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CN114644628A - Pyrimidone derivatives and their use in medicine - Google Patents

Pyrimidone derivatives and their use in medicine Download PDF

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CN114644628A
CN114644628A CN202111545576.2A CN202111545576A CN114644628A CN 114644628 A CN114644628 A CN 114644628A CN 202111545576 A CN202111545576 A CN 202111545576A CN 114644628 A CN114644628 A CN 114644628A
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isopropyl
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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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    • 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
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    • 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
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses pyrimidone derivatives and application thereof in medicines, and particularly relates to novel pyrimidone derivatives and a pharmaceutical composition containing the compounds. The invention also relates to methods for preparing said compounds and pharmaceutical compositions, and to the use thereof for the manufacture of a medicament for the treatment of diseases and/or conditions mediated by KRASG12C, in particular for the treatment of cancer.

Description

Pyrimidone derivatives and their use in medicine
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel compound serving as a KRAS activity inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in treating various diseases. More specifically, the compounds of the present invention may act as inhibitors of the activity or function of KRAS G12C.
Background
KRAS is a murine sarcoma virus gene, and there are three genes related to human tumors in the ras gene family-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. Among the RAS genes, KRAS has the greatest effect on human cancer, accounting for 86% of all RAS mutations, as if the molecular switch: when normal, the cell growth regulation path can be controlled; when abnormality occurs, the cells are caused to grow continuously and are prevented from self-destruction. It is involved in intracellular signal transmission, and when K-ras gene is mutated, the gene is permanently activated, and can not produce normal ras protein, so that intracellular signal conduction is disturbed, and cell proliferation is out of control and cancerated.
The G12C mutation is a common subtype in KRAS gene mutation, and refers to the mutation from No. 12 glycine to cysteine. The KRAS G12C mutation is most common in lung cancer, and the KRAS G12C mutation accounts for about 10% of all lung cancer patients according to data reported in the literature (Nat Rev Drug Discov 2014; 13: 828-851).
Currently, researchers have conducted some studies to find therapeutic agents that can effectively inhibit KRAS G12C mutant protein. PCT applications WO2014152588, WO2015054572, WO2016049524, WO2016164675, WO2016168540, WO2017015562, WO2017058915, WO2017058807, WO2017058792, WO2017058902, WO2017087528, WO2017201161, WO2018064510, WO2018068017, WO2018119183, WO2018140600, WO2018140512, WO2018143315, WO2018206539, WO2018217651, WO2018218070, WO2019051291, WO2019099524, WO2019110751, WO 2013791985, WO 2012019141250, WO 2019213513516 and WO 2022020050890 disclose small molecule compounds that are inhibitors of KRAS G12C mutant proteins for the prevention or treatment of cancer. However, there is still a need for more and better KRAS G12C mutein inhibitors in the clinic.
Disclosure of Invention
The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as an inhibitor of KRAS. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by inhibition of KRAS activity by said compounds. The invention further describes a synthetic method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound, which is a compound shown as formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as formula (I),
Figure BDA0003415708940000011
wherein:
x is-L-X1-, where L is a bond or NH, X1Is a 4-8 membered monocyclic ring, a 5-12 membered fused ring, a 5-12 membered spiro ring or a 5-12 membered bridged ring containing a nitrogen atom, and the 4-8 membered monocyclic ring, the 5-12 membered fused ring, the 5-12 membered spiro ring and the 5-12 membered bridged ring may be independently optionally substituted by m RxSubstitution;
y is N or CH;
z is N or CR2e；
R1is-C (═ O) -CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rcor-S (═ O)2-C≡C-Rc；
RaAnd RbEach independently is hydrogen, deuterium, a halogen atom, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Alkoxy, wherein, said C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxy is independently optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted by the radical hydroxyalkoxy;
Rcis hydrogen, deuterium, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino, 5-6 membered heteroaryl, C 3-6Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino, 5-6 membered heteroaryl, C3-6Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Hydroxyalkoxy and 3-6 membered heterocyclyl;
R3is C6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C6-12Aryl and 5-10 membered heteroaryl are independently optionally substituted by n RySubstitution;
R2a、R2b、R2c、R2dand R2eEach independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C 1-3Substituted with a hydroxyalkoxy group;
each RxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C3-8Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted by the radical hydroxyalkoxy;
each RyIndependently is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OC1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms; wherein, said-C (═ O) OC1-6Alkyl radical, C1-6Alkylamino radical、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkoxy, C 3-6Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C6-10Aryl and 5-10 atom consisting heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted with a hydroxyalkoxy group;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
n is 1, 2, 3, 4, 5, 6 or 7.
In some embodiments, X is
Figure BDA0003415708940000021
Figure BDA0003415708940000031
Wherein, said m and RxHave the meaning as described in the present invention.
In some embodiments, RaAnd RbEach independently hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH is substituted by a group;
RcIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2OH、-OCH2CH2OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl.
In some embodimentsIn the scheme, R3Is C6-10Aryl or 5-to 10-membered heteroaryl, wherein, said C6-10Aryl and 5-10 membered heteroaryl are independently optionally substituted by n RyAnd (4) substitution.
In some embodiments, R3Is composed of
Figure BDA0003415708940000032
Figure BDA0003415708940000033
Figure BDA0003415708940000034
Wherein, the
Figure BDA0003415708940000035
Figure BDA0003415708940000041
Figure BDA0003415708940000042
Independently optionally substituted by n RyAnd (4) substitution.
In some embodiments, R2a、R2b、R2c、R2dAnd R2eEach independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4An alkylamino group; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In some embodiments, R2a、R2b、R2c、R2dAnd R2eEach independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
In some embodiments, each R isxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylamino radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylamino radical, C3-6Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In some embodiments, each R isxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, 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 and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl are independently optionally substituted with 1, 2, 3, 4, or 5 independentlyIs selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy and-OCH 2OH and-OCH2CH2OH groups are substituted.
In some embodiments, each R isyIndependently is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OC1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms; wherein, said-C (═ O) OC1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl and heteroaryl of 5 to 6 atoms are independently optionally substituted by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In some embodiments, each R isyIndependently is deuterium, fluoro, chloro, bromo, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OCH3Dimethylamino, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or triazolyl; wherein, the methyl groupEthyl, n-propyl, isopropyl, t-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, -OCH2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl and triazolyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups are substituted.
In one aspect, the present invention relates to pharmaceutical compositions comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.
In one aspect, the present invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a subject.
In some embodiments, the KRAS G12C-mediated disease is cancer.
In some embodiments, the cancer of the invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, appendiceal cancer, small intestine cancer, leukemia, and melanoma.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can 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 documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may 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, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, 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.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, the articles are used herein to refer to articles of one or more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in embodiments of the described embodiments.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
"stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereoisomers" refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, e.g., the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or of mixtures thereof, for example racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms). The 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 group, the substituents of the cycloalkyl group may have cis or trans configuration.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (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)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
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 instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.
The term "substituted" means that one or more hydrogen atoms in a given structure is replaced with a particular substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein; when the number of the substituents is more than 1, the substituents may be the same or different from each other. For example, the "optionally substituted with 1, 2, 3, 4 or 5 groups selected from … …" according to the present invention, when the number of the substituents is more than 1, the substituents may be the same or different.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable, and should be understood in a broad sense, which means that the specific items expressed between the same symbols do not affect each other in different groups, or that the specific items expressed between the same symbols in the same groups do not affect each other.
In each part of this specification, substituents for the disclosed compounds are disclosed in terms of group type or range. It is specifically contemplated that each separate subcombination of the various members of these groups and ranges is encompassed by the invention. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In the present invention, "Cn1-n2"means that the group contains carbon atoms in the number of n1-n2, n1 and n2 are both natural numbers other than 0, and n2 is greater than n1, and the" n1-n2 "includes n1, n2 and any natural number therebetween. Such as C1-6Alkyl represents an alkyl group having 1 to 6 carbon atoms; c1-6Alkoxy represents an alkoxy group having 1 to 6 carbon atoms; c 3-6Carbocyclyl means carbocyclyl containing 3 to 6 carbon atoms.
In each of the sections of the present invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms and is represented by C1-6An alkyl group; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms and is represented by C1-4An alkyl group; in still other embodiments, the first and second electrodes are,the alkyl radical containing from 1 to 3 carbon atoms and being represented by C 1-3An alkyl group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms and is represented by C 2-6An alkenyl group; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms, represented as C2-4An alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) 1-propenyl (propenyl, -CH ═ CH-CH)3) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms and are represented by C2-6An alkynyl group; in still other embodiments, alkynyl groups contain 2-4 carbon atoms and are represented by C2-4An alkenyl group. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (propynyl, -C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms and is represented as C 1-6An alkoxy group; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms and is represented by C1-4An alkoxy group; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms and is represented as C1-3An alkoxy group. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl group and alkoxy group are specifically defined as described herein. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "hydroxyalkoxy" means that the alkoxy group is substituted with one or more hydroxy groups, examples of which include, but are not limited to, -OCH2OH、-OCH2CH2OH and the like.
The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic, fused carbobicyclic, and bridged carbobicyclic groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. 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.
The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein and refer to a mono-or polyvalent mono-, bi-or tricyclic ring system containing 3 to 14 ring atoms, wherein one or more atoms in the ring are independently replaced by a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but not one aromatic ring. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-8 membered ring monocyclic (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring system like SO, SO2，PO，PO2Or 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 with one or more oxygen atoms to give compounds like SO, SO2，PO，PO2The group of (1). In other embodiments, a "heterocycle",a "heterocyclyl" or "heterocyclic" group is a 3-to 6-membered ring monocyclic (2-4 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring system like SO, SO 2，PO，PO2The group of (ii). The heterocyclyl group is optionally substituted with one or more substituents described herein.
The heterocyclic group may be a carbon-based or heteroatom group; wherein, cyclic-CH2The group may optionally be replaced by-C (═ O) -, the sulfur atom of the ring may optionally be oxidized to S-oxide, and the nitrogen atom of the ring may optionally be oxidized to N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl
Figure BDA0003415708940000091
Radical, diaza
Figure BDA0003415708940000092
Radical, S-N-aza
Figure BDA0003415708940000093
Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH 2Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. Said heterocyclyl radical being optionally substituted by one or moreSubstituted by the substituents described in the invention.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
The term "heteroaryl" or "heteroaromatic ring" means a mono-, bi-or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, of mono-or polyvalent, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group of 5 to 10 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S and N; in other embodiments, the heteroaryl of 5 to 6 ring atoms is a monocyclic ring system and contains 1, 2, 3, or 4 heteroatoms independently selected from O, S and N.
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 (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), azaquinoline, imidazo [1,2-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, and the like.
The term "monocyclic ring containing nitrogen atoms" refers to a monocyclic ring of 4 to 8 ring atoms containing 1 or 2 nitrogen atoms, which ring may be fully saturated or contain one or more degrees of saturation, but no aromaticity. Examples of monocyclic rings containing nitrogen atoms include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like. The nitrogen atom containing monocyclic ring is optionally substituted with one or more substituents described herein.
The terms "fused bicyclic ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein and all refer to monovalent or multivalent saturated or partially unsaturated fused ring systems containing 5 to 12 ring atoms, said fused ring systems referring to non-aromatic bicyclic ring systems in which two rings share two adjacent carbon atoms. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon). The term "fused ring containing nitrogen atoms" means a fused ring containing 1 or 2 nitrogen atoms, and examples of the fused ring containing nitrogen atoms include, but are not limited to, octahydropyrrolo [3,4-c ] pyrrole and the like. The fused rings are optionally substituted with one or more substituents described herein.
The terms "spirocyclic", "spirobicyclic" or "spirobicyclic" are used interchangeably herein and refer to a monovalent or polyvalent saturated or partially unsaturated bicyclic ring system containing 5 to 12 ring atoms, one of which is derived from a specific ring carbon atom on the other ring. As shown in formula (a), ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spirocyclic" or "spirobicyclic", while ring B and ring B' are referred to as "fused bicyclic". Each ring in the spirobicyclic group may be a carbocyclic or heterocyclic group. The term "nitrogen atom-containing spiro ring" refers to a spiro ring containing 1 or 2 nitrogen atoms, and examples of nitrogen atom-containing spiro rings include, but are not limited to, 2, 7-diazaspiro [3.5] nonane, 2, 6-diazaspiro [3.3] heptane and the like. Said spiro ring being optionally substituted with one or more substituents as described herein.
Figure BDA0003415708940000101
The term "bridged ring" or "bridged ring group" denotes a saturated or partially unsaturated bridged ring system, relating to a non-aromatic bicyclic ring system, for example as shown in formula (b), i.e. ring A1 shares an alkane or a heteroalkane chain with ring A2, wherein each X3Independently optionally a carbon atom or a heteroatom, j is 1, 2, 3 or 4. Such systems contain 5 to 12 ring atoms and may contain independent or conjugated unsaturation, but do not contain aromatic or aromatic rings in their core structure (although aromatics may be substituents thereon). Wherein each ring, such as A1 or A2, contains 4 to 7 atoms, the term "nitrogen atom-containing bridged ring" refers to a bridged ring containing 1 or 2 nitrogen atoms, examples of which include, but are 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 BDA0003415708940000102
The terms "j-k ring atoms" or "j-k member" are used interchangeably herein to indicate that the cyclic group consists of j-k ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P. J and k are each independently any non-zero natural number, and k > j; the term "j-k" includes j, k and any natural number therebetween. For example, "3 to 8 atoms or 3 to 8 members", "3 to 6 atoms or 3 to 6 members", "5 to 10 atoms or 5 to 10 members" or "5 to 6 atoms or 5 to 6 members" means that the cyclic group consists of 3 to 8 (i.e., 3, 4, 5, 6, 7 or 8), 3 to 6 (i.e., 3, 4, 5 or 6), 5 to 10 (i.e., 5, 6, 7, 8, 9 or 10) or 5 to 6 (i.e., 5 or 6) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P. Specifically, for example, "heteroaryl group consisting of 5 to 10 ring atoms" or "5-to 10-membered heteroaryl group" represents a heteroaryl group consisting of 5, 6, 7, 8, 9 or 10 ring atoms, wherein 5, 6, 7, 8, 9 or 10 represents the number of ring atoms, such as pyridyl is a heteroaryl group consisting of 6 ring atoms or a 6-membered heteroaryl group.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R being a substituent as described herein).
The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C1-6Alkyl groups are attached to nitrogen atoms to form alkylamino groups. In other embodiments, the alkylamino group is substituted with one or two C1-3An alkyl-substituted amino group of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino) And the like), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like.
The term "aminoalkyl" includes C substituted with one or more amino groups1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups1-6Aminoalkyl groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
As described herein, the substituent (R)x)mThe ring system formed by a ring bound to the center represents m substituents RxSubstitutions may be made at any substitutable position or at any reasonable position on the ring in which it is placed. For example, formula d represents a G ring which may be substituted by m RxSubstituted, when m is greater than 1, each RxMay be independently selected from the same or different substituent groups.
Figure BDA0003415708940000111
The attachment point may be attached to the rest of the molecule at any point on the ring that is attachable, as described herein. For example, formula e represents the point of attachment at any possible attachment position on the C-ring or D-ring.
Figure BDA0003415708940000112
As described herein, the group X has a substructure with two attachment sites that can be connected to the rest of the molecule, and the attachment of the two attachment sites can be interchanged. For example, when X is
Figure BDA0003415708940000113
In the present invention, the general formula (I) represents X1Upper N connecting terminal connected to R1The other C connecting end is connected with the rest part of the general formula (I) and is shown as a formula f; or represents the C-link connection R on X1The other N connecting end is connected with the rest part of the general formula (I),
as shown in formula g.
Figure BDA0003415708940000114
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley &Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such 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. Aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable Pharmaceutical carriers are described in e.w. martin, "Remington's Pharmaceutical Sciences".
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound contains a hydroxy group, i.e., it can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, 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.
As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive pharmacologically acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming 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 obtained by other methods described in the literature above 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 through XII of the periodic table, and organic base salts such as salts with primary, secondary and tertiary amines.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates 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 of solvent molecules that is water.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as 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 moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or 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 both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I. isotopically enriched compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described herein using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
The term "cancer" as used herein refers to or describes a physiological condition in a patient that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancers include, but are not limited to, carcinomas (carcinoma), lymphomas, blastomas, sarcomas and leukemias, or lymphoproliferative disorders (lymphoids). More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung, and squamous carcinoma of the lung), esophageal cancer, cancer of the peritoneum, hepatocellular cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, hepatoma (hepatoma), breast cancer, colon cancer, rectal cancer, colorectal cancer, appendiceal cancer, small kidney, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or kidney (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma (renal carcinoma), anal cancer, penile carcinoma, and head and neck cancer.
The term "KRAS G12C inhibitor" as used herein refers to a substance which binds to and inhibits the activity of KRAS G12C.
Detailed description of the Compounds of the invention
The present invention provides a compound or a pharmaceutical composition thereof which is useful as an inhibitor of KRAS, particularly KRAS G12C. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by inhibiting the activity of KRAS G12C with said compounds. The invention further describes methods for synthesizing said compounds. The compounds of the invention show improved biological activity and pharmacokinetic properties.
In one aspect, the invention relates to a compound, which is a compound shown as formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as formula (I),
Figure BDA0003415708940000141
wherein each X, Y, Z, R1、R2a、R2b、R2c、R2dAnd R3All have the meaning described herein.
In some embodiments, X is-L-X1-, where L is a bond or NH, X1Is a 4-8 membered monocyclic ring, a 5-12 membered fused ring, a 5-12 membered spiro ring or a 5-12 membered bridged ring containing a nitrogen atom, and the 4-8 membered monocyclic ring, the 5-12 membered fused ring, the 5-12 membered spiro ring and the 5-12 membered bridged ring may be independently optionally substituted by m R xSubstitution; wherein R isxAnd m has the meaning described in the present invention. In the invention, the nitrogen atom-containing 4-8 membered monocyclic ring, 5-12 membered fused ring, 5-12 membered spiro ring or 5-12 membered bridged ring means that the monocyclic ring, the fused ring, the spiro ring and the bridged ring each independently contain 1 or 2 nitrogen atoms.
In other embodiments, X is
Figure BDA0003415708940000142
Figure BDA0003415708940000143
Wherein R isxAnd m has the meaning described in the present invention.
In some embodiments, Y is N or CH.
In some embodiments, Z is N or CR2e(ii) a Wherein R is2eHave the meaning as described in the present invention.
In some embodiments, R1is-C (═ O) -CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rcor-S (═ O)2-C≡C-Rc(ii) a Wherein R isa、RbAnd RcEach having the meaning described in the present invention.
In some embodiments, RaIs hydrogen, deuterium, halogen atom, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Alkoxy, wherein, said C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxy is independently optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, RaIs hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are independently optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2OH and-OCH2CH2OH groups are substituted.
In some embodiments, RbIs hydrogen, deuterium, halogen atom, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Alkoxy, wherein, said C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxy is independently optionally selected from 1, 2, 3, 4 or 5 independentlyDeuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, RbIs hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are independently optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
In some embodiments, RcIs hydrogen, deuterium, C1-6Alkyl radical, C 2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino, 5-6 membered heteroaryl, C3-6Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino, 5-6 membered heteroaryl, C3-6Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Hydroxyalkoxy and 3-6 membered heterocyclyl.
In other embodiments, RcIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF 2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH2OH、-OCH2CH2OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl.
