CN113135924A

CN113135924A - Pyrimidine derivatives and their use in medicine

Info

Publication number: CN113135924A
Application number: CN202110069859.8A
Authority: CN
Inventors: 习宁; 李敏雄; 吴双; 廖敏; 张涛; 李晓波; 席云龙; 杨芳; 陈疏影
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2020-01-19
Filing date: 2021-01-19
Publication date: 2021-07-20
Anticipated expiration: 2041-01-19

Abstract

The invention discloses a pyrimidine derivative and application thereof in medicines, and particularly relates to a novel pyrimidine derivative and a pharmaceutical composition containing the compound. The invention also relates to methods for preparing said compounds and pharmaceutical compositions, and to the use thereof for the preparation of medicaments for the treatment of diseases and/or disorders mediated by KRAS G12C, in particular for the treatment of cancer.

Description

Pyrimidine derivatives and their use in medicine

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel compound serving as a KRAS activity inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in treating various diseases. More specifically, the compounds of the present invention may act as inhibitors of the activity or function of KRAS G12C.

Background

KRAS is a murine sarcoma virus gene, and there are three genes related to human tumors in the ras gene family-H-ras, K-ras and N-ras, which are located on chromosomes 11, 12 and 1, respectively. The K-ras gene encodes a 21kD ras protein also known as the p21 gene. Among RAS genes, K-RAS has the greatest effect on human cancer, accounting for 86% of all RAS mutations, as if it were a molecular switch: when normal, the cell growth regulation path can be controlled; when abnormality occurs, the cells are caused to grow continuously and are prevented from self-destruction. It is involved in intracellular signal transmission, and when K-ras gene is mutated, the gene is permanently activated, and can not produce normal ras protein, so that intracellular signal conduction is disturbed, and cell proliferation is out of control and cancerated.

The G12C mutation is a more common subtype of KRAS gene mutation, which means that No. 12 glycine is mutated into cysteine. The KRAS G12C mutation is most common in lung cancer, and the KRAS G12C mutation accounts for about 10% of all lung cancer patients according to data reported in the literature (Nat Rev Drug Discov 2014; 13: 828-851).

Currently, researchers have conducted some studies in an attempt to find therapeutic agents that can effectively inhibit KRAS G12C mutant protein. PCT applications WO2014152588, WO2015054572, WO2016049524, WO2016164675, WO2016168540, WO2017015562, WO2017058915, WO2017058807, WO2017058792, WO2017058902, WO2017087528, WO2017201161, WO2018064510, WO2018068017, WO2018119183, WO2018140600, WO2018140512, WO2018143315, WO2018206539, WO2018217651, WO2018218070, WO2019051291, WO2019099524, WO2019110751, WO 2013791985 and WO 2012019141250 disclose small molecule compounds as inhibitors of KRAS G12C mutant proteins for the prevention or treatment of cancer. However, there is still a need for more and better KRAS G12C mutein inhibitors in the clinic.

Disclosure of Invention

The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as an inhibitor of KRAS. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by inhibition of KRAS activity by said compounds. The invention further describes a synthetic method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound, which is a compound shown as formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as formula (I),

wherein:

x is-L-X¹-, wherein L is a bond or-NH-, X¹Is a 4-12 membered saturated or partially unsaturated monocyclic, fused, spiro or bridged ring containing a nitrogen atom, which monocyclic, fused, spiro and bridged ring may be independently optionally substituted by m R^xSubstitution;

y is

R¹is-C (═ O) -CR^a＝CR^b-R^c、-C(＝O)-C≡C-R^c、-S(＝O)₂-CR^a＝CR^b-R^cor-S (═ O)₂-C≡C-R^c；

R^aAnd R^bEach independently is hydrogen, deuterium, a halogen atom, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

R^cis hydrogen, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino, 5-6 membered heteroaryl, C_3-6Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino, 5-6 membered heteroaryl, C_3-6Carbocyclyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Hydroxyalkoxy and 3-6 membered heterocyclyl;

w is a bond, -O- (CR)^mRⁿ)_p-、-S-(CR^mRⁿ)_p-or-NR^d-(CR^mRⁿ)_p-；

R^dIs hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

R²is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_6-12Aryl, 5-12 membered heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or-CR^eR^f-NR^gR^hWherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_6-12Aryl, 5-12 membered heteroaryl, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6Substituted by the radical hydroxyalkoxy;

R^m、Rⁿ、R^eand R^fEach independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

R^gand R^hEach independently of the others is hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy; or

R^f、R^gAnd the atoms to which they are attached form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

R³is C_6-12Aryl or 5-12 membered heteroaryl, wherein, said C_6-12Aryl and 5-12 membered heteroaryl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6Substituted by the radical hydroxyalkoxy;

each R^xIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

Rⁱand R^jEach independently of the others is hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently optionally substituted by 1,2,3,4 or 5 selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

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

n is 0, 1,2,3, 4,5, 6,7 or 8;

p is 0, 1,2,3, 4,5 or 6.

In some embodiments, X is

Wherein, said m and R^xHave the meaning as described in the present invention.

In some embodiments, R^aAnd R^bEach independently hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups may independently optionally be substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^cIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl can be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH₂OH、-OCH₂CH₂OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl.

In some embodiments, R^dIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl or difluoromethyl may be independently optionally substituted by 1,2,3,4 or 5 selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R²Is hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_6-10Aryl, 5-10 membered heteroaryl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or-CR^eR^f-NR^gR^hWherein, said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_6-10Aryl, 5-10 membered heteroaryl, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy; wherein R is^e、R^f、R^gAnd R^hHave the meaning as described in the present invention.

In some embodiments, R²Is hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidineYl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or-CR^eR^f-NR^gR^hWherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group; wherein R is^e、R^f、R^gAnd R^hHave the meaning as described in the present invention.

In some embodiments, R^m、Rⁿ、R^eAnd R^fEach independently is hydrogen, deuterium, a halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups may independently optionally be substituted by 1,2,3, 4Or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, and-OCH₂OH and-OCH₂CH₂OH is substituted by a group;

R^gand R^hEach independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may independently optionally be substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group; or

R^f、R^gAnd the atoms to which they are attached form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein said azetidine, pyrrolidine, piperidine ring, piperazine ring, and morpholine ring may independently optionally be substituted with 1,2,3, 4, or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R³Is C_6-10Aryl or 5-to 10-membered heteroaryl, wherein, said C_6-10Aryl and 5-10 membered heteroaryl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_1-4A group substituted with a group of hydroxyalkoxy groups.

