Pyrimidinone derivatives and their use in medicine

Abstract

Disclosed are pyrimidinone derivatives and their use in medicine. Specifically, the present invention relates to a novel class of pyrimidinone derivatives and pharmaceutical compositions comprising such compounds. The invention also relates to methods of preparing the compounds and pharmaceutical compositions, and to their use in the manufacture of a medicament for the treatment of a KRAS G12C-mediated disease and / or disorder, in particular for the treatment of cancer.

Description

Invention Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a class of novel compounds as inhibitors of KRAS activity, methods for preparing them, pharmaceutical compositions comprising said compounds, and the use of said compounds and pharmaceutical compositions thereof in the treatment of a variety of different diseases. More specifically, the compounds of this invention can act as inhibitors of the activity or function of KRAS G12C. Background Technology

[0002] KRAS is a murine sarcoma virus gene. There are three types of genes in the ras gene family associated with human tumors—H-ras, K-ras, and N-ras, 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 the ras genes, K-Ras has the greatest impact on human cancer, accounting for 86% of all RAS mutations. It acts like a molecular switch: when normal, it controls and regulates cell growth pathways; when abnormal, it leads to continuous cell growth and prevents cell self-destruction. It participates in intracellular signal transduction. When the K-ras gene mutates, it becomes permanently activated, unable to produce normal ras protein, causing disordered intracellular signal transduction, uncontrolled cell proliferation, and ultimately, cancer.

[0003] The G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine at position 12 to cysteine. KRAS G12C mutation is most common in lung cancer; according to data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutation accounts for approximately 10% of all lung cancer patients.

[0004] Currently, researchers have conducted several studies in hopes of finding therapeutic agents that can effectively inhibit the KRAS G12C mutant protein. PCT applications are filed under the numbers WO2014152588, WO2015054572, WO2016049524, WO2016164675, WO2016168540, WO2017015562, WO2017058915, WO2017058807, WO2017058792, WO2017058902, WO2017087528, WO2017201161, WO2018064510, and WO2018. Numerous small molecule compounds have been disclosed as KRAS G12C mutant protein inhibitors for the prevention or treatment of cancer, as disclosed in codes 068017, WO2018119183, WO2018140600, WO2018140512, WO2018143315, WO2018206539, WO2018217651, WO2018218070, WO2019051291, WO2019099524, WO2019110751, WO2019137985, and WO2019141250. However, there is still a pressing clinical need for more and better KRAS G12C mutant protein inhibitors. Summary of the Invention

[0005] This invention provides a compound, or a pharmaceutical composition thereof, which can act as an inhibitor of KRAS. The invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats diseases and / or conditions by inhibiting KRAS activity through said compound. The invention further describes a method for synthesizing said compound. The compounds of this invention exhibit excellent biological activity and pharmacokinetic properties.

[0006] Specifically:

[0007] On one hand, the present invention relates to a compound, which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0008]

[0009] in:

[0010] Z is N or CR 2e ;

[0011] R 1 -C(=O)-CR a =CR b -R c-C(=O)-C≡CR c -S(=O)2-CR a =CR b -R c or -S(=O)2-C≡CR c ;

[0012] R a and R b Each is independently composed of hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 alkoxy, wherein the C 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 The alkoxy group is independently and optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced;

[0013] R c For hydrogen, deuterium, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, 5-6-membered heteroaryl, C 3-6 A carbocyclic group or a 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, 5-6-membered heteroaryl, C 3-6 The carbocyclic group and the 3-6 membered heterocyclic group are independently and optionally selected by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 The groups are replaced by hydroxyalkoxy groups and 3-6 membered heterocyclic groups;

[0014] R 3 C6-12 Aryl or 5-10 heteroaryl, wherein the C 6-12 Aryl and 5-10 heteroaryl groups are independently and optionally bounded by n R groups. y replace;

[0015] R 4 The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 hydroxyalkoxy;

[0016] R 5 The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced;

[0017] R 2a R 2b R 2c R 2d and R 2e Each of these can be independently represented as hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced;

[0018] Each R x Independently, it can be deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are independently and optionally surrounded by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atom, hydroxyl group, oxo group, amino group, nitro group, cyano group, C group, etc. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced;

[0019] Each R y Independently, it can be a deuterium, halogen atom, hydroxyl group, amino group, nitro group, cyano group, or C group. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 atoms; wherein, the C... 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 The aryl group and 5-10 heteroaryl groups are independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced;

[0020] m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0021] n is 1, 2, 3, 4, 5, 6, or 7;

[0022] p can be 0, 1, 2, 3, 4 or 5.

[0023] In some implementation schemes, R a and R b Each of the following is independently hydrogen, deuterium, 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 and optionally replaced by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH groups;

[0024] R cHydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2C F2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazineyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophene The thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups are independently and optionally replaced by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH2OH, -OCH2CH2OH, isopropoxy, ethylene oxide, aziridine, oxaziridine, thiohexacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl groups.

[0025] In some implementation schemes, R 3 C 6-10 Aryl or 5-10 heteroaryl, wherein the C 6-10 Aryl and 5-10 heteroaryl groups are independently and optionally bounded by n R groups. y replace.

[0026] In some implementation schemes, R 3 for Among them, the Independently and arbitrarily assigned to n Ry replace.

[0027] In some implementation schemes, R 4 It can be 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.

[0028] In some implementation schemes, R 5 The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0029] In some implementation schemes, R 5The following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF2 are... F2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0030] In some implementation schemes, R 2a R 2b R 2c R 2d and R 2e Each of these can be independently represented as hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0031] In some implementation schemes, R2a R 2b R 2c R 2d and R 2e Each of these elements independently represents hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -C HF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally replaced by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0032] In some implementation schemes, each R x Independently, it can be deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are independently and optionally surrounded by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0033] In some implementation schemes, each R x Independently, it can be deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHF CH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, thiocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, - CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0034] In some implementation schemes, each R y Independently, it can be a deuterium, halogen atom, hydroxyl group, amino group, nitro group, cyano group, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-6 atoms; wherein, the C... 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 3-6Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 atoms are independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0035] In some implementation schemes, each R y Independently, it is a deuterium, halogen atom, hydroxyl group, amino group, nitro group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, trifluoromethyl group, difluoromethyl group, methoxy group, ethoxy group, isopropoxy group, trifluoromethoxy group, -OCH2OH group, -OCH2CH2OH group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, aziridine group, pyrrolyl group, tetrahydrofuranyl group, piperidinyl group, piperazinyl group, morpholinyl group, phenyl group, pyridinyl group, pyrimidinyl group, pyrroleyl group, pyrazolyl group, imidazoyl group, thiophenyl group, thiazoyl group, furanyl group, or triazolyl group; wherein, the methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, difluoromethyl group, methoxy group, ethoxy group, or isopropoxy group are... The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, thiophene, thiazolyl, furanyl, or triazolyl groups are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0036] On one hand, the present invention relates to pharmaceutical compositions comprising a compound represented by formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, mediator or combination thereof.

[0037] On one hand, the present invention relates to the use of the aforementioned compounds or pharmaceutical compositions thereof in the preparation of medicaments for the prevention, treatment or relief of KRAS G12C-mediated diseases in patients.

[0038] In some embodiments, the KRAS G12C-mediated disease described in this invention is cancer.

[0039] Some of the embodiments described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0040] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I).

[0041] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0042] Detailed Description of the Invention

[0043] Definitions and general terms

[0044] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within its scope. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0045] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0046] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0047] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0048] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0049] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0050] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0051] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0052] "Chirality" refers to molecules that have the property that they cannot be superimposed on their mirror image; while "chirality" refers to molecules that can be superimposed on their mirror image.

[0053] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0054] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0055] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some 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.

[0056] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures 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 E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0057] Racemates of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating the salts of their diastereomers. Racemate products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ndEd.Robert E.Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0058] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0059] The terms "optional" or "optionally" mean that an event or situation described below may, but is not guaranteed to, occur, and the description includes both the occurrence of said event or situation and other situations where it does not occur. For example, "optional key" means that the key may or may not be present, and the description includes single, double, or triple keys.

[0060] The term "substituted" indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. As described in this invention, the compounds of this invention may optionally be substituted by one or more substituents, such as the general formula compounds above, or as in the specific examples, subclasses, and classes of compounds included in this invention. The term "optionally substituted by" may be used interchangeably with the term "unsubstituted or substituted by," meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention; when the number of substituents is greater than one, the substituents may be the same or different from each other. For example, the phrase "optionally substituted by 1, 2, 3, 4, or 5 groups selected from" as described in this invention means that when the number of substituents is greater than one, the substituents may be the same or different.

[0061] Unless otherwise indicated, an optional substituent may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner. The substituents described may be, but are not limited to, deuterium, oxo, halogen, cyano, nitro, hydroxyl, mercapto, amino, alkylamino, aromaticamino, aminoalkyl, alkyl, alkenyl, alkynylthio, alkylalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylacyloxy, carboxyl, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, etc.

[0062] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0063] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0064] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0065] As used in this invention, the term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. Unless otherwise specified, the alkyl group contains 1 to 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; and in yet other embodiments, the alkyl group contains 1 to 3 carbon atoms.

[0066] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), and tert-butyl (t-B). u、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1 -Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0067] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be replaced by one or more substituents described in this invention, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-8 carbon atoms; in another embodiment, the alkenyl group comprises 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (propenyl, -CH=CH-CH3), etc.

[0068] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; and in still other embodiments, the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (propynyl, -C≡C-CH3), etc.

[0069] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0070] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0071] The terms “haloalkyl” or “haloalkoxy” indicate that an alkyl or alkoxy group is replaced by one or more halogen atoms. Examples of such replacements include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc.

[0072] The term "hydroxyalkoxy" means that the alkoxy group is replaced by one or more hydroxyl groups. Examples of such substitutions include, but are not limited to, -OCH2OH, -OCH2CH2OH, etc.

[0073] The term "carbocyclic" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. Carbocyclic groups include spirobicyclic, fused, and bridged carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and so on.

[0074] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms. In some embodiments, the cycloalkyl group comprises 3-12 carbon atoms; in others, it comprises 3-8 carbon atoms; and in still others, it comprises 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may optionally be substituted by one or more substituents described in this invention.

[0075] The terms “heterocyclic,” “heterocyclic group,” or “heterocyclic” are used interchangeably herein to refer to a monocyclic, bicyclic, or tricyclic system comprising 3-14 ring atoms, in which one or more atoms on the ring are independently replaced by heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more degrees of unsaturation, but no aromatic rings may be present. In some embodiments, the “heterocyclic,” “heterocyclic group,” or “heterocyclic” group is a 3-8 membered monocyclic ring (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2), or a 7-12 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2). In other embodiments, the “heterocyclic,” “heterocyclic group,” or “heterocyclic” group is a 3-6 membered monocyclic ring (2-4 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 obtain a group like SO, SO2, PO, PO2). The heterocyclic group is optionally substituted by one or more substituents described in this invention.

[0076] The heterocyclic group can be carbon-based or heteroatom-based; wherein the -CH2- group of the ring can optionally be replaced by -C(=O)-, the sulfur atom of the ring can optionally be oxidized to S-oxide, and the nitrogen atom of the ring can optionally be oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, ethylene oxide, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaalkyl, thiaalkyl, homopiperazine, homopiperidinyl, oxacycloheptyl, thioheptanyl, oxacycloheptyl, oxacyclobutyl... 2-diazine Base, sulfur nitrogen Examples of heterocyclic groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, pyrimidinedionyl, etc. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, etc. The heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0077] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may optionally be substituted by one or more substituents described in this invention.

[0078] The term "heteroaryl" or "heteroary ring" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing 5-14 ring atoms, 5-10 ring atoms, or 5-6 ring atoms, 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, linked to the parent molecule via the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroary ring" or "heteroary compound." The heteroaryl group is optionally substituted by one or more substituents described in this invention. In some embodiments, a heteroaryl group consisting of 5-10 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, a heteroaryl group consisting of 5-6 ring atoms is a monocyclic system and contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0079] Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 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), 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-Thiodiazole, 1,3,4-Thiodiazole, 1,2,5-Thiodiazole, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-... Isoquinolinyl or 4-isoquinolinyl), azirquinoline, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0080] The terms "composed of jk ring atoms" or "jk element" are used interchangeably here, indicating that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc. j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k, and any natural number between them. For example, "composed of 3-8 atoms or 3-8 element", "composed of 3-6 atoms or 3-6 element", "composed of 5-10 atoms or 5-10 element", or "composed of 5-6 atoms or 5-6 element" indicate that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc. Specifically, for example, "5-10 ring atoms" or "5-10 cyclic heteroaryl" means that it consists of 5, 6, 7, 8, 9 or 10 ring atoms, where 5, 6, 7, 8, 9 or 10 indicates the number of ring atoms. For example, pyridyl is a heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.