In some embodiments, R3Is C6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C6-12Aryl and 5-10 membered heteroaryl are independently optionally substituted by n RySubstitution; wherein n is 1, 2, 3, 4, 5, 6 or 7, R yHave the meaning described in the present invention.
In other embodiments, R3Is C6-10Aryl or 5-to 10-membered heteroaryl, wherein, said C6-10Aryl and 5-10 membered heteroaryl are independently optionally substituted by n RySubstitution; n is 1, 2, 3, 4, 5, 6 or 7, wherein RyHave the meaning as described in the present invention.
In other embodiments, R3Is composed of
Figure BDA0003415708940000151
Figure BDA0003415708940000152
Figure BDA0003415708940000161
Figure BDA0003415708940000162
Wherein, the
Figure BDA0003415708940000163
Figure BDA0003415708940000164
Figure BDA0003415708940000165
Independently optionally substituted by n RySubstitution; wherein n is 1, 2, 3, 4, 5, 6 or 7, RyHave the meaning as described in the present invention.
In some embodiments, R2aIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2aIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4An alkylamino group; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2aIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2A methylamino group,Dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2OH and-OCH2CH2OH groups are substituted.
In some embodiments, R2bIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2bIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4An alkylamino group; wherein, theC1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C 1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2bIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
In some embodiments of the present invention, the substrate is,R2cis hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C 1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2cIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4An alkylamino group; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2cIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF 2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, iso-propoxypropoxy-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
In some embodiments, R2dIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2dIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4An alkylamino group; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2dIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF 2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, diFluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups are substituted.
In some embodiments, R2eIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2eIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4An alkylamino group; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, R2eIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2OH and-OCH2CH2OH groups are substituted.
In some embodiments, each R isxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C3-8Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, each R isxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylamino radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylamino radical, C3-6Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, each R isxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl and propargylAlkyl, propynyl, -CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2OH and-OCH2CH2OH groups are substituted.
In some embodiments, each R isyIndependently is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OC1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms; wherein, said-C (═ O) OC1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl and heteroaryl consisting of 5 to 10 atoms are independently optionally substituted by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, each R isyIndependently is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OC1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10Aryl or 5-6 atom heteroaryl; wherein said-C (═ O) OC1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl and heteroaryl of 5 to 6 atoms are independently optionally substituted by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In other embodiments, RyIs deuterium, fluorine, chlorine, bromine, hydroxyl, amino, nitro, cyano, oxo, -C (═ O) OCH3Dimethylamino, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl, or triazolyl; wherein, the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy and-OCH 2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidineIndependently optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
In other embodiments, each R isyIndependently is deuterium, fluoro, chloro, bromo, hydroxy, amino, nitro, cyano, oxo, methyl, methoxy, -C (═ O) OCH3Dimethylamino, methoxymethyl, or pyrazolyl.
In another aspect, the present invention relates to a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof, of a compound of one of the following, but is in no way limited to:
Figure BDA0003415708940000201
Figure BDA0003415708940000211
Figure BDA0003415708940000221
Figure BDA0003415708940000231
Figure BDA0003415708940000241
Figure BDA0003415708940000251
Figure BDA0003415708940000261
in another aspect, the present invention relates to a pharmaceutical composition comprising a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.
In another aspect, the present invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention, treatment or alleviation of a KRAS G12C mediated disease in a patient.
In some embodiments, the KRAS G12C-mediated disease is cancer.
In some embodiments, the cancer of the invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, appendiceal cancer, small intestine cancer, leukemia, and melanoma.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention
According to another aspect, the pharmaceutical compositions of the invention feature a compound of formula (I), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of compound in the pharmaceutical composition of the present invention is effective to treat or alleviate KRAS G12C mediated diseases in a subject.
The compounds of the invention exist in free form or, where appropriate, 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 adduct or derivative capable of being administered directly or indirectly to a patient in need thereof, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any solvent, diluent, or other liquid vehicle, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate 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-Ash 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicate that different carriers may be employed In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the present invention, e.g., any adverse biological effects that may result or interact in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.
Substances which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, 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 sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.
Preferably, the compounds are administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (referred to herein as pharmaceutical carriers) selected with regard to the form of administration and conventional pharmaceutical practice, which may be in the form of oral tablets, capsules, elixirs, syrups, and the like.
For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical composition may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and the like. Moreover, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture, as desired or necessary. 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 glycol, waxes and the like. 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 the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. 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 pharmaceutical arts. They may be administered separately, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.
The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or by the transdermal route using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered throughout the administration period is continuous rather than intermittent.
The compounds of the invention may also be administered in the form of liposome 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 phosphatidylcholines.
The compounds of the invention are also conjugated to soluble polymers that serve as drug carriers for targeting. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
The dosage regimen for a compound of the invention will vary depending upon a variety of factors known, such as the pharmacokinetic characteristics of the particular agent and its mode and route of administration; race, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent therapy; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make the decision and prescribe the effective amount of the drug to prevent, counter, or arrest the progress of the cancer.
In accordance with the general guidelines, daily oral dosages of each active ingredient are used in the range of about 0.001 to 1000mg/kg body weight in order to achieve the indicated effect. For intravenous administration, the most preferred dosage range during infusion at conventional rates is from about 1 to about 10mg/kg body weight/minute. The compounds of the present invention may be administered once daily, or may be administered in divided doses of two, three or four times daily.
Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1mg to about 1000mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be from about 0.5% to about 95% of the total weight of the pharmaceutical composition.
When the compounds of the present invention are administered with other therapeutic agents, generally, the amount of each component in a typical daily dose and a typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effect of the therapeutic agents when administered in combination.
The compound or the medicinal salt or the hydrate thereof can be effectively used for preventing, treating or relieving diseases mediated by KRAS G12C of patients, and particularly can be effectively used for treating lung cancer, lymphoma, esophagus cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, appendiceal cancer, small intestine cancer, leukemia, melanoma and the like.
General synthetic procedure
To describe the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples, but is provided only to practice the invention.
In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined herein. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the 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 modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius. 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, general reagents were purchased from Shantou Wen Long chemical plant, Guangdong Guanghua chemical plant, Guangzhou chemical plant, Tianjin Haoyu Chemicals Co., Ltd, Tianjin Shuchen chemical plant, Wuhan Xin Hua Yuan science and technology development Co., Ltd, Qingdao Tenglong chemical plant Co., Ltd, and Qingdao maritime chemical plant.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. Glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
1H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.1H NMR Spectrum in CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets), d (doublets), t (triplets), q (quatets), m (multiplets), br (broadpeds), br (broadpedsinglets), dd (doublets of doublets), dt (doublets of triplets). Coupling constant J, expressed in Hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following acronyms are used throughout the invention:
Figure BDA0003415708940000281
Figure BDA0003415708940000291
the following reaction scheme describes the steps for preparing the compounds of the present invention. Each X, Y, Z, R therein, unless otherwise stated2a、R2b、R2c、R2dAnd R3Having the definitions set out in the present invention.
Reaction scheme 1
Figure BDA0003415708940000292
Formula (A), (B) and15) The compounds shown can be prepared by reaction scheme 1: formula (A), (B) and1) The compound reacts with oxalyl chloride and ammonia water to obtain a compound shown in the formula (A)2) The compounds shown. Formula (A), (B) and2) A compound represented by the formula (I)3) A compound of the formula4) The compound shown in the formula (I) is reacted to obtain5) The compounds shown. Formula (A), (B) and5) The compound reacts under the action of bis (trimethylsilyl) amino potassium to obtain a compound shown in the formula (A)6) The compounds shown. Formula (A), (B) and6) The compound reacts under the action of phosphorus oxychloride to obtain a compound shown in a formula (A) 7) The compounds shown. Formula (A), (B)7) A compound represented by the formula (I) and8) The compound reacts under the action of N, N-diisopropylethylamine to obtain a compound shown in a formula (A), (B), (C)9) The compounds shown. Formula (A), (B)9) A compound of the formula10) The compound is shown in [1,1'- [1,1' -bis (diphenylphosphino) ferrocene]Reacting palladium dichloride dichloromethane complex with potassium acetate (or cesium carbonate) to obtain a compound shown in a formula (I)11) The compounds shown. Formula (A), (B) and11) The compound is prepared by reacting zinc cyanide, bis (tri-tert-butylphosphine) palladium and tri-tert-butylphosphine (or zinc cyanide and chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl ]]Palladium (II)) to obtain a compound of the formula (I)12) The compounds shown. Formula (A), (B) and12) The Boc of the compound is removed under the action of trifluoroacetic acid to obtain a compound of a formula (I)13) The compounds shown. Formula (A), (B) and13) A compound of the formula14) The compound is obtained by the formula (I) under the action of N, N-diisopropylethylamine15) The compounds shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example 14- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000301
First step synthesis of 2,5, 6-trichloronicotinamide
Figure BDA0003415708940000302
2,5, 6-trichloropyridine-3-carboxylic acid (5.0g,22mmol), dichloromethane (60.0mL) and N, N-dimethylformamide (0.05mL,0.6mmol) were added to a reaction flask, the temperature was reduced to 0 deg.C, oxalyl chloride (2.4mL,28mmol) was added dropwise, the reaction was stirred at 0 deg.C for 24h, a solution of ammonia in isopropanol (17.0mL,2.0mol/L,34mmol) was added, stirring was continued for 4h, suction filtration was carried out, the cake was washed with dichloromethane (50 mL. times.2), and the title compound was obtained as a white solid after drying (1.6g, yield 32.0%).
MS(ESI,pos.ion)m/z:224.9[M+H]+.
Second step synthesis of 2,5, 6-trichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide
Figure BDA0003415708940000303
2,5, 6-trichloronicotinamide (1.46g,6.48mmol) and tetrahydrofuran (10mL) were added to a reaction flask, warmed to 75 deg.C, oxalyl chloride (1.0g,7.9mmol) was added dropwise, the reaction was stirred at 75 deg.C for 1h, allowed to cool to room temperature, the solvent was removed by concentration, cooled to 0 deg.C, tetrahydrofuran (5mL) was added to dissolve, then a solution of 2-isopropyl-4-methyl-pyridin-3-amine (1.0g,6.7mmol) in tetrahydrofuran (5mL) was added dropwise, the reaction was stirred at 0 deg.C overnight, saturated ammonium chloride (10mL) was added and quenched, extracted three times with ethyl acetate (50 mL. times.3), the organic phases were combined and concentrated to give the title compound as a yellow solid (1.4g, yield 54.0%).
MS(ESI,pos.ion)m/z:401.0[M+H]+.
Step three, synthesizing 6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -diketone
Figure BDA0003415708940000304
The reaction flask was charged with 2,5, 6-trichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (1.4g,3.5mmol) and tetrahydrofuran (10.0mL), cooled to 0 ℃, dropwise added with a tetrahydrofuran solution of potassium bis (trimethylsilyl) amide (8.7mL,1mol/L,8.7mmol), stirred at room temperature overnight, quenched with saturated ammonium chloride (5mL), extracted with ethyl acetate (50mL), and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (300.6mg, 24.0% yield).
Fourth step Synthesis of 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003415708940000311
6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (200.0mg,0.5476mmol), N-diisopropylethylamine (0.6mL,4mmol) and acetonitrile (2.0mL) were added to a reaction flask, and dissolved with stirring, phosphorus oxychloride (0.3mL,3mmol) was added dropwise, the mixture was heated to reflux and stirred for reaction overnight, and the solvent was removed under reduced pressure to give the title compound as a brown oil (210.1mg, 100% yield).
Fifth step Synthesis of tert-butyl (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000312
A reaction flask was charged with 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2-one (525.0mg,1.368mmol), (3S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (411.1mg,2.053mmol), N-diisopropylethylamine (1.2mL,7.2mmol) and acetonitrile (6mL), warmed to 80 ℃, stirred for reaction overnight, concentrated to remove the solvent, and then purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (455.6mg, yield 60.8%).
MS(ESI,pos.ion)m/z:547.2[M+H]+.
Sixth step Synthesis of tert-butyl (3S) -4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000313
To a reaction flask were added tert-butyl (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (500.0mg,0.91mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (80.4mg,0.1mmol), potassium acetate (451.2mg,4.6mmol) and dioxane (18.0mL), the reaction was stirred at 90 ℃ for 10min under nitrogen protection, a solution of 2-fluoro-6-methoxy-phenylboronic acid (175.3mg,1.0mmol) in dioxane (2.0mL) was added, two drops of water were added, the reaction was continued for 7h, filtered, the filtrate evaporated to dryness under reduced pressure and then purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a yellow solid (190.0mg, yield 32.7%).
MS(ESI,pos.ion)m/z:637.2[M+H]+.
Seventh step Synthesis of tert-butyl (3S) -4- (6-cyano-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000321
To a microwave bottle were added in this order (3S) -4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -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 (170.0mg,0.27mmol), zinc cyanide (166.7mg,1.42mmol), N-dimethylformamide (5.0mL), bis (tri-tert-butylphosphine) palladium (160.5mg,0.31mmol) and tri-tert-butylphosphine (0.2mL), nitrogen gas was blown, the mixture was heated at 120 ℃ under microwave for 16 hours, the reaction mixture was filtered, ethyl acetate (200mL) was added to the filtrate, the mixture was stirred for 1min, and washed with saturated saline (20 mL. times.5), the organic phase was evaporated to dryness under reduced pressure to give the title compound as a white solid (80.0mg, yield 47.8%).
MS(ESI,pos.ion)m/z:628.3[M+H]+.
Eighth step Synthesis of 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
Figure BDA0003415708940000322
To a reaction flask were added in this order (3S) -4- (6-cyano-7- (2-fluoro-6-methoxyphenyl) -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 (40.0mg,0.06mmol), dichloromethane (3.0mL) and trifluoroacetic acid (0.3mL), and the reaction was stirred at room temperature for 2h, and the reaction solution was evaporated under reduced pressure to dryness to give the title compound as a colorless viscous liquid (31.7mg, yield 100.0%).
Ninth step Synthesis of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000323
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 (31.7mg,0.06mmol), dichloromethane (5.0mL) and triethylamine (25.6mg,0.25mmol) were added in this order to a reaction flask at-5 ℃, followed by acryloyl chloride (10.2mg,0.11mmol) and stirred at 5 ℃ for 20min, followed by silica gel powder spin-drying and column chromatography (ethyl acetate) to give the title compound as a white solid (18.0mg, yield 49.7%).
MS(ESI,pos.ion)m/z:582.2[M+H]+.
1H NMR(400MHz,CDCl3)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).
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 BDA0003415708940000331
Synthesis of first step tert-butyl (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
Figure BDA0003415708940000332
To a reaction flask were added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (403.1mg,0.7363mmol), 2-fluoro-5-methylbenzeneboronic acid (426.1mg,2.768mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (76.2mg,0.0933mmol), potassium acetate (118.7mg,1.209mmol) and dioxane (15.0mL), stirred at 90 ℃ for 3h, cooled to room temperature, evaporated to dryness under reduced pressure to give a brown solid, and saturated brine (30mL) was added, stirring for 10min, extraction with ethyl acetate (100mL × 3), combination of the organic phases, evaporation to dryness under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) gave the title compound as a yellow solid (378.7mg, yield 82.8%).
MS(ESI,pos.ion)m/z:621.1[M+H]+.
Second step Synthesis of tert-butyl (S) -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-methylpiperazine-1-carboxylate
Figure BDA0003415708940000341
To the microwave tube were added (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-carboxylic acid tert-butyl ester (101.5mg,0.1634mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (25.5mg,0.0324mmol), zinc cyanide (190.2mg,1.620mmol) and N, N-dimethylformamide (3.0mL), the reaction mixture was placed in a microwave reactor, warmed to 130 ℃ and reacted for 7 hours, saturated brine (10.0mL) was added, ethyl acetate was extracted (30.0mL × 3), the organic phase was evaporated to dryness under reduced pressure, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) was performed to purify the title compound as a yellow solid (63.4mg, yield 63.4%).
MS(ESI,pos.ion)m/z:612.3[M+H]+.
Third step Synthesis of (S) -7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000342
To a reaction flask was added (S) -tert-butyl 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-methylpiperazine-1-carboxylate (91.0mg,0.1430mmol), trifluoroacetic acid (0.5mL,7mmol) and dichloromethane (5.0mL), the reaction was stirred at room temperature for 1h, concentrated to dryness under reduced pressure to give the title compound as a brown solid after drying in vacuo (73.0mg, yield 100.0%).
The fourth step Synthesis of (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 BDA0003415708940000351
To a reaction flask were added (S) -7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (73.0mg,0.1430mmol), N-diisopropylethylamine (33.4mg,0.2584mmol) and dichloromethane (5mL), cooled to 0 ℃, a solution of acryloyl chloride (15.3mg,0.1690mmol) in dichloromethane (1mL) was slowly added dropwise, the reaction was stirred for 10 minutes, concentrated under reduced pressure to dryness, column chromatography (dichloromethane/methanol (v/v) ═ 20/1) was performed to give the title compound as a yellow solid (73.9mg, yield 91.6%).
MS(ESI,pos.ion)m/z:567.3[M+H]+.
1H NMR(400MHz,CDCl3)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).
13C NMR(151MHz,CDCl3)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.
Example 3(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000352
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000361
Adding (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (200mg,0.37mmol), 2-methoxy-4-fluorobenzeneboronic acid (70mg,0.4mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (61mg,0.073mmol), potassium acetate (190mg,1.8mmol) and dioxane (6mL) into a reaction flask, heating to 90 ℃, stirring for reaction for 3h, cooling to room temperature, evaporating the reaction solution under reduced pressure, purifying by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2:1), the title compound was obtained as a yellow solid (139mg, yield 60%).
MS(ESI,pos.ion)m/z:637.3[M+H]+.
1H NMR(400MHz,CDCl3)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).
Second step Synthesis of tert-butyl (S) -4- (6-cyano-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000362
To a microwave tube were added (S) -4- (6-chloro-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (139mg,0.22mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (45mg,0.056mmol), zinc cyanide (261mg,2.2mmol) and N, N-dimethylformamide (2mL), placed in a microwave reactor and allowed to warm to 130 ℃ for 8 hours, diluted with ethyl acetate (100mL), washed three times with water (5mL), the organic phase concentrated under reduced pressure to dryness, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a yellow solid (103mg, 75% yield).
MS(ESI,pos.ion)m/z:628.2[M+H]+.
The third step of Synthesis of (S) -7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000371
To a reaction flask was added (S) -tert-butyl 4- (6-cyano-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (103mg,0.16mmol), trifluoroacetic acid (1mL) and dichloromethane (2.0mL), the reaction was stirred at room temperature for 2h and concentrated to dryness under reduced pressure to give the title compound (257mg, yield 100%).
MS(ESI,pos.ion)m/z:528.7[M+H]+.
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000372
(S) -7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (257mg,0.4mmol), triethylamine (90mg, 0.88) and dichloromethane (2mL) were added to a reaction flask, the mixture was cooled to 0 ℃, acryloyl chloride (50mg,0.54mmol) was slowly added dropwise, the reaction was stirred at room temperature for 2 hours, the reaction solution was evaporated under reduced pressure, then, column chromatography (dichloromethane/methanol (v/v) ═ 200/1) was performed to obtain the title compound as a yellow solid (30mg, yield 13%).
MS(ESI,pos.ion)m/z:582.1[M+H]+.
1H NMR(400MHz,CDCl3)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).
