CN114075195A - Pyrimidone derivatives and their use in medicine - Google Patents

Pyrimidone derivatives and their use in medicine Download PDF

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CN114075195A
CN114075195A CN202110940927.3A CN202110940927A CN114075195A CN 114075195 A CN114075195 A CN 114075195A CN 202110940927 A CN202110940927 A CN 202110940927A CN 114075195 A CN114075195 A CN 114075195A
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isopropyl
chf
radical
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oxo
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习宁
吴双
李敏雄
席云龙
廖敏
李晓波
杨芳
陈疏影
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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 preparation of medicaments for the treatment of diseases and/or disorders mediated by KRAS G12C, 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-H-ras, K-ras and N-ras, which are located on chromosomes 11, 12 and 1, respectively. K-ras is also known as the p21 gene because it encodes a 21kD ras protein. Among Ras genes, K-Ras has the greatest effect on human cancer, accounting for 86% of all Ras mutations, as if it were a 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 more common subtype of KRAS gene mutation, which means that No. 12 glycine is mutated into 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 in an attempt 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 and WO 2012019141250 disclose small molecule compounds as 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 BDA0003214918440000011
wherein:
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, 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;
R4is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy or C1-3A hydroxyalkoxy group;
R5is 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 radicalOptionally 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;
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 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 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 C1-3Radical of hydroxyalkoxyl radicalsGroup substitution;
each RyIndependently is deuterium, halogen atom, hydroxyl, amino, nitro, cyano, 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 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;
p is 0, 1,2,3, 4 or 5.
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, -OCH2OH、-OCH2CH2OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholineRadical of the formula (I).
In some 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 RyAnd (4) substitution.
In some embodiments, R3Is composed of
Figure BDA0003214918440000031
Figure BDA0003214918440000032
Figure BDA0003214918440000033
Wherein, the
Figure BDA0003214918440000034
Figure BDA0003214918440000035
Figure BDA0003214918440000036
Independently optionally substituted by n RyAnd (4) substitution.
In some embodiments, R4Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH or-OCH2CH2OH。
In some embodiments, R5Is 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, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy and C1-4Alkylamino is independently optionallyIs selected from 1,2,3, 4 or 5 independently from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy and C1-3The group of hydroxyalkoxy.
In some embodiments, R5Is 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-propoxy, isopropoxy, -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, 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, 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, -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, 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, 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.
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, 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.
In some embodiments, each R isyIndependently is deuterium, halogen atom, hydroxyl, amino, nitro, cyano, 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 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, halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methylOxy, 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-OCH2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or 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.
In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) 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 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, 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, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use 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. includes the elements indicated in the present invention, but does not exclude other elements.
"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.
"diastereomer" refers to a stereoisomer 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, such as 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 of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). 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 substituents 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.
Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, oxo, halogen, cyano, nitro, hydroxy, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkynyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkanoyloxy, carboxy, alkoxyacyl, aryloxoyl, heteroaryloxy, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, and the like.
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 to mean 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 the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where 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; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (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; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. 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; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), alkynesPropyl (-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, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. 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, examples of which 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" groupMonocyclic rings of 3-8 membered rings (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give compounds 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", "heterocyclyl" or "heterocyclic" group is a 3-6 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, SO2，PO，PO2The group of (1). 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, is 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 BDA0003214918440000091
Radical, diaza
Figure BDA0003214918440000092
Radical, S-N-aza
Figure BDA0003214918440000093
Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH2Examples 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. The heterocyclyl group is optionally substituted with one or more substituents described herein.
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 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 herein 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, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like.
As described herein, the substituent (R)4)pThe ring system formed by a ring bound to the center represents p substituents R4Substitutions 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 p R4Substituted, when p is greater than 1, each R4May be independently selected from the same or different substituent groups.
Figure BDA0003214918440000101
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 BDA0003214918440000102
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. 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.14of 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 Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.
"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" refer to 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, description of the scientific 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 hydrogen, carbon, nitrogen, oxygen,Isotopes of phosphorus, sulfur, fluorine and chlorine, e.g.2H，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 often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia, or lymphoproliferative disorder (lymphoproliferative disorders). More specific examples of such cancers include squamous cell cancer (such as 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, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (kidney cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.
The term "KRAS G12C inhibitor" as used herein refers to a substance that binds to and inhibits the activity of KRAS G12C.
Detailed description of the Compounds of the invention
The invention provides a compound or a pharmaceutical composition thereof, which can be used as a KRAS G12C inhibitor. 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 the 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 BDA0003214918440000121
wherein each m, p, Z, R1、R2a、R2b、R2c、R2d、R3、R4、R5And RxAll have the meaning described herein.
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 RcHave the meaning as 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, -OCH2OH and-OCH2CH2OH groups.
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 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, 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 casesIn embodiments, RcIs hydrogen, deuterium, C1-6Alkyl radical, C2-6Alkenyl 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 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, -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 and RyHave the meaning as 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; wherein n and RyHave the meaning as described in the present invention.
In other embodiments, R3Is composed of
Figure BDA0003214918440000141
Figure BDA0003214918440000142
Figure BDA0003214918440000143
Wherein, the
Figure BDA0003214918440000144
Figure BDA0003214918440000145
Figure BDA0003214918440000146
Independently optionally substituted by n RySubstitution; wherein n and RyHave the meaning as described in the present invention.
In some embodiments, R4Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy or C1-3A hydroxyalkoxy group.
In other embodiments, R4Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH or-OCH2CH2OH。
In some embodiments, R5Is 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, R5Is 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, 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, R5Is 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-propoxy, isopropoxy, -OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2Methylamino, dimethylaminoAnd ethylamino is 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, 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, 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, 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, bromineIodine, hydroxy, 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 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, 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, aminoNitro, 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, said C1-4Alkyl radical, 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, 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, R2cIs 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, 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, 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-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, 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, 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, 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, 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 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, 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, 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, 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, -OCH2OH and-OCH2CH2OH groups.
In some embodiments, RxIs deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, 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, RxIs deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, 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, 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.
In other embodiments, RxIs deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, 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, tetrahydrofuryl, 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, 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.
In some embodiments, RyIs deuterium, halogen atom, hydroxyl, amino, nitro, cyano, 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 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, RyIs deuterium, halogen atom, hydroxyl, amino, nitro, cyano, 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 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, halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy or-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-OCH2OH、-OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolylFuryl or triazolyl is 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 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 BDA0003214918440000191
Figure BDA0003214918440000201
Figure BDA0003214918440000211
Figure BDA0003214918440000221
Figure BDA0003214918440000231
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 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, 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, a pharmaceutical composition of the invention features 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 invention is effective to treat or ameliorate 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 that can be administered directly or indirectly in accordance with the needs of the patient, 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 excipient, as used herein, including any solvent, diluent, or other liquid excipient, 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 the following documents: 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. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different carriers can be used 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 invention, e.g., any adverse biological effect produced or interaction 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 formulations) 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 filler 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 wetting agent, 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 targeted drug carriers. 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 a decision and prescribe the effective amount of the drug to prevent, counter or arrest the progress of the cancer.
In accordance with general guidelines, daily oral dosages of each active ingredient used are 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 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 the 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, leukemia, melanoma and the like.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing 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 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, are all temperatures set forth in degrees Celsius. The 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 calcium hydride reflux drying. 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 (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad single), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), and dt (doublet of triplets). Coupling constant J, expressed in Hertz (Hz).
Low resolutionThe conditions for measuring 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:
CDCl3deuterated chloroform mL/mL
DMSO-d6mu.L of deuterated dimethyl sulfoxide
g MPa
mg of DTT dithiothreitol
M mol of Glutathione per liter of Glutathione
mM millimole of NaCl sodium chloride per liter
mol mole EDTA ethylene diamine tetraacetic acid
mmol of mmole of hepes 4-hydroxyethylpiperazine ethanesulfonic acid
DCM dichloromethane MeOH methanol
PE Petroleum Ether EtOAc ethyl acetate
CAN acetonitrile TFA trifluoroacetic acid
THF tetrahydrofuran DIPEA N, N-diisopropylethylamine
Pd(dppf)Cl2[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
XPhos Pd G2 chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II)
XPhos Pd G3 methanesulfonic acid (2-dicyclohexylphosphine-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)
The following reaction scheme describes the steps for preparing the compounds of the present invention. Each Z, R therein, unless otherwise statedx、R2a、R2b、R2c、R2d、R3、R4M and p have the definitions stated in the present invention.
Reaction scheme 1
Figure BDA0003214918440000261
Formula (A), (B) and17) 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) and7) A compound of the formula8) The compound reacts under the action of N, N-diisopropylethylamine to obtain a compound shown in a formula (I)9) The compounds shown. Formula (A), (B) and9) A compound of the formula10) The compound reacts under the action of potassium acetate to obtain a compound shown in a formula (A)11) A compound shown in the specification; then, formula (A)11) A compound of the formula12) The compound is represented by [1,1' -bis (diphenylphosphino) ferrocene]The palladium dichloride dichloromethane complex can react with cesium carbonate to obtain a compound shown in the formula (I)14) A compound shown in the specification; or, formula (A)11) A compound of the formula13) The compound is prepared by reacting chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl ]]Palladium (II) and sodium carbonate can also react under the action of the catalyst to obtain the formula (I)14) The compounds shown. Formula (A), (B) and14) The compound is shown in the specificationRemoving Boc under the action of acetic acid to obtain a product of the formula (I)15) The compounds shown. Formula (A), (B) and15) A compound of the formula16) The compound can react under the action of N, N-diisopropylethylamine to obtain a compound shown in the formula (A)17) 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) -6-cyclopropyl-7- (2-fluoro-6-hydroxybenzene) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000271
First step synthesis of 2,5, 6-trichloropyridine-3-formamide
2,5, 6-trichloropyridine-3-carboxylic acid (5.00g,22.0mmol), dichloromethane (60.0mL) and N, N-dimethylformamide (0.05mL,0.6mmol) were added to the reaction flask, the temperature was reduced to 0 deg.C, and oxalyl chloride (2.4mL,28mmol) was added dropwise. After the dripping is finished, stirring is carried out for 24 hours. A solution of ammonia in isopropanol (17.0mL,34mmol,2.0mol/L) was added and stirring was continued for 4h, whereupon a large amount of white solid precipitated. Suction filtration was carried out, and the residue was washed with dichloromethane (50 mL. times.2) and dried to give the title compound as a white solid (1.6g, 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
2,5, 6-trichloropyridine-3-carboxamide (1.46g,6.48mmol) and tetrahydrofuran (10mL) were added to the reaction flask, warmed to 75 ℃ and oxalyl chloride (1.0g,7.9mmol) was added dropwise and stirred for 1 h. Cooled to room temperature, concentrated to remove the solvent, cooled to 0 ℃ and dissolved in THF (5 mL). 2-isopropyl-4-methyl-pyridin-3-amine (1.0g,6.7mmol) was dissolved in tetrahydrofuran (5mL), added dropwise to the mixture and stirred overnight. Quenched by addition of saturated ammonium chloride (10mL), extracted with ethyl acetate (50 mL. times.3), the organic phases combined and concentrated to give the title compound as a yellow solid (1.4g, 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
Adding 2,5, 6-trichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (1.4g,3.5mmol) and tetrahydrofuran (10.0mL) into a reaction bottle, cooling to 0 ℃, dropwise adding a tetrahydrofuran solution (8.7mL,1mol/L and 8.7mmol) of bis (trimethylsilyl) amino potassium, transferring to the normal temperature after dropwise adding, and stirring overnight. Quenched by addition of saturated ammonium chloride (5mL), extracted with ethyl acetate (50mL), and concentrated to give the title compound as a yellow solid (0.30g, 24%).
Fourth step Synthesis of 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridyl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (0.20g,0.55mmol), N, N-diisopropylethylamine (0.6mL,4mmol) and acetonitrile (2.0mL) were added to a reaction flask, dissolved with stirring, phosphorus oxychloride (0.3mL,3mmol) was added dropwise, warmed to reflux, and stirred overnight. The solvent was removed under reduced pressure to give the title compound as a brown oil (210.1mg, 100%) which was used in the next step without purification.