In some embodiments, R³Is composed of

Wherein, the

Can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, each R is^xIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In some embodiments, each R is^xIndependently from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxoAmino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, each R is^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkyl halidesOxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In some embodiments, each R is^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrindinPyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, RⁱAnd R^jEach independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may independently optionally be substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.

In one aspect, the invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a subject.

In some embodiments, the KRAS G12C-mediated disease is cancer.

In some embodiments, the cancer of the invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

The term "substituted" means that one or more hydrogen atoms in a given structure is replaced with a particular substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein; when the number of the substituents is more than 1, the substituents may be the same or different from each other. For example, the "optionally substituted with 1,2,3, 4 or 5 groups selected from … …" according to the present invention, when the number of the substituents is more than 1, the substituents may be the same or different.

Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, hydrogen, deuterium, oxo, halogen, cyano, nitro, hydroxy, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkynyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkanoyloxy, carboxy, alkoxyacyl, aryloxoyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentan)Radical (-C (CH)₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂)3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) 1-propenyl (propenyl, -CH ═ CH-CH)₃) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl ((propynyl, -C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

The term "hydroxyalkoxy"Representing an alkoxy group substituted with one or more hydroxyl groups, examples of which include, but are not limited to, -OCH₂OH、-OCH₂CH₂OH and the like.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic, fused carbobicyclic, and bridged carbobicyclic groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein and refer to a mono-or polyvalent mono-, bi-or tricyclic ring system containing 3 to 14 ring atoms, wherein one or more atoms in the ring are independently replaced by a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but not one aromatic ring. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-8 membered ring monocyclic (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atomsTo like SO, SO₂，PO，PO₂Or 7-12 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂The group of (1). In other embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-6 membered ring monocyclic (2-4 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring system like SO, SO₂，PO，PO₂The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The heterocyclic group may be a carbon-based or heteroatom group; wherein, is cyclic-CH₂The group may optionally be replaced by-C (═ O) -, the sulfur atom of the ring may optionally be oxidized to S-oxide, and the nitrogen atom of the ring may optionally be oxidized to N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH₂Examples of the substitution of the-group by-C (═ O) -include, but are not limited toWithout limitation, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" or "heteroaromatic ring" means a mono-, bi-or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, of mono-or polyvalent, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group of 5 to 10 ring atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S and N; in other embodiments, the heteroaryl of 5 to 6 ring atoms is a monocyclic ring system and contains 1,2,3, or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "nitrogen atom-containing monocyclic ring" refers to a monocyclic ring of 4 to 8 ring atoms containing a nitrogen atom, which ring may be fully saturated or contain one or more degrees of saturation, but is not aromatic. Examples of nitrogen atom-containing monocyclic rings include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like. The nitrogen atom-containing monocyclic ring is optionally substituted with one or more substituents described herein.

The terms "fused bicyclic ring", "fused bicyclic group" and "fused ring group" are used interchangeably herein and all refer to monovalent or multivalent saturated or partially unsaturated fused ring systems containing from 4 to 12 ring atoms, said fused ring systems referring to non-aromatic bicyclic ring systems. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon). The term "fused ring containing nitrogen atoms" means a fused ring containing 1 or 2 nitrogen atoms, and examples of the fused ring containing nitrogen atoms include, but are not limited to, octahydropyrrolo [3,4-c ] pyrrole and the like. The fused rings are optionally substituted with one or more substituents described herein.

The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein and refer to a monovalent or polyvalent saturated or partially unsaturated ring system containing 5 to 12 ring atoms, one of which is derived from a specific ring carbon atom on the other ring. As shown in formula (a), ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spirocyclic" or "spirobicyclic", while ring B and ring B' are referred to as "fused bicyclic". Each ring in the spirobicyclic group may be a carbocyclic or heterocyclic group. The term "nitrogen atom-containing spiro ring" refers to a spiro ring containing 1 or 2 nitrogen atoms, and examples of nitrogen atom-containing spiro rings include, but are not limited to, 2, 7-diazaspiro [3.5] nonane, 2, 6-diazaspiro [3.3] heptane and the like.

Said spiro ring being optionally substituted with one or more substituents as described herein.

The term "bridged ring" or "bridged ring group" denotes a saturated or partially unsaturated bridged ring system, relating to a non-aromatic bicyclic ring system, for example as shown in formula (b), i.e. ring A1 shares an alkane or a heteroalkane chain with ring A2, wherein each X³Independently optionally a carbon atom or a heteroatom, j is 1,2,3 or 4. Such systems contain 5 to 12 ring atoms and may contain independent or conjugated unsaturation, but do not contain aromatic or aromatic rings in their core structure (although aromatics may be substituents thereon). Wherein each ring, such as A1 or A2, contains 4 to 7 atoms, the term "nitrogen atom-containing bridged ring" refers to a bridged ring containing 1 or 2 nitrogen atoms, examples of which include, but are not limited to, (1R,5S) -3, 8-diazabicyclo [3.2.1]Octane, and the like. The bridged ring is optionally substituted with one or more substituents described herein.

The term "k atoms make up" or "k-member", where k is an integer, typically describes the number of atoms making up a ring in a molecule in which the number of atoms making up a ring is k. For example, piperidinyl is a 6 atom heterocycle or 6-membered heterocycle, while pyridinyl is a 6 atom heteroaryl or 6-membered heteroaryl.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

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

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

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C_1-6Alkyl groups are attached to nitrogen atoms to form alkylamino groups. In other embodiments, the alkylamino group is substituted with one or two C_1-3An alkyl-substituted amino group of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like.

The term "aminoalkyl" includes C substituted with one or more amino groups_1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups_1-6Aminoalkyl groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

As described herein, substituent (R)_fThe ring system formed by a ring linked to the center by a bond represents that the f substituents R may be substituted at any substitutable position or at any reasonable position on the ring in which they are located. For example, formula d represents that the G ring may be substituted with f R, and when f is greater than 1, each R may be independently selected from the same or different substituent groups.

The attachment point may be attached to the rest of the molecule at any point on the ring that is attachable, as described herein. For example, formula e represents the point of attachment at any possible attachment position on the C-ring or D-ring.