Example 4(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000381
First step Synthesis of tert-butyl (S) -4- (6-chloro-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000382
To a reaction flask were added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (300mg,0.55mmol), 3-fluoro-2-methoxybenzeneboronic acid (93.2mg,0.55mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (44.8mg,0.055mmol), cesium carbonate (446.3mg,1.37mmol) and dioxane (10.0mL), warmed to 100 ℃ and stirred overnight, cooled to room temperature, the reaction was evaporated to dryness under reduced pressure, and column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) was performed, the title compound was obtained as a yellow solid (185.8mg, yield 53.2%).
MS(ESI,pos.ion)m/z:637.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyano-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000383
To a microwave tube were added (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-carboxylic acid tert-butyl ester (80.6mg,0.127mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (19.9mg,0.025mmol), zinc cyanide (149.3mg,1.27mmol), and N, N-dimethylformamide (2mL), placed in a microwave reactor and allowed to warm to 130 ℃ with stirring for 8 hours, diluted with ethyl acetate (100mL), washed three times with water (5mL), the organic phase evaporated to dryness under reduced pressure and then purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (79.4mg, 99% yield).
MS(ESI,pos.ion)m/z:628.3[M+H]+.
The third step of Synthesis of (S) -7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000391
To a reaction flask was added (S) -tert-butyl 4- (6-cyano-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (79.4mg,0.126mmol), trifluoroacetic acid (2mL) and dichloromethane (4.0mL), the reaction was stirred at room temperature for 2h, concentrated to dryness under reduced pressure, and dried under vacuum at room temperature overnight to give the title compound as a yellow liquid (66.7mg, yield 100%).
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000392
To a reaction flask were added (S) -7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (66.7mg,0.126mmol), DIPEA (200.5mg, 1.536mmol) and dichloromethane (4.0mL), the temperature was reduced to 0 ℃, a dichloromethane solution of acryloyl chloride (13.6mg,0.15mmol) was slowly added dropwise (2.0mL), the reaction was stirred at room temperature for 2 hours, the reaction solution was evaporated under reduced pressure, and then the title compound was purified by column chromatography (dichloromethane: methanol (v/v) ═ 20:1) to obtain a yellow solid (10.0mg, yield 13.7%).
MS(ESI,pos.ion)m/z:582.2[M+H]+.
1H NMR(400MHz,CDCl3)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).
Example 5(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -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 ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000401
First step synthesis of 5-bromo-1, 3-dimethylpyridin-2 (1H) -one
Figure BDA0003415708940000402
To a steel reactor was added 5-bromo-3-methylpyridin-2 (1H) -one (0.51g,2.69mmol), N, N-dimethylformamide (6.0mL), potassium tert-butoxide (0.65g,5.79mmol) and iodomethane (0.5mL,8 mmol). The reaction kettle is sealed and heated to 80 ℃ for reaction overnight. 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 give the title compound as a yellow liquid (0.41g, yield 75.9%).
MS(ESI,pos.ion)m/z:202.0[M+H]+.
Second step synthesis of 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one
Figure BDA0003415708940000403
To a reaction flask was added 5-bromo-1, 3-dimethylpyridin-2 (1H) -one (0.41g,2.04mmol), potassium acetate (0.71g,7.26mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.18g,0.22mmol), dioxane (15.0mL) and pinacol diborate (1.30g,5.10 mmol). The reaction system is heated to 85 ℃ under the protection of nitrogen and reacted overnight. After the reaction was complete, the reaction mixture was cooled to room temperature and dried by spinning 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 liquid (0.45g, yield 89.2%).
MS(ESI,pos.ion)m/z:250.0[M+H]+.
Third step Synthesis of tert-butyl (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-carboxylate
Figure BDA0003415708940000411
To a reaction flask was added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.24g,0.44mmol), 1, 3-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (0.11g,0.44mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (32mg,0.039mmol), dioxane (10.0mL) and cesium carbonate (0.33g,1.01 mmol). Heating the reaction system to 85 ℃ for reaction for 24 hours under the protection of nitrogen. After cooling to room temperature, water (50mL) was added, and the mixture was extracted with ethyl acetate (150 mL. times.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) ═ 10/1-0/1) to give the title compound as a yellow solid (70.0mg, yield 25.2%).
MS(ESI,pos.ion)m/z:634.3[M+H]+.
The fourth step Synthesis of tert-butyl (S) -4- (6-cyano-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-carboxylate
Figure BDA0003415708940000412
To the microwave tube was added (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-carboxylic acid tert-butyl ester (50mg,0.08mmol), XPhos Pd G2(12.5mg,0.016mmol), DMF (2.0mL) and zinc cyanide (0.10G,0.85 mmol). The reaction system is placed in a microwave reaction instrument and reacts for 8 hours at 130 ℃. Then cooled to room temperature and the system was spin dried under reduced pressure. To the residue were added water (10mL) and ethyl acetate (20mL) to separate the mixture. The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined and spin dried under reduced pressure to give the title compound as a yellow solid (49.6mg, yield 99.9%).
MS(ESI,pos.ion)m/z:525.2[M–Boc+H]+.
The fifth step Synthesis of (S) -7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000421
To a reaction flask were added (S) -tert-butyl 4- (6-cyano-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-carboxylate (49.6mg,0.079mmol), dichloromethane (4.0mL) and trifluoroacetic acid (2.0 mL). The reaction was reacted at room temperature for 2.5h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (42mg, yield 100%).
Sixth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -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 ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000422
To a bottle were added (S) -7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (42mg,0.079mmol), dichloromethane (2.0mL) and N, N-diisopropylethylamine (0.2mL,1.15 mmol). The reaction was cooled to 0 deg.C and a solution of acryloyl chloride (12.5mg,0.14mmol) in dichloromethane (2mL) was slowly added dropwise. After the dropwise addition, the system is kept warm and reacts for 2.5 h. Then, it was dried under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (26mg, yield 56.1%).
MS(ESI,pos.ion)m/z:579.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
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 BDA0003415708940000431
Synthesis of tert-butyl (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 in the first step
Figure BDA0003415708940000432
Sequentially adding (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle at room temperature]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50g, 0.91mmol), (2, 5-difluorophenyl) boronic acid (0.19g, 1.20mmol), potassium acetate (0.14g, 1.40mmol), Pd (dppf) Cl2DCM (0.08g,0.10 mmol). Under the protection of nitrogen, dioxane (10mL) was added, the mixture was purged with nitrogen again, and the mixture was heated to 90 ℃ for reaction for 14 hours. Cooling to room temperature, and spin-drying under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a yellow solid (0.52g, yield 91.6%).
MS(ESI,pos.ion)m/z:625.2[M+H]+.
Second step Synthesis of tert-butyl (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
Figure BDA0003415708940000433
To the microwave tube were added (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-carboxylic acid tert-butyl ester (0.15G, 0.24mmol), XPhos Pd G2(0.04G, 0.05mmol), zinc cyanide (0.29G, 2.46mmol) and anhydrous N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor and reacts for 8 hours at 136 ℃. 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 yellow solid (27mg, yield 18.3%).
MS(ESI,pos.ion)m/z:616.3[M+H]+；
Step three Synthesis of (S) -7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile trifluoroacetic acid salt
Figure BDA0003415708940000441
To the reaction flask were added (S) -tert-butyl 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 (27mg, 0.044mmol), dichloromethane (2mL) and trifluoroacetic acid (1 mL). The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow oil (28mg, yield 100%) which was used directly in the next reaction.
Fourth step Synthesis of (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 BDA0003415708940000442
To a reaction flask were added (S) -7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile trifluoroacetic acid salt (28mg, 0.044mmol), dichloromethane (2mL) and N, N-diisopropylethylamine (0.1mL,0.56mmol), while the system was cooled, acryloyl chloride (26mg,0.29mmol) was added dropwise. After the dropwise addition, the reaction system was reacted at room temperature for 0.5h, followed by spin-drying under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a beige solid (20mg, yield 80.1%).
MS(ESI,pos.ion)m/z:570.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 7 methyl (S) -3- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate
Figure BDA0003415708940000451
Synthesis of (S) -tert-butyl 4- (6-chloro-7- (2-fluoro-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 in the first step
Figure BDA0003415708940000452
To a reaction flask was added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.30g,0.55mmol), (2-fluoro-5- (methoxycarbonyl) phenyl) boronic acid (0.12g,0.6mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (91mg,0.11mmol), potassium acetate (283mg,2.7mmol) and dioxane (8 mL). The reaction system is heated to 90 ℃ for reaction for 3 h. Then cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 2/1) to give the title compound as a yellow solid (0.32g, yield 86%).
MS(ESI,pos.ion)m/z:665.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Second step Synthesis of tert-butyl (S) -4- (6-cyano-7- (2-fluoro-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
Figure BDA0003415708940000461
To a microwave bottle were added (S) -4- (6-chloro-7- (2-fluoro-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 (0.25g,0.38mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (0.10g,0.13mmol), zinc cyanide (0.45g,3.8mmol) and ultra dry N in this order, n-dimethylformamide (2 mL). The reaction system is placed in a microwave reactor and heated to 130 ℃ for reaction for 8 h. Then cooled to room temperature, ethyl acetate (20mL) was added, and the mixture was washed with water (5 mL. times.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 give the title compound as a yellow solid (80mg, yield 32%).
MS(ESI,pos.ion)m/z:656.3[M+H]+；
Step three Synthesis of methyl (S) -3- (6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate trifluoroacetate
Figure BDA0003415708940000462
Adding (S) -4- (6-cyano-7- (2-fluoro-5- (methoxycarbonyl) phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] to the reaction flask]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (80mg,0.12mmol), trifluoroacetic acid (2mL) and dichloromethane (4 mL). The reaction was allowed to react at room temperature for 2h and then dried by spinning under reduced pressure to give the title compound as a yellow viscous semisolid (82mg, yield 100%). MS (ESI, pos. ion) M/z 556.2[ M + H ] ]+；
The fourth step Synthesis of methyl (S) -3- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate
Figure BDA0003415708940000471
To a reaction flask was added (S) -methyl 3- (6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate trifluoroacetate (82mg,0.12mmol), triethylamine (0.14g, 1.38mmol) and dichloromethane (4.0mL). the system was cooled to 0 ℃, acryloyl chloride (40mg,0.43mmol) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 2 hours, and then is decompressed and dried. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 200/1) to give the title compound as a yellow solid (7mg, yield 9.4%).
MS(ESI,pos.ion)m/z:610.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
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 BDA0003415708940000472
First step Synthesis of tert-butyl (S) -4- (6-chloro-7- (2-hydroxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000481
To a bottle was added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.50g,0.91mmol), (2-hydroxy-3-methylphenyl) boronic acid (0.42g,2.77mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (81mg,0.10mmol), potassium acetate (0.12g,1.21mmol) and dioxane (15.0 mL). The reaction system is heated to 90 ℃ under the protection of nitrogen for reaction for 3 hours. Then cooled to room temperature and spin dried under reduced pressure. Saturated brine (30mL) was added to the residue, and the mixture was stirred for 10min, extracted with ethyl acetate (30 mL. times.3), and 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 give the title compound as a yellow solid (0.51mg, yield 90.3%).
MS(ESI,pos.ion)m/z:620.1[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-chloro-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
Figure BDA0003415708940000482
To a reaction flask were added (S) -tert-butyl 4- (6-chloro-7- (2-hydroxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.40g,0.64mmol), potassium hydroxide (0.19g,3.39mmol) and iodomethane (0.3mL,5.0 mmol). The reaction system was reacted at room temperature for 3 hours. Then, saturated brine (10.0mL) was added thereto, and the mixture was extracted with ethyl acetate (30 mL. times.3). The organic phases were combined and spin-dried 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 give the title compound as a yellow solid (0.36g, yield 86.8%).
MS(ESI,pos.ion)m/z:634.3[M+H]+；
Third step Synthesis of tert-butyl (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
Figure BDA0003415708940000491
To the microwave tube were added (S) -4- (6-chloro-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-carboxylic acid tert-butyl ester (0.10g,0.16mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (41mg,0.05mmol), zinc cyanide (0.20g,1.71mmol) and ultra-dry DMF (2.0 mL). The reaction system is placed in a microblog reactor, the temperature is raised to 130 ℃, and the reaction is carried out for 7 hours. After cooling to room temperature, saturated brine (10.0mL) was added and the mixture was extracted with ethyl acetate (30.0 mL. times.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 give the title compound as a yellow solid (46mg, yield 45.8%).
MS(ESI,pos.ion)m/z:624.3[M+H]+；
Fourth step Synthesis of (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000492
To the reaction flask was added (S) -tert-butyl 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 (46mg,0.07mmol), trifluoroacetic acid (0.1mL,1mmol) and dichloromethane (3.0 mL). The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (38.4mg, yield 100%) which was used directly in the next step.
MS(ESI,pos.ion)m/z:524.3[M+H]+；
The fifth step Synthesis of (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 BDA0003415708940000501
To the reaction flask were added (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (38.4mg,0.07mmol), N, N-diisopropylethylamine (0.1mL, 0.56mmol) and dichloromethane (3.0 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (0.1mL,0.6mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 10 minutes, and then is subjected to reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (40mg, yield 95.6%).
MS(ESI,pos.ion)m/z:578.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 9 methyl (S) -3- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4- (dimethylamino) benzoate
Figure BDA0003415708940000502
Synthesis of tert-butyl (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 in the first step
Figure BDA0003415708940000511
To the microwave tube were added (S) -4- (6-chloro-7- (2-fluoro-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 (0.25g,0.38mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (100mg,0.13mmol), zinc cyanide (454mg,3.8mmol) and extra dry N, n-dimethylformamide (2 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 130 ℃, and the reaction is carried out for 8 hours. Then cooled to room temperature, ethyl acetate (100mL) was added, and the mixture was washed with water (5 mL. times.3). The organic phase was spun down under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 2/1) to give the title compound as a yellow solid (0.16g, yield 63%).
MS(ESI,pos.ion)m/z:681.4[M+H]+.
Second step Synthesis of methyl (S) -3- (6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4- (dimethylamino) benzoate
Figure BDA0003415708940000512
To the reaction flask was added (S) -tert-butyl 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 (85mg,0.12mmol), trifluoroacetic acid (1mL) and dichloromethane (2 mL). The reaction was reacted at room temperature for 2h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (73mg, yield 100%) which was used directly in the next reaction.
Third step Synthesis of methyl (S) -3- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4- (dimethylamino) benzoate
Figure BDA0003415708940000521
To a reaction flask was added methyl (S) -3- (6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4- (dimethylamino) benzoate (73mg,0.12mmol), triethylamine (0.15g, 1.48mmol) and dichloromethane (4.0 mL). The system was cooled to 0 ℃ and acryloyl chloride (40mg,0.43mmol) was slowly added dropwise. After the addition was completed, the reaction was reacted at room temperature for 2h, followed by spin-drying under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 200/1) to give the title compound as a yellow solid (11mg, yield 13.8%).
MS(ESI,pos.ion)m/z:635.3[M+H]+；
1H NMR(400MHz,CDCl3)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)
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 BDA0003415708940000522
Synthesis of first step tert-butyl (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
Figure BDA0003415708940000531
To a reaction flask were added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.51g,0.93mmol), (8-methylnaphthalen-1-yl) boronic acid (0.26g,1.40mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (77.1mg,0.09mmol), sodium carbonate (0.13g,1.23mmol) and dioxane (10.0 mL). The reaction system is heated to 90 ℃ for reaction for 3 h. Then cooled to room temperature and spin dried under reduced pressure. To the residue was added saturated brine (30mL), and the mixture was stirred for 10min and extracted with ethyl acetate (100 mL. times.3). The organic phases were combined, spun dry under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow solid (0.40g, 65.2% yield).
MS(ESI,pos.ion)m/z:653.4[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyano-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
Figure BDA0003415708940000532
To a microwave tube was added (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-carboxylic acid tert-butyl ester (0.11mg,0.16mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (0.12g,0.16mmol), zinc cyanide (0.20g,1.71mmol) and extra dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 130 ℃, and the reaction is carried out for 7 hours. Then, the mixture was cooled to room temperature, and saturated brine (10.0mL) was added thereto, followed by extraction with ethyl acetate (30.0 mL. times.3). The organic phases were combined, spun dry under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow solid (46mg, yield 44.3%).
MS(ESI,pos.ion)m/z:644.3[M+H]+；
The third step of Synthesis of (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -7- (8-methylnaphthalen-1-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000541
To a reaction flask was added (S) -tert-butyl 4- (6-cyano-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 (62mg,0.10mmol), trifluoroacetic acid (0.1mL) and dichloromethane (5.0 mL). The reaction was allowed to react at room temperature for 1h, then spin-dried under reduced pressure to give the title compound as a brown solid (52mg, yield 100%).
MS(ESI,pos.ion)m/z:544.3[M+H]+；
The fourth step (S) -Synthesis of 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 BDA0003415708940000542
To the reaction flask were added (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -7- (8-methylnaphthalen-1-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (52mg,0.10mmol), N, N-diisopropylethylamine (0.3mL, 1.68mmol) and dichloromethane (5 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (0.1mL,0.1mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the system is subjected to heat preservation reaction for 10min, and then is subjected to reduced pressure spin drying. The residue was subjected to silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (50mg, yield 87.0%).
MS(ESI,pos.ion)m/z:598.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
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 BDA0003415708940000551
Synthesis of tert-butyl (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 in the first step
Figure BDA0003415708940000552
To a reaction flask was added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50g,0.91mmol), (2-methoxyphenyl) boronic acid (0.15g,1.01mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (75mg,0.09mmol), potassium carbonate (0.43g,4.30mmol) and dioxane (10.0 mL). The reaction system is heated to 100 ℃ for reaction for 24 h. Then cooled to room temperature and spin-dried under reduced pressure. Water (30mL) was added to the residue, and the mixture was stirred for 10min and extracted with ethyl acetate (100 mL. times.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) ═ 1/0-0/1) to give the title compound as a yellow solid (0.42g, yield 74.4%).
MS(ESI,pos.ion)m/z:619.4[M+H]+；
Second Synthesis of tert-butyl (S) -4- (6-cyano-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
Figure BDA0003415708940000561
To the microwave tube were added (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-carboxylic acid tert-butyl ester (0.17g,0.27mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (54mg,0.067mm ol), zinc cyanide (0.32g,2.7mmol) and ultra-dry N, N-dimethylformamide (2 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 130 ℃, and the reaction is carried out for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL) and washed with water (5 mL. times.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 give the title compound as a yellow solid (74mg, yield 45%).
MS(ESI,pos.ion)m/z:610.3[M+H]+；
The third step is the synthesis of (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000562
To the reaction flask was added (S) -tert-butyl 4- (6-cyano-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 (80mg,0.13mmol), trifluoroacetic acid (1mL) and dichloromethane (2 mL). The reaction was reacted at room temperature for 1.5h, followed by spin-drying under reduced pressure to give the title compound as a brown solid (67mg, yield 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:510.2[M+H]+；
Fourth step Synthesis of (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 BDA0003415708940000571
To the reaction flask were added (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (67mg,0.13mmol), triethylamine (0.12g,1.2mmol) and dichloromethane (2 mL). The system was cooled to 0 ℃ and acryloyl chloride (40mg,0.43mmol) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 3 hours. And (5) after the reaction is completed, carrying out decompression and spin-drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 200/1) to give the title compound as a yellow solid (25mg, yield 33.7%).