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
4,6, 7-trichloro-1- (2-isopropyl-4-methyl-3-pyridyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.53g,1.37mmol), (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.41g,2.05mmol), N, N-diisopropylethylamine (1.2mL,7.2mmol) and acetonitrile (6mL) were added to a reaction flask, warmed to 80 ℃ and stirred overnight. The solvent was removed by concentration, and the obtained residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.46g, 60.82%)
MS(ESI,pos.ion)m/z:547.2[M+H]+.
Sixth step Synthesis of tert-butyl (3S) -4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
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 (0.43g,0.78mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (0.18g,1.17mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (63.8mg,0.078mmol), potassium acetate (0.33g,3.11mmol) and 1, 4-dioxane (10mL), warmed to 100 ℃, and stirred for 24 h. The solvent was removed by concentration, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-0/1) to give the title compound as a yellow solid (0.24g, 48.9%).
MS(ESI,pos.ion)m/z:623.3[M+H]+.
Seventh step Synthesis of tert-butyl (3S) -4- (6-cyclopropyl-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask was added tert-butyl (3S) -4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (12.5mg,0.02mmol), cyclopropylboronic acid (6.9mg,0.08mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (63.8mg,0.078mmol), cesium carbonate (13.2mg,0.04mmol) and 1, 4-dioxane (2.0mL), warmed to 100 ℃, and stirred for 10 h. Cooled to room temperature and stirred overnight. The solvent was removed by concentration, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-0/1) to give the title compound as a yellow solid (6.4mg, 51%).
MS(ESI,pos.ion)m/z:629.3[M+H]+.
Eighth step Synthesis of 6-cyclopropyl-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- ((S) -2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
The reaction flask is added with (3S) -4- (6-cyclopropyl-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butylMethyl ester (95.5mg,0.15mmol), dichloromethane (5.0mL), trifluoroacetic acid (1.0mL,13mmol) was added dropwise and stirred at ambient temperature for 1.5 h. Concentration directly under reduced pressure gave the title compound as a yellow viscous liquid (80.3mg, 100%). MS (ESI, pos. ion) M/z 529.3[ M + H ]]+.
Ninth step Synthesis of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-6-hydroxybenzene) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added 6-cyclopropyl-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- ((S) -2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (80.3mg,0.085mmol), dichloromethane (2mL), cooled to-30 ℃, a solution of acryloyl chloride (15.1mg,0.17mmol) in DCM (1mL) was slowly added dropwise, stirred for 2H, the solvent was removed by concentration, and the title compound was isolated via preparative column as a white solid (10.9mg, 12.31%).
1H NMR(400MHz,CDCl3)δ(ppm)9.02(s,1H),8.61(d,J＝4.9Hz,1H),7.77(s,1H),7.19(d,J＝5.4Hz,2H),6.75-6.60(m,3H),6.42(d,J＝16.0Hz,1H),5.82(dd,J＝10.5,1.7Hz,1H),5.43-5.21(m,1H),4.84-4.66(m,1H),4.61-4.42(m,1H),3.97-3.79(m,1H),3.77-3.40(m,3H),3.25(dd,J＝19.8,15.3Hz,1H),2.91-2.71(m,1H),2.04(s,3H),1.34-1.28(m,4H),1.23(s,6H),1.05(d,J＝6.5Hz,3H).
Example 2(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000291
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Adding (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle]Pyrimidin-4-yl) -3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.24g,0.44mmol), (5)-fluoro-2-hydroxyphenyl) boronic acid (0.10g,0.67mmol), Pd (dppf) Cl2(35.8mg,0.044mmol), potassium acetate (0.19g,1.75mmol) and 1, 4-dioxane (10.0mL), warmed to 100 ℃ and stirred for 24 h. The solvent was removed by concentration. The resulting 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 (0.18g, 66.9%).
MS(ESI,pos.ion)m/z:623.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Adding (S) -4- (6-chloro-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.18g,0.29mmol), cyclopropylboronic acid (0.50g,5.78mmol), Pd (dppf) Cl2(47.2mg,0.058mmol), potassium carbonate (0.12g,0.87mmol), water (0.10g) and 1, 4-dioxane (6.0mL), warmed to 100 ℃ and stirred for 24 h. Cooled to normal temperature and the solvent was removed under reduced pressure. To the resulting residue was added water (30mL), stirred for 10min, extracted with ethyl acetate (100 mL. times.3), and the organic phases combined and concentrated under reduced pressure to give the title compound as a yellow solid (0.18g, 100%).
The third step is the synthesis of (S) -6-cyclopropyl-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.18g,0.29mmol), dichloromethane (10.0mL) and trifluoroacetic acid (2.0mL) and stirred for 5 h. The solvent was removed by concentration under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a brown solid (0.15g, 100%).
The fourth step (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one synthesis
To a reaction flask was added (S) -6-cyclopropyl-7- (5-fluoro-2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.16g,0.29mmol), N-diisopropylethylamine (0.38g,2.93mmol), and dichloromethane (4 mL). The temperature of the system is reduced to-30 ℃, a dichloromethane (2mL) solution of acryloyl chloride (31.9mg,0.35mmol) is slowly dropped, and after dropping, the temperature is kept and the stirring is carried out for 3 h. After the raw materials are completely reacted, the solvent is removed by decompression and concentration. The resulting residue was isolated and purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (3.9mg, 2.3%).
MS(ESI,pos.ion)m/z:583.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)10.53-10.33(m,1H),8.66(d,J＝4.8Hz,1H),8.38-8.21(m,1H),7.00-6.84(m,2H),6.80-6.65(m,2H),6.46-6.32(m,1H),5.92-5.79(m,1H),5.40-5.29(m,1H),4.78-4.64(m,1H),4.54-4.40(m,1H),3.90(ddd,J＝10.0,7.3,5.5Hz,1H),3.73-3.49(m,2H),3.31-2.95(m,2H),2.91-2.74(m,1H),2.30-1.96(m,4H),1.44(dd,J＝5.0,2.1Hz,2H),1.33-1.27(m,6H),1.10(d,J＝6.7Hz,3H),0.89-0.80(m,2H).
Example 3(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000311
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
To a reaction flask was added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridyl) -2-oxo-pyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.20g,0.37mmol), (2-fluorophenyl) boronic acid (0.10g,0.74mmol), (1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (30.1mg,0.037mmol), cesium carbonate (0.14g,0.73mmol) and 1, 4-dioxane (10.0mL), water (0.20g,11.10mmol), warmed to 100 ℃, and stirred for 3 h. Cooled to room temperature and concentrated to remove the solvent. Water (30mL) was added, the mixture was stirred for 10min, extracted with ethyl acetate (100 mL. times.3), and the organic phases were combined and concentrated. The obtained residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a yellow solid (223.7mg, 100%).
MS(ESI,pos.ion)m/z:607.3[M+H]+.
Second Synthesis of tert-butyl (S) -4- (6-cyclopropyl-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
To a reaction flask were added 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 (0.36g,0.59mmol), 1, 4-dioxane (6.0mL), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (73.6mg,0.094mmol), sodium carbonate (0.36g,4.32mmol), nitrogen was replaced and protected, a tetrahydrofuran solution of cyclopropyl zinc bromide (12.0mL,0.5mol/L,6.00mmol) was added rapidly, the temperature was raised to 100 ℃ and stirred for 24 h. The solvent was removed by concentration, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-0/1), and preparative by reverse phase was followed to isolate the title compound as a yellow solid (85.3mg, 23.5%).
MS(ESI,pos.ion)m/z:613.3[M+H]+.
Third step Synthesis of (S) -6-cyclopropyl-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a single-necked flask were added (S) -4- (6-cyclopropyl-7- (2-fluorophenyl) -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,0.065mmol), trifluoroacetic acid (0.5mL,7mmol) and dichloromethane (4.0mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration to give the title compound as a brown solid (33.5mg, 100%).
Fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a single-necked flask were added (S) -6-cyclopropyl-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (33.5mg,0.065mmol) and dichloromethane (4mL), the temperature was reduced to 0 ℃ and a solution of acryloyl chloride (7.2mg,0.080mmol) in dichloromethane (2mL) was slowly added dropwise and stirred for 3H after completion. After the raw materials are completely reacted, the solvent is removed by concentration. The obtained residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (22.8mg, 61.6%).
MS(ESI,pos.ion)m/z:567.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.47(d,J＝4.9Hz,1H),7.66(d,J＝10.6Hz,1H),7.40-7.34(m,1H),7.16-7.12(m,2H),7.08(t,J＝8.4Hz,2H),6.69-6.56(m,1H),6.41(d,J＝16.7Hz,1H),5.81(d,J＝10.5Hz,1H),5.12(s,1H),4.75(s,1H),3.68(dd,J＝73.0,60.2Hz,3H),3.26(s,1H),3.07(s,1H),2.75(s,1H),2.02(d,J＝4.4Hz,3H),1.89-1.85(m,1H),1.56(s,2H),1.48(s,2H),1.27-1.20(m,6H),1.05(d,J＝6.4Hz,3H).
Example 4(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000321
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridyl) -2-oxo-pyrido [2,3-d ] pyrimidin-4-yl) -3-methyl-piperazine-1-carboxylate (0.50g,0.91mmol), (4-fluorophenyl) boronic acid (0.14g,1.01mmol), (1, 1'- [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (74.9mg,0.092mmol), cesium carbonate (0.23g,1.19mmol) and 1, 4-dioxane (10.0mL), warmed to 100 ℃, and stirred for 4 h. Cooled to room temperature and concentrated to remove the solvent to give a brown solid. Water (30mL) was added, the mixture was stirred for 10min, extracted with ethyl acetate (100 mL. times.3), and the organic phases were combined and concentrated. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (480.1mg, 86.59%).
MS(ESI,pos.ion)m/z:607.3[M+H]+.
Second Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Adding (S) -4- (6-chloro-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.11g,0.19mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (21.8mg,0.028mmol) and sodium carbonate (76.8mg,0.93mmol) were added rapidly under nitrogen with a solution of cyclopropyl zinc bromide in tetrahydrofuran (10.0mL,0.5mol/L,5.0mmol), warmed to 70 ℃ and stirred overnight. The solvent was removed by concentration, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.11g, 94.23%). MS (ESI, pos. ion) M/z 613.3[ M + H ]]+.
Third step Synthesis of (S) -6-cyclopropyl-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a single neck flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.13g,0.21mmol), trifluoroacetic acid (0.5mL) and dichloromethane (4.0mL) and stirred at room temperature for 3 h. The solvent was removed by concentration and dried in vacuo to give the title compound as a brown solid (0.11g, 100.0%).
MS(ESI,pos.ion)m/z:513.3[M+H]+.
Fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a single vial was added (S) -6-cyclopropyl-7- (4-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.11g,0.21mmol) and dichloromethane (2mL), the temperature was reduced to 0 deg.C, a solution of acryloyl chloride (23.2mg,0.26mmol) in dichloromethane (2mL) was slowly added dropwise, and the mixture was stirred for 3H. The solvent was removed by concentration, and the resulting residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a yellow solid (84.3mg, 70.6%).
MS(ESI,pos.ion)m/z:567.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.52(d,J＝4.4Hz,1H),7.69(s,1H),7.55(s,2H),7.18-6.97(m,3H),6.72-6.53(m,1H),6.40(d,J＝16.5Hz,1H),5.81(d,J＝10.3Hz,1H),4.41(ddd,J＝33.1,18.9,6.6Hz,2H),4.11-3.42(m,4H),3.16(dd,J＝79.9,6.9Hz,1H),2.72(dd,J＝33.3,9.1Hz,1H),2.03(s,3H),1.80(s,2H),1.52(d,J＝29.6Hz,3H),1.38-1.15(m,5H),1.14-1.01(m,4H).