[0081] The term "unsaturated" as used in this invention means that the group contains one or more degrees of unsaturation.

[0082] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NR (like NR in N-substituted pyrrolidinyl, where R is a substituent as described in this invention).

[0083] The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0084] The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino," wherein the amino group is independently substituted by one or two alkyl groups. In some embodiments, the alkylamino group is one or two C14 groups. 1-6 An alkyl group is formed by attaching an alkyl group to a nitrogen atom. In other embodiments, the alkylamine group is formed by one or two C atoms. 1-3 The alkyl-substituted amino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.

[0085] As described in this invention, the substituent (R) 4 ) p A ring system formed by a single bond attached to a central ring represents p substituents R. 4 It can be substituted at any replaceable or reasonable position on the ring. For example, equation d represents that ring G can be replaced by p R. 4 Replacement, when p is greater than 1, each R 4 They can be independently selected from the same or different substituents.

[0086]

[0087] As described in this invention, the attachment point can be connected to the rest of the molecule at any connectable location on the ring. For example, formula e represents any possible connectable location on the C-ring or D-ring as the attachment point.

[0088]

[0089] The term "protecting group" or "PG" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, etc. For a general description of protecting groups, please refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0090] The term "pharmaceuticalally acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar undesirable reactions, such as gastrointestinal upset, dizziness, etc. Preferably, as used in this invention, "pharmaceuticalally acceptable" means those approved by federal regulatory agencies or national governments or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, particularly in humans.

[0091] The term "carrier" refers to a diluent, excipient, formulation, or matrix that is applied together with the compound. These drug carriers can be sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0092] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound containing a hydroxyl group can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0093] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0094] As used in this invention, "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, etc., or salts obtained by other methods described in the literature, such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of Groups I to XII of the periodic table, and organic base salts, such as salts formed with primary, secondary, and tertiary amines.

[0095] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this 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 formed when the solvent molecules are water.

[0096] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0097] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0098] The pharmaceutically acceptable salts of the present invention can be synthesized using conventional chemical methods from a parent compound, a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other suitable salts can be listed, for example, in “Remington’s Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0099] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form of a solvent containing them (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0100] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I. The isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotope-labeled reagents instead of the previously used unlabeled reagents, as described in the examples and preparation processes of the present invention.

[0101] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0102] As used in this invention, the term "cancer" refers to or describes a physiological condition in patients that is typically characterized by uncontrolled cell growth. "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, germ cell tumor, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of this type of cancer include squamous cell carcinoma (such as epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), esophageal cancer, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, malignant glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile cancer, and head and neck cancer.

[0103] The term "KRAS G12C inhibitor" as used in this invention refers to a substance that can bind to KRAS G12C and inhibit its activity.

[0104] Detailed description of the compounds of the present invention

[0105] This invention provides a compound or a pharmaceutical composition thereof that can act as a KRAS G12C inhibitor. The invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats diseases and / or conditions by inhibiting the activity of KRAS G12C with said compound. The invention further describes a method for synthesizing said compound. The compounds of this invention exhibit improved biological activity and pharmacokinetic properties.

[0106] On one hand, the present invention relates to a compound, which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0107]

[0108] Among them, each m, p, Z, R 1 R 2a R 2b R 2c R 2d R 3 R 4 R 5 and R x All of these have the meanings described in this invention.

[0109] In some implementations, Z is N or CR 2e ;where R 2e It has the meaning described in this invention.

[0110] In some implementation schemes, R 1 -C(=O)-CR a =CR b -R c -C(=O)-C≡CR c -S(=O)2-CR a =CR b -R c or -S(=O)2-C≡CR c ;where R a R b and R c It has the meaning described in this invention.

[0111] In some implementation schemes, R a Hydrogen, deuterium, halogen atoms, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 alkoxy, wherein the C 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 The alkoxy group is independently and optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0112] In other implementations, R a The group is hydrogen, deuterium, 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 and optionally replaced by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0113] In some implementation schemes, R b Hydrogen, deuterium, halogen atoms, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 alkoxy, wherein the C 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 The alkoxy group is independently and optionally surrounded by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0114] In other implementations, R b The group is hydrogen, deuterium, 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 and optionally replaced by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0115] In some implementation schemes, R c For hydrogen, deuterium, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, 5-6-membered heteroaryl, C 3-6 A carbocyclic group or a 3-6 membered heterocyclic group, wherein the C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, 5-6-membered heteroaryl, C 3-6 The carbocyclic group and the 3-6 membered heterocyclic group are independently and optionally selected by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 The group is replaced by hydroxyalkoxy groups and 3-6 membered heterocyclic groups.

[0116] In other implementations, R cHydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2C F2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazineyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophene The thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups are independently and optionally replaced by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH2OH, -OCH2CH2OH, isopropoxy, ethylene oxide, aziridine, oxaziridine, thiohexacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl groups.

[0117] In some implementation schemes, R 3 C 6-12 Aryl or 5-10 heteroaryl, wherein the C 6-12 Aryl and 5-10 heteroaryl groups are independently and optionally bounded by n R groups. y Replace; where n and R y It has the meaning described in this invention.

[0118] In other implementations, R 3 C 6-10 Aryl or 5-10 heteroaryl, wherein the C 6-10Aryl and 5-10 heteroaryl groups are independently and optionally bounded by n R groups. y Replace; where n and R y It has the meaning described in this invention.

[0119] In other implementations, R 3 for Among them, the Independently and arbitrarily assigned to n R y Replace; where n and R y It has the meaning described in this invention.

[0120] In some implementation schemes, R 4 The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 1-3 Hydroxyalkoxy group.

[0121] In other implementations, R 4 It can be 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.

[0122] In some implementation schemes, R 5 The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0123] In other implementations, R 5 The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0124] In other implementations, R 5 The following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF2 are... F2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0125] In some implementation schemes, R 2a The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0126] In other implementations, R 2a The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0127] In other implementations, R 2aThe following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF... 2. -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0128] In some implementation schemes, R 2b The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0129] In other implementations, R 2bThe radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0130] In other implementations, R 2b The following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF... 2. -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0131] In some implementation schemes, R 2c The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0132] In other implementations, R 2c The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0133] In other implementations, R 2cThe following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF... 2. -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0134] In some implementation schemes, R 2d The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0135] In other implementations, R 2dThe radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0136] In other implementations, R 2d The following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF... 2. -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0137] In some implementation schemes, R 2e The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 1-6 Alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0138] In other implementations, R 2e The radicals are hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 1-4 Alkylamino; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 The alkylamino group is independently and optionally surrounded by 1, 2, 3, 4, or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0139] In other implementations, R 2eThe following are compounds: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, or ethylamino; wherein, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, and -CHF... 2. -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, and ethylamino are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0140] In some implementation schemes, R x The radicals are deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are independently and optionally surrounded by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atom, hydroxyl group, oxo group, amino group, nitro group, cyano group, C group, etc. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0141] In other implementations, R x The radicals are deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are independently and optionally surrounded by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0142] In other implementations, R xThe following are compounds: deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH 2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, thiohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propynyl, propynyl, -CH F2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxadiazine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, and morpholinyl are independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0143] In some implementation schemes, R y For deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 atoms; wherein, the C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10The aryl group and 5-10 heteroaryl groups are independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0144] In other implementations, R y For deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-6 atoms; wherein, the C... 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 atoms are independently and optionally surrounded by 1, 2, 3, 4 or 5 atoms independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 The hydroxyalkoxy group is replaced.

[0145] In other implementations, R yThe group can be deuterium, halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, -OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrroloyl, pyrazolyl, imidazoleyl, thiophene, thiazolyl, furanyl, or triazolyl; wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, ... -OCH2OH, -OCH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, thiophenyl, thiazolyl, furanyl, or triazolyl is independently and optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH, and -OCH2CH2OH.

[0146] On the other hand, the present invention relates to a compound or its stereoisomers, geometric isomers, tautomers, nitrides, solvates, hydrates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs thereof, but is by no means limited to:

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] On the other hand, the present invention relates to pharmaceutical compositions comprising stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the aforementioned compounds, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, mediators, or any combination thereof.

[0153] On the other hand, the present invention relates to the use of the aforementioned compounds or pharmaceutical compositions thereof in the preparation of medicaments for the prevention, treatment or relief of KRAS G12C-mediated diseases in patients.

[0154] Some of these examples are KRAS G12C-mediated diseases that are cancer.

[0155] Some of the embodiments described in this invention are lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

[0156] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I).

[0157] Pharmaceutical compositions, formulations, administration and uses of the compounds of the present invention

[0158] According to another aspect, the pharmaceutical compositions of the present invention are characterized by comprising a compound represented by formula (I), a compound listed in the present invention, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical compositions of the present invention is sufficient to effectively treat or alleviate KRAS G12C-mediated disease in patients.

[0159] The compounds of the present invention exist in free form or as suitable, 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 adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0160] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0161] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides 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, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0162] Preferably, the compound is administered in combination with a suitable drug diluent, excipient, or carrier (in this context, a pharmaceutical preparation) selected according to the form of administration and conventional pharmaceutical practice. The administration method may be oral tablets, capsules, elixirs, syrups, etc.

[0163] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an orally administered, non-toxic, pharmaceutically acceptable inert filler, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical ingredient can be combined with any orally administered, non-toxic, pharmaceutically acceptable inert wetting agent, such as ethanol, glycerin, water, etc. Furthermore, suitable binders, lubricants, dissolving agents, and colorants can be added to the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Decomposing agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0164] The compounds of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0165] The compounds of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0166] The compounds of this invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0167] The compounds of this invention are also coupled with soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0168] The dosing regimen of the compounds of this invention will vary depending on various known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective dose of the drug to prevent, counteract, or halt the development of cancer.

[0169] According to general guidelines, the daily oral dose of each active ingredient used to achieve the specified effect ranges from approximately 0.001 to 1000 mg / kg body weight. For intravenous administration, the most preferred dose range during a conventional infusion rate is approximately 1 to approximately 10 mg / kg body weight / minute. The compounds of the present invention can be administered once daily, or in two, three, or four divided doses daily.

[0170] Each unit dose of a suitable dosage form (pharmaceutical composition) may contain from about 1 mg to about 1000 mg of the active ingredient. In these pharmaceutical compositions, the active ingredient typically accounts for about 0.5-95% of the total weight of the pharmaceutical composition.

[0171] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0172] The compounds or their pharmaceutical salts or hydrates involved in this invention are effective in preventing, treating or alleviating diseases mediated by KRAS G12C, particularly lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia and melanoma.

[0173] General Synthesis Process

[0174] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0175] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0176] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0177] The examples described below, unless otherwise stated, all temperatures are in degrees Celsius. Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification. Unless otherwise stated, general reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0178] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0179] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0180] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0181] 1H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 ¹H NMR spectra are performed using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0182] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min; mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0183] Pure compounds were detected using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80mm DAC) at 210 nm / 254 nm with UV detection.

[0184] The following abbreviations are used throughout this invention:

[0185] CDCl3 (deuterated chloroform) mL / ml

[0186] DMSO-d6 deuterated dimethyl sulfoxide μL

[0187] g (grams per MPa)

[0188] mg DTT dithiothreitol

[0189] M moles per liter of glutathione

[0190] mM millimoles per liter of NaCl (sodium chloride)

[0191] mol EDTA (ethylenediaminetetraacetic acid)

[0192] mmol (millimoles) of hepes 4-hydroxyethylpiperazine ethanesulfonic acid

[0193] DCM (dichloromethane) MeOH (methanol)

[0194] PE, petroleum ether, EtOAc, ethyl acetate

[0195] CAN Acetonitrile TFA Trifluoroacetic acid

[0196] THF Tetrahydrofuran (DIPEA) N,N-Diisopropylethylamine

[0197] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride

[0198] XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0199] XPhos Pd G3 Methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0200] The following reaction scheme describes the steps for preparing the compounds of the present invention. Unless otherwise stated, each Z, R x R 2a R 2b R 2c R 2d R 3 R 4 m and p have the definitions described in this invention.