MS(ESI,pos.ion)m/z:564.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 12(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000572
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000581
To a reaction flask was added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.20g,0.37mmol), (2-fluorophenyl) boronic acid (0.15g,1.10mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (30.3mg,0.04mmol), potassium acetate (71.4mg,0.73mmol) and dioxane (10.0 mL). Adding the mixture to 90 ℃ for reaction for 3 hours under the protection of nitrogen in the reaction system. Then cooled to room temperature and spin-dried under reduced pressure. The residue was added with saturated brine (30mL), stirred for 10min, and extracted with ethyl acetate (30 mL. times.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 give the title compound as a yellow solid (0.22g, yield 99.6%).
MS(ESI,pos.ion)m/z:608.3[M+H]+；
Second step Synthesis of tert-butyl (S) -4- (6-cyano-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000582
To the microwave tube were added (S) -tert-butyl 4- (6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.10mg,0.17mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (72.3mg,0.10mmol), zinc cyanide (0.20g,1.71mmol) and anhydrous DMF (2.0 mL). The reaction system is placed in a microwave reactor, and the temperature is raised to 130 ℃ for reaction for 7 hours. Then cooled to room temperature and spin-dried under reduced pressure. The residue was added with saturated brine (10.0mL) and extracted with ethyl acetate (30.0 mL. times.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 give the title compound as a yellow solid (54mg, yield 54.5%).
MS(ESI,pos.ion)m/z:598.3[M+H]+.
Third step Synthesis of (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 BDA0003415708940000591
Adding (S) -4- (6-cyano-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] to the reaction flask ]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (54mg,0.09mmol), trifluoroacetic acid (0.1mL) and dichloromethane (3.0 mL). The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (45mg, yield 100%) which was used directly in the next step. MS (ESI, pos.ion) M/z 498.2[ M + H ]]+；
Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile as a fourth step
Figure BDA0003415708940000592
To the reaction flask were added (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 (45mg,0.09mmol), N-diisopropylethylamine (34mg, 0.26mmol) and dichloromethane (3.0 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (16.7mg,0.19mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 10min, and then is subjected to reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (31mg, yield 61.7%).
MS(ESI,pos.ion)m/z:552.2[M+H]+；
1H NMR(400MHz,CDCl3)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)；
19F NMR(376MHz,CDCl3)δ(ppm)-112.48(s).
Example 134- (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 BDA0003415708940000601
Synthesis of tert-butyl 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 in the first step
Figure BDA0003415708940000602
To the reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.53g,1.37mmol), tert-butyl 2, 7-diazaspiro [4.4] nonane-2-carboxylate (0.31g,1.37mmol), anhydrous acetonitrile (10mL) and N, N-diisopropylethylamine (1.1mL,6.32mmol) in that order. The reaction system is heated to 55 ℃ for reaction for 3.5h under the protection of nitrogen. After the raw materials are reacted, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow solid (0.60g, yield 76.1%).
MS(ESI,pos.ion)m/z:573.2[M+H]+；
Second step Synthesis of tert-butyl 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
Figure BDA0003415708940000611
To the reaction flask were added tert-butyl 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 (0.15g, 0.26mmol), (2-methoxyphenyl) boronic acid (48mg, 0.32mmol), 1, 4-dioxane (5mL) and potassium acetate (39mg, 0.40mmol) in that order. Under the protection of nitrogen, add [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (25mg, 0.03 mmol). The reaction was heated to 90 ℃ 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 give the title compound as a yellow solid (0.16g, yield 94.8%).
MS(ESI,pos.ion)m/z:645.3[M+H]+；
Step three Synthesis of tert-butyl 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
Figure BDA0003415708940000612
To the microwave tube were added in this order 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-carboxylic acid tert-butyl ester (0.10g, 0.16mmol), bis (tri-tert-butylphosphine) palladium (42mg, 0.08mmol), zinc cyanide (56mg, 0.47mmol), tri-tert-butylphosphine (96mg, 0.47mmol, 10% N-hexane solution) and anhydrous N, N-dimethylformamide (5 mL). And after the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, heating to 138 ℃, reacting for 1h, then cooling to room temperature, and carrying out reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a white solid (34mg, yield 33.8%).
MS(ESI,pos.ion)m/z:636.3[M+H]+；
Fourth step Synthesis of 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
Figure BDA0003415708940000621
To a reaction flask was added tert-butyl 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 (34mg, 0.05mmol), dichloromethane (2mL) and trifluoroacetic acid (1 mL). The reaction was reacted at room temperature for 30min, followed by spin-drying under reduced pressure to give the title compound as a yellow oil (29mg, yield 100%) which was used directly in the next reaction.
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 BDA0003415708940000622
To the reaction flask were added 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 (35mg, 0.05mmol), dichloromethane (3mL) and N, N-diisopropylethylamine (0.1mL, 0.57mmol) in that order. The system was cooled to 0 ℃ and acryloyl chloride (30mg, 0.33mmol) was added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 1h, and then is dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 60/1) to give the title compound (27mg, yield 85.6%).
MS(ESI,pos.ion)m/z:590.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 144- (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 BDA0003415708940000631
Synthesis of tert-butyl 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 in the first step
Figure BDA0003415708940000632
To the reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.21g, 0.55mmol), tert-butyl 2, 7-diazaspiro [3.5] nonane-2-carboxylate (0.13g, 0.55mmol), anhydrous acetonitrile (10mL) and N, N-diisopropylethylamine (0.5mL,3mmol) in that order. The reaction system was heated to 55 ℃ under nitrogen protection for overnight reaction. After the raw materials are reacted, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow solid (0.25g, yield 78.4%).
MS(ESI,pos.ion)m/z:573.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Second step Synthesis of tert-butyl 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
Figure BDA0003415708940000641
To the reaction flask were added tert-butyl 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 (0.10g, 0.17mmol), (2-methoxyphenyl) boronic acid (32mg, 0.21mmol), 1, 4-dioxane (5mL) and potassium acetate (27mg, 0.28mmol) in that order. Under the protection of nitrogen, add [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (16mg, 0.02 mmol). The reaction system is heated to 90 ℃ for reaction for 7.5h, then cooled to room temperature, and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (0.11g, yield 98.7%).
MS(ESI,pos.ion)m/z:645.4[M+H]+；
Third step Synthesis of tert-butyl 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
Figure BDA0003415708940000642
To the microwave tube were added 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-carboxylic acid tert-butyl ester (74mg, 0.11mmol), bis (tri-tert-butylphosphine) palladium (59mg, 0.12mmol), zinc cyanide (67mg, 0.58mmol), tri-tert-butylphosphine (0.69g, 0.34mmol, 10% N-hexane solution) and anhydrous N, N-dimethylformamide (4mL) in that order. And after the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, heating to 130 ℃, reacting for 4 hours, then cooling to room temperature, and carrying out reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a white solid (45mg, yield 61.7%).
MS(ESI,pos.ion)m/z:636.3[M+H]+.
Fourth step Synthesis of 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
Figure BDA0003415708940000651
To a reaction flask was added tert-butyl 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 (45mg, 0.07mmol), dichloromethane (2mL) and trifluoroacetic acid (1 mL). The reaction was reacted at room temperature for 45min, followed by spin-drying under reduced pressure to give the title compound as a yellow oil (29mg, 100%) which was used directly in the next reaction. The reaction was stirred at room temperature for about 45min and distilled under reduced pressure to give a yellow oil (38mg, yield 100%) which was used directly in the next reaction.
Fifth step Synthesis of 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 BDA0003415708940000652
To the reaction flask were added 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 (38mg, 0.07mmol), dichloromethane (3mL) and N, N-diisopropylethylamine (0.1mL, 0.57mmol) in that order. The system was cooled to 0 ℃ and acryloyl chloride (32mg, 0.35mmol) was slowly added dropwise. After the dropwise addition, the reaction system is transferred to room temperature for reaction for 1.5h, and then is dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 60/1) to give the title compound as a white solid (27mg, yield 64.7%).
MS(ESI,pos.ion)m/z:590.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 154- (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 BDA0003415708940000661
Synthesis of tert-butyl 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 in the first step
Figure BDA0003415708940000662
To the reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.32g,0.82mmol), tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (0.18g,0.83mmol), anhydrous acetonitrile (10mL) and N, N-diisopropylethylamine (0.7mL,4.02mmol) in that order. Heating the reaction system to 55 ℃ for reaction for 4h under the protection of nitrogen. After the raw materials are reacted, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow solid (0.28g, yield 61.8%).
MS(ESI,pos.ion)m/z:559.2[M+H]+；
Second step Synthesis of tert-butyl 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
Figure BDA0003415708940000663
Adding 5- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle in sequence ]Pyrimidin-4-yl) hexahydropyrrolo [3,4-c ] compounds]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (0.10g, 0.18mmol), (2-methoxyphenyl) boronic acid (35mg, 0.23mmol), 1, 4-dioxane (5mL) and potassium acetate (30mg, 0.31 mmol). Under the protection of nitrogen, adding [1,1'- [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (17mg, 0.02 mmol). The reaction was heated to 90 ℃ for overnight reaction, then cooled to room temperature and spun dry under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (0.11g, yield 97.5%). MS (ESI, pos. ion) M/z 631.3[ M + H ]]+；
Step three Synthesis of tert-butyl 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
Figure BDA0003415708940000671
To the microwave tube were added, in order, 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) -carboxylic acid tert-butyl ester (0.11g, 0.18mmol), bis (tri-tert-butylphosphine) palladium (46mg, 0.09mmol), zinc cyanide (66mg, 0.56mmol), tri-tert-butylphosphine (0.17g, 0.08mmol, 10% in N-hexane) and anhydrous N, N-dimethylformamide (4 mL). And after the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, heating to 140 ℃ for reaction for 3 hours, then cooling to room temperature, and carrying out reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (94mg, yield 86.8%).
MS(ESI,pos.ion)m/z:622.3[M+H]+；
The fourth step Synthesis of 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
Figure BDA0003415708940000672
To a reaction flask was added 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) -carboxylic acid tert-butyl ester (94mg,0.15mmol), dichloromethane (2mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 30min, followed by distillation under reduced pressure to give the title compound as a yellow oil (79mg, yield 99.9%) which was used directly in the next reaction.
Fifth step Synthesis of 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 BDA0003415708940000681
To the reaction flask were added 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 (79mg, 0.15mmol), dichloromethane (3mL) and N, N-diisopropylethylamine (0.1mL, 0.57mmol) in that order. The system was cooled to 0 ℃ and acryloyl chloride (30mg, 0.33mmol) was slowly added dropwise. After the dropwise addition, the reaction system is transferred to room temperature for reaction for 1.5h, and then is dried by spinning 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 (25mg, yield 28.8%).
MS(ESI,pos.ion)m/z:576.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 16(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazoline-6-carbonitrile
Figure BDA0003415708940000682
First step synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate
Figure BDA0003415708940000683
To the reaction flask were added methyl 4-amino-2-fluorobenzoate (5.00g,29.60mmol) and chloroform (90 mL). The system was cooled to 0 ℃ and N-bromosuccinimide (5.26g,29.60mmol) was added thereto in portions. After the addition was completed, the reaction system was transferred to room temperature for overnight reaction. After completion of the starting material, ethyl acetate (100mL) was added and washed with water (50 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 10/1) to give the title compound as a white solid (4.00g, yield 54.6%).
MS(ESI,pos.ion)m/z:248.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.03(d,J＝7.4Hz,1H),6.45(d,J＝12.2Hz,1H),4.63(s,2H),3.87(s,3H).
Second step synthesis of methyl 5-bromo-2-fluoro-4-iodobenzoate
Figure BDA0003415708940000691
To the reaction flask was added methyl 4-amino-5-bromo-2-fluorobenzoate (0.23g,0.93mmol) and acetone (5 mL). The system was cooled to 0 ℃ and hydrochloric acid (1.5mL,9.0mmol,6.00mol/L) was added dropwise thereto, and after stirring for 10min with heat preservation, an aqueous solution of sodium nitrite (0.4mL,1.4mmol,3.5mol/L) was slowly added dropwise. After the dripping is finished, the reaction system is kept at the temperature for reaction for 1 hour. An aqueous solution of potassium iodide (0.5mL,1.75mmol,3.5mol/L) was then slowly added dropwise to the above system. After the dripping is finished, the reaction system is subjected to heat preservation reaction for 2 hours. After the starting material had reacted completely, saturated sodium thiosulfate (30mL) was added and extracted with ethyl acetate (30 mL. times.2). The combined organic phases were washed with brine (60mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 20/1) to give the title compound as a white solid (0.24g, yield 73.6%). MS (ESI, pos. ion) M/z 358.8[ M + H ] ]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.13(d,J＝6.9Hz,1H),7.68(d,J＝9.6Hz,1H),3.93(s,3H).
The third step is the synthesis of 5-bromo-2-fluoro-4-iodobenzoic acid
Figure BDA0003415708940000692
To the reaction flask were added methyl 5-bromo-2-fluoro-4-iodobenzoate (9.37g,26.1mmol), tetrahydrofuran (20mL), methanol (100mL), water (20mL) and lithium hydroxide monohydrate (4.45g,0.11mol) in that order. The reaction system was reacted at room temperature for 30 min. And after the raw materials are completely reacted, carrying out reduced pressure spin drying. To the residue was added water (100mL), the system was adjusted to pH 4 with citric acid solid, stirred for 30min, and filtered. The filter cake was washed with water (100mL) and dried under vacuum at 60 ℃ for 12h to give the title compound as a white solid (9.00g, 100% yield).
MS(ESI,pos.ion)m/z:344.8[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm)8.02(d,J＝7.0Hz,1H),7.96(d,J＝10.0Hz,1H).
The fourth step is the synthesis of 5-bromo-2-fluoro-4-iodobenzamide
Figure BDA0003415708940000701
To a reaction flask were added 5-bromo-2-fluoro-4-iodobenzoic acid (9.00g,26.1mmol) and thionyl chloride (50.0 mL). The reaction system is heated to 80 ℃ for reaction for 4h, then cooled to room temperature, and dried by spinning under reduced pressure. Anhydrous dioxane (50mL) was added to the residue. To the above mixture was slowly added dropwise ammonia (5.0mL, 28%). After the completion of the dropwise addition, the system was reacted at room temperature for 20min, and then water (50.0mL) and ethyl acetate (50.0mL) were added to separate the solution. The aqueous phase was extracted with ethyl acetate (50.0 mL). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. To the residue was added a mixture of ethyl acetate and petroleum ether (120mL, v/v. 1/10), and the mixture was stirred at room temperature for 1 hour and filtered. The filter cake was dried under vacuum at 60 ℃ for 12h to give the title compound as an off-white solid (7.30g, 81.3% yield).
MS(ESI,pos.ion)m/z:343.8[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.30(d,J＝7.5Hz,1H),7.67(d,J＝10.6Hz,1H),6.59(s,1H),6.25(s,1H).
The fifth step of synthesis of 5-bromo-2-fluoro-4-iodo-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) benzamide
Figure BDA0003415708940000702
To a reaction flask was added 5-bromo-2-fluoro-4-iodobenzamide (6.98g,20.30mmol), tetrahydrofuran (50mL) and oxalyl chloride (4.38g,34.51 mmol). The reaction system is heated to 75 ℃ for reaction for 3h, then cooled to room temperature, and dried by spinning under reduced pressure. Tetrahydrofuran (40mL) was added to the residue, and 2-isopropyl-4-methylpyridin-3-amine (3.20g,21.32mmol) was added dropwise thereto. After the addition, the reaction system was reacted at room temperature for 30min and filtered. The filtrate was rotary 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 (7.84g, yield 74.3%).
MS(ESI,pos.ion)m/z:519.9[M+H]+；
1H NMR(400MHz,DMSO-d6)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).
The sixth step of synthesis of 6-bromo-7-iodo-1- (2-isopropyl-4-methylpyridin-3-yl) quinazoline-2, 4(1H,3H) -dione
Figure BDA0003415708940000703
To the reaction flask was added 5-bromo-2-fluoro-4-iodo-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) benzamide (7.84g,15.10mmol) and tetrahydrofuran (110 mL). The system was cooled to-20 ℃ and KHMDS (33.2mL,33.2mmol,1.0M) was slowly added dropwise. After the dropwise addition, the reaction system was transferred to room temperature for 5 hours. It was again cooled to-20 ℃ and supplemented with KHMDS (4.5mL,4.5mmol, 1.0M). After the dropwise addition, the reaction system was transferred to room temperature for overnight reaction. After completion of the reaction, the reaction was quenched by addition of water (50mL) and 10% aqueous citric acid (50mL), and extracted with ethyl acetate (120 mL. times.3). The organic phases were combined, washed with brine (200mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give the title compound as a white solid (6.83g, yield 90.6%) which was used in the next step.
MS(ESI,pos.ion)m/z:499.9[M+H]+；
1H NMR(400MHz,DMSO-d6)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).
The seventh step is the synthesis of 6-bromo-4-chloro-7-iodo-1- (2-isopropyl-4-methylpyridin-3-yl) quinazolin-2 (1H) -one
Figure BDA0003415708940000711
To the reaction flask were added 6-bromo-7-iodo-1- (2-isopropyl-4-methylpyridin-3-yl) quinazoline-2, 4(1H,3H) -dione (2.00g,4.00mmol), acetonitrile (30mL), N, N-diisopropylethylamine (2.8mL,16.00mmol), and phosphorus oxychloride (2.45g,16.00mmol) in that order. The reaction was heated to 80 ℃ for 5h, then cooled to room temperature and spun dry under reduced pressure to give the title compound as a yellow solid (2.07g, 100% yield) which was used directly in the next reaction.
Eighth step Synthesis of tert-butyl (S) -4- (6-bromo-7-iodo-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000712
To the reaction flask were added 6-bromo-4-chloro-7-iodo-1- (2-isopropyl-4-methylpyridin-3-yl) quinazolin-2 (1H) -one (2.07g,3.99mmol), acetonitrile (30mL), N-diisopropylethylamine (1.03g,7.97mmol), and tert-butyl (S) -3-methylpiperazine-1-carboxylate (0.80g,3.99mmol) in that order. The reaction system is heated to 80 ℃ for reaction for 2 h. After the reaction of the starting materials was completed, the reaction mixture was cooled to room temperature, and ethyl acetate (50mL) and water (50mL) were added thereto for liquid separation. The aqueous phase was extracted with ethyl acetate (100 mL. times.2). All organic phases were combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, 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 pale yellow solid (1.84g, yield 67.6%).
MS(ESI,pos.ion)m/z:682.1[M+H]+；
1H NMR(400MHz,DMSO-d6)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).
Ninth step Synthesis of tert-butyl (S) -4- (6-bromo-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000721
To the reaction flask were added (S) -tert-butyl 4- (6-bromo-7-iodo-1- (4-isopropyl-2-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -3-methylpiperazine-1-carboxylate (0.80g,1.17mmol), (2-fluorophenyl) boronic acid (0.16g,1.17mmol), tetrakis (triphenylphosphine) palladium (67mg,0.06mmol), aqueous sodium carbonate solution (2.5mL,5.0mmol,2.0M) and 1, 4-dioxane (16mL) in that order. The reaction system is heated to 60 ℃ under the protection of nitrogen for reaction overnight. 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 (0.40g, yield 52.4%).
MS(ESI,pos.ion)m/z:650.2[M+H]+；
Tenth step Synthesis of tert-butyl (S) -4- (6-cyano-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940000722
To the microwave tube were added (S) -4- (6-bromo-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.30g,0.46mmol), zinc cyanide (0.54g,4.61mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (72mg,0.09mmol), N-dimethylformamide (3mL) in this order. Placing the reaction system in a microwave reactor under the protection of nitrogen, and heating to 120 ℃ for reaction for 7 h. 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 give the title compound as a light brown solid (90mg, yield 32.7%).