Example 5(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000331
Synthesis of tert-butyl (S) -4- (6-chloro-7- (2-methoxyphenyl) -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
The reaction flask is filled with (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridyl) -2-oxo-pyrido [2,3-d ]]Pyrimidin-4-yl) -3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.50g,0.91mmol), (2-methoxybenzene) boronic acid (0.15g,1.01mmol), Pd (dppf) Cl2(74.8mg,0.092mmol), potassium carbonate (0.43g,4.30mmol) and 1, 4-dioxane (10.0mL), heated to 100 ℃ and stirred for 24 h. Cooled to room temperature and concentrated to remove the solvent to give a brown solid. Then, water (30mL) was added thereto, the mixture was stirred for 10min, and the mixture was extracted with ethyl acetate (100 mL. times.3), the organic phases were combined and concentrated. 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, 74.38%).
MS(ESI,pos.ion)m/z:619.4[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -tert-butyl 4- (6-chloro-7- (2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.42G,0.68mmol), xphos Pd G2(82.9mg,0.11mmol), sodium carbonate (0.29G,3.44mmol) and zinc cyclopropyl bromide (10.0mL,1.0mol/L,10.0mmol), warmed to 60 ℃ and stirred overnight. The system was concentrated under reduced pressure to remove the solvent, and 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 (0.39g, 92.21%).
MS(ESI,pos.ion)m/z:625.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (S) -tert-butyl 4- (6-cyclopropyl-7- (2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.13g, 0.22mmol), trifluoroacetic acid (1.0mL) and dichloromethane (6.0mL), and stirred at room temperature overnight. The solvent was removed by concentration to give the title compound as a yellow solid (0.11g, 100.0%).
Fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To the reaction flask were added (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.11g,0.22mmol), dichloromethane (2 mL). The system was cooled to 0 deg.C, a solution of acryloyl chloride (21.5mg,0.24mmol) in dichloromethane (1mL) was slowly added dropwise, after the addition was complete, stirring was maintained for 6 h. The solvent was removed by concentration. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a yellow solid (28.7mg, 23.0%).
MS(ESI,pos.ion)m/z:579.4[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.45(d,J＝4.8Hz,1H),7.57(s,1H),7.34(t,J＝7.1Hz,1H),7.09-6.80(m,4H),6.71-6.53(m,1H),6.40(d,J＝16.5Hz,1H),5.85-5.75(m,1H),5.27-4.91(m,1H),4.76(dd,J＝9.6,7.0Hz,1H),4.65-4.20(m,2H),4.10-3.46(m,7H),3.30-3.01(m,1H),2.03(s,3H),1.75(dd,J＝12.0,6.8Hz,1H),1.47(d,J＝1.7Hz,2H),1.25(dd,J＝20.3,9.2Hz,6H),1.05(d,J＝6.4Hz,3H),0.86-0.77(m,2H).
Example 6(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (pyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000351
Synthesis of tert-butyl (S) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (pyridin-3-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate in the first step
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 (0.20g,0.36mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (60.2mg,0.07mmol), potassium acetate (0.18g,1.90mmol), 1, 4-dioxane (5.0mL) were added separately to the reaction flask. After the nitrogen gas in the system was replaced three times, the mixture was stirred at 90 ℃ for 10min, then 3-pyridineboronic acid (82.3mg,0.7mmol) was dissolved in 1, 4-dioxane (1.0mL), and after the system was added, water (0.5mL) was added and the reaction was continued for 3 h. Heating was stopped, the mixture was cooled to room temperature, the system was filtered with suction, the filtrate was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) ═ 1/4) to give the title compound as a dark green solid (90.0mg, 41.8%).
MS(ESI,pos.ion)m/z:590.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (pyridin-3-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
The reaction flask is charged with (S) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (pyridin-3-yl) -1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (90.0mg,0.15mmol), XPhos Pd G3(15.6mg,0.017mmol), Na2CO3(60.5mg,0.73mmol), a solution of cyclopropylzinc bromide in tetrahydrofuran (3.5mL,2mmol) was added after replacement of nitrogen, and the mixture was heated to 70 ℃ for reaction for 10 hours. And after the reaction is completed, stopping heating, cooling to room temperature, and performing suction filtration. The filtrate was rotary dried under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/9) to give the title compound as a dark green solid (65.0mg, 64.4%).
MS(ESI,pos.ion)m/z:596.4[M+H]+.
The third step is (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- (pyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
The reaction flask is filled with (S) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (pyridin-3-yl) -1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (60.0mg,0.10mmol), CH2Cl2(2.5mL), trifluoroacetic acid (0.5mL), and reacted at room temperature for 2 h. The system was directly spin dried and dried in vacuo to give the title compound as a light brown viscous mass (73.0mg, 119%).
MS(ESI,pos.ion)m/z:496.3[M+H]+.
Fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (pyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
(S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- (pyridin-3-yl) pyrido [2,3-d ] was added to the reaction flask at-1 deg.C]Pyrimidin-2 (1H) -one (73.0mg,0.12mmol), CH2Cl2(20.0mL)，Et3N (32.5mg,0.32mmol), and acryloyl chloride (13.0mg,0.14mmol) were added. After the reaction was allowed to stand for 30min, the reaction mixture was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) ═ 1/0-0/1) to give the title compound as a pale yellow solid (17.0mg, 25.8%).
MS(ESI,pos.ion)m/z:550.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.89(s,1H),8.62(d,J＝3.6Hz,1H),8.55(d,J＝4.9Hz,1H),7.84-7.74(m,2H),7.31-7.34(m,1H),7.12(d,J＝4.9Hz,1H),6.68–6.60(m,1H),6.44-6.37(m,1H),5.83(dd,J＝10.4,1.5Hz,1H),4.62-4.76(m,1H),4.29-4.49(m,1H),3.89-4.05(m,1H),3.66-3.73(m,2H),3.52-3.50(m,1H),3.29-3.33(m,1H),3.10(dd,J＝14.6,7.3Hz,1H),2.65-2.80(m,1H),2.05(s,3H),1.27(s,3H),1.26-1.23(m,3H),1.09-1.11(m,2H),1.02-1.05(m,3H),0.91-0.84(m,2H).
Example 7(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7-phenylpyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000361
Synthesis of first step tert-butyl (S) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7-phenyl-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask was added (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-pyrido [2,3-d ] pyrimidin-4-yl) -3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.02g,1.86mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.15g,0.19mmol), cesium carbonate (0.92g,2.80mmol), 1, 4-dioxane (20.0mL), phenylboronic acid (0.25g,2.04 mmol). The nitrogen was replaced three times and the reaction was carried out at 100 ℃ for 2 hours. Filtered through celite. The filtrate was dried under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/0-3/1) to give the title compound as a pale yellow solid (0.85g, 77.4%).
MS(ESI,pos.ion)m/z:589.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7-phenyl-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
The reaction flask is added with (S) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7-phenyl-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.44G,0.74mmol), XPhos Pd G3(75.6mg,0.08mmol), Na2CO3(0.20g,2.40mmol), a solution of cyclopropylzinc bromide in tetrahydrofuran (20mL,10mmol) was added after nitrogen gas had been replaced. The system is heated to 70 ℃ and reacted for 7 h. After the reaction, the reaction mixture was cooled to room temperature and filtered under suction. The filtrate was spun dry under reduced pressure and the residue passed through a prep column (43% CAN-57% H)2O, 0.2% TFA) to give the title compound as a white solid (0.22g, 49.07%).
MS(ESI,pos.ion)m/z:595.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7-phenylpyrido [2,3-d ] pyrimidin-2 (1H) -one
To the reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7-phenyl-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.22g,0.36mmol), dichloromethane (3.5mL), trifluoroacetic acid (1.5 mL). The system was reacted at room temperature for 2 h. After the reaction of the starting materials was complete, the system was spun dry and dried overnight at 60 ℃ under vacuum to give the title compound as a light brown viscous mass (0.30g, 134%).
MS(ESI,pos.ion)m/z:495.3[M+H]+.
The fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7-phenylpyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7-phenylpyrido [2,3-d ] pyrimidin-2 (1H) -one (0.25mg,0.41mmol), dichloromethane (20.0mL), triethylamine (0.11g,1.07mmol), further acryloyl chloride (46.5mg,0.5mmol), and the reaction was incubated at-5 ℃ for 20 min. Dried under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/0-10/3) to give the title compound as a white solid (10.0mg, 44.5%).
MS(ESI,pos.ion)m/z:549.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.55(d,J＝4.9Hz,1H),7.68(s,1H),7.57-7.52(m,2H),7.34-7.39(m,3H),7.12(d,J＝4.9Hz,1H),6.71-6.56(m,1H),6.23-6.13(m,1H),5.82(d,J＝12.0Hz,1H),4.77-4.47(m,2H),4.04-3.88(m,2H),3.68-3.55(m,2H),3.13(d,J＝7.3Hz,2H),2.81-2.69(m,1H),2.06(s,3H),1.58-1.50(m,3H),1.30(d,J＝7.3Hz,3H),1.25(d,J＝6.7Hz,3H),1.07-1.04(m,4H).
Example 8(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000381
First step Synthesis of (S) -6-cyclopropyl-7- (2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added tert-butyl (S) -4- (6-cyclopropyl-7- (2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.13g,0.21mmol), dichloromethane (5.0mL), anhydrous aluminum chloride (0.13g,2.10mmol), and after stirring for 10min, ethanethiol (0.13g,2.08mmol) was added dropwise and the mixture was stirred at room temperature overnight. Water (10mL) was slowly added dropwise and extracted with dichloromethane (50 mL. times.3). The organic phases were combined, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a yellow solid (0.11g, 100%).
Second step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -6-cyclopropyl-7- (2-methoxy-phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.11g,0.21mmol), dichloromethane (2mL), N-diisopropylethylamine (0.27g,2.08 mmol). The temperature is reduced to minus 30 ℃, the solution of acryloyl chloride (20.7mg,0.23mmol) in dichloromethane (1mL) is slowly dropped, and after the dropping is finished, the mixture is kept warm and stirred for 5 h. After the raw materials are completely reacted, concentrating 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 (15.3mg, 13.1%).
MS(ESI,pos.ion)m/z:565.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.61(d,J＝4.7Hz,1H),7.69(s,1H),7.48(d,J＝7.2Hz,1H),7.33(t,J＝7.5Hz,1H),7.17(s,1H),6.92(dd,J＝16.0,8.1Hz,2H),6.71-6.54(m,1H),6.41(d,J＝16.5Hz,1H),5.81(d,J＝10.3Hz,1H),5.10(s,1H),4.84-4.65(m,1H),4.59-4.38(m,1H),4.33-4.17(m,1H),4.03(dd,J＝10.5,5.5Hz,1H),3.87(dd,J＝10.8,5.5Hz,1H),3.73-3.64(m,1H),3.30-3.00(m,1H),2.85-2.66(m,1H),2.05(s,3H),1.66-1.61(m,1H),1.47(dd,J＝4.7,2.6Hz,2H),1.26(s,6H),1.07(dd,J＝15.9,9.6Hz,5H).
Example 9(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000391
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
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), 2-fluoro-5-methoxyphenylboronic acid (0.21g,1.21mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (78.0mg,0.096mmol), potassium acetate (0.14g,1.38mmol) and 1, 4-dioxane (40.0mL), warmed to 100 ℃, and stirred for 3 h. Cooled to room temperature and concentrated to remove the solvent. To the residue was added saturated brine (30mL), stirred for 10min, extracted with ethyl acetate (100mL × 3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a pale yellow solid (0.44g, 75.3%).
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -tert-butyl 4- (6-chloro-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.40g,0.63mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (57.0mg,0.073mmol) and cyclopropylzinc bromide (10.0mL,5.0mmol), and the temperature was raised to 68 ℃, the reaction was carried out for 7 hours. After completion of the reaction of the starting materials, the reaction mixture was cooled to room temperature, saturated brine (10.0mL) was added, ethyl acetate was extracted (30mL × 3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.19g, 47.1%).
