-amino-3-fluorophenyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-1-(2-iso Propyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.08 g, 0.16 mmol), dichloro Methane (2.0 mL) and N,N-diisopropylethylamine (80 mg, 0.62 mmol). The system was cooled to -20°C, and acryloyl chloride (0.02 g, 0.18 mmol) was slowly added dropwise. The reaction system was reacted at room temperature for 1 h. After the reaction was completed, water (200 mL) was added to the above mixture, and the mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by thick prep plate (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow-green solid (56 mg, 60% yield).

MS(ESI,pos.ion)m/z:581.4[M+H] +； MS(ESI, pos.ion) m/z: 581.4[M+H] + ;

1H NMR(400MHz,DMSO-d 6)δ(ppm)9.16(s,1H),8.59-8.54(m,1H),7.74-7.63(m,2H),7.59(d,J＝7.8Hz,1H),7.42-7.29(m,2H),7.11-7.02(m,1H),6.89-6.78(m,1H),6.24-6.14(m,1H),5.80-5.70(m,1H),5.01(s,1H),4.76-4.37(m,1H),4.19-4.03(m,2H),3.91(s,1H),3.67-3.47(m,1H),2.87-2.54(m,1H),2.05-1.85(m,3H),1.38-1.29(m,3H),1.19-1.01(m,6H),1.00-0.82(m,3H). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm) 9.16(s, 1H), 8.59-8.54(m, 1H), 7.74-7.63(m, 2H), 7.59(d, J=7.8Hz, 1H ),7.42-7.29(m,2H),7.11-7.02(m,1H),6.89-6.78(m,1H),6.24-6.14(m,1H),5.80-5.70(m,1H),5.01(s ,1H),4.76-4.37(m,1H),4.19-4.03(m,2H),3.91(s,1H),3.67-3.47(m,1H),2.87-2.54(m,1H),2.05-1.85 (m,3H),1.38-1.29(m,3H),1.19-1.01(m,6H),1.00-0.82(m,3H).

实施例42 4-((2S,6S)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈Example 42 4-((2S,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( 2-Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000265
Figure PCTCN2021138693-appb-000265

第一步 (3S,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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (3S,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)-3,5-dimethylpiperazine-1-carboxylate

Figure PCTCN2021138693-appb-000266
Figure PCTCN2021138693-appb-000266

向反应瓶中依次加入4,6-二氯-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(0.20g,0.46mmol)，(3S,5S)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.10g,0.46mmol)，N,N-二甲基甲酰胺(3.0mL)和N,N-二异丙基乙胺(0.30g,2.30mmol)。反应体系加热至90℃反应过夜。然后冷却至室温，将混合物倒入碎冰(50g)中。所得混合物经乙酸乙酯(50mL×2)萃取。合并有机相，经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色油状物(65mg,收率22％)。4,6-Dichloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[ 2,3-d]pyrimidin-2(1H)-one (0.20 g, 0.46 mmol), (3S,5S)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.10 g, 0.46 mmol), N,N-dimethylformamide (3.0 mL) and N,N-diisopropylethylamine (0.30 g, 2.30 mmol). The reaction system was heated to 90°C for overnight reaction. It was then cooled to room temperature and the mixture was poured into crushed ice (50 g). The resulting mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow oil (65 mg, yield 22%).

MS(ESI,pos.ion)m/z:635.3[M+H] +. MS(ESI,pos.ion)m/z:635.3[M+H] + .

第二步 (3S,5S)-4-(6-氰基-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (3S,5S)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Figure PCTCN2021138693-appb-000267
Figure PCTCN2021138693-appb-000267

向微波管中依次加入(3S,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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.06g,0.10mmol)，氰化锌(0.06g,0.50mmol)，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)(0.02g,0.04mmol)和N,N-二甲基甲酰胺(2.0mL)。反应体系氮气保护后，置于微波反应器中，升温至140℃反应7h。反应结束后，冷却至室温，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为无色透明油状物(30mg,收率48％)。Add (3S,5S)-4-(6-chloro-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine-3 to the microwave tube in turn) -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.06 g, 0.10 mmol), zinc cyanide (0.06 g, 0.50 mmol), chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-Amino-1,1'-biphenyl)]palladium(II) (0.02 g, 0.04 mmol) and N,N-dimethylformamide (2.0 mL). After the reaction system was protected by nitrogen, it was placed in a microwave reactor, and the temperature was raised to 140 °C for 7 h. After the reaction was completed, it was cooled to room temperature, and was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a colorless transparent oil (30 mg, yield 48%).