MS(ESI,pos.ion)m/z:597.3[M+H]+.
The eleventh step Synthesis of (S) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydroquinazoline-6-carbonitrile
Figure BDA0003415708940000731
To the reaction flask were added (S) -4- (6-cyano-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (90mg,0.15mmol), DCM (3mL) and trifluoroacetic acid (1mL) in that order. The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (75mg, yield 100%) which was used directly in the next step.
MS(ESI,pos.ion)m/z:497.2[M+H]+；
The twelfth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazoline-6-carbonitrile
Figure BDA0003415708940000732
To the reaction flask were added (S) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydroquinazoline-6-carbonitrile (75mg,0.15mmol), dichloromethane (3mL) and triethylamine (45mg,0.44 mmol). The system was cooled to-10 ℃ and acryloyl chloride (20mg,0.22mmol) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 30min, and then is subjected to reduced pressure spin drying. 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 (41mg, yield 49.2%).
MS(ESI,pos.ion)m/z:551.3[M+H]+；
1H NMR(400MHz,DMSO-d6)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-d6)δ(ppm)-115.65(s),-115.72(s).
Example 174- ((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
example 184- ((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 BDA0003415708940000741
Synthesis of tert-butyl (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 in the first step
Figure BDA0003415708940000742
To a reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (1.05g,2.88mmol), (2R,5S) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.62g,2.90mmol), acetonitrile (30mL) and DIPEA (1.81g,14.00 mmol). The reaction system is heated to 55 ℃ for reaction for 2 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. Water (50mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL. times.3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and 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 (1.51g, yield 98.3%).
MS(ESI,pos.ion)m/z:561.3[M+H]+；
Second step Synthesis of tert-butyl (2R,5S) -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) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940000751
To a reaction flask was added (2R,5S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyridine [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.37g,0.66mmol), (2-fluoro-5-methylphenyl) boronic acid (0.30g,1.98mmol), (1, 1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.11g,0.13mmol), potassium acetate (0.13mg,1.32mmol), and dioxane (10.0 mL). The reaction system is heated to 90 ℃ for reaction for 3 h. Then cooled to room temperature and spin-dried under reduced pressure. The residue was added with saturated brine (30mL), stirred for 10min, and extracted with ethyl acetate (100 mL. times.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 give the title compound as a yellow solid (0.34g, yield 80.6%).
MS(ESI,pos.ion)m/z:635.3[M+H]+.
Third step Synthesis of tert-butyl (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
Figure BDA0003415708940000752
To the microwave tube were added (2R,5S) -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) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.13g,0.20mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (80mg,0.10mmol), zinc cyanide (0.25g,2.13mmol) and extra dry N, n-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 130 ℃, and the reaction is carried out for 7 hours. Then, the mixture was cooled to room temperature, and saturated brine (10.0mL) was added to the mixture to extract the mixture with ethyl acetate (30.0 mL. times.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 give the title compound as a yellow solid (76mg, yield 61.4%).
MS(ESI,pos.ion)m/z:626.4[M+H]+.
Fourth step Synthesis of 4- ((2S,5R) -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
Figure BDA0003415708940000761
To the reaction flask were added (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-carboxylic acid tert-butyl ester (49.5mg,0.08mmol), trifluoroacetic acid (0.1mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After the starting material had reacted to completion, it was spin-dried under reduced pressure to give the title compound as a brown solid (42mg, yield 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:526.3[M+H]+；
Fifth step Synthesis of 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
Figure BDA0003415708940000762
To a reaction flask were added 4- ((2S,5R) -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 (42mg,0.08mmol), N-diisopropylethylamine (16mg, 0.13mmol) and dichloromethane (3mL), the system was cooled to 0 ℃, and a solution of acryloyl chloride (8.3mg,0.09mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 10min, and then is subjected to reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (24mg, yield 53.4%).
MS(ESI,pos.ion)m/z:580.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)8.56(d,J＝4.9Hz,1H),8.36(s,1H),7.30-7.27(m,1H),7.14(d,J＝4.9Hz,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,CDCl3)δ(ppm)-117.88.
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 BDA0003415708940000771
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 ]Synthesis of pyrimidine-6-carbonitrile (atropisomer 2)
Figure BDA0003415708940000772
Mixing 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 (1.0g,1.7mmol) was resolved on a chiral column (Dacellosolve AD-H chiral column, 10mm X250 mm,5 μm, 20% isopropanol/CO)28mL/min) to yield the desired compound atropisomer 1 as a yellow solid (0.30g, yield 30%) and the desired compound atropisomer 2 as a yellow solid (0.17g, yield 17%).
Example 17 atropisomer 1:
MS(ESI,pos.ion)m/z:580.5[M+H]+；
1H NMR(400MHz,DMSO-d6)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).
example 18 atropisomer 2:
MS(ESI,pos.ion)m/z:580.5[M+H]+；
1H NMR(400MHz,DMSO-d6)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).
example 194- (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 BDA0003415708940000781
Synthesis of tert-butyl 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 in the first step
Figure BDA0003415708940000782
To the reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.21g, 0.55mmol), tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate (0.11g, 0.56mmol), anhydrous acetonitrile (5.0mL) and N, N-diisopropylethylamine (0.5mL,2.87mmol) in that order. The reaction system is heated to 55 ℃ for reaction for 4.5h, then cooled to room temperature, and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow solid (0.11g, yield 36.8%).
MS(ESI,pos.ion)m/z:545.2[M+H]+；
Second Synthesis of tert-butyl 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
Figure BDA0003415708940000791
To the reaction flask were added tert-butyl 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 (0.11g, 0.20mmol), (2-methoxyphenyl) boronic acid (36mg, 0.24mmol), 1, 4-dioxane (5.0mL) and potassium acetate (32mg, 0.33mmol) in that order. Under nitrogen protection of the system, a [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (19mg, 0.02mmol) was added. The reaction system is heated to 90 ℃ for reaction for 5h, then cooled to room temperature, and dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (96mg, yield 77.2%).
MS(ESI,pos.ion)m/z:617.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Third step Synthesis of tert-butyl 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
Figure BDA0003415708940000792
To the microwave tube were added, in order, 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-carboxylic acid tert-butyl ester (96mg,0.16mmol), bis (tri-tert-butylphosphine) palladium (86mg,0.17mmol), zinc cyanide (92mg,0.78mmol), tri-tert-butylphosphine (0.45g, 0.22mmol, 10% N-hexane solution) and anhydrous N, N-dimethylformamide (4 mL). After the nitrogen replacement of the reaction system, placing the reaction system in a microwave reactor, and heating to 130 ℃ for reaction for 5 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a white solid (31mg, yield 32.8%).
MS(ESI,pos.ion)m/z:608.3[M+H]+；
Synthesis of 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 as a fourth step
Figure BDA0003415708940000801
To a reaction flask was added tert-butyl 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 (31mg, 0.05mmol), dichloromethane (2mL) and trifluoroacetic acid (1 mL). The reaction system was reacted at room temperature for 45 min. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a yellow oil (26mg, yield 100%) which was used directly in the next reaction.
Fifth step Synthesis of 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 BDA0003415708940000802
To the reaction flask were added 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 (26mg,0.05mmol), dichloromethane (3mL) and N, N-diisopropylethylamine (0.1mL,0.57mmol) in that order. The system was cooled to 0 ℃ and acryloyl chloride (26mg,0.28mmol) was slowly added dropwise. After the dropwise addition, the reaction system is transferred to room temperature for reaction for 1 hour, and then is decompressed and dried. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 60/1) to give the title compound as an off-white solid (17mg, yield 59.3%).
MS(ESI,pos.ion)m/z:562.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 207- (2-fluoro-6-methoxyphenyl) -4- ((S) -4- (2-fluoropropenyl) -2-methylpiperazin-1-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000811
First step Synthesis of 7- (2-fluoro-6-methoxyphenyl) -4- ((S) -4- (2-fluoropropenyl) -2-methylpiperazin-1-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000812
To a reaction flask was added 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,0.65mmol), HATU (0.24g,0.61mmol), triethylamine (0.10g,0.61mmol) and extra dry N, N-dimethylformamide (3 mL). The reaction was allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100mL) 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 (9mg, yield 5%).
MS(ESI,pos.ion)m/z:600.3[M+H]+.
Example 214- (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 BDA0003415708940000821
Synthesis of tert-butyl 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 in the first step
Figure BDA0003415708940000822
To a reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.53g,1.38mmol), tert-butyl 2, 5-diazabicyclo [2.2.2] octane-2-carboxylate (0.29g,1.38mmol), acetonitrile (15.0mL) and N, N-diisopropylethylamine (0.8mL,4.59 mmol). The reaction system is heated to 55 ℃ for reaction for 1.5 h. After completion of the reaction of the starting materials, the reaction mixture was cooled to room temperature, and saturated brine (30mL) was added thereto, followed by extraction with ethyl acetate (20 mL. times.3). The combined organic phases were 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 (0.33g, yield 43.2%).
MS(ESI,pos.ion)m/z:559.2[M+H]+.
Second Synthesis of tert-butyl 5- (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) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate
Figure BDA0003415708940000823
Adding 5- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle ]Pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester (0.33g,0.60mmol), (2-fluoro-5-methylphenyl) boronic acid (0.28g,1.79mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (0.10g,0.12mmol), potassium acetate (0.11g,1.20mmol) and dioxane (10.0 mL). The reaction system is heated to 90 ℃ for reaction for 3 h. Then cooled to room temperature and spin-dried under reduced pressure. The residue was added with saturated brine (10mL) and extracted with ethyl acetate (10 mL. times.3). The combined organic phases were 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 (0.32g, yield 84.6%). MS (ESI, pos. ion) M/z 633.3[ M + H ]]+.
Third step Synthesis of tert-butyl 5- (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-diazabicyclo [2.2.2] octane-2-carboxylate
Figure BDA0003415708940000831
To the microwave tube was added tert-butyl 5- (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) -2, 5-diazabicyclo [2.2.2] octane-2-carboxylate (0.20g,0.31mmol), bis (tri-tert-butylphosphine) palladium (0.16g,0.32mmol), tri-tert-butylphosphine (2.4mL,1.0mmol), zinc cyanide (0.37g,3.20mmol) and ultra-dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10.0mL) was added to the reaction mixture to extract the mixture with ethyl acetate (30.0 mL. times.3). The combined organic phases were 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 (80mg, yield 40.9%).
MS(ESI,pos.ion)m/z:624.3[M+H]+.
Fourth step Synthesis of 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
Figure BDA0003415708940000832
To a reaction flask was added tert-butyl 5- (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-diazabicyclo [2.2.2] octane-2-carboxylate (80mg,0.13mmol), trifluoroacetic acid (0.1mL,1.0mmol) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a brown solid (70mg, yield 100%).
MS(ESI,pos.ion)m/z:524.3[M+H]+.
Fifth step Synthesis of 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 BDA0003415708940000841
To a reaction flask was added 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 (70mg,0.13mmol), N, N-diisopropylethylamine (25.3mg, 0.20mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (12.2mg,0.14mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 10 min. Then decompression and spin-drying are carried out. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (72mg, yield 97.3%).
MS(ESI,pos.ion)m/z:578.3[M+H]+；
1H NMR(400MHz,CDCl3)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,CDCl3)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；
19F NMR(376MHz,CDCl3)δ(ppm)-75.60.
Example 22(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (2,3, 4-trifluorophenyl) -1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000851
Synthesis of first step tert-butyl (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
Figure BDA0003415708940000852
To a reaction flask was added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.30g,0.55mmol), (2,3, 4-trifluorophenyl) boronic acid (0.15g,0.84mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (91mg,0.11mmol), potassium acetate (0.29g,2.8mmol) and dioxane (8 mL). The reaction system is added to 90 ℃ to react for 4 h. 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 (0.30g, yield 85%).
MS(ESI,pos.ion)m/z:643.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Second step Synthesis of tert-butyl (S) -4- (6-cyano-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
Figure BDA0003415708940000861
To the microwave tube were added (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-carboxylic acid tert-butyl ester (0.29g,0.45mmol), bis (tri-tert-butylphosphine) palladium (0.12g,0.23mmol), 10% tri-tert-butylphosphine in n-hexane (0.92g,0.45mmol), zinc cyanide (542mg,4.5mmol) and ultra-dry dimethyl sulfoxide (6 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 130 ℃, and the reaction is carried out for 8 hours. After the reaction was completed, ethyl acetate (100mL) was added for dilution, and the mixture was washed with water (12 mL. times.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 (0.17g, yield 60%).
MS(ESI,pos.ion)m/z:634.3[M+H]+；
Third step Synthesis of (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-7- (2,3, 4-trifluorophenyl) -1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000862
To the reaction flask was added (S) -tert-butyl 4- (6-cyano-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 (0.17g,0.27mmol), trifluoroacetic acid (3mL) and dichloromethane (6 mL). The reaction system is reacted for 2 hours at normal temperature. Then, spin-dried under reduced pressure to give the title compound as a yellow semisolid (0.14g, 97.8% yield) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:534.2[M+H]+；
The fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (2,3, 4-trifluorophenyl) -1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000871
Adding (S) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-7- (2,3, 4-trifluorophenyl) -1, 2-dihydropyrido [2,3-d ] to a reaction flask]Pyrimidine-6-carbonitrile (0.14g,0.26mmol), triethylamine (0.28g, 2.77mmol) and dichloromethane (6 mL). The system was cooled to 0 ℃ and acryloyl chloride (80mg,0.87mmol) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 3 hours, and then is dried by spinning 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 (6mg, yield 3.9%). MS (ESI, pos. ion) M/z 588.2[ M + H ]]+；
Example 234- (3-acryloyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000872
Synthesis of tert-butyl 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 in the first step
Figure BDA0003415708940000873
To a reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.52g,1.37mmol), tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (0.29g,1.37mmol), acetonitrile (20.0mL) and N, N-diisopropylethylamine (0.7mL,4.02 mmol). The reaction system is heated to 55 ℃ for reaction for 1.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (30mL) was added to the reaction mixture to extract the mixture with ethyl acetate (20 mL. times.3). The combined organic phases were 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 (0.58g, yield 75.4%).
MS(ESI,pos.ion)m/z:559.2[M+H]+.
Second step Synthesis of tert-butyl 8- (6-chloro-7- (2-fluorophenyl) -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
Figure BDA0003415708940000881
To a reaction flask was added tert-butyl 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 (0.58g,1.03mmol), (2-fluorophenyl) boronic acid (0.55g,3.93mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.17g,0.21mmol), potassium acetate (0.41g,4.20mmol) and dioxane (10.0 mL). The reaction system is heated to 90 ℃ for reaction for 3 h. Then cooled to room temperature and spin-dried under reduced pressure. To the residue was added saturated brine (10mL), and the mixture was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were 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 (0.56g, yield 88.0%).
MS(ESI,pos.ion)m/z:620.2[M+H]+；
Third step Synthesis of tert-butyl 8- (6-cyano-7- (2-fluorophenyl) -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
Figure BDA0003415708940000891
To the microwave tube was added tert-butyl 8- (6-chloro-7- (2-fluorophenyl) -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 (0.11g,0.18mmol), bis (tri-tert-butylphosphine) palladium (0.11g,0.22mmol), tri-tert-butylphosphine (0.36g,0.18mmol, 10%), zinc cyanide (0.25g,2.15mmol) and ultra-dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10.0mL) was added to the reaction mixture to extract the mixture with ethyl acetate (15.0 mL. times.3). The combined organic phases were 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 (83mg, yield 74.9%).
MS(ESI,pos.ion)m/z:610.3[M+H]+；
Fourth step Synthesis of 4- (3, 8-diazabicyclo [3.2.1] octan-8-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000892
To the reaction flask was added tert-butyl 8- (6-cyano-7- (2-fluorophenyl) -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 (83mg,0.14mmol), trifluoroacetic acid (0.2mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a brown solid (70mg, yield 100%).
MS(ESI,pos.ion)m/z:510.3[M+H]+.
Fifth step Synthesis of 4- (3-acryloyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000901
To the reaction flask was added 4- (3, 8-diazabicyclo [3.2.1] octan-8-yl) -7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (70mg,0.14mmol), N, N-diisopropylethylamine (55.6mg, 0.43mmol) and dichloromethane (3 mL). The reaction was cooled to 0 deg.C and a solution of acryloyl chloride (26mg,0.29mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 10 min. Then decompression and spin-drying are carried out. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (48mg, yield 63.0%).
MS(ESI,pos.ion)m/z:564.2[M+H]+；
1H NMR(400MHz,CDCl3)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)；
19F NMR(376MHz,CDCl3)δ(ppm)-112.5.
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 BDA0003415708940000902
Synthesis of first step tert-butyl (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
Figure BDA0003415708940000911
To a reaction flask were added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.20g,0.37mmol), (3-fluoro-2-methylphenyl) boronic acid (0.11g,0.74mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (60mg,0.08mmol), potassium acetate (90mg,0.89mmol), 1, 4-dioxane (10mL) and water (0.2 mL). Heating the reaction system to 95 ℃ under the protection of nitrogen, and reacting for 6 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. Water (50mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL. times.3). The organic phases were combined, washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and 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-green solid (0.23g, yield 100%).
MS(ESI,pos.ion)m/z:621.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyano-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
Figure BDA0003415708940000912
Adding (S) -4- (6-chloro-7- (3-fluoro-2-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) to a microwave tube ) -2-oxo-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.23g,0.37mmol), zinc cyanide (0.42g,3.63mmol), bis (tri-tert-butylphosphine) palladium (0.74g,0.36mmol), tri-tert-butylphosphine in N-hexane (10%, 0.5mL) and ultra-dry N, N-dimethylformamide (2.0 mL). The reaction system is placed in a microwave reactor and heated to 135 ℃ for reaction for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was rotary dried under reduced pressure. The residue was purified (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow solid (90mg, yield 39.9%). MS (ESI, pos. ion) M/z 612.3[ M + H ]]+.
The third step is the synthesis of (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 BDA0003415708940000921
To a reaction flask was added tert-butyl (S) -4- (6-cyano-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 (90mg,0.15mmol) and dichloromethane (15 mL). Trifluoroacetic acid (0.11mL,1.50mmol) was added dropwise thereto at room temperature. After the dropwise addition, the reaction system reacts for 3 hours at room temperature, and then is dried by spinning under reduced pressure. To the residue were added dichloromethane (15mL) and DIPEA (30mg,0.23 mmol). The system was cooled to 0 ℃ and acryloyl chloride (20mg, 0.19mmol) was slowly added dropwise. After the addition, the reaction system chamber is reacted for 2 hours at room temperature. After the reaction was completed, the system was washed with water (20mL), dried over anhydrous sodium sulfate, filtered, and 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 (25mg, yield 31.3%).
MS(ESI,pos.ion)m/z:566.2[M+H]+；
1H NMR(400MHz,CDCl3)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)；
19F NMR(376MHz,CDCl3)δ-114.21,-115.65.
Example 254- (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 BDA0003415708940000922
Synthesis of (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate in the first step
Figure BDA0003415708940000931
To a reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.32g,0.84mmol), tert-butyl 4, 7-diazaspiro [2.5] octane-7-carboxylate (0.18g,0.86mmol), acetonitrile (20.0mL) and N, N-diisopropylethylamine (0.4mL,2.30 mmol). The reaction system is heated to 55 ℃ for reaction for 1.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (30mL) was added to the reaction mixture to extract the mixture with ethyl acetate (20 mL. times.3). The combined organic phases were 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 (0.45g, yield 95.3%).