MS(ESI,pos.ion)m/z:643.3[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyridine [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (79.7mg,0.13mmol), trifluoroacetic acid (3.0mL,40mmol) and dichloromethane (4.0mL), and stirred at room temperature for 1 h. After the starting material had reacted to completion, the solvent was removed by concentration under reduced pressure and dried under vacuum at 60 ℃ to give the title compound as a brown solid (67.0mg, 100.0%) which was used directly in the next reaction.
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyridin [2,3-d ] pyrimidin-2 (1H) -one (63.3mg,0.117mmol), N, N-diisopropylethylamine (0.1mL,1.0mmol), dichloromethane (4.0mL), cooled to 0 deg.C, a solution of acryloyl chloride (0.1g,1.0mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 min. After the reaction, the solvent was removed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (69.3mg, 99.6%).
MS(ESI,pos.ion)m/z:597.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.60(d,J＝5.0Hz,1H),7.67(s,1H),7.18(d,J＝4.9Hz,1H),7.00(t,J＝9.1Hz,1H),6.92–6.86(m,1H),6.64(dd,J＝5.4,3.1Hz,2H),6.41(d,J＝16.6Hz,1H),5.84–5.79(m,1H),4.54(ddd,J＝70.3,59.2,12.8Hz,4H),3.69(s,3H),2.78(s,1H),2.11–2.03(m,4H),1.97–1.88(m,1H),1.53(d,J＝28.6Hz,3H),1.26(t,J＝7.3Hz,5H),1.11(d,J＝6.4Hz,3H),0.94(s,2H),0.55(s,2H).
Example 10(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000401
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
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 (0.30g,0.55mmol), 2-fluoro-5-methylphenylboronic acid (0.11g,0.73mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (48.3mg,0.059mmol), potassium acetate (71.4mg,0.73mmol) and 1, 4-dioxane (30.0mL), and under nitrogen, warmed to 100 ℃ and stirred for 3 h. Cooled to room temperature and concentrated under reduced pressure to remove the solvent. To the residue was added saturated brine (30mL), stirred for 10min, extracted with ethyl acetate (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.32g, 92.8%).
MS(ESI,pos.ion)m/z:622.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-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
To a reaction flask 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 (0.30g,0.48mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (44.3mg,0.056mmol), and cyclopropyl zinc bromide (15.0mL,8.0 mmol). The temperature of the system was raised to 68 ℃ and the reaction was carried out for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (30.0mL × 3), the organic phases were combined, the solvent was removed by concentration under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.16g, 53.5%).
MS(ESI,pos.ion)m/z:627.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyridine [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (S) -tert-butyl 4- (6-cyclopropyl-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 (0.16g,0.26mmol), trifluoroacetic acid (5.0mL,50mmol) and dichloromethane (6.0mL), and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and dried under vacuum at 60 ℃ to give the title compound as a brown solid (0.14g, 100.0%) which was used in the next step.
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (S) -6-cyclopropyl-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyridin [2,3-d ] pyrimidin-2 (1H) -one (0.14g,0.26mmol), N, N-diisopropylethylamine (0.1mL,1.0mmol), dichloromethane (8.0mL), cooled to 0 deg.C, a solution of acryloyl chloride (0.1g,1.0mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 min. The reaction was completed to noble yang, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (0.11g, 71.6%).
MS(ESI,pos.ion)m/z:581.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.39(d,J＝3.5Hz,1H),7.73(s,1H),7.27–7.12(m,3H),6.99(d,J＝5.9Hz,1H),6.86(dd,J＝23.1,11.5Hz,1H),6.20(dd,J＝16.7,5.6Hz,1H),5.76(d,J＝9.8Hz,1H),4.85(s,1H),3.75–3.55(m,2H),3.09(s,1H),2.67(s,2H),2.24(s,3H),1.93–1.87(m,3H),1.67(s,1H),1.37(d,J＝5.6Hz,3H),1.29–1.20(m,2H),1.06(s,3H),0.95(d,J＝5.3Hz,3H),0.84(d,J＝7.9Hz,2H),0.73(s,2H).
Example 11(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000421
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
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-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.30g,0.55mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (52.0mg,0.06mmol), potassium acetate (0.28g,2.80mmol), 1, 4-dioxane (18.0mL), nitrogen was replaced three times, followed by stirring at 90 ℃ for 10min, followed by addition of 1 of (2-fluoro-3-hydroxyphenyl) boronic acid (0.17g,1.10mmol), 4-dioxane (2.0mL), and three drops of water. After the reaction was continued for 2.5h, it was cooled to room temperature, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10/0-20/1) to give the title compound as a yellow solid (0.28g, 82.0%).
MS(ESI,pos.ion)m/z:623.2[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-chloro-7- (2-fluoro-3- ((4-methoxyphenyl) oxy) -phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask was added (S) -tert-butyl 4- (6-chloro-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.25g,0.40mmol), acetonitrile (10.0mL), potassium carbonate (65.8mg,0.48 mmol). The system was heated to 85 ℃ and 4-methoxybenzyl bromide (0.15g,0.75mmol) was added portionwise and the reaction was allowed to incubate. After completion of the reaction, it was cooled to room temperature, methanol (10.0mL) was added, stirred for 2min, filtered through celite, the filtrate was spun off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/0-2/1) to give the title compound as a yellow solid (0.26g, 86.5%).
MS(ESI,pos.ion)m/z:743.4[M+H]+.
Third step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (2-fluoro-3- ((4-methoxyphenyl) oxy) -phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
A reaction flask was charged with (S) -4- (6-chloro-7- (2-fluoro-3- ((4-methoxyphenyl) oxy) -phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.25G,0.34mmol), Xphos Pd G3(35.8mg,0.04mmol), sodium carbonate (0.14G,1.72mmol), a solution of cyclopropylzinc bromide in tetrahydrofuran (10.0mL,0.5mol/L,5.0mmol) was added under nitrogen, heated to 70 ℃ for 12h, cooled to room temperature, and filtered. The filtered mother liquor was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-0/1) to give the title compound as a white solid (0.19g, 75.4%).
MS(ESI,pos.ion)m/z:749.5[M+H]+.
Fourth step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask was added (S) -4- (6-cyclopropyl-7- (2-fluoro-3- ((4-methoxyphenyl) oxy) -phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.18g,0.24mmol), 10% Pd/C (0.15g), methanol (20.0mL), reacted at room temperature for 6.5h after replacement of hydrogen, filtered, and the filtrate was rotary dried under reduced pressure to give the title compound as a gray solid (0.12g, 82.1%) which was directly put into the next step.
MS(ESI,pos.ion)m/z:629.3[M+H]+.
The fifth step (S) -6-cyclopropyl-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.12g,0.20mmol), dichloromethane (15.0mL), trifluoroacetic acid (2.0mL) and reacted at room temperature for 1.5 h. After the reaction was complete, the system was directly spin-dried under reduced pressure to give the title compound as a pale brown viscous liquid (0.10g, 100.0%) which was directly charged into the next step.
MS(ESI,pos.ion)m/z:529.3[M+H]+.
Sixth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (S) -6-cyclopropyl-7- (2-fluoro-3-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.10g,0.16mmol), dichloromethane (10.0mL), triethylamine (58.5mg,0.58mmol), further acryloyl chloride (15.5mg,0.17mmol), and the reaction was incubated at-20 ℃ for 30 min. After the starting materials had reacted completely, the system was spun off under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/0-10/3) to give the title compound as a pale brown solid (20.0mg, 22.1%).
MS(ESI,pos.ion)m/z:583.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.53–8.38(m,1H),7.67(s,1H),7.06–6.93(m,3H),6.68-6.57(m,2H),6.43(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),4.78-4.70(m,1H),4.11–3.89(m,2H),3.76–3.65(m,2H),3.17-3.08(m,2H),2.85–2.70(m,2H),2.02(d,J＝14.6Hz,3H),1.27(s,9H),1.10-1.98(m,4H).
Example 12(S) -2- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -6-methoxyphenyl acetate
Figure BDA0003214918440000441
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (2-hydroxy-3-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Adding (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] into a reaction bottle]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50g,0.91mmol), (2-hydroxy-3-methoxy) phenylboronic acid (0.17g,0.95mmol), Pd (dppf) Cl2(78.6mg,0.096mmol), Potassium carbonate (0)45g,4.57mmol) and 1, 4-dioxane (10.0mL), warmed to 100 ℃ and reacted for 24 h. Cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (50mL) was added to the residue, and the mixture was stirred for 10min, extracted with ethyl acetate (200mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-1/1) to give the title compound as a yellow solid (0.20g, 34.6%).
MS(ESI,pos.ion)m/z:635.2[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (7- (2-acetoxy-3-methoxyphenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask was added (S) -tert-butyl 4- (6-chloro-7- (2-hydroxy-3-methoxy-phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.43g,0.67mmol), triethylamine (1.0mL,7.2mmol), dichloromethane (10 mL). Acetyl chloride (0.1mL,1.0mmol) was then added slowly dropwise and stirred at ambient temperature for 6 h. After the starting materials had reacted completely, the system was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-0/1) to give the title compound as a yellow solid (0.39g, 85.8%).
MS(ESI,pos.ion)m/z:677.3[M+H]+.
Third step Synthesis of tert-butyl (S) -4- (7- (2-acetoxy-3-methoxyphenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask was added (S) -tert-butyl 4- (7- (2-acetoxy-3-methoxyphenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.10G,0.15mmol), xphos Pd G2(23.2mg,0.030mmol), potassium carbonate (29.6mg,0.30mmol), zinc cyclopropyl bromide (10.0mL,0.5mol/L,5mmol), and the mixture was warmed to 60 ℃ and stirred overnight. After the starting materials had reacted completely, the system was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-1/1) to give the title compound as a yellow solid (69.2mg, 68.4%).
MS(ESI,pos.ion)m/z:683.4[M+H]+.
The fourth step (S) -2- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -6-methoxyphenyl acetate
To a reaction flask were added (S) -tert-butyl 4- (7- (2-acetoxy-3-methoxyphenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (20.5mg,0.030mmol), dichloromethane (4.0mL) and trifluoroacetic acid (2.5mL), and stirred at room temperature for 4.5 h. After the starting material had reacted to completion, the system was spun dry under reduced pressure to give the title compound as a brown liquid (17.5mg, 100%).
The fifth step (S) -2- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -6-methoxyphenyl acetate
To a reaction flask were added (S) -2- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -6-methoxyphenyl acetate (17.5mg,0.030mmol) and dichloromethane (2mL), cooled to 0 ℃, and a solution of acryloyl chloride (6.6mg,0.073mmol) in dichloromethane (2mL) was slowly added dropwise, after which stirring was continued for 3 h. After the starting materials reacted completely, the system was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (5.6mg, 29.0%).
MS(ESI,pos.ion)m/z:637.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.48(d,J＝4.8Hz,1H),7.55(dd,J＝8.7,5.0Hz,1H),7.24–7.17(m,1H),7.05(dd,J＝30.0,6.3Hz,2H),6.74(d,J＝5.3Hz,1H),6.63(dd,J＝20.7,6.0Hz,1H),6.43(d,J＝16.1Hz,1H),5.84(d,J＝9.9Hz,1H),3.86(s,3H),3.80–3.72(m,2H),3.63(dd,J＝6.6,3.4Hz,2H),2.29–2.19(m,2H),2.09–2.02(m,4H),2.02–1.94(m,3H),1.45(d,J＝5.4Hz,2H),1.15–1.09(m,4H),1.07–1.01(m,4H),0.88(d,J＝3.9Hz,3H),0.86(s,4H),0.75(dd,J＝13.6,6.2Hz,2H).
Example 13(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000451
Synthesis of tert-butyl (S) -4- (6-chloro-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate in the first step
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 (0.28g,0.51mmol), 2, 3-dimethoxyphenylboronic acid (0.30g,1.67mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (47.3mg,0.058mmol), potassium acetate (70.0mg,0.71mmol) and 1, 4-dioxane (10.0mL), warmed to 90 ℃, stirred for 10min, a mixed solution of dioxane and water (v/v ═ 1/1,0.5mL) and stirred for 3h with constant temperature. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was added with saturated brine (30mL), stirred for 10min, extracted with ethyl acetate (100mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1-1/1) to obtain the title compound as a pale yellow solid (0.21g, 63.1%).