[0201] Reaction Scheme 1

[0202]

[0203] Mode( 17 The compound shown in the figure can be prepared by reaction scheme 1: (Formula 1) 1 The compound shown in the figure reacts with oxalyl chloride and ammonia to obtain the product of formula ( 2 The compound shown in formula () 2 The compound shown in the formula () 3 The compounds shown in the figure and those of formula ( 4 The compound shown reacts to obtain the product of formula () 5 The compound shown in formula () 5The compound shown in the figure reacts with potassium di(trimethylsilyl)amino to give formula ( 6 The compound shown in formula () 6 The compound shown in the figure reacts with phosphorus oxychloride to give formula ( 7 The compound shown in formula () 7 The compounds shown in the formula () and () 8 The compound shown in the figure reacts with N,N-diisopropylethylamine to give formula ( 9 The compound shown in formula () 9 The compounds shown in the formula () and () 10 The compound shown in the figure reacts with potassium acetate to obtain the product of formula ( 11 The compound shown in the formula (); then, the compound of formula ( 11 The compounds shown in the formula () and () 12 The compound shown can be reacted with [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex and cesium carbonate to give formula ( 14 The compound shown in the formula (); or, the compound of formula ( 11 The compounds shown in the formula () and () 13 The compound shown can also be reacted with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) and sodium carbonate to give formula ( 14 The compound shown in formula () 14 The compound shown in the figure undergoes deBoc removal under the action of trifluoroacetic acid to obtain the compound of formula ( 15 The compound shown in formula () 15 The compounds shown in the formula () and () 16 The compound shown can react with N,N-diisopropylethylamine to give formula ( 17 The compound shown is ).

[0204] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention. Example

[0205] Example 1 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-7-(2-fluoro-6-hydroxybenzene)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0206]

[0207] Step 1: Synthesis of 2,5,6-trichloropyridine-3-carboxamide

[0208] 2,5,6-trichloropyridine-3-carboxylic acid (5.00 g, 22.0 mmol), dichloromethane (60.0 mL), and N,N-dimethylformamide (0.05 mL, 0.6 mmol) were added to a reaction flask. The mixture was cooled to 0 °C, and oxalyl chloride (2.4 mL, 28 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 24 h. A solution of ammonia in isopropanol (17.0 mL, 34 mmol, 2.0 mol / L) was added, and stirring was continued for 4 h, resulting in the precipitation of a large amount of white solid. The solid was filtered, and the residue was washed with dichloromethane (50 mL × 2). After drying, the white solid containing the title compound was obtained (1.6 g, 32.0%).

[0209] MS(ESI,pos.ion)m / z:224.9[M+H] + .

[0210] Step 2: Synthesis of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide

[0211] 2,5,6-trichloropyridine-3-carboxamide (1.46 g, 6.48 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask, the mixture was heated to 75 °C, and oxalyl chloride (1.0 g, 7.9 mmol) was added dropwise. The mixture was stirred for 1 h. After cooling to room temperature, the solvent was removed by concentration, and the mixture was cooled to 0 °C and dissolved in THF (5 mL). 2-Isopropyl-4-methyl-pyridine-3-amine (1.0 g, 6.7 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the above mixture. The mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride (10 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and the mixture was concentrated to give the title compound as a yellow solid (1.4 g, 54.0%).

[0212] MS(ESI,pos.ion)m / z:401.0[M+H] + .

[0213] Step 3: Synthesis of 6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

[0214] 2,5,6-Trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (1.4 g, 3.5 mmol) and tetrahydrofuran (10.0 mL) were added to a reaction flask. The mixture was cooled to 0 °C, and a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (8.7 mL, 1 mol / L, 8.7 mmol) was added dropwise. After the addition was complete, the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride (5 mL), extracted with ethyl acetate (50 mL), and concentrated to give the title compound as a yellow solid (0.30 g, 24%).

[0215] Step 4: Synthesis of 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0216] 6,7-Dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.20 g, 0.55 mmol), N,N-diisopropylethylamine (0.6 mL, 4 mmol), and acetonitrile (2.0 mL) were added to a reaction flask and stirred to dissolve. Phosphorus oxychloride (0.3 mL, 3 mmol) was added dropwise, and the mixture was heated to reflux and stirred overnight. The solvent was removed under reduced pressure to obtain a brown oily substance (210.1 mg, 100%) containing the title compound, which was used directly in the next step without purification.

[0217] Step 5: Synthesis of (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

[0218] 4,6,7-trichloro-1-(2-isopropyl-4-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.53 g, 1.37 mmol), (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.41 g, 2.05 mmol), N,N-diisopropylethylamine (1.2 mL, 7.2 mmol), and acetonitrile (6 mL) were added to a reaction flask, and the mixture was heated to 80 °C and stirred overnight. The solvent was removed by concentration, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.46 g, 60.82%).

[0219] MS(ESI,pos.ion)m / z:547.2[M+H] + .

[0220] Step 6: Synthesis of (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-carboxylic acid tert-butyl ester

[0221] The reaction flask was filled with (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 (0.43 g, 0.78 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (0.18 g, 1.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (63.8 mg, 0.078 mmol), potassium acetate (0.33 g, 3.11 mmol), and 1,4-dioxane (10 mL). The mixture was heated to 100 °C and stirred for 24 h. The solvent was removed by concentration, and the 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 (0.24 g, 48.9%).

[0222] MS(ESI,pos.ion)m / z:623.3[M+H] + .

[0223] Step 7: Synthesis of (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-butyl ester

[0224] Add (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-carboxylic acid tert-butyl ester (12.5 mg, 0.02 mmol), cyclopropylboronic acid (6.9 mg, 0.08 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (63.8 mg, 0.078 mmol), cesium carbonate (13.2 mg, 0.04 mmol), and 1,4-dioxane (2.0 mL) to the reaction flask, heat to 100 °C, and stir for 10 h. Cool to room temperature and continue stirring overnight. The solvent was removed by concentration, and the 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 (6.4 mg, 51%).

[0225] MS(ESI,pos.ion)m / z:629.3[M+H] + .

[0226] Step 8: 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

[0227] (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-butyl ester (95.5 mg, 0.15 mmol), dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL, 13 mmol) were added dropwise. The mixture was stirred at room temperature for 1.5 h. The solution was then concentrated under reduced pressure to give a yellow viscous liquid containing the title compound (80.3 mg, 100%). MS (ESI, pos.ion) m / z: 529.3 [M+H] + .

[0228] Step 9: 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

[0229] 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 (80.3 mg, 0.085 mmol) and dichloromethane (2 mL) were added to the reaction flask. The mixture was cooled to -30 °C, and a solution of acryloyl chloride (15.1 mg, 0.17 mmol) in DCM (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 2 h. The solvent was removed by concentration, and the solution was separated by preparative column chromatography to obtain the title compound as a white solid (10.9 mg, 12.31%).

[0230] 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, 2 H),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).

[0231] 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

[0232]

[0233] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0234] Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 0.44 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (0.10 g, 0.67 mmol), Pd(dppf)Cl2 (35.8 mg, 0.044 mmol), potassium acetate (0.19 g, 1.75 mmol), and 1,4-dioxane (10.0 mL) to the reaction flask, heat to 100 °C, and stir for 24 h. Concentrate to remove the solvent. 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 (0.18 g, 66.9%).

[0235] MS(ESI,pos.ion)m / z:623.3[M+H] + .

[0236] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0237] To the reaction flask, (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-carboxylic acid tert-butyl ester (0.18 g, 0.29 mmol), cyclopropylboronic acid (0.50 g, 5.78 mmol), Pd(dppf)Cl2 (47.2 mg, 0.058 mmol), potassium carbonate (0.12 g, 0.87 mmol), water (0.10 g), and 1,4-dioxane (6.0 mL) were added. The mixture was heated to 100 °C and stirred for 24 h. After cooling to room temperature, the solvent was removed under reduced pressure. Water (30 mL) was added to the residue, stirred for 10 min, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, and concentrated under reduced pressure to give the title compound as a yellow solid (0.18 g, 100%).

[0238] Step 3: 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

[0239] (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-carboxylic acid tert-butyl ester (0.18 g, 0.29 mmol), dichloromethane (10.0 mL), and trifluoroacetic acid (2.0 mL) were added to the reaction flask, and the mixture was stirred for 5 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to give the title compound as a brown solid (0.15 g, 100%).

[0240] Step 4: Synthesis of (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

[0241] (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 (0.16 g, 0.29 mmol), N,N-diisopropylethylamine (0.38 g, 2.93 mmol), and dichloromethane (4 mL) were added to the reaction flask. The system was cooled to -30 °C, and a solution of acryloyl chloride (31.9 mg, 0.35 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 3 h. After the reactants had reacted completely, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 100 / 1-20 / 1) to give the title compound as a yellow solid (3.9 mg, 2.3%).

[0242] MS(ESI,pos.ion)m / z:583.3[M+H] + .

[0243] 1 H 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, 2 H),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).

[0244] 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

[0245]

[0246] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0247] To a reaction flask, (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.37 mmol), (2-fluorophenyl)boronic acid (0.10 g, 0.74 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (30.1 mg, 0.037 mmol), cesium carbonate (0.14 g, 0.73 mmol), and 1,4-dioxane (10.0 mL), and water (0.20 g, 11.10 mmol) were added. The mixture was heated to 100 °C and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration. Add water (30 mL), stir for 10 min, extract with ethyl acetate (100 mL × 3), combine the organic phases, and concentrate. The resulting residue was purified by column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to give the title compound as a yellow solid (223.7 mg, 100%).

[0248] MS(ESI,pos.ion)m / z:607.3[M+H] + .

[0249] Step 2: Synthesis of (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

[0250] Add (S)-4-(6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.36 g, 0.59 mmol), 1,4-dioxane (6.0 mL), and chloro(2-dicyclohexylphosphino-2',4',6') to the reaction flask. -triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (73.6 mg, 0.094 mmol), sodium carbonate (0.36 g, 4.32 mmol), under nitrogen purging and protection, rapidly add a tetrahydrofuran solution of cyclopropyl zinc bromide (12.0 mL, 0.5 mol / L, 6.00 mmol), heat to 100 °C, and stir for 24 h. The solvent is removed by concentration, and the residue is purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-0 / 1), followed by reverse-phase preparative separation to obtain the title compound as a yellow solid (85.3 mg, 23.5%).

[0251] MS(ESI,pos.ion)m / z:613.3[M+H] + .

[0252] Step 3: 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

[0253] (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 (40.0 mg, 0.065 mmol), trifluoroacetic acid (0.5 mL, 7 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask and stirred at room temperature for 1 h. The solvent was removed by concentration to give the title compound as a brown solid (33.5 mg, 100%).

[0254] Step 4: 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

[0255] (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 (33.5 mg, 0.065 mmol) and dichloromethane (4 mL) were added to a single-necked flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (7.2 mg, 0.080 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 3 h. After the reactants had reacted completely, the solvent was removed by concentration. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a yellow solid (22.8 mg, 61.6%).

[0256] MS(ESI,pos.ion)m / z:567.3[M+H] + .

[0257] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.47 (d, J = 4.9 Hz, 1H), 7.66 (d, J = 10.6 Hz, 1H), 7.40-7.34 (m, 1H), 7.16-7. 12(m,2H),7.08(t,J=8.4Hz,2H),6.69-6.56(m,1H),6.41(d,J=16.7Hz,1H),5.81(d,J=10.5Hz,1H),5. 12(s,1H),4.75(s,1H),3.68(dd,J=73.0,60.2Hz,3H),3.26(s,1H),3.07(s,1H),2.75(s,1H),2.02(d ,J=4.4Hz,3H),1.89-1.85(m,1H),1.56(s,2H),1.48(s,2H),1.27-1.20(m,6H),1.05(d,J=6.4Hz,3H).