MS(ESI,pos.ion)m/z:559.2[M+H]+.
Second step Synthesis of tert-butyl 4- (6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate
Figure BDA0003415708940000932
To a reaction flask was added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate (0.25g,0.45mmol), (2-fluorophenyl) boronic acid (0.19g,1.35mmol), (1, 1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (75mg,0.09mmol), potassium carbonate (0.19g,1.34mmol), and dioxane (10.0 mL). The reaction system is heated to 100 ℃, and after 10min, the mixed solution of water (0.1mL) and dioxane (0.5mL) is added, and the system is kept warm and continues to react for 3 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. To the residue was added saturated brine (10mL), and the mixture was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary 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 (96mg, yield 34.8%).
MS(ESI,pos.ion)m/z:620.1[M+H]+.
Step three, Synthesis of tert-butyl 4- (6-cyano-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate
Figure BDA0003415708940000941
To the microwave tube was added 4- (6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylic acid tert-butyl ester (96mg,0.16mmol), bis (tri-tert-butylphosphine) palladium (0.24g,0.47mmol), tri-tert-butylphosphine (0.33g, 0.16mmol, 10%), zinc cyanide (0.19g,1.58mmol) and ultra-dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10mL) was added to the reaction mixture to extract the mixture with ethyl acetate (15 mL. times.3). The combined organic phases were 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 (79mg, yield 83.0%).
MS(ESI,pos.ion)m/z:610.3[M+H]+；
Fourth step Synthesis of 7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-4- (4, 7-diazaspiro [2.5] octane-4-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000942
Adding 4- (6-cyano-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle]Pyrimidin-4-yl) -4, 7-diazaspiro [2.5]Octane-7-carboxylic acid tert-butyl ester (79mg,0.13mmol), trifluoroacetic acid (0.1mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a brown solid (66mg, yield 100%). MS (ESI, pos.ion) M/z 510.3[ M + H ]]+.
Fifth step Synthesis of 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 BDA0003415708940000951
To a reaction flask was added 7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-4- (4, 7-diazaspiro [2.5] octan-4-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (66mg,0.13mmol), N, N-diisopropylethylamine (47mg, 0.36mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (13.6mg,0.13mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 10 min. After the reaction is finished, the reaction product is dried by spinning 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 (46mg, yield 63.6%).
MS(ESI,pos.ion)m/z:564.3[M+H]+；
1H NMR(400MHz,CDCl3)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,CDCl3)δ-112.48，-75.65.
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 BDA0003415708940000952
First step Synthesis of tert-butyl (S) -4- (6-chloro-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
Figure BDA0003415708940000961
To a reaction flask were added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.10g,0.18mmol), (2, 6-difluorophenyl) boronic acid (0.13g,0.83mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (48mg,0.05mmol), potassium acetate (77mg,0.79mmol) and dioxane (10.0 mL). The reaction system is heated to 100 ℃, and after 10min, a mixed solution of water (0.1mL) and dioxane (0.5mL) is added, and the system is kept warm and continues to react for 3 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was added with saturated brine (10mL) and extracted with ethyl acetate (10 mL. times.3). The combined organic phases were 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 (45mg, yield 39.6%).
MS(ESI,pos.ion)m/z:626.2[M+H]+.
Second step Synthesis of tert-butyl (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
Figure BDA0003415708940000962
To the microwave tube was added (S) -4- (6-chloro-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-carboxylic acid tert-butyl ester (45mg,0.07mmol), bis (tri-tert-butylphosphine) palladium (0.12g,0.24mmol), tri-tert-butylphosphine (0.14g, 0.07mmol, 10%), zinc cyanide (92mg,0.79mmol) and ultra-dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10mL) was added to the reaction mixture to extract the mixture with ethyl acetate (15 mL. times.3). The combined organic phases were 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 (40mg, yield 90.1%).
MS(ESI,pos.ion)m/z:616.2[M+H]+.
The third step is the synthesis of (S) -7- (2, 6-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940000971
Adding (S) -4- (6-cyano-7- (2, 6-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] to the reaction flask ]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (45mg,0.07mmol), trifluoroacetic acid (0.1mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After completion of the reaction, spin-dried under reduced pressure to give the title compound as a brown solid (34mg, yield 100%). MS (ESI, pos.ion) M/z 516.4[ M + H ]]+.
Fourth step Synthesis of (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 BDA0003415708940000972
To the reaction flask were added (S) -7- (2, 6-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (34mg,0.07mmol), N-diisopropylethylamine (27mg, 0.21mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (10.3mg,0.11mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 10 min. After the reaction is finished, the reaction product is dried by spinning 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 (12mg, yield 32.5%).
MS(ESI,pos.ion)m/z:570.2[M+H]+；
1H NMR(400MHz,CDCl3)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)；
19F NMR(376MHz,CDCl3)δ(ppm)-112.48，-112.57.
Example 274- ((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 BDA0003415708940000981
First step Synthesis of tert-butyl (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
Figure BDA0003415708940000982
To a reaction flask was added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50g,0.92mmol), (5-methyl-1H-indazol-4-yl) boronic acid (0.65g,3.68mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.15g,0.18mmol), sodium carbonate (0.39g, 3.68mmol) and dioxane (15.0 mL). The reaction system is heated to 90 ℃, after 10min of reaction, the mixed solution of water (0.1mL) and dioxane (0.5mL) is added, and the system is kept warm and continues to react for 3 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. To the residue was added saturated brine (10mL), and the mixture was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were 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 (0.11g, yield 19.3%).
MS(ESI,pos.ion)m/z:626.2[M+H]+.
Second step Synthesis of tert-butyl (3S) -4- (6-cyano-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
Figure BDA0003415708940000991
To a microwave tube was added (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-carboxylic acid tert-butyl ester (93mg,0.15mmol), bis (tri-tert-butylphosphine) palladium (76mg,0.15mmol), tri-tert-butylphosphine (0.34g, 0.17mmol, 10%), zinc cyanide (0.17g,1.47mmol) and extra dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10mL) was added to the reaction mixture to extract the mixture with ethyl acetate (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary 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 (77mg, yield 83.5%).
MS(ESI,pos.ion)m/z:634.3[M+H]+.
Step three Synthesis of 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
Figure BDA0003415708940000992
To a reaction flask was added (3S) -4- (6-cyano-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-carboxylic acid tert-butyl ester (77mg,0.12mmol), trifluoroacetic acid (0.1mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After completion of the reaction, spin-dried under reduced pressure to give the title compound as a brown solid (65mg, yield 100%). MS (ESI, pos. ion) M/z 534.3[ M + H ] ]+.
Synthesis of 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 as fourth step
Figure BDA0003415708940001001
To a reaction flask was added 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 (65mg,0.12mmol), N-diisopropylethylamine (25.3mg, 0.20mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (11.2mg,0.12mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is kept for 10 min. After the reaction is finished, decompression spin-drying is carried out. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a pale yellow oily liquid (51mg, yield 71.8%).
MS(ESI,pos.ion)m/z:588.3[M+H]+.
Example 284- ((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 BDA0003415708940001002
First step Synthesis of tert-butyl (2R,5S) -4- (6-chloro-7- (2-hydroxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940001003
To a reaction flask was added (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-carboxylic acid tert-butyl ester (0.30g,0.53mmol), (2-hydroxy-3-methylphenyl) boronic acid (0.13g,0.81mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (90mg,0.11mmol), potassium acetate (0.28g,2.7mmol) and dioxane (8 mL). The reaction system is heated to 90 ℃ for reaction for 5 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 3/1) to give the title compound as a yellow solid (0.24g, yield 69%).
MS(ESI,pos.ion)m/z:633.2[M+H]+；
1H NMR(400MHz,CDCl3)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)
Second step Synthesis of tert-butyl (2R,5S) -4- (6-chloro-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
Figure BDA0003415708940001011
To a reaction flask were added (2R,5S) -4- (6-chloro-7- (2-hydroxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.22g,0.34mmol), iodomethane (0.25g,1.7mmol), potassium hydroxide (0.11g,1.7mmol) and dichloromethane (6 mL). The reaction system is reacted for 4 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with dichloromethane (100mL) and 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 (0.15g, yield 66%).
MS(ESI,pos.ion)m/z:647.2[M+H]+.
The third step is the synthesis of tert-butyl (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
Figure BDA0003415708940001012
To the microwave tube were added (2R,5S) -4- (6-chloro-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-carboxylic acid tert-butyl ester (0.16g,0.24mmol), bis (tri-tert-butylphosphine) palladium (0.13g,0.25mmol), 10% tri-tert-butylphosphine N-hexane solution (0.5g,0.25mmol), zinc cyanide (0.30g,2.5mmol) and extra dry N, N-dimethylformamide (4 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL) and washed with water (8 mL. times.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 (65mg, yield 43%).
MS(ESI,pos.ion)m/z:638.3[M+H]+.
Fourth step Synthesis of 4- ((2S,5R) -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 BDA0003415708940001021
To the reaction flask were 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-carboxylic acid tert-butyl ester (65mg,0.10mmol), trifluoroacetic acid (2mL) and dichloromethane (4 mL). The reaction system is reacted for 2 hours at normal temperature. After the starting material had reacted completely, it was spin dried under reduced pressure to give the title compound as a brown solid (55mg, yield 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:538.3[M+H]+；
Fifth step Synthesis of 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 BDA0003415708940001022
To the reaction flask was added 4- ((2S,5R) -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 (55mg,0.10mmol), triethylamine (0.15g, 1.48mmol) and dichloromethane (4 mL). The system was cooled to 0 ℃ and acryloyl chloride (40mg,0.43mmol) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 3 hours. After the reaction is finished, the reaction product is dried by spinning 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 (25mg, yield 41.3%).
MS(ESI,pos.ion)m/z:592.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 294- (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 BDA0003415708940001031
Synthesis of tert-butyl 4- (6-chloro-7- (2-hydroxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate in a first step
Figure BDA0003415708940001032
To a reaction flask was added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate (0.20g,0.36mmol), (2-hydroxy-3-methylphenyl) boronic acid (0.22g,1.44mmol), (1, 1'- [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (62.6mg,0.08mmol), potassium acetate (0.15g,1.49mmol) and dioxane (10.0 mL). The reaction system is heated to 100 ℃, after 10min of reaction, the mixed solution of water (0.1mL) and dioxane (0.5mL) is added, and the system is kept warm and continues to react for 3 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was added with saturated brine (10mL) and extracted with ethyl acetate (10 mL. times.3). The combined organic phases were 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 (96mg, yield 34.8%).
MS(ESI,pos.ion)m/z:631.2[M+H]+.
Second step Synthesis of tert-butyl 4- (6-chloro-7- (2-methoxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate
Figure BDA0003415708940001041
To a reaction flask was added tert-butyl 4- (6-chloro-7- (2-hydroxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate (0.18g, 0.29mmol), potassium hydroxide (80.3mg, 1.43mmol), dichloromethane (8.0mL) and iodomethane (0.1mL, 2.0 mmol). The reaction system is reacted for 3 hours at room temperature. After completion of the reaction of the starting materials, saturated brine (10.0mL) was added to the system, followed by extraction with ethyl acetate (10.0 mL. times.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 give the title compound as a yellow solid (0.18g, yield 95.8%).
MS(ESI,pos.ion)m/z:645.3[M+H]+.
Third step Synthesis of tert-butyl 4- (6-cyano-7- (2-methoxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate
Figure BDA0003415708940001042
To the microwave tube was added 4- (6-chloro-7- (2-methoxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylic acid 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 is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10mL) was added to the reaction mixture to extract the mixture with ethyl acetate (15 mL. times.3). The combined organic phases were 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 (0.13g, yield 73.2%).
MS(ESI,pos.ion)m/z:636.4[M+H]+.
Fourth step Synthesis of 1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) -2-oxo-4- (4, 7-diazaspiro [2.5] oct-4-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001051
To a reaction flask was added tert-butyl 4- (6-cyano-7- (2-methoxy-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octane-7-carboxylate (0.13g,0.20mmol), trifluoroacetic acid (0.2mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a brown solid (0.11g, yield 100%).
MS(ESI,pos.ion)m/z:536.3[M+H]+.
Fifth step Synthesis of 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 BDA0003415708940001052
To a reaction flask was added 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 (0.11g,0.20mmol), N, N-diisopropylethylamine (72mg, 0.55mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (22mg,0.24mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 10 min. After the reaction is finished, the reaction product is dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (22mg, yield 18.8%).
MS(ESI,pos.ion)m/z:590.3[M+H]+.
1H NMR(400MHz,CDCl3)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).
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 BDA0003415708940001061
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003415708940001062
To a reaction flask was added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.21g,0.38mmol), (2-fluoro-3-methylphenyl) boronic acid (0.18g,1.17mmol), (1, 1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.06g,0.08mmol), potassium acetate (0.12g,1.25mmol), 1, 4-dioxane (10mL) and water (0.2 mL). The reaction system is heated to 95 ℃ for reaction for 6h under the protection of nitrogen. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. Water (50mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL. times.3). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and 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-green solid (0.23g, yield 95.1%).
MS(ESI,pos.ion)m/z:621.3[M+H]+.
Second step Synthesis of tert-butyl (S) -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-methylpiperazine-1-carboxylate
Figure BDA0003415708940001071
To the microwave tube was added (S) -4- (6-chloro-7- (2-fluoro-3-methylphenyl) -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 (0.20g,0.32mmol), bis (tri-tert-butylphosphine) palladium (0.33g,0.65mmol), tri-tert-butylphosphine (0.33g, 0.16mmol, 10%), zinc cyanide (0.38g,3.25mmol) and extra dry N, N-dimethylformamide (3.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10mL) was added to the reaction mixture to extract the mixture with ethyl acetate (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary 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 (96mg, yield 48.6%).
MS(ESI,pos.ion)m/z:612.3[M+H]+.
The third step of Synthesis of (S) -7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001072
Adding (S) -4- (6-cyano-7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] to the reaction flask]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.12g,0.20mmol), trifluoroacetic acid (0.2mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After the starting material had reacted completely, it was dried by spinning under reduced pressure to give the title compound as a brown solid (0.10g, yield 100%). MS (ESI, pos. ion) M/z 512.3[ M + H ]]+.
The fourth step Synthesis of (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 BDA0003415708940001081
To the reaction flask were added (S) -7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile (0.10g,0.20mmol), N-diisopropylethylamine (67mg, 0.46mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (23.6mg,0.31mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 10 min. After the reaction is finished, the reaction product is dried by spinning under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (53mg, yield 52.3%).
MS(ESI,pos.ion)m/z:566.3[M+H]+；
1H NMR(400MHz,CDCl3)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)；
19F NMR(376MHz,CDCl3)δ(ppm)-112.48，-75.62.
Example 314- ((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 BDA0003415708940001091
First step Synthesis of 6-bromo-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) quinazoline-2, 4(1H,3H) -dione
Figure BDA0003415708940001092
To the reaction flask were added 6-bromo-7-iodo-1- (2-isopropyl-4-methylpyridin-3-yl) quinazoline-2, 4(1H,3H) -dione (1.00g,2.00mmol), (2-fluoro-5-methylphenyl) boronic acid (0.37g,2.40mmol), sodium carbonate (0.64g,6.00mmol), tetrakis (triphenylphosphine) palladium (0.12g,0.10mmol), 1, 4-dioxane (15.0mL) and water (3.5mL) in that order. The reaction system is heated to 100 ℃ under the protection of nitrogen and reacted overnight. After the reaction was completed, it was cooled to room temperature and filtered. The filtered mother liquor was spun dry under reduced pressure and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title product as a light yellow solid (0.96g, 100% yield).
MS(ESI,pos.ion)m/z:482.1[M+H]+.
Second step Synthesis of 6-bromo-4-chloro-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) quinazolin-2 (1H) -one
Figure BDA0003415708940001093
To the reaction flask were added 6-bromo-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) quinazoline-2, 4(1H,3H) -dione (0.98g,2.03mmol), acetonitrile (20.0mL) and N, N-diisopropylethylamine (1.05g,8.13mmol) in that order. Phosphorus oxychloride (1.25g,8.15mmol) was added dropwise with stirring. The reaction was heated to 90 ℃ and allowed to react overnight. After the reaction was completed, it was cooled to room temperature and dried by spinning under reduced pressure to obtain the title compound as a brown semisolid (1.02g, yield 100%) which was used directly in the next reaction.
Step three, synthesis of (2R,5S) -4- (6-bromo-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003415708940001101
To a reaction flask was added 6-bromo-4-chloro-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) quinazolin-2 (1H) -one (1.02g,2.03mmol), N-dimethylformamide (12.0mL), (tert-butyl 2R,5S) -2, 5-dimethylpiperazine-1-carboxylate (0.44g,2.03mmol) and N, N diisopropylethylamine (0.5mL,2.87 mmol). The reaction was heated to 60 ℃ and allowed to react overnight. After completion of the reaction, it was cooled to room temperature, and the system was poured into crushed ice (50g) and extracted with ethyl acetate (50 mL. times.2). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and 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 a light yellow solid (0.65g, yield 48%).
MS(ESI,pos.ion)m/z:678.2[M+H]+.
The fourth step Synthesis of tert-butyl (2R,5S) -4- (6-cyano-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940001102
To the microwave tube were added (2R,5S) -4- (6-bromo-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.40g,0.59mmol), zinc cyanide (0.62g,5.30mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (92mg,0.12mmol) and N, N-dimethylformamide (4.0mL) in this order. After the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, placing the reaction system in the microwave reactor, and heating to 125 ℃ for reaction for 8 hours. Cooling to room temperature, and spin-drying 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 colorless transparent liquid (0.19g, yield 51%).
MS(ESI,pos.ion)m/z:625.3[M+H]+.
Fifth step Synthesis of 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
Figure BDA0003415708940001111
To the reaction flask were added (2R,5S) -4- (6-cyano-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.19g,0.30mmol), dichloromethane (2.5mL) and trifluoroacetic acid (1mL) in this order. The reaction was reacted at room temperature for 30min, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (0.16g, yield 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:525.3[M+H]+.
Sixth step Synthesis of 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 BDA0003415708940001112
To a reaction flask were added 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 (0.16g,0.30mmol), dichloromethane (4.0mL) and N, N diisopropylethylamine (0.19g,1.46mmol) in this order, the system was cooled to-10 ℃, and acryloyl chloride (49mg,0.54mmol) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 30 min. After completion of the reaction, the reaction was quenched by adding water (20mL) and extracted with methylene chloride (20 mL. times.2). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a white solid (90.0mg, yield 51%).
MS(ESI,pos.ion)m/z:579.3[M+H]+；
1H NMR(400MHz,CDCl3)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,CDCl3)δ(ppm)-120.20,-120.26,-120.48,-120.55.
Example 324- ((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 BDA0003415708940001121
Synthesis of tert-butyl (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 in the first step
Figure BDA0003415708940001122
To a reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.55g,1.43mmol), (3S,5R) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.32g,1.50mmol), acetonitrile (15.0mL) and N, N-diisopropylethylamine (0.7mL,4.02 mmol). The reaction system is heated to 55 ℃ for reaction for 1.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (30mL) was added to the reaction mixture to extract the mixture with ethyl acetate (20 mL. times.3). The combined organic phases were 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 (0.40g, yield 50.6%).
MS(ESI,pos.ion)m/z:561.3[M+H]+.