MS(ESI,pos.ion)m/z:649.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -4- (6-chloro-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.21g,0.32mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (26.0mg,0.033mmol), cyclopropylzinc bromide (15.0mL,8.0mmol), and the temperature was raised to 66 ℃ for 5 hours. After cooling to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (85.8mg, 40.9%).
MS(ESI,pos.ion)m/z:655.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (50.9mg,0.078mmol), trifluoroacetic acid (3.0mL) and dichloromethane (5.0mL), and stirred at room temperature for 1 h. After the starting material had reacted to completion, it was spin dried under reduced pressure and dried in vacuo to give the title compound as a brown solid (43.2mg, 100.0%) which was used directly in the next step.
Fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -6-cyclopropyl-7- (2, 3-dimethoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (43.2mg,0.078mmol), N, N-diisopropylethylamine (0.1mL,0.6mmol), dichloromethane (4.0mL), cooled to-30 deg.C, a solution of acryloyl chloride (0.1mL,0.1mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 min. After the starting materials reacted completely, the system was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (26.8mg, 56.5%).
MS(ESI,pos.ion)m/z:609.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.47(d,J＝4.7Hz,1H),7.63(s,1H),7.05(t,J＝6.6Hz,2H),6.95(d,J＝8.0Hz,1H),6.63(t,J＝16.0Hz,2H),6.42(d,J＝16.6Hz,1H),5.83(d,J＝10.8Hz,1H),3.89(s,3H),3.76–3.62(m,2H),3.42(s,3H),1.81(s,6H),1.65(s,1H),1.58(s,2H),1.50(s,2H),1.34(d,J＝10.3Hz,2H),1.23(d,J＝6.4Hz,3H),1.04(s,3H),0.89(d,J＝6.7Hz,4H).
Example 14(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000471
First step tert-butyl (S) -4- (6-chloro-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
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-fluoro-5-methoxy) benzeneboronic acid (0.19g,1.13mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (33.4mg,0.041mmol), potassium acetate (50.2mg,0.51mmol) and 1, 4-dioxane (20.0mL), and under nitrogen, warmed to 90 ℃ and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was added with saturated brine (30mL), stirred for 10min, extracted with ethyl acetate (100mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.15g, 61.7%).
Second step tert-butyl (S) -4- (6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -tert-butyl 4- (6-chloro-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.33g,0.52mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (45.0mg,0.057mmol) and cyclopropylzinc bromide (30.0mL,20.0mmol), and the temperature was raised to 66 ℃, the reaction was carried out for 7 hours. After cooling to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.14g, 40.9%).
MS(ESI,pos.ion)m/z:643.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (2-fluoro-5-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
The reaction flask is added with (S) -4- (6-cyclopropyl-7- (2-fluoro-5-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (63.2mg,0.098mmol), dichloromethane (8.0mL), was stirred at-78 ℃ for 5min, a solution of boron tribromide in dichloromethane (0.1mL) was slowly added dropwise, and after the dropwise addition was completed, the mixture was transferred to an ice-water bath and stirred for 10 min. After the starting material had reacted to completion, the system was spun dry under reduced pressure and dried to give the title compound as a brown solid (37.6mg, 72.3%) which was used directly in the next step. MS (ESI, pos.ion) M/z 529.2[ M + H [)]+.
The fourth step (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one synthesis
To a reaction flask were added (S) -6-cyclopropyl-7- (2-fluoro-5-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (37.6mg,0.071mmol), N, N-diisopropylethylamine (0.1mL,0.6mmol), dichloromethane (5.0mL), cooled to-30 deg.C, and a solution of acryloyl chloride (0.1mL,0.1mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 minutes. After the starting materials reacted completely, the system was spin-dried under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (26.1mg, 63.0%).
MS(ESI,pos.ion)m/z:583.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.25(d,J＝18.1Hz,1H),7.65(s,1H),6.88(dd,J＝21.2,12.1Hz,2H),6.76(d,J＝8.1Hz,1H),6.60(d,J＝1.7Hz,2H),6.43(d,J＝16.5Hz,1H),5.83(d,J＝11.5Hz,1H),5.50–5.30(m,1H),5.12(d,J＝71.1Hz,1H),4.74(t,J＝18.2Hz,1H),4.58–4.40(m,1H),3.95–3.79(m,1H),3.68(dd,J＝19.4,13.4Hz,2H),2.81(s,1H),2.04–1.86(m,6H),1.66–1.47(m,4H),1.07(d,J＝6.2Hz,3H),0.95–0.84(m,3H),0.54(s,2H).
Example 15(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000481
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
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), 4-fluoro-2-methoxyphenylboronic acid (70mg,0.4mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (61mg,0.073mmol), potassium acetate (0.19g,1.8mmol) and 1, 4-dioxane (6mL), warmed to 90 ℃, and stirred for 3 h. Cooled to room temperature and concentrated to remove the solvent. The concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (0.14g, 60.0%).
MS(ESI,pos.ion)m/z:637.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.49(d,J＝4.9Hz,1H),8.04(s,1H),7.08(d,J＝4.9Hz,1H),7.03–6.93(m,1H),6.69–6.59(m,2H),5.22–4.54(m,1H),4.54–4.21(m,2H),4.21–3.85(m,2H),3.74(s,3H),3.47–2.97(m,2H),2.84–2.59(m,1H),2.05(s,3H),1.52(s,9H),1.27–1.16(m,6H),1.05(dd,J＝6.7,2.8Hz,3H).
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added 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 (0.26g,0.41mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (33mg,0.041mm ol), cyclopropylzinc bromide tetrahydrofuran solution (8.5mL,4.3mmol) and sodium carbonate (0.22g,2.1mmol), displaced with nitrogen, warmed to 65 ℃ and reacted overnight. Cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (0.10g, 38.0%).
MS(ESI,pos.ion)m/z:643.3[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (95mg,0.15mmol), trifluoroacetic acid (1mL) and dichloromethane (2mL), and stirred at room temperature for 2 h. The solvent was removed by concentration, and the concentrate was used directly in the next reaction.
MS(ESI,pos.ion)m/z:543.3[M+H]+.
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (S) -6-cyclopropyl-7- (4-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.16g,0.29mmol), DIPEA (80mg,0.61mmol), dichloromethane (2mL), cooled to 0 ℃, acryloyl chloride (40mg,0.43mmol) was slowly added dropwise, the dropwise addition was completed, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 200/1) to give the title compound as a yellow solid (50mg, 28.0%).
MS(ESI,pos.ion)m/z:597.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.53–8.43(m,1H),7.58(d,J＝3.7Hz,1H),7.08(d,J＝4.6Hz,1H),7.03–6.92(m,1H),6.67–6.62(m,3H),6.40(d,J＝16.8Hz,1H),5.81(d,J＝10.5Hz,1H),4.52–4.37(m,1H),4.38–4.19(m,1H),4.10–3.94(m,1H),3.70(s,3H),3.61–3.43(m,1H),3.37–3.19(m,1H),3.16–2.95(m,1H),2.87–2.69(m,1H),2.10–2.00(m,1H),1.81–1.68(m,1H),1.61–1.43(m,4H),1.25(d,J＝5.7Hz,6H),1.05(d,J＝6.5Hz,3H).
Example 164- (4-Acryloylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000501
Synthesis of first tert-butyl 4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To a reaction flask was added tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (0.21g,0.39mmol), 2-methoxyphenylboronic acid (0.21g,1.35mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (34.9mg,0.043mmol), potassium acetate (52.3mg,0.53mmol) and 1, 4-dioxane (10.0mL), under nitrogen, warmed to 90 ℃, stirred for 10 minutes, water (0.5mL) was added and stirring was continued for 3 hours. After cooling to room temperature, the solvent was removed by concentration, a saturated brine (30mL) was added, the mixture was stirred for 10min, extracted with ethyl acetate (10mL × 3), the organic phases were combined, concentrated, and the resulting residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.19g, 81.8%).
MS(ESI,pos.ion)m/z:605.2[M+H]+.
Second Synthesis of tert-butyl 4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
The reaction flask is added with 4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.19g,0.32mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (26.5mg,0.034mmol) and cyclopropyl zinc bromide (10.0mL,5.0mmol) were reacted for 7 hours at 66 ℃. After cooling to room temperature, saturated brine (10mL) was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, the solvent was removed by concentration, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (96.5mg, 50.1%). MS (ESI, pos. ion) M/z 611.3[ M + H ]]+.
Third step synthesis of 6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -4- (piperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added tert-butyl 4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (80.0mg,0.13mmol), dichloromethane (5.0mL), trifluoroacetic acid (2.0mL), and stirred at room temperature for 1 h. After the starting material had reacted to completion, the system was concentrated under reduced pressure and dried to give the title compound as a brown solid (66.9mg, 100%) which was used directly in the next step.
MS(ESI,pos.ion)m/z:511.2[M+H]+.
Fourth step Synthesis of 4- (4-acryloylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -4- (piperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (66.9mg,0.13mmol), N, N-diisopropylethylamine (0.1mL,0.6mmol), dichloromethane (5.0mL) were added to a reaction flask, placed at 0 deg.C, a solution of acryloyl chloride (0.05mL,0.6mmol) in dichloromethane (1mL) was slowly added dropwise, and after the addition was complete, the mixture was stirred for 10 minutes. After the starting materials had reacted to completion, the system was spun dry under reduced pressure and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate (v/v) ═ 1/1-0/1) to give the title compound as a yellow solid (18.0mg, 24.3%).
MS(ESI,pos.ion)m/z:565.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.66(d,J＝4.8Hz,1H),7.65(s,1H),7.38(t,J＝7.4Hz,1H),7.23(d,J＝4.3Hz,1H),7.02–6.91(m,3H),6.65(dd,J＝17.0,10.3Hz,1H),6.43(d,J＝17.9Hz,1H),5.84(d,J＝10.5Hz,1H),3.72(s,3H),2.86–2.81(m,1H),2.12(s,3H),1.78(dd,J＝9.6,4.3Hz,1H),1.31(d,J＝5.3Hz,5H),1.14(d,J＝6.8Hz,4H),0.88(dd,J＝18.9,7.0Hz,7H),0.54(d,J＝4.1Hz,2H).
Example 17(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000511
First step Synthesis of 5-bromo-1, 3-dimethylpyridin-2 (1H) -one
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,8mmol) were added to a steel reaction vessel, which was then sealed and heated to 80 deg.C, and stirred overnight. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-1/1) to give the title compound as a yellow liquid (0.41g, 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
The reaction flask was charged with 5-bromo-1, 3-dimethylpyridin-2 (1H) -one (0.41g,2.04mmol), potassium acetate (0.71g,7.26mmol), Pd (dppf) Cl2(0.18g,0.22mmol), 1, 4-dioxane (15.0mL), pinacol diboron (1.30g,5.10mmol), under nitrogen, the temperature was raised to 85 ℃ and the mixture was stirred overnight. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-1/1) to give the title compound as a yellow liquid (0.45g, 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
The reaction flask is charged with (S) -4- [6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-pyrido [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), Pd (dppf) Cl2(32.2mg,0.039mmol), 1, 4-dioxane (10.0mL), cesium carbonate (0.33g,1.01 mmol). Under the protection of nitrogen, the temperature is raised to 85 ℃, and the mixture is stirred for 24 hours. After cooling to room temperature, water (50mL) was added, extraction was performed with ethyl acetate (150mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-0/1) to give the title compound as a yellow solid (70.0mg, 25.2%).
MS(ESI,pos.ion)m/z:634.3[M+H]+.
Fourth step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask 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 (0.36G,0.59mmol), 1, 4-dioxane (6.0mL), xphos Pd G2(73.6mg,0.094mmol), sodium carbonate (0.36G,4.32mmol), nitrogen was replaced and protected, and cyclopropyl zinc bromide (12.0mL,0.5mol/L,6mmol) was added rapidly. The temperature of the system is raised to 100 ℃, and the stirring is carried out for 24 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-0/1), and preparative isolated to give the title compound as a yellow solid (85.3mg, 23.5%).