[0258] 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

[0259]

[0260] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0261] To a reaction flask, (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 (0.50 g, 0.91 mmol), (4-fluorophenyl)boronic acid (0.14 g, 1.01 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (74.9 mg, 0.092 mmol), cesium carbonate (0.23 g, 1.19 mmol), and 1,4-dioxane (10.0 mL) were added. The mixture was heated to 100 °C and stirred for 4 h. After cooling to room temperature, the solvent was removed by concentration to obtain a brown solid. Add water (30 mL), stir for 10 min, extract with ethyl acetate (100 mL × 3), combine the organic phases, and concentrate. 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 (480.1 mg, 86.59%).

[0262] MS(ESI,pos.ion)m / z:607.3[M+H] + .

[0263] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0264] Add (S)-4-(6-chloro-7-(4-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.19 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (21.8 mg, 0.028 mmol) and sodium carbonate (76.8 mg, 0.93 mmol) to the reaction flask under nitrogen protection. Quickly add a tetrahydrofuran solution of cyclopropyl zinc bromide (10.0 mL, 0.5 mol / L, 5.0 mmol), heat to 70 °C, and stir overnight. The solvent was removed by concentration, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.11 g, 94.23%). MS (ESI, pos.ion) m / z: 613.3 [M+H] + .

[0265] Step 3: 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

[0266] (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-carboxylic acid tert-butyl ester (0.13 g, 0.21 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (4.0 mL) were added to a single-necked flask and stirred at room temperature for 3 h. The solvent was removed by concentration, and the mixture was dried under vacuum to give the title compound as a brown solid (0.11 g, 100.0%).

[0267] MS(ESI,pos.ion)m / z:513.3[M+H] + .

[0268] Step 4: 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

[0269] (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 (0.11 g, 0.21 mmol) and dichloromethane (2 mL) were added to a single-necked flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (23.2 mg, 0.26 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 3 h. The solvent was removed by concentration, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a yellow solid (84.3 mg, 70.6%).

[0270] MS(ESI,pos.ion)m / z:567.3[M+H] + .

[0271] 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=33.1,1 8.9,6.6Hz,2H),4.11-3.42(m,4H),3.16(dd,J=79.9,6.9Hz,1H),2.72(dd,J=33.3,9.1Hz,1 H),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).

[0272] 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

[0273]

[0274] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0275] (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 (0.50 g, 0.91 mmol), (2-methoxyphenyl)boronic acid (0.15 g, 1.01 mmol), Pd(dppf)Cl2 (74.8 mg, 0.092 mmol), potassium carbonate (0.43 g, 4.30 mmol), and 1,4-dioxane (10.0 mL) were added to the reaction flask. The mixture was heated to 100 °C and stirred for 24 h. After cooling to room temperature, the solvent was removed by concentration to obtain a brown solid. Water (30 mL) was added, and the mixture was stirred for 10 min. The solid was extracted with ethyl acetate (100 mL × 3), and 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 (0.42 g, 74.38%).

[0276] MS(ESI,pos.ion)m / z:619.4[M+H]+ .

[0277] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0278] (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-carboxylic acid tert-butyl ester (0.42 g, 0.68 mmol), xphos Pd G2 (82.9 mg, 0.11 mmol), sodium carbonate (0.29 g, 3.44 mmol), and cyclopropyl zinc bromide (10.0 mL, 1.0 mol / L, 10.0 mmol) were added to the reaction flask. The mixture was heated to 60 °C and stirred overnight. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc(v / v) = 1 / 0-0 / 1) to give the title compound as a yellow solid (0.39 g, 92.21%).

[0279] MS(ESI,pos.ion)m / z:625.4[M+H] + .

[0280] Step 3: 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

[0281] (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-carboxylic acid tert-butyl ester (0.13 g, 0.22 mmol), trifluoroacetic acid (1.0 mL), and dichloromethane (6.0 mL) were added to a reaction flask and stirred overnight at room temperature. The solvent was removed by concentration to give the title compound as a yellow solid (0.11 g, 100.0%).

[0282] Step 4: 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]pyrimidine-2(1H)-one

[0283] (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 (0.11 g, 0.22 mmol) and dichloromethane (2 mL) were added to the reaction flask. The system was cooled to 0 °C, and a solution of acryloyl chloride (21.5 mg, 0.24 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature 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 (28.7 mg, 23.0%).

[0284] MS(ESI,pos.ion)m / z:579.4[M+H] + .

[0285] 1 H 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, 4 H),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=12.0,6.8 Hz,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).

[0286] 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

[0287]

[0288] The first step was the synthesis of (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.

[0289] Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.36 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (60.2 mg, 0.07 mmol), potassium acetate (0.18 g, 1.90 mmol), and 1,4-dioxane (5.0 mL) to the reaction flask. After purging with nitrogen three times, the mixture was stirred at 90 °C for 10 min. Then, 3-pyridineboronic acid (82.3 mg, 0.7 mmol) was dissolved in 1,4-dioxane (1.0 mL) and added to the system. Water (0.5 mL) was then added, and the reaction was continued for 3 h. Stop heating, cool to room temperature, filter the system, evaporate the filtrate to dryness under reduced pressure, and purify the residue by silica gel column chromatography (PE / EA(v / v)=1 / 4) to give the title compound as a dark green solid (90.0 mg, 41.8%).

[0290] MS(ESI,pos.ion)m / z:590.3[M+H] + .

[0291] Step 2: Synthesis of (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

[0292] (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 (90.0 mg, 0.15 mmol), XPhos Pd G3 (15.6 mg, 0.017 mmol), and Na2CO3 (60.5 mg, 0.73 mmol) were added to the reaction flask. After purging with nitrogen, a tetrahydrofuran solution of cyclopropyl zinc bromide (3.5 mL, 2 mmol) was added, and the mixture was heated to 70 °C and reacted for 10 h. After the reaction was complete, heating was stopped, the mixture was cooled to room temperature, and filtered. The filtrate was evaporated to dryness 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 (65.0 mg, 64.4%).

[0293] MS(ESI,pos.ion)m / z:596.4[M+H] + .

[0294] Step 3: (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

[0295] (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 (60.0 mg, 0.10 mmol), CH2Cl2 (2.5 mL), and trifluoroacetic acid (0.5 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 2 h. The system was directly evaporated to dryness and then dried under vacuum to obtain a light brown viscous substance (73.0 mg, 119%) containing the title compound.

[0296] MS(ESI,pos.ion)m / z:496.3[M+H] + .

[0297] Step 4: Synthesis of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(pyridin-3-yl)pyridino[2,3-d]pyrimidin-2(1H)-one

[0298] (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 (73.0 mg, 0.12 mmol), CH2Cl2 (20.0 mL), Et3N (32.5 mg, 0.32 mmol), and then acryloyl chloride (13.0 mg, 0.14 mmol) were added to a reaction flask at -1 °C. After reacting at this temperature for 30 min, the mixture was evaporated to dryness under reduced pressure. 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 (17.0 mg, 25.8%).

[0299] MS(ESI,pos.ion)m / z:550.3[M+H] + .

[0300] 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).

[0301] 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

[0302]

[0303] The first step was the synthesis of (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.

[0304] The following substances were added to the reaction flask: (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 (1.02 g, 1.86 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.15 g, 0.19 mmol), cesium carbonate (0.92 g, 2.80 mmol), 1,4-dioxane (20.0 mL), and phenylboronic acid (0.25 g, 2.04 mmol). After purging with nitrogen three times, the reaction was carried out at 100 °C for 2 h. The mixture was then filtered through diatomaceous earth. The filtrate was evaporated to dryness 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 (0.85 g, 77.4%).

[0305] MS(ESI,pos.ion)m / z:589.3[M+H] + .

[0306] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0307] (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 (0.44 g, 0.74 mmol), XPhosPd G3 (75.6 mg, 0.08 mmol), and Na2CO3 (0.20 g, 2.40 mmol) were added to the reaction flask. After purging with nitrogen, a tetrahydrofuran solution of cyclopropyl zinc bromide (20 mL, 10 mmol) was added. The system was heated to 70 °C and reacted for 7 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to a preparative column (43% CAN-57% H2O, 0.2% TFA) to give the title compound as a white solid (0.22 g, 49.07%).

[0308] MS(ESI,pos.ion)m / z:595.4[M+H] + .

[0309] Step 3: 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

[0310] (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-carboxylic acid tert-butyl ester (0.22 g, 0.36 mmol), dichloromethane (3.5 mL), and trifluoroacetic acid (1.5 mL) were added to the reaction flask. The system was reacted at room temperature for 2 h. After the reactants had reacted completely, the system was directly evaporated to dryness and then dried under vacuum at 60 °C overnight to obtain the title compound, a light brown viscous substance (0.30 g, 134%).

[0311] MS(ESI,pos.ion)m / z:495.3[M+H] + .

[0312] Step 4: 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

[0313] (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7-phenylpyrido[2,3-d]pyrimidin-2(1H)-one (0.25 mg, 0.41 mmol), dichloromethane (20.0 mL), triethylamine (0.11 g, 1.07 mmol), and acryloyl chloride (46.5 mg, 0.5 mmol) were added to a reaction flask at -5 °C, and the reaction was maintained at this temperature for 20 min. The mixture was evaporated to dryness 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 (10.0 mg, 44.5%).

[0314] MS(ESI,pos.ion)m / z:549.3[M+H] + .

[0315] 1 H 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).

[0316] 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

[0317]

[0318] The first step was the 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.

[0319] (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-carboxylic acid tert-butyl ester (0.13 g, 0.21 mmol), dichloromethane (5.0 mL), and anhydrous aluminum chloride (0.13 g, 2.10 mmol) were added to the reaction flask. After stirring for 10 min, ethanethiol (0.13 g, 2.08 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. Water (10 mL) was slowly added dropwise, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give the title compound as a yellow solid (0.11 g, 100%).

[0320] Step 2: 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

[0321] (S)-6-cyclopropyl-7-(2-methoxy-phenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.11 g, 0.21 mmol), dichloromethane (2 mL), and N,N-diisopropylethylamine (0.27 g, 2.08 mmol) were added to the reaction flask. The mixture was cooled to -30 °C, and a solution of acryloyl chloride (20.7 mg, 0.23 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 5 h. After the reactants had reacted completely, the mixture was concentrated 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 (15.3 mg, 13.1%).

[0322] MS(ESI,pos.ion)m / z:565.3[M+H] + .

[0323] 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),4.5 9-4.38(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).

[0324] 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

[0325]

[0326] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0327] To a reaction flask, (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 (0.50 g, 0.92 mmol), 2-fluoro-5-methoxyphenylboronic acid (0.21 g, 1.21 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (78.0 mg, 0.096 mmol), potassium acetate (0.14 g, 1.38 mmol), and 1,4-dioxane (40.0 mL) were added. The mixture was heated to 100 °C and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration. Saturated brine (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. The 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 (0.44 g, 75.3%).

[0328] Step 2: Synthesis of (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

[0329] (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-carboxylic acid tert-butyl ester (0.40 g, 0.63 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (57.0 mg, 0.073 mmol) and cyclopropyl zinc bromide (10.0 mL, 5.0 mmol) were added to the reaction flask, and the temperature was raised to 68 °C and the reaction was carried out for 7 hours. After the reactants were completely reacted, the mixture was cooled to room temperature, and saturated brine (10.0 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and the mixture was concentrated under reduced pressure. 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 (0.19 g, 47.1%).

[0330] MS(ESI,pos.ion)m / z:643.3[M+H] + .

[0331] Step 3: Synthesis of (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

[0332] (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 (79.7 mg, 0.13 mmol), trifluoroacetic acid (3.0 mL, 40 mmol), and dichloromethane (4.0 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 1 h. After the reactants had reacted completely, the solvent was removed by concentration under reduced pressure, and the mixture was dried under vacuum at 60 °C to obtain the title compound as a brown solid (67.0 mg, 100.0%), which was used directly in the next reaction step.

[0333] Step 4: Synthesis of (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]pyrimidine-2(1H)-one

[0334] (S)-6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (63.3 mg, 0.117 mmol), N,N-diisopropylethylamine (0.1 mL, 1.0 mmol), and dichloromethane (4.0 mL) were added to the reaction flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (0.1 g, 1.0 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 min. After the reaction was complete, the solvent was removed by concentration under reduced pressure. 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 (69.3 mg, 99.6%).