Second step Synthesis of tert-butyl (3S,5R) -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
Figure BDA0003415708940001131
To a reaction flask was added (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-carboxylic acid tert-butyl ester (0.40g,0.72mmol), (2-fluoro-5-methylphenyl) boronic acid (0.33g,2.17mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.12g,0.15mmol), potassium acetate (0.22g,2.20mmol) and dioxane (10.0 mL). The reaction system is heated to 95 ℃, after the reaction is carried out for 10min, the mixed solution of water (0.1mL) and dioxane (0.5mL) is added, and the system is kept warm and continues to react for 3 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. To the residue was added saturated brine (10mL), and the mixture was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were 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 (0.37g, yield 81.3%).
MS(ESI,pos.ion)m/z:636.3[M+H]+.
Third step Synthesis of tert-butyl (3S,5R) -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
Figure BDA0003415708940001132
To the microwave tube were added (3S,5R) -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-carboxylic acid tert-butyl ester (0.15g,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 extra dry N, N-dimethylformamide (4.0 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated brine (10mL) was added to the reaction mixture to extract the mixture with ethyl acetate (15 mL. times.3). The combined organic phases were 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 (0.11g, yield 76.3%).
MS(ESI,pos.ion)m/z:626.4[M+H]+.
Synthesis of 4- ((2S,6R) -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 as a fourth step
Figure BDA0003415708940001141
To the reaction flask were added (3S,5R) -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-carboxylic acid tert-butyl ester (0.11g,0.18mmol), trifluoroacetic acid (0.2mL) and dichloromethane (3.0 mL). The reaction system is reacted for 1h at room temperature. After completion of the reaction, spin-dried under reduced pressure to give the title compound as a brown solid (96mg, yield 100%). Fifth step Synthesis of 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 BDA0003415708940001142
To the reaction flask was added 4- ((2S,6R) -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 (96mg,0.18mmol), N-diisopropylethylamine (0.1mL, 0.57mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C and a solution of acryloyl chloride (26.7mg,0.30mmol) in dichloromethane (1mL) was slowly added dropwise. After the dropwise addition, the reaction system is kept for 10 min. After the reaction was completed, the reaction was dried under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (51mg, yield 47.8%).
MS(ESI,pos.ion)m/z:580.3[M+H]+.
1H NMR(400MHz,CDCl3)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).
19F NMR(376MHz,CDCl3)δ(ppm)-117.83.
Example 334- (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 BDA0003415708940001151
Synthesis of first tert-butyl 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
Figure BDA0003415708940001152
To a reaction flask were added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (1.05g,2.7mmol), tert-butyl 3, 5-dimethylpiperazine-1-carboxylate (0.68g,3.0mmol), N, N-diisopropylethylamine (2.5mL,15mmol) and acetonitrile (15 mL). The reaction system is heated to 60 ℃ for reaction for 4 h. 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 (0.51g, yield 33%).
MS(ESI,pos.ion)m/z:561.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Second step tert-butyl 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
Figure BDA0003415708940001161
To a 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-carboxylic acid tert-butyl ester (0.30g,0.53mmol), (2-fluoro-5-methylphenyl) boronic acid (0.13g,0.80mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (90mg,0.11mmol), potassium acetate (0.28g,2.7mmol) and dioxane (8 mL). The reaction system is heated to 90 ℃ for reaction for 5 h. 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 (0.31g, yield 90%).
MS(ESI,pos.ion)m/z:635.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Step three Synthesis of tert-butyl 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
Figure BDA0003415708940001162
To the microwave tube were added 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-carboxylic acid tert-butyl ester (0.30g,0.46mmol), bis (tri-tert-butylphosphine) palladium (0.37g,0.70mmol), 10% tri-tert-butylphosphine N-hexane solution (0.94g,0.46mmol), zinc cyanide (0.56g,4.7mmol) and ultra-dry N, N-dimethylformamide (5 mL). The reaction system is placed in a microwave reactor, the temperature is raised to 140 ℃, and the reaction is carried out for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL) and washed with water (8 mL. times.4). The organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning 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 (0.26g, yield 91%).
MS(ESI,pos.ion)m/z:626.3[M+H]+；
Fourth step Synthesis of 4- (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 BDA0003415708940001171
To a reaction flask was added tert-butyl 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 (0.25g,0.40mmol), trifluoroacetic acid (3mL) and dichloromethane (6 mL). The reaction system is reacted for 2 hours at normal temperature. Then, it was spin-dried under reduced pressure to give the title compound as a brown solid (0.21g, yield 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:526.1[M+H]+.
Fifth step Synthesis of 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 BDA0003415708940001172
To the reaction flask was added 4- (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 (0.21g,0.40mmol), triethylamine (0.58g,5.7mmol) and dichloromethane (6 mL). The system was cooled to 0 ℃ and acryloyl chloride (0.16g,1.7mmol) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 3 hours. Then decompression and spin-drying are carried out. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 200/1) to give the title compound as a yellow solid (0.13g, yield 56.1%).
MS(ESI,pos.ion)m/z:580.5[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 344- ((2S,5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7- (1, 3-dimethyl-1H-pyrazol-4-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001181
Synthesis of tert-butyl (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-carboxylate in the first step
Figure BDA0003415708940001182
To a reaction flask was added tert-butyl (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 (0.20g,0.36mmol), 1, 3-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) -1H-pyrazole (0.12g,0.54mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (70mg,0.09mmol), potassium acetate (0.15g,1.58mmol), 1, 4-dioxane (15mL) and water (0.2 mL). Heating the reaction system to 95 ℃ for reaction for 10h under the protection of nitrogen. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. Water (50mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL. times.3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow-green solid (0.12g, yield 53.8%).
MS(ESI,pos.ion)m/z:621.0[M+H]+.
Second step Synthesis of tert-butyl (2R,5S) -4- (6-cyano-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-carboxylate
Figure BDA0003415708940001191
Adding (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 ] to a microwave tube]Pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.12g,0.19mmol), zinc cyanide (0.24g,2.05mmol), di (tri-tert-butyl)Phosphine) palladium (0.30g,0.60mmol), tri-tert-butylphosphine in N-hexane (10%, 0.5mL) and ultra-dry N, N-dimethylformamide (2.0 mL). The reaction system is placed in a microwave reactor and heated to 135 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow solid (0.12g, yield 100%). MS (ESI, pos.ion) M/z:612.5[ M + H ]]+.
Third step Synthesis of 4- ((2S,5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7- (1, 3-dimethyl-1H-pyrazol-4-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001192
Adding (2R,5S) -4- (6-cyano-7- (1, 3-dimethyl-1H-pyrazol-4-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] to the reaction flask ]Pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.12g,0.20mmol), dichloromethane (10mL) and trifluoroacetic acid (0.20 mL). The reaction system is reacted for 3 hours at room temperature. And after the raw materials completely react, performing reduced pressure spin drying. To the residue were added dichloromethane (10mL) and DIPEA (0.04g,0.35 mmol). The system was cooled to 0 ℃ and acryloyl chloride (0.02g, 0.20mmol) was slowly added dropwise. After the dropwise addition, the system was reacted at room temperature for 2 hours. After completion of the reaction, water (20mL) was added to the system, and the mixture was 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 give the title compound as a yellow solid (83mg, yield 75.1%). MS (ESI, pos. ion) M/z 566.3[ M + H ]]+；
1H NMR(400MHz,CDCl3)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).
Example 354- ((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 BDA0003415708940001201
Synthesis of first step tert-butyl (2R,5S) -4- (7- (2-aminopyridin-3-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940001202
To a reaction flask was added tert-butyl (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 (0.44g,0.18mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (0.26g,1.18mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (0.14g,0.17mmol), potassium acetate (0.37g,3.76mmol), 1, 4-dioxane (30mL) and water (0.2 mL). Heating the reaction system to 95 ℃ for reaction for 6h under the protection of nitrogen. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. Water (50mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL. times.3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow-green solid (0.32g, yield 65.3%).
MS(ESI,pos.ion)m/z:619.2[M+H]+.
Second step Synthesis of tert-butyl (2R,5S) -4- (7- (2-aminopyridin-3-yl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940001211
To the microwave tube were added (2R,5S) -4- (7- (2-aminopyridin-3-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.25g,0.40mmol), zinc cyanide (0.48g,4.06mmol), bis (tri-tert-butylphosphine) palladium (0.65g,1.28mmol), a solution of tri-tert-butylphosphine in N-hexane (10%, 0.5mL) and ultra-dry N, N-dimethylformamide (2.0 mL). The reaction system is placed in a microwave reactor, and the temperature is raised to 135 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a yellow solid (0.15g, yield 60.9%).
MS(ESI,pos.ion)m/z:610.2[M+H]+.
Third step Synthesis of 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 BDA0003415708940001212
Adding (2R,5S) -4- (7- (2-aminopyridin-3-yl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle ]Pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.20g,0.32mmol), dichloromethane (10mL) and trifluoroacetic acid (0.20 mL). The reaction system is reacted for 3 hours at room temperature. And after the raw materials completely react, performing reduced pressure spin drying. To the residue were added dichloromethane (10mL) and DIPEA (70mg,0.54 mmol). The system was cooled to 0 ℃ and acryloyl chloride (30mg, 0.37mmol) was slowly added dropwise. After the dropwise addition, the system was reacted at room temperature for 2 hours. After completion of the reaction, water (20mL) was added to the system, and the mixture was 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 give the title compound as a yellow solid (25mg, yield 14.0%). MS (ESI, pos. ion) M/z 564.2[ M + H ]]+.
1H NMR (400MHz, CDCl3) delta (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), example 364- ((2S,5R) -4- (dimethyl-propyl) -piperazine (1H) -2- (2-propyl-2-propyl-2- (2-dimethyl-phenyl) -piperazine Pyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001221
First step Synthesis of 6-chloro-7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione
Figure BDA0003415708940001222
6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4- (1H,3H) -dione (0.91g,2.49mmol), (2-fluoro-3-methylphenyl) boronic acid (0.77g,4.98 mmol), potassium acetate (0.73g,7.47mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (60mg,0.07mmol), 1, 4-dioxane (20.0mL) and water (3.0mL) were added to a reaction flask in this order, the reaction was refluxed overnight under heating under nitrogen protection, after the reaction of the starting materials was completed, the reaction mixture was cooled to room temperature, filtered, ethyl acetate (30mL) and water (30mL) were added to the mother liquor, the separated liquid was extracted with ethyl acetate (30mL), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, 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 light yellow solid (0.64g, yield 59%).
MS(ESI,pos.ion)m/z:439.1[M+H]+.
Second step Synthesis of 4, 6-dichloro-7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003415708940001223
To the reaction flask were added 6-chloro-7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.60g,1.37mmol), acetonitrile (7.0mL), N, N-diisopropylethylamine (0.71g,5.48mmol), phosphorus oxychloride (0.84g,5.48mmol) in that order. The reaction system is heated to reflux for 6 h. After completion of the reaction, it was cooled to room temperature and dried by rotary drying under reduced pressure to give the title compound as a yellow solid (0.62g, yield 100%) which was used directly in the next reaction.
Step three Synthesis of tert-butyl (2R,5S) -4- (6-chloro-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
Figure BDA0003415708940001231
To a reaction flask were 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-carboxylic acid tert-butyl ester (0.31g,1.45mmol), N, N-diisopropylethylamine (0.36g,2.76mmol), and N, N-dimethylformamide (10.0 mL). The reaction system is heated to 80 ℃ for reaction for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and water (30mL) was sequentially added thereto, followed by extraction with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated brine (50 mL. times.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 give the title compound as a light yellow solid (0.43g, yield 49%).
MS(ESI,pos.ion)m/z:635.3[M+H]+.
Fourth step Synthesis of tert-butyl (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
Figure BDA0003415708940001232
To the microwave tube were added (2R,5S) -4- (6-chloro-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-carboxylic acid tert-butyl ester (0.27g,0.42mmol), zinc cyanide (0.49g,4.2mmol), bis (tri-tert-butylphosphine) palladium (0.64g,1.26mmol), and N, N-dimethylformamide (4.0mL) in that order. The reaction system is placed in a microwave reactor, and the temperature is raised to 140 ℃ for reaction for 7 h. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a white solid (90mg, yield 34%).
MS(ESI,pos.ion)m/z:626.2[M+H]+；
Fifth step Synthesis of 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
Figure BDA0003415708940001241
To the reaction flask were added (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-carboxylic acid tert-butyl ester (90mg,0.14mmol), dichloromethane (2.0mL) and trifluoroacetic acid (0.77g,6.71mmol) in that order. The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (76mg, yield 100%) which was used directly in the next reaction.
Sixth step Synthesis of 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 BDA0003415708940001242
To the reaction flask were added 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 (76mg,0.14mmol), dichloromethane (2.0mL) and triethylamine (32mg,0.32mmol) in this order. The system was cooled to-20 ℃ and a solution of acryloyl chloride (17mg,0.19mmol) in dichloromethane (1.0mL) was slowly added dropwise. After the dropwise addition, the reaction system is subjected to heat preservation reaction for 30 min. After completion of the reaction, water (10mL) was added and extracted with dichloromethane (10 mL. times.2). The combined organic phases were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a pale yellow solid (45mg, yield 53.7%).
MS(ESI,pos.ion)m/z:580.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 374- ((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 BDA0003415708940001251
Synthesis of first step tert-butyl (2R,5S) -4- (6-chloro-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
Figure BDA0003415708940001252
To a reaction flask were added in this order (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-carboxylic acid tert-butyl ester (0.17g,0.30mmol), 2- (cyclohex-1-en-1-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.12g,0.60mmol), potassium acetate (0.09g,0.90mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.02g,0.03mmol), 1, 4-dioxane (4mL) and water (1 mL). The reaction was heated to reflux and reacted overnight. Then, the mixture was cooled to room temperature, water (10mL) was added, and the mixture was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and 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 pale yellow solid (0.10g, yield 55%).
MS(ESI,pos.ion)m/z:607.3[M+H]+.
Second step Synthesis of tert-butyl (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
Figure BDA0003415708940001261
To a microwave tube were added (2R,5S) -4- (6-chloro-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-carboxylic acid tert-butyl ester (0.18g,0.30mmol), zinc cyanide (0.18g,1.5mmol), bis (tri-tert-butylphosphine) palladium (0.15g,0.30mmol) and N, N-dimethylformamide (3mL) in that order. The reaction system is placed in a microwave reactor and heated to 140 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a pale yellow solid (0.14g, yield 78%).
MS(ESI,pos.ion)m/z:598.3[M+H]+.
Step three Synthesis of 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
Figure BDA0003415708940001262
To a bottle were added tert-butyl (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 (80mg,0.13mmol), dichloromethane (2mL) and trifluoroacetic acid (0.5mL) in this order. The reaction was reacted at room temperature for 2h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (67mg, yield 100%) which was used directly in the next reaction.
Synthesis of 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 as a fourth step
Figure BDA0003415708940001263
To the reaction flask were added 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 (60mg,0.12mmol), dichloromethane (2.0mL) and N, N-diisopropylethylamine (50mg,0.39mmol) in this order. The system was cooled to-20 ℃ and acryloyl chloride (10mg,0.12mmol) was slowly added dropwise. After the dropwise addition, the reaction system reacts at room temperature for 1 h. After completion of the reaction, water (20mL) was added and extracted with dichloromethane (20 mL. times.2). The combined organic phases were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified over thick prep plate (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a light yellow solid (15.1mg, yield 23%).
MS(ESI,pos.ion)m/z:552.3[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 384- ((2S,5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7-cyclohexyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001271
Synthesis of first step tert-butyl (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
Figure BDA0003415708940001272
To the reaction flask were added in this order (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-carboxylic acid tert-butyl ester (60mg,0.10mmol), ethyl acetate (4.0mL), 10% palladium on charcoal (10 mg). Reacting for 4h at room temperature under the hydrogen atmosphere of the reaction system. After the raw materials are completely reacted, filtering. The filtered mother liquor was spin-dried under reduced pressure to give the title compound as a brown solid (60mg, yield 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:600.4[M+H]+.
Second step Synthesis of 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 BDA0003415708940001281
To the reaction flask were added (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-carboxylic acid tert-butyl ester (35mg,0.06mmol), dichloromethane (2.0mL) and trifluoroacetic acid (0.5mL) in this order. The reaction system is reacted for 1h at room temperature. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a brown solid (29mg, yield 100%) which was used directly in the next reaction.
Third step Synthesis of 4- ((2S,5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -7-cyclohexyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidine-6-carbonitrile
Figure BDA0003415708940001282
To the reaction flask were added 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 (29mg,0.06mmol), dichloromethane (2mL) and N, N-diisopropylethylamine (20mg,0.15mmol) in that order. The system was cooled to-20 ℃ and acryloyl chloride (10mg,0.11mmol) was slowly added dropwise. The reaction system is reacted for 1h at room temperature. After completion of the reaction, water (20mL) was added to the above mixture, and the mixture was extracted with methylene chloride (20 mL. times.2). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified over thick prep. plate (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a light yellow solid (10.0mg, yield 31%).
MS(ESI,pos.ion)m/z:554.5[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 394- ((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 BDA0003415708940001291
Synthesis of first step tert-butyl (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
Figure BDA0003415708940001292
To the reaction flask were added (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-carboxylic acid tert-butyl ester (0.30g,0.53mmol), N, N-diisopropylethylamine (0.14g,1.06mmol), piperidine (0.14g,1.59mmol) and N, N-dimethylformamide (5.0ml) in this order. The reaction system is heated to 90 ℃ for reaction for 1 h. 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 give the title compound as a light yellow solid (0.25g, yield 77%).
MS(ESI,pos.ion)m/z:610.3[M+H]+.
Second step Synthesis of tert-butyl (2R,5S) -4- (6-cyano-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
Figure BDA0003415708940001301
To the microwave tube were added (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-carboxylic acid tert-butyl ester (0.15g,0.25mmol), zinc cyanide (0.23g,2.00mmol), bis (tri-tert-butylphosphine) palladium (0.06g,0.13mmol), tri-tert-butylphosphine tetrafluoroborate (0.01g,0.05mmol), and N, N-dimethylformamide (3mL) in this order. After the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, and heating to 140 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a pale yellow solid (0.14g, yield 95%).
MS(ESI,pos.ion)m/z:601.5[M+H]+.
Step three Synthesis of 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
Figure BDA0003415708940001302
To the reaction flask were added (2R,5S) -4- (6-cyano-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-carboxylic acid tert-butyl ester (50mg,0.08mmol), dichloromethane (2mL) and trifluoroacetic acid (0.5mL) in this order. The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (42mg, yield 100%) which was used directly in the next reaction.
Synthesis of 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 as a fourth step
Figure BDA0003415708940001311
To the reaction flask were added 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 (42mg,0.08mmol), dichloromethane (2.0mL) and N, N-diisopropylethylamine (20mg,0.15mmol) in this order. The system was cooled to-20 ℃ and acryloyl chloride (0.01g,0.17mmol) was slowly added dropwise. The reaction system is reacted for 1h at room temperature. After completion of the reaction, water (20mL) was added to the above mixture, and the mixture was extracted with dichloromethane (20 mL. times.2). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified over thick prep. plate (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a light yellow solid (24mg, yield 52%).
MS(ESI,pos.ion)m/z:555.5[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 404- ((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 BDA0003415708940001312
Synthesis of tert-butyl (3R,5S) -4- (6-chloro-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 in the first step
Figure BDA0003415708940001321
To the reaction flask were added 4, 6-dichloro-7- (2-fluoro-3-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.60g,1.31mmol), (3R,5S) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.29g,1.38mmol), N, N-diisopropylethylamine (0.34g,2.63mmol), and N, N-dimethylformamide (10.0mL) in that order. The reaction was heated to 85 ℃ and reacted overnight. After nitrogen substitution, the mixture was warmed to 85 ℃ and stirred overnight. Then, the mixture was cooled to room temperature, water (30mL) was added, and the mixture was extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered and dried by spinning 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 white solid (0.10g, yield 12%).