The group "-O- (CR) as described in the present invention^mRⁿ)_p"two attachment sites are available for attachment to the rest of the molecule, and the attachment of the two attachment sites may be interchanged. For example, formula f represents the group-O- (CR)^mRⁿ)_pThe linkage to the rest of the molecule can be via the E-terminus or the E' -terminus. For example, E-O- (CR)^mRⁿ)_p-E 'or E' -O- (CR)^mRⁿ)_p-E。

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable Pharmaceutical carriers are described in e.w. martin, "Remington's Pharmaceutical Sciences".

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester, (aliphat)C_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound contains a hydroxy group, i.e., it can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound via oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or obtained by other methods described in the literature above such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts such as ammonium salts and metal salts of groups I through XII of the periodic table, and organic base salts such as salts with primary, secondary and tertiary amines.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and the severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，¹⁸F，³¹P，³²P，³⁵S，³⁶Cl and¹²⁵I. isotopically enriched compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described herein using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The term "cancer" as used herein refers to or describes a physiological condition in a patient that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia, or lymphoproliferative disorder (lymphoproliferative disorders). More specific examples of such cancers include squamous cell cancer (such as epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung), esophageal cancer, cancer of the peritoneum, hepatocellular cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (liver cancer), bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (kidney cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

The term "KRAS G12C inhibitor" as used herein refers to a substance that binds to and inhibits the activity of KRAS G12C.

Description of the Compounds of the invention

The invention provides a compound or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS G12C. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or conditions by inhibiting KRAS G12C activity with said compounds. The invention further describes methods for synthesizing the compounds. The compounds of the invention show improved biological activity and pharmacokinetic properties.

wherein each R is¹、R²X, Y and W all have the meanings described herein.

In some embodiments, X is-L-X¹-, wherein L is a bond or-NH-, X¹Is a 4-12 membered saturated or partially unsaturated monocyclic, fused, spiro or bridged ring containing a nitrogen atom, which monocyclic, fused, spiro and bridged ring may be independently optionally substituted by m R^xSubstitution; wherein R is^xAnd m has the meaning described in the present invention.

In other embodiments, X is

Wherein R is^xAnd m has the meaning described in the present invention.

In some embodiments, Y is

Wherein R is³、R^y、Rⁱ、R^jAnd n has the meaning described in the present invention.

In some embodiments, R¹is-C (═ O) -CR^a＝CR^b-R^c、-C(＝O)-C≡C-R^c、-S(＝O)₂-CR^a＝CR^b-R^cor-S (═ O)₂-C≡C-R^c(ii) a Wherein R is^a、R^bAnd R^cHave the meaning as described in the present invention.

In some embodimentsIn, R^aIs hydrogen, deuterium, halogen atom, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^aIs hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^bIs hydrogen, deuterium, halogen atom, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^bIs hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups can be independently optionally substituted by 1,23,4 or 5 selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^cIs hydrogen, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino, 5-6 membered heteroaryl, C_3-6Carbocyclyl or 3-6 membered heterocyclyl, wherein said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino, 5-6 membered heteroaryl, C_3-6Carbocyclyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_1-3Hydroxyalkoxy and 3-6 membered heterocyclyl.

In other embodiments, R^cIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, and trizolylAn azolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl group; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl can be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH₂OH、-OCH₂CH₂OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl.

In some embodiments, W is-O- (CR)^mRⁿ)_p-、-S-(CR^mRⁿ)_p-or-NR^d-(CR^mRⁿ)_p-, wherein R^d、R^m、RⁿAnd p has the meaning described in the present invention.

In some embodiments, R^dIs hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxoAmino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^dIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl or difluoromethyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R²Is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_6-12Aryl, 5-12 membered heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or-CR^eR^f-NR^gR^hWherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_6-12Aryl, 5-12 membered heteroaryl, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6Substituted by the radical hydroxyalkoxy; wherein R is^e、R^f、R^gAnd R^hHave the meaning as described in the present invention.

In other embodiments, R²Is hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical、C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_6-10Aryl, 5-10 membered heteroaryl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or-CR^eR^f-NR^gR^hWherein, said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_6-10Aryl, 5-10 membered heteroaryl, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy; wherein R is^e、R^f、R^gAnd R^hHave the meaning as described in the present invention.

In other embodiments, R²Is hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CR^eR^f-NR^gR^hWherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group; wherein R is^e、R^f、R^gAnd R^hHave the meaning as described in the present invention.

In some embodiments, R^mIs hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^mIs hydrogen, deuterium, a halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are mentionedThe radicals may be independently optionally substituted by 1,2,3, 4 or 5 radicals selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, RⁿIs hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, RⁿIs hydrogen, deuterium, a halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^eIs hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^eIs hydrogen, deuterium, a halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^fIs hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^fIs hydrogen, deuterium, a halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, a halogen atom, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^gIs hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^gIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^hIs hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^hIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OHand-OCH₂CH₂OH groups.

In some embodiments, R^f、R^gAnd the atoms to which they are attached form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^f、R^gAnd the atoms to which they are attached form an azetidine, pyrrolidine, piperidine ring, piperazine ring, or morpholine ring, wherein said azetidine, pyrrolidine, piperidine ring, piperazine ring, and morpholine ring may independently optionally be substituted with 1,2,3, 4, or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R³Is C_6-12Aryl or 5-12 membered heteroaryl, wherein, said C_6-12Aryl and 5-12 membered heteroaryl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_1-6The group of hydroxyalkoxy.

In other embodiments, R³Is C_6-10Aryl or 5-to 10-membered heteroaryl, wherein, said C_6-10Aryl and 5-10 membered heteroaryl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_1-4The group of hydroxyalkoxy.

In other embodimentsIn the scheme, R³Is composed of

Wherein, the

In some embodiments, R^xIs deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^xIs deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^xIs deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^yIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^yIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^yIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanylPyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, RⁱIs hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, RⁱIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, R^jIs hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

In other embodiments, R^jIs hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl or triFluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

In some embodiments, m is 0, 1,2,3, 4,5, 6,7, or 8.

In some embodiments, n is 0, 1,2,3, 4,5, 6,7, or 8.

In some embodiments, p is 0, 1,2,3, 4,5, or 6.