MS(ESI,pos.ion)m/z:626.3[M+H] +. MS(ESI,pos.ion)m/z:626.3[M+H] + .

第三步 4-((2S,6S)-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The third step 4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl) Synthesis of -4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000268
Figure PCTCN2021138693-appb-000268

向反应瓶中依次加入(3S,5S)-4-(6-氰基-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)-3,5-二甲基哌嗪-1-羧酸叔丁酯(30mg,0.05mmol)，二氯甲烷(2mL)和三氟乙酸(0.4mL)。反应体系室温反应1h，然后减压旋干，得到标题化合物为黄色固体(25mg,收率100％)，直接用于下一步反应。Add (3S,5S)-4-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridine- 3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester ( 30 mg, 0.05 mmol), dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure to obtain the title compound as a yellow solid (25 mg, yield 100%), which was directly used in the next reaction.

第四步 4-((2S,6S)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈的合成The fourth step 4-((2S,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-( Synthesis of 2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile

Figure PCTCN2021138693-appb-000269
Figure PCTCN2021138693-appb-000269

向反应瓶中依次加入4-((2S,6S)-2,6-二甲基哌嗪-1-基)-7-(2-氟-5-甲基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-甲腈(25mg,0.05mmol)，二氯甲烷(2.0mL)和N,N-二异丙基乙胺(15.0mg,0.02mmol)。向其中缓慢滴加丙烯酰氯(4.3mg,0.05mmol)。滴完后，反应体系保温反应30min。反应结束后，向上述混合物中加入水(20mL)，经二氯甲烷(20mL×2)萃取。合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为白色固体(12mg,收率43％)。Add 4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7-(2-fluoro-5-methylphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (25 mg, 0.05 mmol), dichloro Methane (2.0 mL) and N,N-diisopropylethylamine (15.0 mg, 0.02 mmol). Acryloyl chloride (4.3 mg, 0.05 mmol) was slowly added dropwise thereto. After dropping, the reaction system was incubated for 30 min. After the reaction was completed, water (20 mL) was added to the above mixture, and the mixture was extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a white solid (12 mg, yield 43%).

MS(ESI,pos.ion)m/z:580.4[M+H] +； MS(ESI, pos.ion) m/z: 580.4[M+H] + ;

1H NMR(400MHz,CDCl 3)δ(ppm)8.57-8.46(m,2H),8.10(s,1H),7.13(d,J＝4.8Hz,1H),7.09-7.00(m,2H),6.67-6.55(m,1H),6.46-6.37(m,1H),5.86-5.78(m,1H),4.40(s,2H),4.07-3.83(m,3H),3.74(s,1H),2.73-2.60(m,1H),2.28(s,3H),2.06-1.98(m,3H),1.44(d,J＝5.9Hz,6H),1.22(d,J＝3.2Hz,3H),1.13-1.04(m,3H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.57-8.46(m, 2H), 8.10(s, 1H), 7.13(d, J=4.8Hz, 1H), 7.09-7.00(m, 2H), 6.67-6.55(m, 1H), 6.46-6.37(m, 1H), 5.86-5.78(m, 1H), 4.40(s, 2H), 4.07-3.83(m, 3H), 3.74(s, 1H), 2.73-2.60(m, 1H), 2.28(s, 3H), 2.06-1.98(m, 3H), 1.44(d, J=5.9Hz, 6H), 1.22(d, J=3.2Hz, 3H), 1.13 -1.04(m,3H).