[0335] MS(ESI,pos.ion)m / z:597.3[M+H] + .

[0336] 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).

[0337] 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

[0338]

[0339] The first step was the synthesis of (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.

[0340] To the reaction flask, (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 (0.30 g, 0.55 mmol), 2-fluoro-5-methylphenylboronic acid (0.11 g, 0.73 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (48.3 mg, 0.059 mmol), potassium acetate (71.4 mg, 0.73 mmol), and 1,4-dioxane (30.0 mL) were added. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. Saturated brine (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated under reduced pressure. 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 (0.32 g, 92.8%).

[0341] MS(ESI,pos.ion)m / z:622.3[M+H] + .

[0342] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0343] (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 (0.30 g, 0.48 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (44.3 mg, 0.056 mmol), and cyclopropyl zinc bromide (15.0 mL, 8.0 mmol) were added to the reaction flask. The system was heated to 68 °C and reacted for 7 hours. After the reaction was complete, the mixture was cooled to room temperature, and saturated brine (10.0 mL) was added. The mixture was extracted with ethyl acetate (30.0 mL × 3). The organic phases were combined, and the solvent was removed by concentration under reduced pressure. 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 (0.16 g, 53.5%).

[0344] MS(ESI,pos.ion)m / z:627.4[M+H] +.

[0345] Step 3: Synthesis of (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

[0346] (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-carboxylic acid tert-butyl ester (0.16 g, 0.26 mmol), trifluoroacetic acid (5.0 mL, 50 mmol), and dichloromethane (6.0 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was dried under vacuum at 60 °C to obtain the title compound as a brown solid (0.14 g, 100.0%), which was used directly in the next step.

[0347] Step 4: Synthesis of (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

[0348] (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 (0.14 g, 0.26 mmol), N,N-diisopropylethylamine (0.1 mL, 1.0 mmol), and dichloromethane (8.0 mL) were added to the reaction flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (0.1 g, 1.0 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 min. The reaction was allowed to proceed to completion. The solvent was removed by concentration under reduced pressure. 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 (0.11 g, 71.6%).

[0349] MS(ESI,pos.ion)m / z:581.3[M+H] + .

[0350] 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, 1 H),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).

[0351] 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

[0352]

[0353] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0354] Add (S)-4-[6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.55 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (52.0 mg, 0.06 mmol), potassium acetate (0.28 g, 2.80 mmol), and 1,4-dioxane (18.0 mL) to the reaction flask. After purging with nitrogen three times, stir at 90 °C for 10 min. Then add a solution of (2-fluoro-3-hydroxyphenyl)boric acid (0.17 g, 1.10 mmol) in 1,4-dioxane (2.0 mL) and three drops of water. After the system continued to react for 2.5 h, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness under reduced pressure. 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 (0.28 g, 82.0%).

[0355] MS(ESI,pos.ion)m / z:623.2[M+H] + .

[0356] Step 2: Synthesis of (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

[0357] Add (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-carboxylic acid tert-butyl ester (0.25 g, 0.40 mmol), acetonitrile (10.0 mL), and potassium carbonate (65.8 mg, 0.48 mmol) to the reaction flask. Heat the system to 85 °C, and add 4-methoxybenzyl bromide (0.15 g, 0.75 mmol) in portions, maintaining the temperature for reaction. After the reaction was complete, the mixture was cooled to room temperature, methanol (10.0 mL) was added, and the mixture was stirred for 2 min. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure. 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 (0.26 g, 86.5%).

[0358] MS(ESI,pos.ion)m / z:743.4[M+H] + .

[0359] Step 3: Synthesis of (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

[0360] (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 (0.25 g, 0.34 mmol), Xphos Pd G3 (35.8 mg, 0.04 mmol), and sodium carbonate (0.14 g, 1.72 mmol) were added to the reaction flask. Under nitrogen protection, cyclopropyl zinc bromide tetrahydrofuran solution (10.0 mL, 0.5 mol / L, 5.0 mmol) was added. The mixture was heated to 70 °C and reacted for 12 h. After cooling to room temperature, the mixture was filtered. The filtered mother liquor was evaporated to dryness under reduced pressure, and the 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 (0.19 g, 75.4%).

[0361] MS(ESI,pos.ion)m / z:749.5[M+H] + .

[0362] Step 4: Synthesis of (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-carboxylic acid tert-butyl ester

[0363] (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 (0.18 g, 0.24 mmol), 10% Pd / C (0.15 g), and methanol (20.0 mL) were added to the reaction flask. After purging with hydrogen, the reaction was carried out at room temperature for 6.5 h. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the title compound as a gray solid (0.12 g, 82.1%), which was directly added to the next step.

[0364] MS(ESI,pos.ion)m / z:629.3[M+H] + .

[0365] Step 5: (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

[0366] (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-carboxylic acid tert-butyl ester (0.12 g, 0.20 mmol), dichloromethane (15.0 mL), and trifluoroacetic acid (2.0 mL) were added to the reaction flask, and the reaction was carried out at room temperature for 1.5 h. After the reaction was complete, the system was directly evaporated to dryness under reduced pressure to obtain a light brown viscous liquid (0.10 g, 100.0%) containing the title compound, which was directly added to the next step.

[0367] MS(ESI,pos.ion)m / z:529.3[M+H] + .

[0368] Step 6: 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

[0369] At -20°C, (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 (0.10 g, 0.16 mmol), dichloromethane (10.0 mL), triethylamine (58.5 mg, 0.58 mmol), and acryloyl chloride (15.5 mg, 0.17 mmol) were added to a reaction flask, and the reaction was maintained at this temperature for 30 min. After the reactants had reacted completely, the system was evaporated to dryness 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 light brown solid (20.0 mg, 22.1%).

[0370] MS(ESI,pos.ion)m / z:583.3[M+H] + .

[0371] 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).

[0372] 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-methoxyphenylacetic acid ester

[0373]

[0374] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0375] Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50 g, 0.91 mmol), (2-hydroxy-3-methoxy)phenylboronic acid (0.17 g, 0.95 mmol), Pd(dppf)Cl2 (78.6 mg, 0.096 mmol), potassium carbonate (0.45 g, 4.57 mmol), and 1,4-dioxane (10.0 mL) to the reaction flask, heat to 100 °C, and react for 24 h. Cool to room temperature and concentrate under reduced pressure to remove the solvent. Water (50 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (200 mL × 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 (0.20 g, 34.6%).

[0376] MS(ESI,pos.ion)m / z:635.2[M+H] + .

[0377] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0378] (S)-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-carboxylic acid tert-butyl ester (0.43 g, 0.67 mmol), triethylamine (1.0 mL, 7.2 mmol), and dichloromethane (10 mL) were added to the reaction flask. Acetyl chloride (0.1 mL, 1.0 mmol) was then slowly added dropwise, and the mixture was stirred at room temperature for 6 h. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure. 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 (0.39 g, 85.8%).

[0379] MS(ESI,pos.ion)m / z:677.3[M+H] + .

[0380] Step 3: Synthesis of (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-carboxylic acid tert-butyl ester

[0381] (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-carboxylic acid tert-butyl ester (0.10 g, 0.15 mmol), xphos Pd G2 (23.2 mg, 0.030 mmol), potassium carbonate (29.6 mg, 0.30 mmol), and cyclopropyl zinc bromide (10.0 mL, 0.5 mol / L, 5 mmol) were added to the reaction flask. The mixture was heated to 60 °C and stirred overnight. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure. 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 (69.2 mg, 68.4%).

[0382] MS(ESI,pos.ion)m / z:683.4[M+H] + .

[0383] Step 4: (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-methoxyphenylacetate

[0384] (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-carboxylic acid tert-butyl ester (20.5 mg, 0.030 mmol), dichloromethane (4.0 mL), and trifluoroacetic acid (2.5 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 4.5 h. After the reactants had reacted completely, the system was evaporated to dryness under reduced pressure to obtain a brown liquid containing the title compound (17.5 mg, 100%).

[0385] Step 5: (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-methoxyphenylacetic acid ester

[0386] (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 (17.5 mg, 0.030 mmol), dichloromethane (2 mL) was added to the reaction flask, the mixture was cooled to 0 °C, and a solution of acryloyl chloride (6.6 mg, 0.073 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 3 h. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure. 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 (5.6 mg, 29.0%).

[0387] MS(ESI,pos.ion)m / z:637.2[M+H] + .

[0388] 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).

[0389] 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

[0390]

[0391] The first step was the synthesis of (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.

[0392] Add (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.28 g, 0.51 mmol), 2,3-dimethoxyphenylboronic acid (0.30 g, 1.67 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (47.3 mg, 0.058 mmol), potassium acetate (70.0 mg, 0.71 mmol), and 1,4-dioxane (10.0 mL) to the reaction flask. Heat to 90 °C and stir for 10 min. Then add a mixed solution of dioxane and water (v / v = 1 / 1, 0.5 mL) and keep warm and stir for 3 h. Cool to room temperature, concentrate under reduced pressure to remove solvent, add saturated brine (30 mL) to the residue, stir for 10 min, extract with ethyl acetate (100 mL × 3), combine organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1–1 / 1) to give the title compound as a pale yellow solid (0.21 g, 63.1%).

[0393] MS(ESI,pos.ion)m / z:649.3[M+H] + .

[0394] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0395] (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 (0.21 g, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (26.0 mg, 0.033 mmol), and cyclopropyl zinc bromide (15.0 mL, 8.0 mmol) were added to the reaction flask, and the temperature was raised to 66 °C and the reaction was carried out for 5 hours. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (85.8 mg, 40.9%).

[0396] MS(ESI,pos.ion)m / z:655.4[M+H] + .

[0397] Step 3: 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

[0398] (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-carboxylic acid tert-butyl ester (50.9 mg, 0.078 mmol), trifluoroacetic acid (3.0 mL), and dichloromethane (5.0 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 1 h. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure and then dried under vacuum to obtain the title compound as a brown solid (43.2 mg, 100.0%), which was used directly in the next step.

[0399] Step 4: 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]pyrimidine-2(1H)-one

[0400] (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 (43.2 mg, 0.078 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), and dichloromethane (4.0 mL) were added to the reaction flask. The mixture was cooled to -30 °C, and a solution of acryloyl chloride (0.1 mL, 0.1 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 min. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure. 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 (26.8 mg, 56.5%).

[0401] MS(ESI,pos.ion)m / z:609.3[M+H] + .

[0402] 1H NMR (400MHz, CDCl3) δ (ppm) 8.47 (d, J = 4.7Hz, 1H), 7.63 (s, 1H), 7.05 (t, J = 6.6Hz, 2H), 6.9 5(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).

[0403] 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

[0404]

[0405] Step 1 (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-carboxylic acid tert-butyl ester

[0406] (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 (0.20 g, 0.37 mmol), (2-fluoro-5-methoxy)phenylboronic acid (0.19 g, 1.13 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (33.4 mg, 0.041 mmol), potassium acetate (50.2 mg, 0.51 mmol), and 1,4-dioxane (20.0 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 3 h. Cool to room temperature, concentrate under reduced pressure to remove solvent, add saturated brine (30 mL) to the residue, stir for 10 min, extract with ethyl acetate (100 mL × 3), combine organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.15 g, 61.7%).

[0407] Step 2: (S)-4-(6-cyclopropyl-7-(2-fluoro-5-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyridino[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0408] (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-carboxylic acid tert-butyl ester (0.33 g, 0.52 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (45.0 mg, 0.057 mmol) and cyclopropyl zinc bromide (30.0 mL, 20.0 mmol) were added to the reaction flask, and the temperature was raised to 66 °C and the reaction was carried out for 7 hours. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.14 g, 40.9%).

[0409] MS(ESI,pos.ion)m / z:643.4[M+H] + .

[0410] Step 3: 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

[0411] (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 (63.2 mg, 0.098 mmol) and dichloromethane (8.0 mL) were added to a reaction flask and stirred at -78 °C for 5 min. A solution of boron tribromide in dichloromethane (0.1 mL) was slowly added dropwise. After the addition was complete, the mixture was transferred to an ice-water bath and stirred for 10 min. After the reactants had reacted completely, the system was evaporated to dryness under reduced pressure to obtain the title compound as a brown solid (37.6 mg, 72.3%), which was used directly in the next step. MS (ESI, pos.ion) m / z: 529.2 [M+H] + .