In another aspect, the present invention relates to a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof, of a compound of one of the following, but is in no way limited to:

in another aspect, the present invention relates to a pharmaceutical composition comprising a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

In another aspect, the invention relates to the use of a compound as described above, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a subject.

In some embodiments, the KRAS G12C-mediated disease is cancer.

Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention

According to another aspect, a pharmaceutical composition of the invention features a compound of formula (I), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of compound in the pharmaceutical composition of the invention is effective to treat or ameliorate KRAS G12C mediated diseases in a subject.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Substances which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

Preferably, the compounds are administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (referred to herein as pharmaceutical carriers) selected with regard to the form of administration and conventional pharmaceutical practice, which may be in the form of oral tablets, capsules, elixirs, syrups, and the like.

For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical composition may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and the like. Moreover, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They may be administered separately, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.

The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or by the transdermal route using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered throughout the administration period is continuous rather than intermittent.

The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the invention are also conjugated to soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

The dosage regimen for a compound of the invention will vary depending upon a variety of factors known, such as the pharmacokinetic characteristics of the particular agent and its mode and route of administration; race, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent therapy; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make a decision and prescribe the effective amount of the drug to prevent, counter or arrest the progress of the cancer.

In accordance with general guidelines, the daily oral dosage of each active ingredient used is in the range of about 0.001 to 1000mg/kg body weight, preferably about 0.01 to 100mg/kg body weight, in order to achieve the indicated effect. And, most preferably, between about 1.0 and 20mg/kg body weight/day. For intravenous administration, the most preferred dosage range during infusion at conventional rates is from about 1 to about 10mg/kg body weight/minute. The compounds of the invention may be administered once daily, or may be administered in divided doses of two, three or four times daily.

Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1mg to about 100mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be from about 0.5% to about 95% of the total weight of the composition.

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

The compound or the medicinal salt or the hydrate thereof can be effectively used for preventing, treating or relieving the diseases mediated by KRAS G12C of patients, and particularly can be effectively used for treating lung cancer, lymphoma, esophagus cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, melanoma and the like.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined herein. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the invention, and other methods for preparing compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Wen Long chemical plant, Guangdong Guanghua chemical plant, Guangzhou chemical plant, Tianjin Haoyu Chemicals Co., Ltd, Tianjin Shuchen chemical plant, Wuhan Xin Hua Yuan science and technology development Co., Ltd, Qingdao Tenglong chemical plant Co., Ltd, and Qingdao maritime chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. Glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quatet), m (multiplet),br (broad), br (broad single), dd (doublet of doublets), dt (doublet of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

the following reaction scheme describes the steps for preparing the compounds of the present invention. Wherein each R is, unless otherwise specified^x、R^yM and n have the meanings given in the description, R^AIs deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy or C_1-6Hydroxyalkoxy, u is 0, 1,2,3, 4 or 5, s and t are each independently 1,2 or 3, R^BDeuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy or C_1-3Hydroxyalkoxy, v is 0, 1,2,3, 4 or 5.

Reaction scheme 1

The compound represented by the formula (2) can be produced by reactingScheme 1 preparation yields: formula (A), (B) and1) The compound reacts under the action of lithium aluminum hydride to obtain a compound shown as a formula (I)2) The compounds shown.

Reaction scheme 2

Formula (A), (B) and12) The compounds shown can be prepared by reaction scheme 2: formula (A), (B) and3) A compound of the formula4) The compound reacts under the action of DIPEA to obtain a compound shown as a formula (I)5) The compounds shown. Formula (A), (B) and5) A compound of the formula2) The compound is reacted under the action of palladium acetate, cesium carbonate and BINAP to obtain a compound shown as a formula (I)6) The compounds shown. Formula (A), (B) and6) The compound is reacted under the action of trifluoroacetic acid to obtain a compound shown in a formula (I)7) The compounds shown. Formula (A), (B) and7) A compound of the formula8) The compound is shown in Pd₂(dba)₃XantPhos and Cs₂CO₃Under the action of (A) to obtain a compound of the formula (A)9) The compounds shown. Formula (A), (B) and9) The compound reacts under the action of palladium-carbon and methanolic ammonia solution to obtain a compound shown in the formula (A)10) The compounds shown. Formula (A), (B) and10) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)12) The compounds shown.

Reaction scheme 3

Formula (A), (B) and30) The compounds shown can be prepared by reaction scheme 3: formula (A), (B) and13a) The compound reacts under the action of pyridinium chlorochromate to obtain a compound shown in a formula (A)13) The compounds shown. Formula (A), (B) and13) A compound of the formula14) The compound reacts under the action of sodium bis (trimethylsilyl) amide to obtain a compound shown in the formula (A)15) The compounds shown. Formula (A), (B) and15) A compound of the formula16) The compound reacts under the action of triethylamine and bis (triphenylphosphine) palladium dichloride to obtain a compound shown in a formula (I)17) What is needed isThe compounds shown are shown. Formula (A), (B) and17) The compound reacts under the action of palladium carbon and hydrogen to obtain a compound shown in the formula (A)18) The compounds shown. Formula (A), (B) and18) The compound reacts under the action of bis (trimethylsilyl) amino potassium to obtain a compound shown in the formula (A)19) The compounds shown. Formula (A), (B) and19) A compound of the formula20) The compound reacts under the action of methanol and sodium methoxide to obtain a compound shown in a formula (I)21) The compounds shown. Formula (A), (B) and21) A compound of the formula22) The compound reacts under the action of triethylamine and N, N-dimethylamino pyridine to obtain a compound shown in a formula (I)23) The compounds shown. Formula (A), (B) and23) A compound of the formula4) The compound reacts under the action of DIPEA to obtain a compound shown as a formula (I)24) The compounds shown. Formula (A), (B) and24) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)25) The compounds shown. Formula (A), (B) and25) A compound of the formula2) The compound reacts under the action of sodium tert-butoxide to obtain a compound shown in the formula (A)26) The compounds shown. Formula (A), (B) and26) The compound is reacted under the action of hydrochloric acid to obtain a compound shown in a formula (I)27) The compounds shown. Formula (A), (B) and27) A compound of the formula8) The compound is shown in Pd₂(dba)₃XantPhos and Cs₂CO₃Under the action of (A) to obtain a compound of the formula (A)28) The compounds shown. Formula (A), (B) and28) The compound reacts under the action of palladium carbon and hydrogen to obtain a compound shown in the formula (A)29) The compounds shown. Formula (A), (B) and29) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)30) The compounds shown.