The fifth step Synthesis of (S) -6-cyclopropyl-7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (40.0mg,0.065mmol), trifluoroacetic acid (0.5mL) and dichloromethane (4.0 mL). Stirring for 1h at normal temperature. The solvent was removed by concentration under reduced pressure to give the title compound as a brown solid (33.5mg, 100%).
Sixth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
The reaction flask was charged with (S) -6-cyclopropyl-7- (1, 5-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (33.5mg,0.065mmol) and N, N-diisopropylethylamine (0.2mL), dichloromethane (2mL), cooled to 0 deg.C and a solution of acryloyl chloride (13.6mg,0.15mmol) in dichloromethane (2mL) was slowly added dropwise, after dropping, stirring with incubation for 2.5H. After the starting materials had reacted completely, they were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1), and further by preparative chromatography to give the title compound as a yellow solid (5.6mg, 11%).
MS(ESI,pos.ion)m/z:594.4[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.56(d,J＝4.9Hz,1H),7.84–7.58(m,3H),7.14(d,J＝4.9Hz,1H),6.71–6.54(m,1H),6.41(d,J＝16.7Hz,1H),5.81(d,J＝10.4Hz,1H),4.73(dd,J＝18.2,11.0Hz,1H),4.45(dd,J＝12.3,8.3Hz,1H),4.26(dd,J＝10.5,5.1Hz,1H),4.11–3.80(m,2H),3.66(d,J＝1.8Hz,2H),3.49(s,3H),2.14–1.96(m,7H),1.58–1.55(m,1H),1.51–1.44(m,2H),1.29(s,3H),1.22(s,6H),0.84(dd,J＝12.0,5.3Hz,2H).
Example 18(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000531
Synthesis of first step 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
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), 3-fluoro-2-methoxyphenylboronic acid (93.2mg,0.55mmol), Pd (dppf) Cl2(44.8mg,0.055mmol), 1, 4-dioxane (10.0mL), cesium carbonate (0.45g,1.37 mmol). Under the protection of nitrogen, the temperature is raised to 85 ℃, and the mixture is stirred for 24 hours. After cooling to room temperature, water (50mL) was added, extraction was performed with ethyl acetate (100mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-0/1) to give the title compound as a yellow solid (0.19g, 53.2%). MS (ESI, pos. ion) M/z 637.3[ M + H ]]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -4- (6-chloro-7- (3-fluoro-2-methoxy-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 (0.10G,0.16mmol), xphos Pd G2(49.4mg,0.063mmol), sodium carbonate (83.2mg,0.79mmol) and cyclopropyl zinc bromide (10.0mL,10 mmol). The system was warmed to 50 ℃ and stirred overnight. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-0/1) to give the title compound as a yellow solid (53.5mg, 53.1%).
MS(ESI,pos.ion)m/z:643.2[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (53.5mg,0.083mmol), dichloromethane (4.0mL) and trifluoroacetic acid (2.0 mL). The system was stirred at ambient temperature for 2h, concentrated under reduced pressure to remove the solvent and dried under vacuum to give the title compound as a yellow solid (45.2mg, 100%). The fourth step (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one synthesis
To a reaction flask were added (S) -6-cyclopropyl-7- (3-fluoro-2-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (45.2mg,0.083mmol), dichloromethane (4mL) and N, N-diisopropylethylamine (0.2mL,1 mmol). The system was cooled to 0 deg.C, a solution of acryloyl chloride (12.1mg,0.13mmol) in dichloromethane (2mL) was slowly added dropwise, and after dropping, stirring was maintained for 2.5 h. After the starting materials reacted completely, they were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1), and further subjected to preparative chromatography to give the title compound (22.9mg, 46.1%).
MS(ESI,pos.ion)m/z:597.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.47(d,J＝4.8Hz,1H),7.65(s,1H),7.07(tt,J＝12.5,8.3Hz,3H),6.85(d,J＝7.1Hz,1H),6.73–6.55(m,1H),6.43(d,J＝16.3Hz,1H),5.83(d,J＝10.6Hz,1H),4.82–4.70(m,1H),4.52–4.27(m,1H),4.07–3.86(m,1H),3.83–3.64(m,2H),3.56(s,3H),3.39–3.23(m,1H),3.16–2.98(m,1H),2.06(s,3H),1.23(d,J＝6.5Hz,6H),1.04(d,J＝5.3Hz,3H).
Example 19(R) -4- (4-acryloyl-3- (hydroxymethyl) piperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000541
And
example 20(R) - (1-acryloyl-4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-hydroxymethylphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-yl) methyl acetate
Figure BDA0003214918440000551
Synthesis of first step (R) -tert-butyl 4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2- (hydroxymethyl) piperazine-1-carboxylate
To a reaction flask was added 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (1.10g,2.87mmol), (R) -tert-butyl 2- (hydroxymethyl) piperazine-1-carboxylate (0.80g,3.73mmol), N, N-diisopropylethylamine (2.5mL,15mmol) and acetonitrile (10 mL). The system was warmed to 50 ℃ and stirred overnight. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/0-1/1) to give the title compound as a yellow solid (1.60g, 99.0%).
MS(ESI,pos.ion)m/z:563.2[M+H]+.
Second step Synthesis of tert-butyl (R) -2- (Acetyloxymethyl) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To the reaction flask were added (R) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (1.60g,2.84mmol), triethylamine (4.0mL,28.7mmol), and dichloromethane (20.0 mL). Acetyl chloride (0.3mL,4mmol) was then added slowly dropwise and the system stirred at room temperature for 39 h. After the starting materials reacted completely, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-0/1) to give the title compound as a yellow solid (0.42g, 24.0%).
Third step Synthesis of tert-butyl (R) -2- (Acetyloxymethyl) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
Adding (R) -2- (acetoxymethyl) -4- (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) piperazine-1-carboxylic acid tert-butyl ester (0.20g,0.33mmol), 2-methoxyphenylboronic acid (60.1mg,0.40mmol), Pd (dppf) Cl2(26.9mg,0.033mmol), cesium carbonate (0.16g,0.82mmol) and 1, 4-dioxane (10.0 mL). Under the protection of nitrogen, the temperature is raised to 100 ℃, and the mixture is stirred for 24 hours. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1/0-10/1) to give the title compound as a yellow solid (0.13g, 57.8%).
MS(ESI,pos.ion)m/z:677.3[M+H]+.
Fourth step Synthesis of tert-butyl (R) -2- (Acetyloxymethyl) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate
To a reaction flask were added (R) -tert-butyl 2- (acetoxymethyl) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (0.13G,0.18mmol), xphos Pd G2(29.0mg,0.037mmol), sodium carbonate (97.8mg,0.92mmol) and cyclopropyl zinc bromide (10.0mL,10.0 mmol). The system was warmed to 50 ℃ and stirred overnight. Cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1-0/1) to give the title compound as a yellow solid (0.11g, 88.2%).
Fifth step Synthesis of (R) - (4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-yl) methyl acetate
The reaction flask is added with (R) -2- (acetoxymethyl) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.11g,0.16mmol), trifluoroacetic acid (2.0mL) and dichloromethane (4.0 mL). The system was stirred at room temperature for 3.5 h. After the starting material had reacted to completion, it was concentrated under reduced pressure to give the title compound as a brown liquid (94.9mg, 100%). MS (ESI, pos.ion) M/z 583.3[ M + H ]]+.
Sixth step (R) -4- (4-acryloyl-3- (hydroxymethyl) piperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (example 19)
And
(R) - (1-acryloyl-4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-hydroxymethylphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-yl) methyl acetate (example 20)
To the reaction flask was added (R) - (4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxyphenyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) piperazin-2-yl) methyl acetate (94.9mg,0.16mmol), N-diisopropylethylamine (0.12g,0.91mmol) and dichloromethane (3 mL). The system was cooled to 0 deg.C, a solution of acryloyl chloride (16.2mg,0.18mmol) in dichloromethane (3mL) was slowly added dropwise, and after dropping, stirring was maintained for 2.5 h. After the starting material had reacted to completion, it was concentrated under reduced pressure and the residue was purified once by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) and preparative isolated to give the title compound example 19 as a yellow solid (4.9mg, 5.1%) and the title compound example 20 as a yellow solid (4.6mg, 4.4%).
Example 19
MS(ESI,pos.ion)m/z:595.31[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.48(d,J＝4.8Hz,1H),7.64(s,1H),7.37(t,J＝7.1Hz,1H),7.10–6.90(m,3H),6.69(s,1H),6.51–6.36(m,1H),5.84(d,J＝11.0Hz,1H),5.36(s,1H),4.98(dd,J＝25.7,14.5Hz,1H),4.47(d,J＝13.5Hz,2H),4.28(d,J＝7.1Hz,1H),3.72(s,3H),3.65–3.60(m,1H),2.03(s,3H),1.65(d,J＝0.5Hz,1H),1.23(d,J＝6.7Hz,6H),1.07(d,J＝6.7Hz,2H),0.85(s,2H).
Example 20
MS(ESI,pos.ion)m/z:637.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.71(d,J＝5.2Hz,1H),8.62(dd,J＝6.7,2.3Hz,1H),8.03(s,1H),7.37(s,1H),7.26(d,J＝5.2Hz,1H),6.96–6.90(m,2H),6.48–6.39(m,1H),5.89–5.82(m,1H),5.46(dd,J＝5.0,4.2Hz,1H),5.38–5.35(m,1H),3.91(t,J＝2.6Hz,1H),3.70(s,3H),2.92(dt,J＝13.3,6.6Hz,2H),2.27–2.22(m,2H),2.19(s,3H),2.02(s,3H),1.68(d,J＝4.6Hz,2H),1.47–1.43(m,1H),1.17(d,J＝6.5Hz,6H),1.04(s,1H),0.77–0.67(m,4H).
Example 21 methyl (S) -3- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate
Figure BDA0003214918440000571
Synthesis of tert-butyl (S) -4- (6-cyclopropyl-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
Adding (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 ] into a reaction bottle]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.32g,0.47mmol), chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (40mg,0.05mmol), cyclopropylzinc bromide in tetrahydrofuran (10mL,5mmol) and sodium carbonate (0.25g,2.4mmol) were allowed to warm to 65 ℃ under nitrogen and reacted overnight. Cooling to room temperature, concentrating under reduced pressure to remove the solvent, and separating and purifying the residue by silica gel column chromatography (petroleum)Ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (0.23g, 71%). MS (ESI, pos. ion) M/z 671.3[ M + H ]]+.
Second step Synthesis of methyl (S) -3- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-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 (0.13g,0.19mmol), trifluoroacetic acid (2mL) and dichloromethane (4 mL). The system was stirred at ambient temperature for 2h, concentrated under reduced pressure to remove the solvent and dried in vacuo to give the title compound as a yellow solid (0.11g, 100%) which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:571.3[M+H]+.
The third step is the synthesis of methyl (S) -3- (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-7-yl) -4-fluorobenzoate
The reaction flask was charged with (S) -3- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-7-yl) -4-fluorobenzoic acid methyl ester (0.11g,0.19mmol), triethylamine (0.11g, 1.1mmol), dichloromethane (4 mL). The system was cooled to 0 deg.C, acryloyl chloride (40mg,0.43mmol) was slowly added dropwise, and after the addition was complete, stirring was carried out at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 200/1) to give the title compound as a yellow solid (49mg, 40.7%). MS (ESI, pos. ion) M/z 625.3[ M + H ]]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.49(d,J＝4.9Hz,1H),8.12–8.01(m,1H),7.92(dd,J＝6.8,1.8Hz,1H),7.70(s,1H),7.15(t,J＝9.0Hz,1H),7.09(d,J＝4.8Hz,1H),6.74–6.53(m,1H),6.41(d,J＝16.6Hz,1H),5.82(dd,J＝10.6,1.2Hz,1H),4.86–4.67(m,1H),4.67–4.42(m,1H),4.31(s,1H),4.10–3.96(m,1H),3.89(s,3H),3.76–3.45(m,2H),3.35–2.98(m,1H),2.90–2.58(m,1H),2.02–1.95(m,1H),1.88–1.77(m,1H),1.64–1.44(m,4H),1.28–1.17(m,6H),1.09(dd,J＝6.7,2.1Hz,3H).