生物试验biological test

分析用的LC/MS/MS系统为Waters Xevo G2-XS Qtof飞行时间质谱仪。质谱条件如表A所示：The LC/MS/MS system used for analysis was a Waters Xevo G2-XS Qtof time-of-flight mass spectrometer. The mass spectrometry conditions are shown in Table A:

表ATable A

项目project 条件condition 毛细管电压(kV)Capillary voltage (kV) 44 锥孔电压(V)Cone voltage (V) 6060 离子源温度e(℃)Ion source temperature e(℃) 120120 锥孔气流速(L/h)Cone gas flow rate (L/h) 5050 干燥气流速(L/h)Drying gas flow rate (L/h) 10001000 扫描模式scan mode ES源,正离子模式ES source, positive ion mode 分析模式Analysis mode 灵敏度Sensitivity 扫描范围Scan range 500-2000m/z500-2000m/z

分析使用Waters Acquity I Class Sepax Bio-C4，2.1×50mm，3μM色谱柱，注入10μL样品。分析条件：流动相为水(含0.1％的甲酸)(A)和乙腈(含0.1％的甲酸)(B)。流速为0.6mL/min。柱温为65℃。流动相梯度如表B所示：Analysis was performed using a Waters Acquity I Class Sepax Bio-C4, 2.1 x 50 mm, 3 μM chromatographic column, injected with 10 μL of sample. Analytical conditions: mobile phases were water (containing 0.1% formic acid) (A) and acetonitrile (containing 0.1% formic acid) (B). The flow rate was 0.6 mL/min. The column temperature was 65°C. The mobile phase gradient is shown in Table B:

表BForm B

时间time 流动相A的梯度Gradient of Mobile Phase A 流动相B的梯度Gradient of Mobile Phase B 0min0min 95％95% 5％5% 0.75min0.75min 95％95% 5％5% 1.0min1.0min 75％75% 25％25% 6.0min6.0min 50％50% 50％50% 6.25min6.25min 0％0% 100％100% 7.5min7.5min 0％0% 100％100% 7.75min7.75min 95％95% 5％5% 9min9min 95％95% 5％5%

实施例A 人和大鼠肝微粒体中的稳定性Example A Stability in Human and Rat Liver Microsomes

将人或小鼠肝微粒体置于聚丙烯试管中双复孔孵育。典型的孵育混合液包括人或小鼠肝微粒体(0.5mg蛋白质/mL)，目标化合物(1μM)和总体积为15μL的NADPH(2.0mM)磷酸钾缓冲液(PBS,100mM,pH值为7.4)，将待测化合物溶解在DMSO中，并使用PBS将其稀释，使其最终的DMSO溶液的浓度为0.05％。并在37℃下与空气相通的水浴中进行孵育，预孵育3min后向混合液中加入蛋白并开始反应。在不同的时间点(0，20和60min)，加入同体积冰冷乙腈终止反应。样品于-80℃下保存直到进行LC/MS/MS分析。Human or mouse liver microsomes were incubated in double wells in polypropylene tubes. A typical incubation mix includes human or mouse liver microsomes (0.5 mg protein/mL), target compound (1 μM) and NADPH (2.0 mM) in a total volume of 15 μL in potassium phosphate buffer (PBS, 100 mM, pH 7.4) ), the compounds to be tested were dissolved in DMSO and diluted with PBS to give a final DMSO solution concentration of 0.05%. Incubate at 37°C in a water bath open to air. After pre-incubating for 3 min, add protein to the mixture and start the reaction. At different time points (0, 20 and 60 min), the reaction was stopped by adding the same volume of ice-cold acetonitrile. Samples were stored at -80°C until LC/MS/MS analysis.

化合物在人或小鼠肝微粒体孵育混合物中的浓度是通过LC/MS/MS的方法来测定的。Compound concentrations in human or mouse liver microsome incubation mixtures were determined by LC/MS/MS methods.

平行孵育试验使用变性的微粒体作为阴性对照，在37℃下孵化，反应在不同的时间点(0，20和60min)终止。Parallel incubation experiments using denatured microsomes as negative controls were incubated at 37°C and the reaction was terminated at different time points (0, 20 and 60 min).