Reaction scheme 4

Formula (A), (B) and34) The compounds shown can be prepared by reaction scheme 4: formula (A), (B) and31)a compound of the formula32) The compound is reacted at low temperature to obtain the formula (A)33) The compounds shown. Formula (A), (B) and33) The compound is reacted under the action of Boc anhydride and triethylamine to obtain a compound shown in a formula (I)34) Shown inA compound (I) is provided.

Reaction scheme 5

Formula (A), (B) and41) The compounds shown can be prepared by reaction scheme 5: formula (A), (B) and35) A compound of the formula36) The compound reacts under the action of boron trifluoride diethyl etherate to obtain a compound shown as a formula (I)37) The compounds shown. Formula (A), (B) and37) Reacting the compound shown in the formula (20) with a compound shown in a formula (20) under the action of methanol and sodium methoxide to obtain a compound shown in a formula (I)39) The compounds shown. Formula (A), (B) and39) A compound of the formula40) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)41) The compounds shown.

Reaction scheme 6

The compound represented by formula (54) can be prepared by reaction scheme 6: formula (A), (B) and42) A compound of the formula43) The compound reacts under the action of sodium carbonate and potassium iodide to obtain a compound shown in a formula (I)44) The compounds shown. Formula (A), (B) and44) A compound of the formula45) The compound reacts under the action of sodium carbonate to obtain a compound of the formula (A)46) The compounds shown. Formula (A), (B) and46) The compound is reacted under the action of potassium carbonate and potassium iodide to obtain a compound shown in a formula (I)47) The compounds shown. Formula (A), (B) and47) A compound of the formula20) The compound reacts under the action of potassium carbonate to obtain a compound shown as a formula (I)49) The compounds shown. Formula (A), (B) and49)a compound of the formula4) The compound reacts under the action of BOP and DBU to obtain a compound of the formula (A)50) The compounds shown. Formula (A), (B) and50) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)51) The compounds shown. Formula (A), (B) and51) A compound of the formula2) The compound reacts under the action of sodium tert-butoxide to obtain a compound shown in the formula (A)52) The compounds shown. Formula (A), (B) and52) The compounds shown areReacting under the action of palladium-carbon to obtain a compound of the formula (A)53) The compounds shown. Formula (A), (B) and53) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)54) The compounds shown.

Reaction scheme 7

Formula (A), (B) and63) The compounds shown can be prepared by reaction scheme 7: formula (A), (B) and55) A compound of the formula20) The compound reacts under the action of methanol and sodium methoxide to obtain a compound shown in a formula (I)56) The compounds shown. Formula (A), (B) and56) A compound of the formula4) The compound reacts under the action of BOP and DBU to obtain a compound of the formula (A)57) The compounds shown. Formula (A), (B) and57) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)58) The compounds shown. Formula (A), (B) and58) A compound of the formula2) The compound reacts under the action of sodium tert-butoxide to obtain a compound shown in the formula (A)59) The compounds shown. Formula (A), (B) and59) The compound is reacted under the action of trifluoroacetic acid to obtain a compound shown in a formula (I)60) The compounds shown. Formula (A), (B) and60) A compound of the formula8) The compound is shown in Pd₂(dba)₃XantPhos and Cs₂CO₃Under the action of (A) to obtain a compound of the formula (A)61) The compounds shown. Formula (A), (B) and61) The compound reacts under the action of palladium carbon and hydrogen to obtain a compound shown in the formula (A)62) The compounds shown. Formula (A), (B) and62) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)63) The compounds shown.

Reaction scheme 8

Formula (A), (B) and74) The compounds shown can be prepared by reaction scheme 8: formula (A), (B) and42) A compound of the formula64) The compound is prepared from sodium acetateBy the reaction to give65) The compounds shown. Formula (A), (B) and65) A compound of the formula66) The compound reacts under the action of sodium carbonate to obtain a compound of the formula (A)67) The compounds shown. Formula (A), (B) and67) The compound is reacted under the action of sodium hydride to obtain a compound shown as a formula (I)68) The compounds shown. Formula (A), (B) and68) A compound of the formula20) The compound reacts under the action of sodium carbonate to obtain a compound of the formula (A)69) The compounds shown. Formula (A), (B) and69)a compound of the formula4) The compound reacts under the action of BOP and triethylamine to obtain a compound of the formula (I)70) The compounds shown. Formula (A), (B) and70) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)71) The compounds shown. Formula (A), (B) and71) A compound of the formula2) The compound reacts under the action of sodium tert-butoxide to obtain a compound shown in the formula (A)72) The compounds shown. Formula (A), (B) and72) The compound reacts under the action of palladium carbon and hydrogen to obtain a compound shown in the formula (A)73) The compounds shown. Formula (A), (B) and73) A compound of the formula11) The compound reacts under the action of DIPEA to obtain a compound shown as a formula (I), (II), (III)74) The compounds shown.

Reaction scheme 9

Formula (A), (B) and87) The compounds shown can be prepared by reaction scheme 9: formula (A), (B) and75) A compound of the formula76) The compound reacts under the action of lithium bis (trimethylsilyl) amide to obtain a compound shown in the formula (A)77) The compounds shown. Formula (A), (B) and77) A compound of the formula20) The compound reacts under the action of sodium acetate to obtain a compound of a formula (I)78) The compounds shown. Formula (A), (B) and78)a compound of the formula4) The compound reacts under the action of BOP and triethylamine to obtain a compound of the formula (I)79) The compounds shown. Formula (A), (B) and79) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)80) The compounds shown. Formula (A), (B) and80) A compound of the formula2) The compound reacts under the action of sodium tert-butoxide to obtain the compound shown in the formula (81)The compounds shown. Formula (A), (B) and81) The compound reacts under the action of palladium-carbon and trifluoroacetic acid to obtain a compound shown in a formula (I)82) The compounds shown. Formula (A), (B) and82) A compound of the formula8) The compound is shown in Pd₂(dba)₃XantPhos and Cs₂CO₃Under the action of (A) to obtain a compound of the formula (A)83) The compounds shown. Formula (A), (B) and83) A compound of the formula84) The compound reacts under the action of DIPEA to obtain a compound shown as a formula (I), (II), (III)85) The compounds shown. Formula (A), (B) and85) The compound reacts under the action of methanol solution of palladium carbon, hydrogen and ammonia to obtain a compound shown in the formula (A)86) The compounds shown. Formula (A), (B) and86) A compound of the formula11) The compound reacts under the action of DIPEA to obtain a compound shown as a formula (I), (II), (III)87) The compounds shown.