[0412] Step 4: Synthesis of (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]pyrimidine-2(1H)-one

[0413] (S)-6-cyclopropyl-7-(2-fluoro-5-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (37.6 mg, 0.071 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), and dichloromethane (5.0 mL) were added to the reaction flask. The mixture was cooled to -30 °C, and a solution of acryloyl chloride (0.1 mL, 0.1 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure. 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 (26.1 mg, 63.0%).

[0414] MS(ESI,pos.ion)m / z:583.2[M+H] + .

[0415] 1 H 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).

[0416] 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

[0417]

[0418] The first step was the synthesis of (S)-4-(6-chloro-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.

[0419] To the reaction flask, (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 (0.20 g, 0.37 mmol), 4-fluoro-2-methoxyphenylboronic acid (70 mg, 0.4 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (61 mg, 0.073 mmol), potassium acetate (0.19 g, 1.8 mmol), and 1,4-dioxane (6 mL) were added. The mixture was heated to 90 °C and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration. 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 (0.14 g, 60.0%).

[0420] MS(ESI,pos.ion)m / z:637.3[M+H] + .

[0421] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.49 (d, J = 4.9 Hz, 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),4.54–4.2 1(m,2H),4.21–3.85(m,2H),3.74(s,3H),3.47–2.97(m,2H),2.84–2.59(m,1 H),2.05(s,3H),1.52(s,9H),1.27–1.16(m,6H),1.05(dd,J=6.7,2.8Hz,3H).

[0422] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0423] Add (S)-4-(6-chloro-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.41 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (33 mg, 0.041 mmol), cyclopropyl zinc bromide tetrahydrofuran solution (8.5 mL, 4.3 mmol), and sodium carbonate (0.22 g, 2.1 mmol) to the reaction flask, purge with nitrogen, heat to 65 °C, and react overnight. The mixture was 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 (0.10 g, 38.0%).

[0424] MS(ESI,pos.ion)m / z:643.3[M+H] + .

[0425] Step 3: 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

[0426] Add (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-carboxylic acid tert-butyl ester (95 mg, 0.15 mmol), trifluoroacetic acid (1 mL), and dichloromethane (2 mL) to the reaction flask, and stir at room temperature for 2 h. Concentrate to remove the solvent; the concentrate is used directly in the next reaction step.

[0427] MS(ESI,pos.ion)m / z:543.3[M+H] + .

[0428] Step 4: Synthesis of (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]pyrimidine-2(1H)-one

[0429] (S)-6-cyclopropyl-7-(4-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.16 g, 0.29 mmol), DIPEA (80 mg, 0.61 mmol), and dichloromethane (2 mL) were added to the reaction flask. The mixture was cooled to 0 °C, and acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise. After the addition was complete, 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 (50 mg, 28.0%).

[0430] MS(ESI,pos.ion)m / z:597.3[M+H] + .

[0431] 1 H 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).

[0432] Example 16 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

[0433]

[0434] Step 1: Synthesis of 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-carboxylic acid

[0435] 4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.21 g, 0.39 mmol), 2-methoxyphenylboronic acid (0.21 g, 1.35 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (34.9 mg, 0.043 mmol), potassium acetate (52.3 mg, 0.53 mmol), and 1,4-dioxane (10.0 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 10 minutes. Then, water (0.5 mL) was added, and stirring was continued for 3 hours. Cool to room temperature, concentrate to remove solvent, add saturated brine (30 mL), stir for 10 min, extract with ethyl acetate (10 mL × 3), combine organic phases, concentrate, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.19 g, 81.8%).

[0436] MS(ESI,pos.ion)m / z:605.2[M+H] + .

[0437] Step 2: 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-carboxylic acid.

[0438] 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 (0.19 g, 0.32 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (26.5 mg, 0.034 mmol) and cyclopropyl zinc bromide (10.0 mL, 5.0 mmol) were added to the reaction flask, and the temperature was raised to 66 °C and the reaction was carried out for 7 hours. Cool to room temperature, add saturated brine (10 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, concentrate to remove solvent, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (96.5 mg, 50.1%). MS (ESI, pos.ion) m / z: 611.3 [M+H] + .

[0439] Step 3: 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

[0440] 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 (80.0 mg, 0.13 mmol), dichloromethane (5.0 mL), and trifluoroacetic acid (2.0 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 1 h. After the reactants had reacted completely, the system was concentrated under reduced pressure and dried to obtain the title compound as a brown solid (66.9 mg, 100%), which was used directly in the next step.

[0441] MS(ESI,pos.ion)m / z:511.2[M+H] + .

[0442] Step 4: 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

[0443] 6-Cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-4-(piperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (66.9 mg, 0.13 mmol), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol), and dichloromethane (5.0 mL) were added dropwise to a reaction flask at 0 °C. The flask was then incubated at 0 °C, and a solution of acryloyl chloride (0.05 mL, 0.6 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure. The residue was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1-0 / 1) to give the title compound as a yellow solid (18.0 mg, 24.3%).

[0444] MS(ESI,pos.ion)m / z:565.2[M+H] + .

[0445] 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).

[0446] 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)pyridino[2,3-d]pyrimidin-2(1H)-one

[0447]

[0448] The first step is the synthesis of 5-bromo-1,3-dimethylpyridin-2(1H)-one.

[0449] 5-Bromo-3-methylpyridin-2(1H)-one (0.51 g, 2.69 mmol), N,N-dimethylformamide (6.0 mL), potassium tert-butoxide (0.65 g, 5.79 mmol), and methyl iodide (0.5 mL, 8 mmol) were added to a steel reaction vessel. The mixture was sealed and heated to 80 °C, and stirred overnight. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-1 / 1) to give a yellow liquid containing the title compound (0.41 g, 75.9%).

[0450] MS(ESI,pos.ion)m / z:202.0[M+H] + .

[0451] Step 2: Synthesis of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2(1H)-one

[0452] 5-Bromo-1,3-dimethylpyridin-2(1H)-one (0.41 g, 2.04 mmol), potassium acetate (0.71 g, 7.26 mmol), Pd(dppf)Cl2 (0.18 g, 0.22 mmol), 1,4-dioxane (15.0 mL), and pinacol diboronate (1.30 g, 5.10 mmol) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 85 °C and stirred overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. 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 (0.45 g, 89.2%).

[0453] MS(ESI,pos.ion)m / z:250.0[M+H] + .

[0454] Step 3: Synthesis of (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

[0455] Add (S)-4-[6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.24 g, 0.44 mmol), 1,3-dimethyl-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2(1H)-one (0.11 g, 0.44 mmol), and Pd(dppf)Cl2 (32) to the reaction flask. 0.2 mg (0.039 mmol), 1,4-dioxane (10.0 mL), cesium carbonate (0.33 g, 1.01 mmol). Under nitrogen protection, the mixture was heated to 85 °C and stirred for 24 h. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 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 (70.0 mg, 25.2%).

[0456] MS(ESI,pos.ion)m / z:634.3[M+H] + .

[0457] Step 4: Synthesis of (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-carboxylic acid tert-butyl ester

[0458] To the reaction flask, add (S)-4-(6-chloro-7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.36 g, 0.59 mmol), 1,4-dioxane (6.0 mL), xphos Pd G2 (73.6 mg, 0.094 mmol), and sodium carbonate (0.36 g, 4.32 mmol). Replace with nitrogen for protection, and rapidly add cyclopropyl zinc bromide (12.0 mL, 0.5 mol / L, 6 mmol). Heat the system to 100 °C and stir for 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0–0 / 1), and then preparatively separated to give the title compound as a yellow solid (85.3 mg, 23.5%).

[0459] Step 5: 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]pyrimidine-2(1H)-one

[0460] (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-carboxylic acid tert-butyl ester (40.0 mg, 0.065 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (4.0 mL) were added to the reaction flask. The mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure to give the title compound as a brown solid (33.5 mg, 100%).

[0461] Step 6: 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)pyridino[2,3-d]pyrimidin-2(1H)-one

[0462] Add (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 (33.5 mg, 0.065 mmol) and N,N-diisopropylethylamine (0.2 mL), and dichloromethane (2 mL) to the reaction flask. Cool to 0 °C and slowly add a solution of acryloyl chloride (13.6 mg, 0.15 mmol) in dichloromethane (2 mL). After the addition is complete, keep warm and stir for 2.5 h. After the reactants had reacted completely, the mixture was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1–20 / 1), and then separated by preparative chromatography to obtain the title compound as a yellow solid (5.6 mg, 11%).

[0463] MS(ESI,pos.ion)m / z:594.4[M+H] + .

[0464] 1 H 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).

[0465] 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

[0466]

[0467] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0468] The following were added to the reaction flask: (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 (0.30 g, 0.55 mmol), 3-fluoro-2-methoxyphenylboronic acid (93.2 mg, 0.55 mmol), Pd(dppf)Cl2 (44.8 mg, 0.055 mmol), 1,4-dioxane (10.0 mL), and cesium carbonate (0.45 g, 1.37 mmol). Under nitrogen protection, the mixture was heated to 85 °C and stirred for 24 h. Cool to room temperature, add water (50 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1 – 0 / 1) to give the title compound as a yellow solid (0.19 g, 53.2%). MS (ESI, pos.ion) m / z: 637.3 [M + H] + .

[0469] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0470] (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 (0.10 g, 0.16 mmol), xphos Pd G2 (49.4 mg, 0.063 mmol), sodium carbonate (83.2 mg, 0.79 mmol), and cyclopropyl zinc bromide (10.0 mL, 10 mmol) were added to the reaction flask. The system was heated to 50 °C and stirred overnight. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. 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 (53.5 mg, 53.1%).

[0471] MS(ESI,pos.ion)m / z:643.2[M+H] + .

[0472] Step 3: 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

[0473] (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-carboxylic acid tert-butyl ester (53.5 mg, 0.083 mmol), dichloromethane (4.0 mL), and trifluoroacetic acid (2.0 mL) were added to the reaction flask. The system was stirred at room temperature for 2 h, concentrated under reduced pressure to remove the solvent, and dried under vacuum to give the title compound as a yellow solid (45.2 mg, 100%). Step 4: Synthesis of (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]pyrimidine-2(1H)-one

[0474] (S)-6-cyclopropyl-7-(3-fluoro-2-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (45.2 mg, 0.083 mmol), dichloromethane (4 mL), and N,N-diisopropylethylamine (0.2 mL, 1 mmol) were added to the reaction flask. The system was cooled to 0 °C, and a solution of acryloyl chloride (12.1 mg, 0.13 mmol) in dichloromethane (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 2.5 h. After the reactants had reacted completely, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1–20 / 1), and then purified by preparative chromatography to obtain the title compound (22.9 mg, 46.1%).

[0475] MS(ESI,pos.ion)m / z:597.2[M+H] + .

[0476] 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),3.3 9–3.23(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).

[0477] 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

[0478] and

[0479] 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)methylacetate

[0480]

[0481] The first step was the synthesis of (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.

[0482] 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (1.10 g, 2.87 mmol), (R)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 3.73 mmol), N,N-diisopropylethylamine (2.5 mL, 15 mmol), and acetonitrile (10 mL) were added to the reaction flask. The system was heated to 50 °C and stirred overnight. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. 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 (1.60 g, 99.0%).

[0483] MS(ESI,pos.ion)m / z:563.2[M+H] + .

[0484] Step 2: Synthesis of (R)-2-(acetoxymethyl)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0485] (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 (1.60 g, 2.84 mmol), triethylamine (4.0 mL, 28.7 mmol), and dichloromethane (20.0 mL) were added to the reaction flask. Acetyl chloride (0.3 mL, 4 mmol) was then slowly added dropwise, and the system was stirred at room temperature for 39 h. After the reactants had reacted completely, the solvent was removed by concentration under reduced pressure. 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 (0.42 g, 24.0%).