维拉帕米(1μΜ)作为阳性对照，在37℃下孵化，反应在不同的时间点(0，20和60min)终止。Verapamil (1 μM) was used as a positive control and incubated at 37°C and the reaction was terminated at different time points (0, 20 and 60 min).

数据分析data analysis

对于每一个反应，将化合物在人或大鼠肝微粒体孵育中的浓度(以百分比表示)按相对零时间点的百分比作图，以此来推断体内肝固有清除率CL int(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.)。 For each reaction, in vivo hepatic intrinsic clearance CL int (ref.: Naritomi ) was inferred by plotting the compound concentration (expressed as a percentage) in human or rat liver microsome incubations as a percentage relative to the zero time point Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29:1316- 1324.).

由实验结果可知，将本发明化合物孵育在人肝微粒体中时，本发明所述化合物表现出适当的稳定性。From the experimental results, it can be known that the compound of the present invention exhibits appropriate stability when incubated in human liver microsomes.

实施例B 小鼠、大鼠、犬和猴子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 B Pharmacokinetic Evaluation of Compounds of the Invention Following Intravenous and Oral Quantification in Mice, Rats, Dogs and Monkeys

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.

由实验可知，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很好的药代动力学性质，包括较好的吸收(AUC last)和好的口服生物利用度(F)。 It can be seen from the experiments that when the compounds provided by the present invention are administered intravenously or orally, the compounds of the present invention show good pharmacokinetic properties, including good absorption (AUC last ) and good oral biological properties. Utilization (F).

实施例C 本发明化合物对细胞增殖的抑制活性Example C Inhibitory activity of the compounds of the present invention on cell proliferation

实验方法：CTG方法检测化合物对细胞增殖的抑制活性。Experimental methods: CTG method was used to detect the inhibitory activity of compounds on cell proliferation.

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

表CForm C

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72小时。c Dosing: Take out the cell culture plate, add 10 μL/well of the above 10× concentration of the drug working solution to the corresponding wells of the cell culture plate, and incubate in a 37°C incubator for 72 hours.

4)读板检测4) plate reading detection

a化合物处理72小时后，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 compound treatment for 72 hours, the cell morphology was observed under an inverted microscope. The cells in the DMSO control wells were in normal growth state, 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10-20分钟。b Put the prepared CTG solution at room temperature to equilibrate for 10-20 minutes.

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20分钟。c Add 50 μL/well of CTG solution according to the CTG operating instructions, and place on a shaker to shake for 20 minutes 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IC 50值。 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 IC50 values were counted.

实验证明，本发明的化合物对KRAS G12C突变的NCI-358细胞具有较高的抑制活性。具体地，本发明的化合物对KRAS G12C突变的NCI-358细胞的抑制活性均小于1000nm；其中大部分化合物的IC 50小于500nm，优选的部分化合物的IC 50小于100nm，更优的部分化合物的IC 50小于50nm。其中，部分实施例化合物的抑制试验结果参见表3。 Experiments show that the compounds of the present invention have higher inhibitory activity on KRAS G12C mutant NCI-358 cells. Specifically, the inhibitory activities of the compounds of the present invention on KRAS G12C mutant NCI-358 cells are all less than 1000 nm; the IC 50 of most of the compounds is less than 500 nm, the IC 50 of the preferred partial compounds is less than 100 nm, and the IC 50 of some of the more excellent compounds is less than 100 nm. 50 is less than 50 nm. Among them, the inhibition test results of some example compounds are shown in Table 3.

表3 本发明部分实施例对细胞增殖的抑制活性实验数据Table 3 Experimental data on the inhibitory activity of some embodiments of the present invention on cell proliferation

Figure PCTCN2021138693-appb-000270
Figure PCTCN2021138693-appb-000270

实施例D 本发明化合物与KRAS4B-G12C蛋白的结合情况Example D Binding situation of the compound of the present invention and KRAS4B-G12C protein

实验方法：LC-MS法检测化合物与KRAS4B-G12C蛋白的结合情况。Experimental method: LC-MS method was used to detect the binding of compounds to KRAS4B-G12C protein.