Reaction scheme 10

Formula (A), (B) and91) The compounds shown can be prepared by reaction scheme 10: formula (A), (B) and7) A compound represented by the formula (8)8) The compound is shown in Pd₂(dba)₃XantPhos and Cs₂CO₃Under the action of (A) to obtain a compound of the formula (A)89) The compounds shown. Formula (A), (B) and89) The compound reacts under the action of palladium-carbon and methanolic ammonia solution to obtain a compound shown in the formula (A)90) The compounds shown. Formula (A), (B) and90) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)91) The compounds shown.

Reaction scheme 11

Formula (A), (B) and97) The compounds shown can be prepared by reaction scheme 11: formula (A), (B) and92) The compound shown in the formula (93) reacts with a compound shown in the formula (93) under the action of p-toluenesulfonic acid to obtain a compound shown in the formula (A)94) The compounds shown. Formula (A), (B) and7) A compound shown andthe compound of formula (94) is represented by Pd₂(dba)₃XantPhos and Cs₂CO₃Under the action of (A) to obtain a compound of the formula (A)95) The compounds shown. Formula (A), (B) and95) The compound reacts under the action of palladium-carbon and methanolic ammonia solution to obtain a compound shown in the formula (A)96) The compounds shown. Formula (A), (B) and96) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)97) The compounds shown.

Reaction scheme 12

Formula (A), (B) and107) The compounds shown can be prepared by reaction scheme 12: formula (A), (B) and98) A compound of the formula43) The compound reacts under the action of sodium carbonate and potassium iodide to obtain a compound shown in a formula (I)99) The compounds shown. Formula (A), (B) and99) A compound of the formula45) The compound reacts under the action of sodium carbonate to obtain a compound of the formula (A)100) The compounds shown. Formula (A), (B) and100) The compound is reacted under the action of potassium carbonate and potassium iodide to obtain a compound shown in a formula (I)101) The compounds shown. Formula (A), (B) and101) A compound of the formula20) The compound reacts under the action of potassium carbonate to obtain a compound shown as a formula (I)102) The compounds shown. Formula (A), (B) and102)a compound of the formula4) The compound reacts under the action of BOP and DBU to obtain a compound of the formula (A)103) The compounds shown. Formula (A), (B) and103) The compound reacts under the action of m-chloroperoxybenzoic acid to obtain a compound shown in the formula (I)104) The compounds shown. Formula (A), (B) and104) A compound of the formula2) The compound reacts under the action of sodium tert-butoxide to obtain a compound shown in the formula (A)105) The compounds shown. The compound shown in the formula (105) reacts under the action of palladium-carbon to obtain a compound shown in the formula (A)106) The compounds shown. Formula (A), (B) and106) A compound of the formula11) The compound reacts under the action of triethylamine to obtain a compound shown in a formula (I)107) The compounds shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example 12- ((S) -1-acryloyl-4- ((6S,9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First step Synthesis of 1-tert-butyl 2-methyl (S) -4-oxopyrrolidine-1, 2-dicarboxylic acid ester

1- (tert-butyl) 2-methyl (2S,4R) -4-hydroxypyrrolidine-1, 2-dicarboxylate (50.00g,203.90mmol) and dichloromethane (500mL) were added to a reaction flask, the temperature was reduced to 0 ℃, pyridinium chlorochromate (87.89g,407.70mmol) was added in portions, the reaction was stirred at room temperature overnight, filtered, the reaction system had a large amount of brown mud, the mud was diluted with dichloromethane (300mL) and filtered again, the organic phases were combined, washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 10/1) to give the title compound as a colorless transparent liquid (27.6g, 56%).

Second step Synthesis of 1- (tert-butyl) 2-methyl (S) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate

Adding sodium bis (trimethylsilyl) amide (68.0mL,136.00mmol) and tetrahydrofuran (60.0mL) into a reaction bottle, reducing the temperature to-78 ℃ under the protection of nitrogen, then dropwise adding a tetrahydrofuran (100mL) solution of 1-tert-butyl 2-methyl (S) -4-oxypyrrolidine-1, 2-dicarboxylic acid ester (30.00g,123.30mmol), stirring for reaction for 30min after dropwise addition, then dropwise adding a tetrahydrofuran (130mL) solution of N-phenyl bis (trifluoromethanesulfonyl) imide (46.25g,129.50mmol), stirring for 2h after dropwise addition, then stirring overnight at room temperature, reducing the temperature to 0 ℃, adding ethyl acetate (200mL) and 10% citric acid aqueous solution (200mL), separating, extracting the aqueous phase with ethyl acetate (100 mL. times.3), combining the organic phases, washing with saturated saline (200mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, column chromatography was then performed (PE/EA (v/v) ═ 20/1) to give the title compound as a colorless oil (30.00g, 65%).

Step three, synthesis of 1- (tert-butyl) 2-methyl (S, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester

1- (tert-butyl) 2-methyl (S) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate (30.00g,79.94mmol), methyl acrylate (13.76g,159.80mmol), triethylamine (22.0mL,158.00mmol), bis (triphenylphosphine) palladium dichloride (2.80g,3.99mmol) and N, N-dimethylformamide (300mL) were charged into a reaction flask, nitrogen was protected, the reaction was stirred at 105 ℃ overnight, ethyl acetate (100mL) and crushed ice (100mL) were added, liquid separation was performed, aqueous ethyl acetate (100 mL. times.3) was extracted, the organic phase was combined, saturated brine (200 mL. times.3) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and then column chromatography purification (PE/EA (v/v) ═ 7/1) was performed to obtain the title compound (15.00g, 68%).

MS(ESI,pos.ion)m/z:212.2[M-Boc+H]⁺。

Step four Synthesis of 1- (tert-butyl) 2-methyl (2S) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a reaction flask were added 1- (tert-butyl) 2-methyl (S, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate (15.00g,48.19mmol), ethyl acetate (300.0mL) and 10% palladium on charcoal (2.00g) in this order, hydrogen-exchanged, stirred at room temperature for 48H, warmed to 50 ℃ and stirred for 8H, cooled to room temperature, filtered to remove the palladium on charcoal, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 10/1) to give the title compound (9.48g, 62%).