[0486] Step 3: Synthesis of (R)-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-carboxylic acid tert-butyl ester

[0487] The following substances were added to the reaction flask: (R)-2-(acetoxymethyl)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.33 mmol), 2-methoxyphenylboronic acid (60.1 mg, 0.40 mmol), Pd(dppf)Cl2 (26.9 mg, 0.033 mmol), cesium carbonate (0.16 g, 0.82 mmol), and 1,4-dioxane (10.0 mL). The system was heated to 100 °C and stirred for 24 h under nitrogen protection. The solvent was removed by cooling to room temperature and concentration under reduced pressure. 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 (0.13 g, 57.8%).

[0488] MS(ESI,pos.ion)m / z:677.3[M+H] + .

[0489] Step 4: Synthesis of (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

[0490] (R)-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-carboxylic acid tert-butyl ester (0.13 g, 0.18 mmol), xphos Pd G2 (29.0 mg, 0.037 mmol), sodium carbonate (97.8 mg, 0.92 mmol), and cyclopropyl zinc bromide (10.0 mL, 10.0 mmol) were added to the reaction flask. The system was heated to 50 °C and stirred overnight. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. 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 (0.11 g, 88.2%).

[0491] Step 5: 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)methylacetate

[0492] (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 (0.11 g, 0.16 mmol), trifluoroacetic acid (2.0 mL), and dichloromethane (4.0 mL) were added to the reaction flask. The system was stirred at room temperature for 3.5 h. After the reactants had reacted completely, the mixture was concentrated under reduced pressure to obtain a brown liquid containing the title compound (94.9 mg, 100%). MS (ESI, pos.ion) m / z: 583.3 [M+H] + .

[0493] Step 6 (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]pyrimidine-2(1H)-one (Example 19)

[0494] and

[0495] (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)

[0496] Add (R)-(4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)methyl acetate (94.9 mg, 0.16 mmol), N,N-diisopropylethylamine (0.12 g, 0.91 mmol), and dichloromethane (3 mL) to the reaction flask. Cool the system to 0 °C, and slowly add a solution of acryloyl chloride (16.2 mg, 0.18 mmol) in dichloromethane (3 mL). After the addition is complete, keep the mixture warm and stir for 2.5 h. After the reactants had reacted completely, the mixture was concentrated under reduced pressure. The residue was purified once by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1–20 / 1), and then separated to obtain the title compound Example 19 yellow solid (4.9 mg, 5.1%) and the title compound Example 20 yellow solid (4.6 mg, 4.4%).

[0497] Example 19

[0498] MS(ESI,pos.ion)m / z:595.31[M+H] + .

[0499] 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).

[0500] Example 20

[0501] MS(ESI,pos.ion)m / z:637.2[M+H] + .

[0502] 1 H 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).

[0503] Example 21(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

[0504]

[0505] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0506] Add (S)-4-(6-chloro-7-(2-fluoro-5-(methoxycarbonyl)phenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.32 g, 0.47 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40 mg, 0.05 mmol), cyclopropyl zinc bromide tetrahydrofuran solution (10 mL, 5 mmol), and sodium carbonate (0.25 g, 2.4 mmol) to the reaction flask. Under nitrogen protection, heat to 65 °C and react overnight. The mixture was cooled to room temperature, concentrated under reduced pressure 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 (0.23 g, 71%). MS (ESI, pos.ion) m / z: 671.3 [M+H] + .

[0507] The second step involves the 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.

[0508] (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-carboxylic acid tert-butyl ester (0.13 g, 0.19 mmol), trifluoroacetic acid (2 mL), and dichloromethane (4 mL) were added to the reaction flask. The system was stirred at room temperature for 2 h, concentrated under reduced pressure to remove the solvent, and dried under vacuum to obtain the title compound as a yellow solid (0.11 g, 100%), which was used directly in the next reaction step.

[0509] MS(ESI,pos.ion)m / z:571.3[M+H] + .

[0510] Step 3: 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-dihydropyridino[2,3-d]pyrimidin-7-yl)-4-fluorobenzoate

[0511] 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 (0.11 g, 0.19 mmol), triethylamine (0.11 g, 1.1 mmol), and dichloromethane (4 mL) were added to the reaction flask. The system was cooled to 0 °C, and acryloyl chloride (40 mg, 0.43 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred 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 (49 mg, 40.7%). MS (ESI, pos.ion) m / z: 625.3 [M+H] + .

[0512] 1 H 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).

[0513] 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

[0514]

[0515] The first step was the synthesis of (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.

[0516] At room temperature, (S)-4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dipyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.50 g, 0.91 mmol), 2,5-difluorophenylboronic acid (0.19 g, 1.20 mmol), potassium acetate (0.14 g, 1.40 mmol), PdCl2(dppf)DCM (0.08 g, 0.10 mmol) were added sequentially to the reaction flask. Under nitrogen protection, 1,4-dioxane (10 mL) was added, and the mixture was purged with nitrogen again. The mixture was then placed in a 90°C oil bath and stirred for 14 h. The mixture was cooled to room temperature and concentrated under reduced pressure. 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 (0.52 g, 91.6%).

[0517] MS(ESI,pos.ion)m / z:625.2[M+H] + .

[0518] Step 2: Synthesis of (S)-4-(6-cyclopropyl-7-(2,5-difluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dichloropyridino[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0519] At room temperature, (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 (0.15 g, 0.24 mmol), sodium carbonate (0.13 g, 1.22 mmol), xphos Pd G2 (0.04 g, 0.05 mmol), and cyclopropyl zinc bromide (8 mL, 4 mmol, 0.5 mol / L in THF) were added sequentially to the reaction flask. Under nitrogen protection, the reaction was carried out at 65 °C for 17 h. The mixture was 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 (0.15 g, 99.1%).

[0520] MS(ESI,pos.ion)m / z:631.3[M+H] + .

[0521] Step 3: 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

[0522] At room temperature, (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-carboxylic acid tert-butyl ester (0.14 g, 0.22 mmol) and dichloromethane (3 mL) were added sequentially to a reaction flask, followed by the addition of trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 30 min. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a brown oily substance (0.12 g, 100%) containing the title compound, which was used directly in the next reaction step.

[0523] Step 4: 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]pyrimidine-2(1H)-one

[0524] At 0 °C, (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 (0.12 g, 0.22 mmol), dichloromethane (3 mL), and N,N-diisopropylethylamine (0.1 mL, 0.43 mmol) were added dropwise with stirring. After the addition was complete, the mixture was transferred to room temperature and stirred for 1 h. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give the title compound as a pale yellow solid (62.0 mg, 48.8%).

[0525] MS(ESI,pos.ion)m / z:585.3[M+H] + .

[0526] 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).

[0527] 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

[0528]

[0529] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0530] The reaction was carried out with (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 (0.20 g, 0.37 mmol), 8-quinolineboronic acid (72 mg, 0.4 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (60 mg, 0.073 mmol), potassium acetate (0.19 g, 1.8 mmol), and dioxane (6 mL). Under nitrogen protection, the temperature was raised to 90 °C and the reaction was stirred overnight. The solvent was removed by cooling to room temperature and concentration under reduced pressure. 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 (0.11 g, 46%).

[0531] MS(ESI,pos.ion)m / z:640.4[M+H] + .

[0532] Step 2: Synthesis of (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

[0533] Add (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-carboxylic acid tert-butyl ester (0.10 g, 0.16 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15 mg, 0.019 mmol), cyclopropyl zinc bromide tetrahydrofuran solution (4 mL, 2 mmol), and sodium carbonate (90 mg, 0.85 mmol) to the reaction flask. Under nitrogen protection, heat to 65 °C and react overnight. The solvent was removed by cooling to room temperature and concentration under reduced pressure. 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 (51 mg, 49%).

[0534] MS(ESI,pos.ion)m / z:646.4[M+H] + .

[0535] Step 3: 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

[0536] (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 (51 mg, 0.079 mmol), trifluoroacetic acid (1 mL), and dichloromethane (2 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to obtain a yellow semi-solid of the title compound (43.1 mg, 100%), which was used directly in the next reaction. MS (ESI, pos.ion) m / z: 546.3 [M+H] + .

[0537] Step 4 (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

[0538] (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 (43.1 mg, 0.079 mmol), triethylamine (80 mg, 0.78 mmol), and dichloromethane (3 mL) were added to a single-necked flask. The mixture was cooled to 0 °C, and acryloyl chloride (20 mg, 0.22 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration, 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 (13 mg, 27.4%).

[0539] MS(ESI,pos.ion)m / z:600.3[M+H] + .

[0540] 1 H 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, 1 H),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=1 6.8Hz,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).

[0541] 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

[0542]

[0543] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0544] To the reaction flask, (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 (0.50 g, 0.91 mmol), 5-chloro-2-fluoro-phenylboronic acid (0.48 g, 2.75 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (77.3 mg, 0.095 mmol), potassium acetate (0.12 g, 1.20 mmol), and 1,4-dioxane (15.0 mL) were added. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 3 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. Saturated brine (30 mL) was added to the residue, stirred for 10 min, and extracted with ethyl acetate (10 mL × 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 (0.53 g, 90.0%).

[0545] MS(ESI,pos.ion)m / z:641.3[M+H] + .

[0546] Step 2: Synthesis of (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-carboxylic acid tert-butyl ester

[0547] (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-carboxylic acid tert-butyl ester (0.10 g, 0.16 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15.3 mg, 0.019 mmol), and cyclopropyl zinc bromide (8.0 mL, 8.0 mmol) were added to the reaction flask, and the temperature was raised to 66 °C and the reaction was allowed to proceed for 7 h. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (30.0 mL × 3), combine the organic phases, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (67.3 mg, 66.1%).

[0548] MS(ESI,pos.ion)m / z:647.4[M+H]+ .

[0549] Step 3: Synthesis of (S)-7-(5-chloro-2-fluoro-phenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

[0550] (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-carboxylic acid tert-butyl ester (67.3 mg, 0.10 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (3.0 mL) were added to the reaction flask, and the system was stirred at room temperature for 1 h. After the reactants had reacted completely, the mixture was evaporated to dryness under reduced pressure to obtain the title compound as a brown solid (56.9 mg, 100.0%), which was used directly in the next step.

[0551] Step 4: Synthesis of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-chloro-2-fluoro-phenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)pyridino[2,3-d]pyrimidin-2(1H)-one

[0552] (S)-7-(5-chloro-2-fluorophenyl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (67.3 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 mL, 1.0 mmol), and dichloromethane (3.0 mL) were added to the reaction flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (0.1 mL, 0.6 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 min. The solvent was removed by concentration under reduced pressure. 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 (50.9 mg, 68.8%).

[0553] MS(ESI,pos.ion)m / z:601.3[M+H] + .

[0554] 1H NMR (400MHz, CDCl3) δ (ppm) 8.53 (d, J = 4.9 Hz, 1H), 7.69 (s, 1H), 7.36–7.31 (m, 1H), 7.13 (dd, J = 9.9, 3.8H z,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)

[0555] 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

[0556]

[0557] The first step was the synthesis of (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-carboxylic acid tert-butyl ester.

[0558] (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 (0.50 g, 0.91 mmol), 2-hydroxy-3-methylphenylboronic acid (0.43 g, 2.77 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (80.6 mg, 0.099 mmol), potassium acetate (0.12 g, 1.21 mmol), and 1,4-dioxane (15.0 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 3 h. Cool to room temperature, concentrate to remove solvent, add saturated brine (30 mL) to the residue, stir for 10 min, extract with ethyl acetate (30 mL × 3), combine organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.51 g, 90.3%).

[0559] MS(ESI,pos.ion)m / z:619.3[M+H] + .

[0560] Step 2: Synthesis of (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0561] (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-carboxylic acid tert-butyl ester (0.40 mg, 0.64 mmol), potassium hydroxide (0.19 g, 3.39 mmol), and iodomethane (0.3 mL, 5.0 mmol) were added to the reaction flask. The system was stirred at room temperature for 3 hours. Saturated brine (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL × 3). The organic phases were combined, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.35 g, 86.8%).

[0562] MS(ESI,pos.ion)m / z:633.3[M+H] + .

[0563] Step 3: Synthesis of (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-carboxylic acid tert-butyl ester

[0564] To the reaction flask, (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.10 g, 0.16 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15.3 mg, 0.019 mmol), and cyclopropyl zinc bromide (8.0 mL, 8.0 mmol) were added. The system was heated to 66 °C and reacted for 7 hours. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (30.0 mL × 3), combine the organic phases, remove the solvent by reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (86.8 mg, 85.5%).