实验步骤：Experimental steps:

1)实验缓冲液准备如表D所示1) Experimental buffer preparation is shown in Table D

表DForm D

Figure PCTCN2021138693-appb-000271
Figure PCTCN2021138693-appb-000271

2)将GDP载入KRAS-4B-G12C蛋白2) Load GDP into KRAS-4B-G12C protein

将KRAS-4B-G12C蛋白2倍稀释至103μM，取2mL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100μL/管，在液氮中迅速冷冻并保存于-80℃冰箱中。Dilute the KRAS-4B-G12C protein 2-fold to 103 μM, take 2 mL of protein and add 1 mL of 2×GDP loading buffer, mix gently, incubate at room temperature for 1.5 h, divide into 100 μL/tube, and place in liquid nitrogen Freeze quickly and store in -80°C freezer.

3)KRAS-4B-G12C分析3) KRAS-4B-G12C analysis

将下表E试剂混合Mix the following table E reagents

表ETable E

试剂reagent 用量Dosage GDP载入的KRAS-4B-G12C(20uM)GDP loaded KRAS-4B-G12C (20uM) 5uL5uL 化合物(10％的DMSO溶液)Compound (10% in DMSO) 5uL5uL 10×孵育缓冲液10x Incubation Buffer 5uL5uL 超纯水Ultra-pure water 35uL35uL 共计total 50uL50uL

4)常温下分别孵育30分钟及3小时4) Incubate at room temperature for 30 minutes and 3 hours respectively

5)加入5μL的5％甲酸终止反应5) Add 5 μL of 5% formic acid to stop the reaction

6)LC-MS检测6) LC-MS detection

上机前先将总共55μL的反应混合物，15000rpm离心10分钟。A total of 55 μL of the reaction mixture was centrifuged at 15,000 rpm for 10 minutes before loading.

7)计算Kras(G12C)结合率％7) Calculate the Kras(G12C) binding rate %

KRAS(G12C)结合率％＝复合物峰高/[复合物峰高+未与KRAS G12C结合峰高]×100KRAS(G12C) binding rate % = complex peak height / [complex peak height + peak height not bound to KRAS G12C] × 100

结果参见表4，表4为本发明部分实施例提供的化合物的蛋白结合1h实验结果。The results are shown in Table 4, and Table 4 is the experimental results of protein binding of the compounds provided in some examples of the present invention for 1 h.

表4 本发明部分实施例提供的化合物的蛋白结合实验结果Table 4 Results of protein binding experiments of compounds provided in some embodiments of the present invention

Figure PCTCN2021138693-appb-000272
Figure PCTCN2021138693-appb-000272

由实验可知，本发明化合物与KRAS4B-G12C蛋白结合率较高。It can be seen from the experiments that the compound of the present invention has a higher binding rate to KRAS4B-G12C protein.

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 (13)