Example 22(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000581
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
Sequentially adding (S) -4- (6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dipyridyl [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-difluorophenylboronic acid (0.19g, 1.20mmol), potassium acetate (0.14g, 1.40mmol), PdCl2(dppf) DCM (0.08g,0.10mmol), 1, 4-dioxane (10mL) was added under nitrogen, purged with nitrogen again, and placed in a 90 ℃ oil bath and stirred for reaction for 14 h. The temperature was reduced to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a yellow solid product (0.52g, 91.6%).
MS(ESI,pos.ion)m/z:625.2[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dichloropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added in this order (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), sodium carbonate (0.13G, 1.22mmol), xphos Pd G2(0.04G, 0.05mmol) and cyclopropyl zinc bromide (8mL, 4mmol, 0.5mol/L in THF) at room temperature under nitrogen protection at 65 ℃ for 17h, concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1), the title compound was obtained as a yellow solid (0.15g, 99.1%).
MS(ESI,pos.ion)m/z:631.3[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added tert-butyl (S) -4- (6-cyclopropyl-7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dichloropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.14g, 0.22mmol) and dichloromethane (3mL) in this order at room temperature, followed by trifluoroacetic acid (1mL) and stirring at room temperature for reaction for 30 min. After completion of the reaction, distillation under reduced pressure was carried out to give the title compound as a brown oil (0.12g, 100%) which was used in the next reaction.
Fourth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (S) -6-cyclopropyl-7- (2, 5-difluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (0.12g,0.22mmol), dichloromethane (3mL) and N, N-diisopropylethylamine (0.1mL,0.43mmol) at 0 deg.C, followed by dropwise addition of acryloyl chloride (0.03g,0.33mmol) with stirring, and after completion of dropwise addition, the reaction was stirred at room temperature for 1H. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) by distillation under the reduced pressure to give the title compound as a beige solid product (62.0mg, 48.8%).
MS(ESI,pos.ion)m/z:585.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.51(d,J＝4.9Hz,1H),7.70(s,1H),7.14–7.00(m,3H),6.91–6.81(m,1H),6.68-6.59(m,1H),6.43(d,J＝16.4Hz,1H),5.83(d,J＝10.5Hz,1H),5.23–5.04(m,1H),4.82–4.25(m,3H),4.07–3.51(m,3H),3.35-3.01(m,1H),2.84–2.61(m,1H),2.02(d,J＝15.1Hz,3H),1.93–1.83(m,1H),1.72(s,3H),1.24(d,J＝6.7Hz,3H),1.06(d,J＝6.3Hz,3H),1.00–0.83(m,4H).
Example 23(S) - (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (quinolin-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000601
Synthesis of tert-butyl (S) -4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (quinolin-8-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate in the first step
To the reaction 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), 8-quinolineboronic acid (72mg,0.4mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (60mg,0.073mmol), potassium acetate (0.19g,1.8mmol) and dioxane (6mL), and under nitrogen, the temperature was raised to 90 ℃, and the reaction was stirred overnight. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (0.11g, 46%).
MS(ESI,pos.ion)m/z:640.4[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (quinolin-8-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -tert-butyl 4- (6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (quinolin-8-yl) -1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.10g,0.16mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (15mg,0.019mmol), a cyclopropylzinc bromide tetrahydrofuran solution (4mL,2mmol) and sodium carbonate (90mg,0.85mmol), under the protection of nitrogen, the temperature is raised to 65 ℃, and the reaction is carried out overnight. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (51mg, 49%).
MS(ESI,pos.ion)m/z:646.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- (quinolin-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
The reaction flask was charged with (S) -4- (6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-7- (quinolin-8-yl) -1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (51mg,0.079mmol), trifluoroacetic acid (1mL) and dichloromethane (2mL) were stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to give the title compound as a yellow semisolid (43.1mg, 100%) which was used directly in the next reaction. MS (ESI, pos.ion) M/z 546.3[ M + H ]]+.
The fourth step (S) - (4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (quinolin-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
(S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- (quinolin-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (43.1mg,0.079mmol), triethylamine (80mg, 0.78mmol) and dichloromethane (3mL) were added to a single-necked flask, the mixture was cooled to 0 ℃ and acryloyl chloride (20mg,0.22mmol) was slowly added dropwise thereto, and after completion of the addition, the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 200/1) to give the title compound as a yellow solid (13mg, 27.4%).
MS(ESI,pos.ion)m/z:600.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.81(s,1H),8.42(d,J＝3.3Hz,1H),8.19(d,J＝8.6Hz,1H),7.88(d,J＝8.2Hz,1H),7.72(s,1H),7.62–7.51(m,1H),7.46–7.36(m,2H),7.18–7.01(m,1H),6.76–6.53(m,1H),6.42(d,J＝16.8Hz,1H),5.82(d,J＝10.0Hz,1H),4.88–4.66(m,1H),4.51(s,1H),4.02(s,1H),3.97–3.81(m,1H),3.66(s,2H),2.78(d,J＝7.8Hz,1H),2.07(s,3H),1.55–1.49(m,6H),1.27(d,J＝11.6Hz,6H),0.94–0.81(m,3H).
Example 24(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (5-chloro-2-fluorophenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000611
Synthesis of first step tert-butyl (S) -4- (6-chloro-7- (5-chloro-2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
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), 5-chloro-2-fluoro-phenylboronic acid (0.48g,2.75mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (77.3mg,0.095mmol), potassium acetate (0.12g,1.20mmol) and 1, 4-dioxane (15.0mL), and stirred under nitrogen at 90 ℃ for 3 h. Cooled to room temperature and concentrated under reduced pressure to remove the solvent. To the resulting residue was added saturated brine (30mL), stirred for 10min, extracted with ethyl acetate (10mL × 3), the organic phases combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.53g, 90.0%).
MS(ESI,pos.ion)m/z:641.3[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (7- (5-chloro-2-fluorophenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
To a reaction flask were added (S) -tert-butyl 4- (6-chloro-7- (5-chloro-2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (0.10g,0.16mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (15.3mg,0.019mmol), cyclopropylzinc bromide (8.0mL,8.0mmol), and the temperature was raised to 66 ℃, and reacting for 7 h. After cooling to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (30.0mL × 3), the organic phases were combined, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (67.3mg, 66.1%).
MS(ESI,pos.ion)m/z:647.4[M+H]+.
Third step synthesis of (S) -7- (5-chloro-2-fluoro-phenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyridine [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (7- (5-chloro-2-fluorophenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (67.3mg,0.10mmol), trifluoroacetic acid (0.5mL) and dichloromethane (3.0mL), and the system was stirred at room temperature for 1 h. After the starting material had reacted completely, it was spin-dried under reduced pressure to give the title compound as a brown solid (56.9mg, 100.0%) which was used directly in the next step.
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (5-chloro-2-fluoro-phenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -7- (5-chloro-2-fluorophenyl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyridin [2,3-d ] pyrimidin-2 (1H) -one (67.3mg,0.12mmol), N, N-diisopropylethylamine (0.1mL,1.0mmol), dichloromethane (3.0mL), cooled to 0 deg.C, a solution of acryloyl chloride (0.1mL,0.6mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 min. The solvent was removed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (50.9mg, 68.8%).
MS(ESI,pos.ion)m/z:601.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.53(d,J＝4.9Hz,1H),7.69(s,1H),7.36–7.31(m,1H),7.13(dd,J＝9.9,3.8Hz,2H),7.04(t,J＝9.0Hz,1H),6.62(dd,J＝26.5,11.6Hz,1H),6.42(d,J＝17.2Hz,1H),5.83(d,J＝11.8Hz,1H),3.33–3.02(m,2H),2.74(t,J＝6.4Hz,1H),2.07–1.99(m,4H),1.83(dd,J＝11.3,5.6Hz,1H),1.53(d,J＝32.8Hz,3H),1.34(s,1H),1.30–1.23(m,6H),1.07(d,J＝6.1Hz,3H),0.94(d,J＝7.6Hz,2H),0.57(s,2H)
Example 25(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000631
Synthesis of first step 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
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 (0.50g,0.91mmol), 2-hydroxy-3-methylphenylboronic acid (0.43g,2.77mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (80.6mg,0.099mmol), potassium acetate (0.12g,1.21mmol) and 1, 4-dioxane (15.0mL), and under nitrogen, warmed to 90 ℃ and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration, a saturated brine (30mL) was added to the residue, the mixture was stirred for 10min, extracted with ethyl acetate (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.51g, 90.3%).
MS(ESI,pos.ion)m/z:619.3[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
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 (0.40mg,0.64mmol), potassium hydroxide (0.19g,3.39mmol), and iodomethane (0.3mL,5.0 mmol). The system was stirred at room temperature for 3 hours. Saturated brine (10.0mL) was added, extracted with ethyl acetate (30.0mL × 3), the organic phases were combined, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.35g, 86.8%).
MS(ESI,pos.ion)m/z:633.3[M+H]+.
Third step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-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
To a reaction flask were added (S) -tert-butyl 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 (0.10g,0.16mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (15.3mg,0.019mmol), and cyclopropyl zinc bromide (8.0mL,8.0 mmol). The temperature of the system was raised to 66 ℃ and the reaction was carried out for 7 hours. After cooling to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (30.0mL × 3), the organic phases were combined and concentrated, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (86.8mg, 85.5%).
MS(ESI,pos.ion)m/z:639.4[M+H]+.
Fourth step Synthesis of (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) -4- (2-methylpiperazin-1-yl) pyridin [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-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 (86.7mg,0.14mmol), trifluoroacetic acid (0.5mL) and dichloromethane (3.0 mL). The system was stirred at ambient temperature for 1h, concentrated under reduced pressure to remove the solvent and dried to give the title compound (73.1mg, 100.0%) which was used directly in the next step.
Fifth step Synthesis of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (2-methoxy-3-methylphenyl) -4- (2-methylpiperazin-1-yl) pyridine [2,3-d ] pyrimidin-2 (1H) -one (73.1mg,0.14mmol), N, N-diisopropylethylamine (0.1mL,1.0mmol), dichloromethane (3.0mL), cooled to 0 deg.C, a solution of acryloyl chloride (0.1mL,0.6mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 minutes. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (32.9mg, 40.9%).
MS(ESI,pos.ion)m/z:593.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.50(d,J＝4.9Hz,1H),7.63(s,1H),7.21(d,J＝7.4Hz,1H),7.07(d,J＝4.8Hz,1H),7.01(t,J＝7.5Hz,1H),6.87(d,J＝7.3Hz,1H),6.63(dd,J＝24.0,13.4Hz,1H),6.42(d,J＝17.0Hz,1H),5.82(d,J＝10.5Hz,1H),3.74–3.67(m,1H),3.28(s,3H),2.29(s,3H),2.05(s,3H),1.58(dd,J＝13.4,4.9Hz,2H),1.49(dd,J＝10.4,5.7Hz,2H),1.34(s,2H),1.29(s,3H),1.23(d,J＝6.7Hz,3H),1.05(s,3H),0.86(dd,J＝11.1,8.3Hz,4H),0.51(s,2H).
Example 26(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (8-methylnaphthalen-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000641
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
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 (0.51g,0.93mmol), 8-methyl-1-naphthylboronic acid (0.26g,1.40mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (77.1mg,0.094mmol), sodium carbonate (0.13g,1.23mmol) and 1, 4-dioxane (10.0mL), under nitrogen, warmed to 90 ℃, stirred for 10min, then water (0.5mL) was added and stirring was continued for 3 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, a saturated saline solution (30mL) was added to the residue, the mixture was stirred for 10min, extracted with ethyl acetate (30mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.40g, 65.2%).