MS(ESI,pos.ion)m/z:635.3[M+H]+.
Second step Synthesis of tert-butyl (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
Figure BDA0003415708940001322
To the microwave tube were added (3R,5S) -4- (6-chloro-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-carboxylic acid tert-butyl ester (66mg,0.10mmol), zinc cyanide (59mg,0.50mmol), bis (tri-tert-butylphosphine) palladium (5.8mg,0.02mmol), and N, N-dimethylformamide (2.0mL) in that order. After the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, and heating to 140 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a colorless transparent solid (35mg, yield 56%).
MS(ESI,pos.ion)m/z:626.5[M+H]+.
Step three Synthesis of 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
Figure BDA0003415708940001331
To the reaction flask were added (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-carboxylic acid tert-butyl ester (35mg,0.06mmol), dichloromethane (2.0mL) and trifluoroacetic acid (0.5mL) in this order. The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (30mg, yield 100%) which was used directly in the next reaction.
Synthesis of 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 as a fourth step
Figure BDA0003415708940001332
To the reaction flask were added 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 (30mg,0.06mmol), dichloromethane (2.0mL) and triethylamine (29.0mg,0.29mmol) in this order. The system was cooled to-20 deg.C and slowly added dropwise, slowly adding a solution of acryloyl chloride (10mg,0.11mmol) in dichloromethane (1 mL). The reaction system is reacted for 1h at room temperature. After completion of the reaction, water (10mL) was added to the above mixture, and the mixture was extracted with dichloromethane (10 mL. times.2). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a pale yellow solid (16mg, yield 48%).
MS(ESI,pos.ion)m/z:580.2[M+H]+；
1H NMR(400MHz,CDCl3)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).
Example 414- ((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 BDA0003415708940001341
First step Synthesis of tert-butyl (2R,5S) -4- (7- (2-amino-3-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940001342
To the reaction flask was added in this order (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-carboxylic acid tert-butyl ester (0.30g,0.53mmol), 2-fluoro-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) aniline (0.25g,1.06mmol), potassium acetate (0.16g,0.59mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.02g,0.03mmol), 1, 4-dioxane (6mL) and water (0.5 mL). The reaction system is heated to reflux under the protection of nitrogen for overnight reaction. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30mL) was added thereto, and the mixture was extracted with ethyl acetate (30 mL. times.2). The combined organic phases were washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered and 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 light yellow solid (0.28g, yield 83%).
MS(ESI,pos.ion)m/z:636.3[M+H]+；
Second step Synthesis of tert-butyl (2R,5S) -4- (7- (2-amino-3-fluorophenyl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate
Figure BDA0003415708940001351
To the microwave tube were added in this order (2R,5S) -4- (7- (2-amino-3-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.18g,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 protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, and heating to 140 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a light yellow solid (0.10g, yield 57%).
MS(ESI,pos.ion)m/z:627.3[M+H]+.
Third step Synthesis of 7- (2-amino-3-fluorophenyl) -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 BDA0003415708940001352
To the reaction flask were added (2R,5S) -4- (7- (2-amino-3-fluorophenyl) -6-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.10g,0.16mmol), dichloromethane (4mL) and trifluoroacetic acid (1mL) in that order. The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (80mg, yield 100%) which was used directly in the next reaction.
Synthesis of 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 as a fourth step
Figure BDA0003415708940001361
To the reaction flask were added 7- (2-amino-3-fluorophenyl) -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 (0.08g,0.16mmol), dichloromethane (2.0mL) and N, N-diisopropylethylamine (80mg,0.62mmol) in this order. The system was cooled to-20 ℃ and acryloyl chloride (0.02g,0.18mmol) was slowly added dropwise. The reaction system is reacted for 1h at room temperature. After completion of the reaction, water (200mL) was added to the above mixture, and the mixture was extracted with methylene chloride (20 mL. times.2). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The residue was purified over thick prep plate (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow-green solid (56mg, yield 60%).
MS(ESI,pos.ion)m/z:581.4[M+H]+；
1H NMR(400MHz,DMSO-d6)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).
Example 424- ((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 BDA0003415708940001362
Synthesis of tert-butyl (3S,5S) -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 in the first step
Figure BDA0003415708940001371
To the reaction flask were added 4, 6-dichloro-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.20g,0.46mmol), (3S,5S) -3, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.10g,0.46mmol), N, N-dimethylformamide (3.0mL) and N, N-diisopropylethylamine (0.30g,2.30mmol) in this order. The reaction was heated to 90 ℃ and allowed to react overnight. 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. times.2). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and 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 light yellow oil (65mg, yield 22%).
MS(ESI,pos.ion)m/z:635.3[M+H]+.
Second step Synthesis of tert-butyl (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
Figure BDA0003415708940001372
To a microwave tube were added (3S,5S) -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-carboxylic acid tert-butyl ester (0.06g,0.10mmol), zinc cyanide (0.06g,0.50mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (0.02g,0.04mmol) and N in this order, n-dimethylformamide (2.0 mL). After the protection of nitrogen in the reaction system, placing the reaction system in a microwave reactor, and heating to 140 ℃ for reaction for 7 hours. After the reaction is finished, cooling to room temperature, and performing reduced pressure spin drying. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/2) to give the title compound as a colorless transparent oil (30mg, yield 48%).
MS(ESI,pos.ion)m/z:626.3[M+H]+.
Third step Synthesis of 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
Figure BDA0003415708940001381
To the reaction flask were added (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-carboxylic acid tert-butyl ester (30mg,0.05mmol), dichloromethane (2mL) and trifluoroacetic acid (0.4mL) in this order. The reaction was reacted at room temperature for 1h, followed by spin-drying under reduced pressure to give the title compound as a yellow solid (25mg, yield 100%) which was used directly in the next reaction.
Fourth step Synthesis of 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 BDA0003415708940001382
To the reaction flask were added 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 (25mg,0.05mmol), dichloromethane (2.0mL) and N, N-diisopropylethylamine (15.0mg,0.02mmol) in this order. Acryloyl chloride (4.3mg,0.05mmol) was slowly added dropwise thereto. After the dripping is finished, the reaction system is kept for reaction for 30 min. After completion of the reaction, water (20mL) was added to the above mixture, and the mixture was extracted with methylene chloride (20 mL. times.2). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and 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 a white solid (12mg, yield 43%).
MS(ESI,pos.ion)m/z:580.4[M+H]+；
1H NMR(400MHz,CDCl3)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).
Biological assay
The LC/MS/MS system used for the analysis was a Waters Xevo G2-XS Qtof time-of-flight mass spectrometer. Mass spectrometry conditions are shown in table a:
TABLE A
Item Condition
Capillary voltage (kV) 4
Taper hole voltage (V) 60
Ion Source temperature e (. degree. C.) 120
Taper hole air flow (L/h) 50
Drying air flow rate (L/h) 1000
Scanning mode ES source, positive ion mode
Analysis mode Sensitivity of the probe
Scanning range 500-2000m/z
Analysis A Waters Acquity I Class Sepax Bio-C4, 2.1X 50mm, 3. mu.M column was used to inject 10. mu.L of sample. Analysis conditions were as follows: the 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 ℃. Mobile phase gradients are shown in table B:
TABLE B
Time Gradient of mobile phase A Gradient of mobile phase B
0min 95％ 5％
0.75min 95％ 5％
1.0min 75％ 25％
6.0min 50％ 50％
6.25min 0％ 100％
7.5min 0％ 100％
7.75min 95％ 5％
9min 95％ 5％
Example A deg.C and stability in rat liver microsomes
Human or mouse liver microsomes were incubated in duplicate wells in polypropylene tubes. A typical incubation mixture comprises human or mouse liver microsomes (0.5mg protein/mL), the compound of interest (1. mu.M) and a total volume of 15. mu.L of NADPH (2.0mM) potassium phosphate buffer (PBS,100mM, pH 7.4), and the test compound is dissolved in DMSO and diluted with PBS to give a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37 ℃ in communication with the air, and after pre-incubation for 3min, protein was added to the mixture and the reaction started. At different time points (0, 20 and 60min), the reaction was stopped by adding the same volume of ice-cold acetonitrile. The samples were stored at-80 ℃ until LC/MS/MS analysis was performed.
The concentration of compound in the human or mouse liver microsome incubation mixture was determined by the LC/MS/MS method.
Parallel incubation experiments using denatured microsomes as negative controls were incubated at 37 ℃ and reactions were stopped at different time points (0, 20 and 60 min).
Verapamil (1 μm) was used as a positive control, incubated at 37 ℃ and the reaction was stopped at different time points (0, 20 and 60 min).
Data analysis
For each reaction, the concentration of compound in human or rat liver microsome incubations (expressed as a percentage) was plotted as a percentage of the time point relative to zero, to infer the intrinsic hepatic clearance CL in vivoint(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.)。
As can be seen from the results of the experiment, the compound of the present invention exhibited appropriate stability when incubated in human liver microsomes.
Example B pharmacokinetics of mice, rats, dogs and monkeys following intravenous injection and oral dosing of a compound of the invention Chemical evaluation
Taking 18-22g male ICR mice, randomly dividing the mice into two groups, wherein one group is intravenously injected with the compound to be tested, the dose is 2.0mg/kg, and the other group is orally administered with the compound to be tested, and the dose is 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 after intravenous administration; tail vein blood was collected at time points 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral administration. A standard curve of the appropriate range was established based on the sample concentration, and the concentration of the test compound in the plasma sample was determined in MRM mode using LC-MS/MS model AB SCIEX API 4000. According to the drug concentration-time curve, pharmacokinetic parameters are calculated by adopting a WinNonLin 6.3 software non-compartmental model method.
As can be seen from experiments, when the compound provided by the invention is administrated in an intravenous injection way or an oral way, the compound provided by the invention has good pharmacokinetic properties, including better Absorption (AUC)last) And good oral bioavailability (F).
EXAMPLE C inhibitory Activity of Compounds of the invention on cell proliferation
The experimental method comprises the following steps: the CTG method measures the inhibitory activity of a compound on cell proliferation.
The cell assay conditions are shown in table C:
watch C
Cell name Cell/well Incubation time (h) Complete culture medium
H358 1000 72 RPMI1640+10％FBS
1) Cell culture
The cells are cultured by adopting a proper culture medium and are placed in a 5% carbon dioxide incubator at 37 ℃. Cells were observed 1 time daily using an inverted microscope and the medium was changed every 2-4 days. The cells were collected, centrifuged at 1200rpm for 5min, the supernatant was discarded, and the cells were transferred to a new sterile petri dish at a ratio of 1:3 to 1:8 for culture.
2) Cell plating
Cells in the exponential growth phase were collected and counted using a cell counter. The cells were resuspended in the corresponding medium and adjusted to the appropriate concentration. 90 μ L of cell suspension was added to each well in a 96-well cell culture plate. The cells were cultured overnight in a 5% carbon dioxide incubator at 37 ℃.
3) Compound preparation and dosing treatment
a, preparing a mother solution: test compounds were dissolved in DMSO to prepare a 10mM stock.
And b, diluting the compound by 3 times by using DMSO (dimethyl sulfoxide) to obtain 9 concentration gradients of the compound, diluting the gradient diluted compound by 20 times by using a complete culture medium, and uniformly mixing to obtain a 10 multiplied by concentration drug working solution.
c, adding medicine: the cell culture plate was removed, 10. mu.L/well of the above 10 Xconcentration of the drug working solution was added to the corresponding well of the cell culture plate, and incubated in an incubator at 37 ℃ for 72 hours.
4) Read plate detection
and (a) after the compound is treated for 72 hours, the cell morphology is observed under an inverted microscope, the cell growth state in the DMSO control hole is normal, no pollution phenomenon is seen, and whether the compound is separated out from each hole or not is judged.
b, the prepared CTG solution is placed at room temperature for balancing for 10-20 minutes.
c Add 50. mu.L/well of CTG solution according to CTG protocol and shake on a shaker for 20 min in the dark.
d measuring the fluorescence signal value by using a microplate reader.
5) Data analysis
Growth inhibition rate%Negative group-VExperimental group)/(VNegative group-VBlank group) X 100% where VNegative groupAverage value of solvent control group, VExperimental groupReading for the drug treatment group, VBlank groupThe readings were from the cell-free drug-free treatment group. Data were analyzed and IC counted using GraphPad Prism 5.0 software 50The value is obtained.
Experiments prove that the compound has higher inhibitory activity on KRAS G12C mutant NCI-358 cells. Specifically, the inhibitory activity of the compound of the invention on the KRAS G12C mutant NCI-358 cells is less than 1000 nm; IC of most compounds therein50Less than 500nm, preferably part of the compound IC50Less than 100nm, preferably IC of partial compound50Less than 50 nm. The results of inhibition tests of some of the example compounds are shown in table 3.
TABLE 3 Experimental data on the inhibitory Activity of some of the examples of the present invention on cell proliferation
Figure BDA0003415708940001411
EXAMPLE D binding of Compounds of the invention to KRAS4B-G12C protein
The experimental method comprises the following steps: the LC-MS method detects the binding of the compound and KRAS4B-G12C protein.
The experimental steps are as follows:
1) experimental buffer preparation is shown in Table D
Table D
Figure BDA0003415708940001412
2) Loading of GDP into KRAS-4B-G12C protein
2 times of KRAS-4B-G12C protein is diluted to 103 μ M, 2mL of protein is taken and added with 1mL of 2 XGDP loading buffer solution, the mixture is gently mixed, incubated at room temperature for 1.5h, subpackaged into 100 μ L/tube, rapidly frozen in liquid nitrogen and stored in a refrigerator at-80 ℃.
3) KRAS-4B-G12C analysis
Mixing the reagents of Table E below
TABLE E
Reagent Dosage of
GDP loaded KRAS-4B-G12C (20uM) 5uL
Compound (10% DMSO solution) 5uL
10 Xincubation buffer 5uL
Ultra-pure water 35uL
In total 50uL
4) Incubated at room temperature for 30 minutes and 3 hours respectively
5) The reaction was stopped by adding 5. mu.L of 5% formic acid
6) LC-MS detection
A total of 55. mu.L of the reaction mixture was centrifuged at 15000rpm for 10 minutes before loading.
7) The Kras (G12C) binding percentage% was calculated
KRAS (G12C) binding rate ═ complex peak height/[ complex peak height + peak height not bound to KRAS G12C ] × 100
Results see table 4, table 4 for the results of the 1h protein binding experiments for the compounds provided in some of the examples of the present invention.
TABLE 4 results of protein binding experiments with compounds provided in some of the examples of the invention
Figure BDA0003415708940001421
Experiments show that the compound has high binding rate with KRAS4B-G12C protein.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (13)

1. A compound which is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure FDA0003415708930000011
wherein:
x is-L-X1-, where L is a bond or NH, X1Is a 4-8 membered monocyclic ring, a 5-12 membered fused ring, a 5-12 membered spiro ring or a 5-12 membered bridged ring containing a nitrogen atom, and the 4-8 membered monocyclic ring, the 5-12 membered fused ring, the 5-12 membered spiro ring and the 5-12 membered bridged ring may be independently optionally substituted by m RxSubstitution;
y is N or CH;
z is N or CR2e；
R1is-C (═ O) -CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rcor-S (═ O)2-C≡C-Rc；
RaAnd RbEach independently is hydrogen, deuterium, a halogen atom, C1-3Alkyl radical, C1-3Haloalkyl or C1-3Alkoxy, wherein, said C1-3Alkyl radical, C1-3Haloalkyl and C1-3Alkoxy is independently optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted by the radical hydroxyalkoxy;
Rcis hydrogen, deuterium, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino, 5-6 memberedHeteroaryl group, C3-6Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino, 5-6 membered heteroaryl, C3-6Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Hydroxyalkoxy and 3-6 membered heterocyclyl;
R3is C6-12Aryl or 5-to 10-membered heteroaryl, wherein, said C6-12Aryl and 5-10 membered heteroaryl are independently optionally substituted by n RySubstitution;
R2a、R2b、R2c、R2dand R2eEach independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy or C1-6An alkylamino group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C 1-6Alkoxy radical, C1-6Haloalkoxy and C1-6Alkylamino is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted by the radical hydroxyalkoxy;
each RxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C3-8Cycloalkyl radicalsOr a 3-8 membered heterocyclic group; wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C3-8Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted by the radical hydroxyalkoxy;
each RyIndependently is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OC1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkoxy, C 3-6Cycloalkyl, heterocyclic radical composed of 3-8 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms; wherein said-C (═ O) OC1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C6-10Aryl and heteroaryl consisting of 5 to 10 atoms are independently optionally substituted by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3Substituted by the radical hydroxyalkoxy;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
n is 1, 2, 3, 4, 5, 6 or 7.
2. The compound of claim 1, wherein X is
Figure FDA0003415708930000021
Figure FDA0003415708930000022
3. The compound of claim 1 or 2, wherein RaAnd RbEach independently hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2OH and-OCH2CH2OH is substituted by a group;
Rcis hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2OH、-OCH2CH2OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl;
R2a、R2b、R2c、R2dand R2eEach independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino and ethylamino are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups are substituted.
4. The compound of claim 1, wherein R 3Is C6-10Aryl or 5-to 10-membered heteroaryl, wherein, said C6-10Aryl and 5-10 membered heteroaryl are independently optionally substituted by n RyAnd (4) substitution.
5. The compound of claim 1, wherein R3Is composed of
Figure FDA0003415708930000031
Figure FDA0003415708930000032
Figure FDA0003415708930000033
Wherein, the
Figure FDA0003415708930000034
Figure FDA0003415708930000035
Figure FDA0003415708930000036
Independently optionally substituted by n RyAnd (4) substitution.
6. The compound of claim 1, wherein each RxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylamino radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylamino radical, C3-6Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
7. The compound of claim 1, wherein each RxIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, 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, -CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
8. The compound of claim 1, wherein each RyIndependently is deuterium, a halogen atom, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OC 1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms; wherein, said-C (═ O) OC1-4Alkyl radical, C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Hydroxyalkoxy, C3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C6-10Aryl and heteroaryl of 5 to 6 atoms are independently optionally substituted by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
9. The compound of claim 1, wherein each RyIndependently is deuterium, fluoro, chloro, bromo, hydroxy, amino, nitro, cyano, oxo, -C (═ O) OCH3Dimethylamino, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl, or triazolyl; wherein, the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy and-OCH 2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl and triazolyl are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and-OCH2CH2OH groups.
10. A compound which is a compound having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound having one of the following structures, or a prodrug thereof:
Figure FDA0003415708930000041
Figure FDA0003415708930000051
Figure FDA0003415708930000061
Figure FDA0003415708930000071
Figure FDA0003415708930000081
Figure FDA0003415708930000091
Figure FDA0003415708930000101
11. a pharmaceutical composition comprising a compound of any one of claims 1-10; and
the pharmaceutical composition optionally comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
12. Use of a compound of any one of claims 1 to 10 or a pharmaceutical composition of claim 11 in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a patient.
13. The use of claim 12, wherein the KRAS G12C mediated disease is cancer;
wherein the cancer is lung cancer, lymph cancer, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urinary epithelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, appendiceal cancer, small intestine cancer, leukemia or melanoma.
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