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 PCTCN2021138693-appb-100001
Figure PCTCN2021138693-appb-100001
 其中：in: X为-L-X 1-，其中，L为键或NH，X 1为含氮原子的4-8元单环、5-12元稠环、5-12元螺环或5-12元桥环，所述4-8元单环、5-12元稠环、5-12元螺环和5-12元桥环可独立任选地被m个R x取代； X is -LX 1 -, wherein L is a bond or NH, X 1 is a 4-8-membered monocyclic ring, 5-12-membered condensed ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms, The 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spiro ring and 5-12-membered bridged ring can be independently optionally substituted with m R x ; Y为N或CH；Y is N or CH; 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 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、氧代、-C(＝O)OC 1-6烷基、C 1-6烷氨基、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(＝O)OC 1-6烷基、C 1-6烷氨基、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, oxo, -C(=O)OC 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocycle consisting of 3-8 atoms group, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms; wherein, the -C(=O)OC 1-6 alkyl group, C 1-6 alkylamino group, C 1-6 alkane group base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms Cyclic group, C 6-10 aryl group and heteroaryl group consisting of 5-10 atoms are 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 ; 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. 根据权利要求1所述的化合物，其中X为
Figure PCTCN2021138693-appb-100002
Figure PCTCN2021138693-appb-100003
The compound of claim 1, wherein X is
Figure PCTCN2021138693-appb-100002
Figure PCTCN2021138693-appb-100003
 根据权利要求1或2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 according to claim 1 or 2, wherein R a and R b are each independently hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl group, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy group independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl group, 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 ; 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。 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, 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-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 separated by 1, 2, 3, 4 or 5 independently is selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethyl oxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups. 根据权利要求1-3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 1-3, 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1-4所述的化合物，其中R 3为
Figure PCTCN2021138693-appb-100004
Figure PCTCN2021138693-appb-100005
Figure PCTCN2021138693-appb-100006
独立任选地被n个R y取代。 The compound of claims 1-4, wherein R is
Figure PCTCN2021138693-appb-100004
Figure PCTCN2021138693-appb-100005
Figure PCTCN2021138693-appb-100006
independently optionally substituted with n R ys . 根据权利要求1-5所述的化合物，其中各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 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。 The compound of claims 1-5, wherein each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4 alkyl, C2 -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 alkylamino, 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 substituted with hydroxyalkoxy groups. 根据权利要求1-6所述的化合物，其中各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。 The compound of claims 1-6, wherein each Rx 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, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, 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 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. 根据权利要求1-7所述的化合物，其中各R y独立地为氘、卤原子、羟基、氨基、硝基、氰基、氧代、-C(＝O)OC 1-4烷基、C 1-4烷氨基、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(＝O)OC 1-4烷基、C 1-4烷氨基、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。 The compound of claims 1-7, wherein each R is independently deuterium, halogen, hydroxyl, amino, nitro, cyano, oxo, -C( = O)OC 1-4 alkyl, C 1-4 alkylamino, 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, heterocyclic group composed of 3-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms; wherein, the -C(=O)OC 1-4 alkyl group, C 1-4 alkylamino, 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 selected from 1, 2, 3, 4, or 5 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. 根据权利要求1-8所述的化合物，其中各R y独立地为氘、氟、氯、溴、羟基、氨基、硝基、氰基、氧代、-C(＝O)OCH 3、二甲氨基、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。 The compound of claims 1-8, wherein each R is independently deuterium, fluorine, chlorine, bromine, hydroxy, amino, nitro, cyano, oxo, -C( = O) OCH3 , dimethyl Amino, 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 and triazolyl are independently optionally selected from 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH radicals replaced by the group. 一种化合物，其为具有下列之一结构的化合物或具有下列之一结构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 that is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of a compound having one of the following structures , a pharmaceutically acceptable salt or a prodrug thereof:
Figure PCTCN2021138693-appb-100007
Figure PCTCN2021138693-appb-100007
Figure PCTCN2021138693-appb-100008
Figure PCTCN2021138693-appb-100008
Figure PCTCN2021138693-appb-100009
Figure PCTCN2021138693-appb-100009
Figure PCTCN2021138693-appb-100010
Figure PCTCN2021138693-appb-100010
Figure PCTCN2021138693-appb-100011
Figure PCTCN2021138693-appb-100011
Figure PCTCN2021138693-appb-100012
Figure PCTCN2021138693-appb-100012
Figure PCTCN2021138693-appb-100013
Figure PCTCN2021138693-appb-100013
 一种药物组合物，包含权利要求1-10任意一项所述的化合物；和A pharmaceutical composition comprising the compound of any one of claims 1-10; and 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。The pharmaceutical composition optionally comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof. 权利要求1-10任意一项所述的化合物或者权利要求11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 1-10 or the pharmaceutical composition of claim 11 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12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 12, wherein the disease mediated by KRAS G12C is cancer; 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、阑尾癌、小肠癌、白血病或黑色素瘤。The cancers described are 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 cancer, colon cancer, appendix cancer, small bowel cancer, leukemia or melanoma.
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