[0565] MS(ESI,pos.ion)m / z:639.4[M+H] + .

[0566] Step 4: 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

[0567] (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-carboxylic acid tert-butyl ester (86.7 mg, 0.14 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (3.0 mL) were added to the reaction flask. The system was stirred at room temperature for 1 h, concentrated under reduced pressure to remove the solvent, and dried to obtain the title compound (73.1 mg, 100.0%), which was used directly in the next step.

[0568] Step 5: 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]pyrimidine-2(1H)-one

[0569] (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 (73.1 mg, 0.14 mmol), N,N-diisopropylethylamine (0.1 mL, 1.0 mmol), and dichloromethane (3.0 mL) were added to the reaction flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (0.1 mL, 0.6 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, 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 (32.9 mg, 40.9%).

[0570] MS(ESI,pos.ion)m / z:593.3[M+H] + .

[0571] 1 H 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).

[0572] Example 26 (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0573]

[0574] The first step was the synthesis of (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.

[0575] (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 (0.51 g, 0.93 mmol), 8-methyl-1-naphthylboronic acid (0.26 g, 1.40 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (77.1 mg, 0.094 mmol), sodium carbonate (0.13 g, 1.23 mmol), and 1,4-dioxane (10.0 mL) were added to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 10 min. Then, water (0.5 mL) was added, and stirring was continued for 3 h. Cool to room temperature, concentrate under reduced pressure to remove solvent, add saturated brine (30 mL) to the residue, stir for 10 min, extract with ethyl acetate (30 mL × 3), combine organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.40 g, 65.2%).

[0576] MS(ESI,pos.ion)m / z:653.4[M+H] + .

[0577] Step 2: Synthesis of (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0578] (S)-4-(6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.18 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (70.3 mg, 0.089 mmol), and cyclopropyl zinc bromide (10.0 mL, 5.0 mmol) were added to the reaction flask, and the temperature was raised to 66 °C and the reaction was carried out for 7 h. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (30.0 mL × 3), combine the organic phases, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (84.7 mg, 73.2%).

[0579] MS(ESI,pos.ion)m / z:659.4[M+H] + .

[0580] Step 3: Synthesis of (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)-4-(2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one

[0581] (S)-4-(6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (84.7 mg, 0.13 mmol), trifluoroacetic acid (0.2 mL), and dichloromethane (3.0 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the product was dried to obtain the title compound as a yellow solid (71.8 mg, 100.0%), which was used directly in the next step.

[0582] MS(ESI,pos.ion)m / z:559.4[M+H] + .

[0583] Step 4: Synthesis of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0584] (S)-6-cyclopropyl-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(8-methylnaphthyl-1-yl)-4-(2-methylpiperazin-1-yl)pyridin[2,3-d]pyrimidin-2(1H)-one (71.8 mg, 0.13 mmol), N,N-diisopropylethylamine (25.6 mg, 0.20 mmol), and dichloromethane (3.0 mL) were added to the reaction flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (15.3 mg, 0.17 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, 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) = 50 / 1-40 / 1) to give the title compound as a yellow solid (36.7 mg, 46.6%).

[0585] MS(ESI,pos.ion)m / z:613.4[M+H] + .

[0586] 1 H 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,3 H),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).

[0587] Example 27 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

[0588]

[0589] The first step was the synthesis of (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.

[0590] The reaction flask was filled with (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 (0.37 g, 0.66 mmol), 2-fluoro-5-methylphenylboronic acid (0.30 g, 1.98 mmol), [1,1′-[1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.11 g, 0.13 mmol), potassium acetate (0.13 g, 1.32 mmol), and 1,4-dioxane (10.0 mL). Under nitrogen protection, the mixture was heated to 90 °C and stirred for 3 h. Cool to room temperature, concentrate to remove solvent, add saturated brine (10 mL) to the residue, stir for 10 min, extract with ethyl acetate (10 mL × 3), combine organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.34 g, 80.6%).

[0591] MS(ESI,pos.ion)m / z:635.4[M+H] + .

[0592] The second step involves the synthesis of (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.

[0593] (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 (0.12 g, 0.19 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (74.3 mg, 0.094 mmol), and cyclopropyl zinc bromide (10.0 mL, 5.0 mmol) were added to the reaction flask, and the temperature was raised to 66 °C. The reaction was carried out for 7 hours. Cool to room temperature, add saturated brine (10.0 mL), extract with ethyl acetate (15.0 mL × 3), combine the organic phases, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (0.11 g, 92.0%).

[0594] MS(ESI,pos.ion)m / z:641.3[M+H] + .

[0595] Step 3: 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

[0596] (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 (0.11 g, 0.17 mmol), trifluoroacetic acid (0.2 mL), and dichloromethane (3.0 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the product was dried under vacuum to obtain the title compound as a yellow solid (92.8 mg, 100%), which was used directly in the next step.

[0597] MS(ESI,pos.ion)m / z:541.3[M+H] + .

[0598] Step 4: 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]pyrimidine-2(1H)-one

[0599] 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 (92.8 mg, 0.17 mmol), N,N-diisopropylethylamine (0.3 mL, 2.0 mmol), and dichloromethane (3.0 mL) were added to a reaction flask. The mixture was cooled to 0 °C, and a solution of acryloyl chloride (0.1 mL, 1.0 mmol) in dichloromethane (1 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for 10 min. The solvent was removed by concentration under reduced pressure. 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 (74.4 mg, 72.3%).

[0600] MS(ESI,pos.ion)m / z:595.3[M+H] + .

[0601] 1 H 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=12.6,6.2H z,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).

[0602] Biological experiments

[0603] Example A: CTG method assay to detect the inhibitory activity of the compound on the proliferation of H358 (KRAS G12C) cells

[0604] The cell experiment conditions are shown in Table A:

[0605] Table A

[0606] Cell Name Cells (number) / well Incubation time (h) Complete culture medium H358 1000 72 RPMI 1640 + 10% FBS

[0607] 1) Cell Culture

[0608] Culture the cells in a suitable culture medium at 37°C in a 5% CO2 incubator. Observe the cells once daily using an inverted microscope, and change the culture medium every 2-4 days. Collect the cells, centrifuge at 1200 rpm for 5 min, discard the supernatant, and transfer the cells to new sterile culture dishes at a ratio of 1:3 to 1:8 for further culture.

[0609] 2) Cell plating

[0610] Collect cells in the exponential growth phase and count them using a cell counter. Resuspend the cells in the appropriate culture medium and adjust to the desired concentration. Add 90 μL of cell suspension to each well of a 96-well cell culture plate. Incubate overnight at 37°C in a 5% CO2 incubator.

[0611] 3) Compound preparation and dosing treatment

[0612] a. Preparation of stock solution: Dissolve the compound to be tested in DMSO to prepare a 10 mM stock solution.

[0613] b. The compound was diluted 3 times with DMSO to obtain 9 concentration gradients of the compound. The above gradient diluted compounds were then diluted 20 times with complete culture medium and mixed evenly to obtain a 10× concentration drug working solution.

[0614] c. Drug addition: Remove the cell culture plate and add 10 μL / well of the above-mentioned 10× concentration of working solution to the corresponding well of the cell culture plate, and incubate in a 37℃ incubator for 72 h.

[0615] 4) Reading board detection

[0616] After treatment with compound a for 72 hours, cell morphology was observed under an inverted microscope. Cells in the DMSO control wells showed normal growth and no contamination was observed. It was also determined whether any compound precipitates out of each well.

[0617] b. Allow the prepared CTG solution to equilibrate at room temperature for 10-20 minutes.

[0618] c. Add 50 μL of CTG solution per well according to the CTG operating instructions, and place on a shaker to shake in the dark for 20 min.

[0619] d. The fluorescence signal value was measured using an ELISA reader.

[0620] 5) Data Analysis

[0621] Growth inhibition rate % = (V 阴性组 -V 实验组 ) / (V 阴性组 -V 空白组 )×100%, where V 阴性组 V represents the average value of the solvent control group.实验组 For the drug treatment group, V 空白组 These are readings from the cell-free, drug-free treatment group. The IC was obtained by analyzing and counting the data using GraphPad Prism 5.0 software. 50 Values. The results are shown in Table 1, which presents the experimental results of the compound provided in the embodiments of the present invention on the inhibition of H358 cell proliferation.

[0622] Table 1. Experimental results of the inhibitory effect of the compounds provided in the embodiments of the present invention on the proliferation of H358 cells.

[0623]

[0624]

[0625] Experimental results showed that, in the test of inhibitory activity against H358 cell proliferation, the compound of the present invention had strong inhibitory activity against H358 cell proliferation, and its activity was superior to that of the positive control ARS1620.

[0626] Example B: LC-MS assay for detecting the binding of a compound to KRAS G12C protein

[0627] Experimental steps:

[0628] 1) The experimental buffer solution is prepared as shown in Table B.

[0629] Table B

[0630]

[0631] 2) Load GDP into KRAS G12C protein

[0632] KRAS G12C protein stock solution (11.13 mg / mL, 550 μM) was prepared with low Mg2+. 2+ Dilute the buffer 5-fold to 110 μM. Take 1 mL of 110 μM KRAS G12C protein and add 1 mL of 2×GDP loading buffer. Mix gently and incubate at room temperature for 1.5 h. Aliquot into 40 μL tubes and freeze immediately at -80°C.

[0633] 3) KRAS G12C binding test

[0634] Dilute the GDP-loaded KRAS G12C to 20 μM with 10× incubation buffer, and mix the reagents according to Table C below.

[0635] Table C

[0636] reagents Add volume GDP loaded with KRAS G12C (20μM) 5μL Compound (10% DMSO solution) 5μL 10× Incubation Buffer 5μL Ultrapure water 35μL total 50μL

[0637] Note: The dosage of each reagent can be varied according to certain proportions as needed.

[0638] 4) Incubate at room temperature for 5 min and 1 h respectively.

[0639] 5) Add 5 μL of 5% formic acid to terminate the reaction (Note: Add 5% formic acid solution at a ratio of 10% based on the volume of the incubation solution).

[0640] 6) LC-MS detection

[0641] After mixing the incubation solution, transfer it to a vial for LC-MS analysis. The analytical conditions are as follows:

[0642]

[0643]

[0644] 7) Calculate the KRAS G12C binding rate (%)

[0645] KRAS G12C binding rate % = (Complex peak area / (Complex peak area + Peak area of ​​unbound KRAS G12C)) × 100

[0646] The results are shown in Table 2, which presents the experimental results of the compound provided in the embodiments of the present invention binding to KRAS G12C protein for 1 hour.

[0647] Table 2. Experimental results of the binding of the compounds provided in the embodiments of the present invention to KRAS G12C protein.

[0648]

[0649] Experimental results show that the compound of this invention has a high binding rate with KRAS-4B-G12C protein.

[0650] Example C: Pharmacokinetic evaluation of mice after intravenous injection and oral administration of quantitative compounds of the present invention

[0651] Male ICR mice weighing 18-22g were randomly divided into two groups. One group received an intravenous injection of the test compound at a dose of 2.0 mg / kg, while the other group received an oral administration of the test compound at a dose of 5 mg / kg. Blood samples were collected from the tail vein at time points of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration. Blood samples were also collected from the tail vein at the same time points after oral administration. A standard curve was established based on the sample concentrations. The concentrations of the test compound in plasma samples were determined using an AB SCIEX API4000 LC-MS / MS in MRM mode. Pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonLin 6.3 software based on the drug concentration-time curves.

[0652] The results showed that when the compounds provided by the present invention were administered intravenously or orally, the compounds exhibited good pharmacokinetic properties, including good absorption and good oral bioavailability.

[0653] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0654] 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. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound comprising one of the following compounds or a stereoisomer of one of the following compounds, or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising the compound of claim 1; and The pharmaceutical composition optionally comprises pharmaceutically acceptable excipients, carriers, adjuvants, or any combination thereof.

3. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention, treatment or relief of a patient’s KRAS G12C-mediated disease.

4. The use according to claim 3, wherein, The KRAS G12C-mediated disease mentioned is cancer.

5. The use according to claim 4, wherein the cancer is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial carcinoma, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, or melanoma.

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