MS(ESI,pos.ion)m/z:653.4[M+H]+.
Second step Synthesis of tert-butyl (S) -4- (6-cyclopropyl-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
To a reaction flask were added (S) -tert-butyl 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 (0.11g,0.18mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (70.3mg,0.089mmol), cyclopropylzinc bromide (10.0mL,5.0mmol), warmed to 66 ℃, and reacting for 7 h. After cooling to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (30.0mL × 3), the organic phases were combined, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (84.7mg, 73.2%).
MS(ESI,pos.ion)m/z:659.4[M+H]+.
The third step is the synthesis of (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (8-methylnaphthalen-1-yl) -4- (2-methylpiperazin-1-yl) pyridine [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -tert-butyl 4- (6-cyclopropyl-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 (84.7mg,0.13mmol), trifluoroacetic acid (0.2mL) and dichloromethane (3.0mL), and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and dried to give the title compound as a yellow solid (71.8mg, 100.0%) which was used in the next step.
MS(ESI,pos.ion)m/z:559.4[M+H]+.
The fourth step (S) -Synthesis of 4- (4-acryloyl-2-methylpiperazin-1-yl) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (8-methylnaphthalen-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask was added (S) -6-cyclopropyl-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (8-methylnaphthalen-1-yl) -4- (2-methylpiperazin-1-yl) pyridin [2,3-d ] pyrimidin-2 (1H) -one (71.8mg,0.13mmol), N, N-diisopropylethylamine (25.6mg, 0.20mmol), dichloromethane (3.0mL), cooled to 0 deg.C, a solution of acryloyl chloride (15.3mg,0.17mmol) in dichloromethane (1mL) was slowly added dropwise, and after the addition was complete, stirring was continued for 10 min. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1-40/1) to give the title compound as a yellow solid (36.7mg, 46.6%).
MS(ESI,pos.ion)m/z:613.4[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm)8.41(s,1H),7.88(d,J＝7.6Hz,1H),7.76(d,J＝7.7Hz,1H),7.54(d,J＝5.8Hz,1H),7.47–7.41(m,1H),7.37(t,J＝7.3Hz,1H),7.22(d,J＝6.1Hz,1H),7.11–6.99(m,2H),6.73–6.58(m,1H),6.43(d,J＝16.7Hz,1H),5.83(d,J＝10.0Hz,1H),3.85(dd,J＝55.9,20.4Hz,2H),2.07–1.96(m,6H),1.55(d,J＝31.4Hz,3H),1.37(d,J＝15.2Hz,2H),1.28(t,J＝10.7Hz,9H),1.12(s,2H),1.05(d,J＝6.0Hz,2H),0.89(d,J＝6.8Hz,2H).
Example 274- ((2S,5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl)) -6-cyclopropyl-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure BDA0003214918440000661
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 in the first step
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 (0.37g,0.66mmol), 2-fluoro-5-methylbenzeneboronic acid (0.30g,1.98mmol), [1,1'- [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.11g,0.13mmol), potassium acetate (0.13g,1.32mmol) and 1, 4-dioxane (10.0mL), with nitrogen protection, warmed to 90 ℃, and stirred for 3 h. After cooling to room temperature and concentration to remove the solvent, the obtained residue was added with saturated brine (10mL), stirred for 10min, extracted with ethyl acetate (10mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.34g, 80.6%).
MS(ESI,pos.ion)m/z:635.4[M+H]+.
Second step Synthesis of tert-butyl (2R,5S) -4- (6-cyclopropyl-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
To a reaction flask 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 (0.12g,0.19mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (74.3mg,0.094mmol), cyclopropylzinc bromide (10.0mL,5.0mmol), the temperature was raised to 66 ℃ and the reaction was carried out for 7 hours. After cooling to room temperature, saturated brine (10.0mL) was added, extraction was performed with ethyl acetate (15.0mL × 3), the organic phases were combined, the solvent was removed by concentration under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (0.11g, 92.0%).
MS(ESI,pos.ion)m/z:641.3[M+H]+.
Third step synthesis of 6-cyclopropyl-4- ((2S,5R) -2, 5-dimethylpiperazin-1-yl) -7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
To a reaction flask were added (2R,5S) -4- (6-cyclopropyl-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 (0.11g,0.17mmol), trifluoroacetic acid (0.2mL) and dichloromethane (3.0mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure and dried in vacuo to give the title compound as a yellow solid (92.8mg, 100%) which was used directly in the next step.
MS(ESI,pos.ion)m/z:541.3[M+H]+.
Fourth step Synthesis of 4- ((2S,5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -6-cyclopropyl-7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
6-cyclopropyl-4- ((2S,5R) -2, 5-dimethylpiperazin-1-yl) -7- (2-fluoro-5-methylphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (92.8mg,0.17mmol), N, N-diisopropylethylamine (0.3mL, 2.0mmol), dichloromethane (3.0mL), cooled to 0 deg.C, a solution of acryloyl chloride (0.1mL,1.0mmol) in dichloromethane (1mL) was slowly added dropwise, and after completion of the addition, the mixture was stirred for 10 min. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 100/1-20/1) to give the title compound as a yellow solid (74.4mg, 72.3%).
MS(ESI,pos.ion)m/z:595.3[M+H]+.
1H NMR(400MHz,CDCl3)δ8.49(d,J＝3.9Hz,1H),7.68–7.62(m,1H),7.17(d,J＝5.7Hz,1H),7.09(dd,J＝4.5,2.4Hz,1H),6.97(t,J＝8.9Hz,2H),6.63(ddd,J＝34.7,16.8,10.5Hz,1H),6.41(t,J＝15.1Hz,1H),5.81(t,J＝8.7Hz,1H),3.97–3.90(m,1H),2.75(dt,J＝13.1,6.6Hz,1H),2.29(s,3H),2.06–2.02(m,3H),1.88(dd,J＝12.6,6.2Hz,1H),1.51–1.39(m,5H),1.34(d,J＝6.6Hz,2H),1.26(dd,J＝18.9,9.2Hz,6H),1.08(dd,J＝15.5,6.7Hz,3H).
Biological assay
Example A: CTG method for detecting inhibitory activity of compound on H358(KRAS G12C) cell proliferation
The cell assay conditions are shown in table a:
TABLE A
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 10mM stock solutions.
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 drug working solution was added to the corresponding well of the cell culture plate, and incubated for 72 hours in an incubator at 37 ℃.
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 min.
c adding 50 mu L/hole of CTG solution according to the CTG operation instructions, and placing on a shaking table to shake for 20min 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 counted using GraphPad Prism 5.0 software to obtain ICs50The value is obtained. The results are shown in table 1, and table 1 shows the results of H358 cell proliferation inhibition experiments using the compounds provided in the examples of the present invention.
TABLE 1 inhibition of H358 cell proliferation by compounds provided in the examples of the invention
Figure BDA0003214918440000681
Figure BDA0003214918440000691
The experimental result shows that in the test of the inhibitory activity on the proliferation of the H358 cells, the compound has stronger inhibitory activity on the proliferation of the H358 cells and the activity is better than that of the positive control ARS 1620.
Example B: LC-MS method for detecting binding condition of compound and KRAS G12C protein
The experimental steps are as follows:
1) experimental buffer preparation is shown in Table B
TABLE B
Figure BDA0003214918440000692
2) Loading of GDP into KRAS G12C protein
KRAS G12C protein stock solution (11.13Mg/mL, 550. mu.M) was diluted with low Mg2+Buffer was diluted 5-fold to 110. mu.M. 1mL of 110. mu.M KRAS G12C protein was added to 1mL of 2 XDDP loading buffer, mixed gently, incubated at room temperature for 1.5h, split into 40. mu.L/tube, and stored rapidly at-80 ℃ in a refrigerator.
3) KRAS G12C binding assay
GDP loaded KRAS G12C was diluted to 20 μ M with 10 × incubation buffer and the reagents were mixed as per table C below.
Watch C
Reagent Volume of addition
GDP loaded KRAS G12C (20. mu.M) 5μL
Compound (10% DMSO solution) 5μL
10 × incubation buffer 5μL
Ultrapure water 35μL
In total 50μL
Note: the dosage of each reagent can be changed according to a certain proportion as required.
4) Incubating at room temperature for 5min and 1h respectively
5) The reaction was stopped by adding 5 μ L of 5% formic acid (note: adding 5% formic acid solution according to the ratio of 10% according to the volume of the incubation solution
6) LC-MS detection
And (4) uniformly mixing the incubation solution, transferring the incubation solution to a sample injection vial, and performing LC-MS analysis and detection. The analysis conditions were as follows:
Figure BDA0003214918440000693
Figure BDA0003214918440000701
7) calculating the KRAS G12C binding Rate%
KRAS G12C binding rate% (% complex peak area/(complex peak area + area of non-binding KRAS G12C peak) × 100
The results are shown in table 2, and table 2 shows the experimental results of the compound provided in the example of the present invention binding to KRAS G12C protein for 1 h.
TABLE 2 Experimental results of the binding of the compounds provided in the examples of the present invention to KRAS G12C protein
Figure BDA0003214918440000702
The experimental result shows that the compound has higher binding rate with KRAS-4B-G12C protein.
Example C: pharmacokinetic evaluation of mice following intravenous and oral dosing of Compounds of the invention
Taking 18-22g male ICR mice, randomly dividing into two groups, wherein one group is injected with a compound to be tested by intravenous injection at a dose of 2.0mg/kg, and the other group is orally administered with the compound to be tested at a dose of 5 mg/kg; tail vein blood was collected at time points 0.083, 0.25, 0.5, 1,2,4, 6, 8, and 24 hours 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.
The results show that when the compound provided by the invention is administered intravenously or orally, the compound provided by the invention shows good pharmacokinetic properties, including better absorption and better oral bioavailability.
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. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, 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 (12)

1. A compound which is a compound represented by 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 FDA0003214918430000011
wherein:
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, 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 selected by 1,2,3, 4 or 5 independentlyFrom 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;
R4is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy or C1-3A hydroxyalkoxy group;
R5is 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 C1-3Substituted by the radical hydroxyalkoxy;
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 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 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, halogen atom, hydroxyl, amino, nitro, cyano, 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 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;
p is 0, 1,2,3, 4 or 5.
2. The compound of claim 1, 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, -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, -OCH2OH、-OCH2CH2OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl.
3. The compound of claim 1, wherein 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.
4. A compound according to claim 1 or 3, wherein R3Is composed of
Figure FDA0003214918430000021
Figure FDA0003214918430000022
Figure FDA0003214918430000033
Wherein, the
Figure FDA0003214918430000034
Figure FDA0003214918430000031
Figure FDA0003214918430000032
Independently optionally substituted by n RyAnd (4) substitution.
5. The compound of claim 1, wherein R4Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH or-OCH2CH2OH；
R5Is 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-propoxy and isopropoxy、-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.
6. The compound of claim 1, wherein 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 C1-3Substituted by the radical hydroxyalkoxy;
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 C1-3Substituted by the radical hydroxyalkoxy;
each RyIndependently is deuterium, halogen atom, hydroxyl, amino, nitro, cyano, 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 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.
7. The compound of claim 1 or 5, wherein 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 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 is substituted by a group;
each RxIndependently 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-propylOxy, 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 is substituted by a group;
each RyIndependently deuterium, halogen atom, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-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-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.
8. A compound comprising a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of one of the following, or a prodrug thereof:
Figure FDA0003214918430000051
Figure FDA0003214918430000061
Figure FDA0003214918430000071
Figure FDA0003214918430000081
Figure FDA0003214918430000091
9. a pharmaceutical composition comprising a compound of any one of claims 1-8; and
the pharmaceutical composition optionally comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
10. Use of a compound of any one of claims 1 to 8 or a pharmaceutical composition of claim 9 in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a patient.
11. The use of claim 10, wherein the KRAS G12C mediated disease is cancer.
12. The use of claim 11, wherein the cancer is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, or melanoma.
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