MS(ESI,pos.ion)m/z:216.2[M-Boc+H]⁺。

Fifth step Synthesis of 6- (tert-butyl) 3-methyl (1S,5S) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylate

1- (tert-butyl) 2-methyl (2S) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (8.90g,28.20mmol) and tetrahydrofuran (560mL) were added to a reaction flask in this order, the mixture was cooled to-78 ℃, potassium bis (trimethylsilyl) amide (61.5mL,61.50mmol,1.00mol/L) was added dropwise, the mixture was stirred overnight with constant temperature, ethyl acetate (100mL) and 10% aqueous citric acid (500mL) were added, the aqueous phase after separation was extracted with ethyl acetate (200mL), the organic phases were combined, washed with saturated brine (400mL), dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography was then performed (PE/EA (v/v) ═ 3/1) to give the title compound as a colorless oil (4.00g, 50%).

MS(ESI,pos.ion)m/z:228.1[M-55]⁺。

Sixthly, synthesizing (6S,9S) -4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester

To a reaction flask were added 6- (tert-butyl) 3-methyl (1S,5S) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylate (4.00g,14.10mmol), 2-methylthiourea sulfate (3.45g,18.30mmol), methanol (40mL), and sodium methoxide (3.81g,70.60mmol) in this order, and the mixture was stirred at room temperature overnight, a saturated aqueous citric acid solution (20mL) was added to the mixture, and ethyl acetate (20mL × 2) was extracted, and the organic phases were combined, washed with a saturated saline (50mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) 3/1) to give the title compound as a white solid (500.0mg, 11%).

MS(ESI,pos.ion)m/z:324.2[M+H]⁺。

Seventh step Synthesis of tert-butyl (6S,9S) -2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

To a reaction flask were added N-phenylbis (trifluoromethanesulfonyl) imide (828.0mg,2.318mmol), (6S,9S) -4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (500.0mg,1.55mmol), triethylamine (312.0mg,3.08mmol), dichloromethane (8mL) and N, N-dimethylaminopyridine (9.0mg,0.07mmol) in this order, the reaction was stirred at room temperature for 2H, then water (20mL) and dichloromethane (10mL) were added in order, liquid-separated, the aqueous phase was extracted with dichloromethane (20mL), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) ═ 10/1) to give the title compound as a colorless oil (10/1) 366.0mg, 52%).

Eighth step Synthesis of tert-butyl (6S,9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

To a reaction flask were added in this order (6S,9S) -2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (500.0mg,1.10mmol), N-dimethylformamide (6mL), N-diisopropylethylamine (0.3mL,2.00mmol) and (2S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (313.0mg,1.21mmol), warmed to 85 ℃ and stirred for reaction for 2H, cooled to room temperature, added in this order ethyl acetate (30mL) and water (30mL), separated, extracted with ethyl acetate in an aqueous phase (20 mL. times.2), the organic phases combined, washed with saturated saline (50mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound (320.0mg, 52%).

Ninth step Synthesis of tert-butyl (6S,9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

The reaction bottle is sequentially added with synthesized tert-butyl (6S,9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate (320.0mg,0.57mmol) and dichloromethane (6.0mL), the temperature is reduced to 0 ℃, 85% m-chloroperoxybenzoic acid (120.0mg,0.59mmol) is added in batches, the mixture is stirred for 10min under heat preservation, dichloromethane (20mL) and water (20mL) are added for separating, the water phase is extracted by dichloromethane (20mL multiplied by 2), the organic phases are combined, saturated sodium bicarbonate water solution (30mL) is washed, saturated saline solution (30mL) is washed, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a colorless oil (300.0mg, 91%).

MS(ESI,pos.ion)m/z:581.2[M+H]⁺。

The tenth step Synthesis of tert-butyl (6S,9S) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

The (6S,9S) -4- ((S) -4- ((benzyloxy) carbonyl group is added into a reaction bottle in sequence) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c]Tert-butyl azepin-8-carboxylate (300.0mg,0.52mmol), N-methyl-L-prolinol (89.0mg,0.77mmol) and toluene (5mL), cooled to 0 ℃, sodium tert-butoxide (99.0mg,1.03mmol) was added, stirred for 1h with incubation after addition, concentrated to dryness and then purified by column chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a light brown solid (230.0mg, 70%). MS (ESI, pos. ion) M/z 632.3[ M + H ]]⁺。

The eleventh step the synthesis of benzyl (S) -2- (cyanomethyl) -4- ((6S,9S) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added (6S,9S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (230.0mg,0.36mmol), ethyl acetate (2.0mL) and aqueous hydrochloric acid (2.0mL,12mmol,6.00mol/L) in this order, stirred at room temperature for 30min, added saturated aqueous sodium carbonate to adjust pH to 9-10, mixed solvent (15mL × 3, DCM/MeOH (v/v) ═ 8/1) was extracted, and the organic phases were combined, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a light brown solid (180.0mg, 93%).

MS(ESI,pos.ion)m/z:532.3[M+H]⁺。

Synthesis of the twelfth step benzyl (S) -2- (cyanomethyl) -4- ((6S,9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added in this order (S) -2- (cyanomethyl) -4- ((6S,9S) -2- (((S) -1-methylpyrrolidinyl-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (180.0mg,0.34mmol), 1-bromo-8-methyl-naphthalene (150.0mg,0.68mmol), tris (dibenzylideneacetone) dipalladium (16.0mg,0.02mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (25.0mg,0.04mmol), cesium carbonate (220.0mg,0.67mmol) and toluene (4mL), with nitrogen protection, and the reaction was stirred at 90 ℃ overnight, cool to room temperature, filter, concentrate, and purify by column chromatography (DCM/MeOH (v/v) ═ 9/1) to give the title compound (97.5mg, 43%).

MS(ESI,pos.ion)m/z:672.4[M+H]⁺。

Thirteenth step Synthesis of 2- ((S) -4- ((6S,9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

The (S) -2- (cyanomethyl) -4- ((6S,9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] is added into a reaction bottle in sequence]Azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (90.0mg,0.13mmol), methanol (4mL) and 10% palladium on charcoal (20.0mg), hydrogen protected, stirred at room temperature overnight, 2 drops acetic acid added dropwise, the mixture stirred at room temperature overnight, the mixture filtered off the palladium on charcoal, the filtrate was concentrated and the title compound was isolated on thick plates (DCM/MeOH (v/v) ═ 8/1) to give the title compound (30.0mg, 42%). MS (ESI, pos. ion) M/z 538.3[ M + H ]]⁺。

Fourteenth step Synthesis of 2- ((S) -1-acryloyl-4- ((6S,9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added 2- ((S) -4- ((6S,9S) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (30.0mg,0.06mmol), dichloromethane (2mL) and triethylamine (11.0mg,0.11mmol) in this order, cooled to-20 ℃, followed by dropwise addition of acryloyl chloride (6.0mg,0.07mmol), stirring at room temperature for 30min, concentration of the reaction solution, separation by thick plate (DCM/MeOH (v/v) ═ 10/1) to give the title compound (20.0mg, 61%).

MS(ESI,pos.ion)m/z:592.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.60(d,J＝4.4Hz,1H),7.45(d,J＝7.9Hz,1H),7.33–7.27(m,1H),7.23(d,J＝6.8Hz,1H),7.06(dd,J＝14.6,7.4Hz,1H),6.56(dd,J＝18.3,7.0Hz,2H),6.38(d,J＝16.8Hz,1H),5.86–5.76(m,1H),5.06(s,1H),4.16–3.74(m,5H),3.69–3.52(m,3H),3.15–2.85(m,8H),2.85–2.39(m,6H),2.37–1.97(m,10H)。

Example 22- ((S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

First step synthesis of 2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine

6-benzyl-2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine (5.00g,17.00mmol) and dichloromethane (60.0mL) were added in this order to a reaction flask, the temperature was reduced to-5 ℃, 1-chloroethyl chloroformate (5.5mL,51.0mmol) was added dropwise, the mixture was allowed to warm to room temperature and stirred for 4 hours, saturated saline (100mL) was added thereto, liquid separation was performed, the organic phase was washed with saturated saline (100mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE/EA (v/v) ═ 3/1) to obtain a colorless transparent oil, which was dissolved in methanol (30mL), stirred at room temperature overnight, and filtered to obtain the title compound as a white solid (2.48g, 72%).

MS(ESI,pos.ion)m/z:204.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)10.19(s,1H),4.26(s,2H),3.44(t,J＝6.1Hz,2H),3.18(t,J＝6.2Hz,2H)。

Second step Synthesis of tert-butyl 2, 4-dichloro-7, 8-dihydropyrido [4,3-d ] pyrimidine-6 (5H) -carboxylate

To a reaction flask were added 2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine (2.48g,12.20mmol), dichloromethane (30.0mL), Boc anhydride (B,3.5mL,15.00 mmol), triethylamine (3.5mL,25.00mmol) in this order, the mixture was stirred at room temperature for 2h, dichloromethane (30mL) and water (50mL) were added, liquid separation was performed, the aqueous phase was extracted with dichloromethane (50mL × 2), the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a colorless transparent liquid (3.30g, 89%).

MS(ESI,pos.ion)m/z:304.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm)4.56(s,2H),3.75(t, J ═ 5.8Hz,2H),2.97(t, J ═ 5.5Hz,2H),1.50(s, 9H). The third step is (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-7, 8-dihydropyridine [4,3-d]Synthesis of pyrimidine-6 (5H) -carboxylic acid tert-butyl ester

To a reaction flask were added tert-butyl 2, 4-dichloro-7, 8-dihydropyrido [4,3-d ] pyrimidine-6 (5H) -carboxylate (1.00g,3.29mmol), (S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (1.00g,3.86mmol), N-diisopropylethylamine (1.0mL,5.7mmol) and N, N-dimethylacetamide (8.0mL) in this order, warmed to 70 ℃, stirred for reaction for 5H, cooled to room temperature, added ethyl acetate (50mL) and water (100mL), separated, aqueous phase ethyl acetate (100mL × 2) extracted, the organic phases combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a light-colored solid (1.38g, 79%).

MS(ESI,pos.ion)m/z:527.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.37(s,5H),5.18(s,2H),4.65(s,1H),4.44(dd,J＝43.6,15.9Hz,2H),4.11(dd,J＝14.2,7.1Hz,1H),3.92(d,J＝12.5Hz,1H),3.83–3.72(m,2H),3.69–3.58(m,1H),3.41(d,J＝12.9Hz,1H),3.31(s,1H),3.12(td,J＝12.3,3.1Hz,1H),2.90(d,J＝5.8Hz,2H),2.83–2.63(m,2H),1.47(s,9H)。

Fourth step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7, 8-dihydropyridine [4,3-d ] pyrimidine-6 (5H) -carboxylate

To a reaction flask were added in order (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-7, 8-dihydropyridine [4,3-d ] pyrimidine-6 (5H) -carboxylic acid tert-butyl ester (3.60g,6.83mmol), [ (2S) -1-methylpyrrolidin-2-yl ] methanol (1.02g,8.88mmol), (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (425.0mg,0.68mmol), palladium acetate (76.0mg,0.34mmol), cesium carbonate (4.45g,13.70mmol) and toluene (50.0mL), under nitrogen, warmed to 90 ℃ with stirring for 10H, filtered, the filtrate was concentrated to dryness, followed by column chromatography purification (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a pale yellow solid (4.14g, 100%).

Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The reaction bottle is sequentially added with synthesized 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazine-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -7, 8-dihydropyridine [4,3-d]Pyrimidine-6 (5H) -carboxylic acid tert-butyl ester (4.14g,6.84mmol), dichloromethane (32.0mL) and trifluoroacetic acid (8.0mL) were reacted for 2H with stirring at room temperature, the reaction solution was evaporated to dryness under reduced pressure, EA (30mL) and an aqueous solution of sodium carbonate were added to adjust pH to 9 to 10, the mixed solvent (80mL × 3, DCM/MeOH (v/v) ═ 10/1) was extracted, the organic phases were combined, a saturated saline solution (60mL) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography purification (DCM/MeOH (v/v) ═ 10/1) gave the title compound as a pale yellow solid (1.60g, 46%). MS (ESI, pos.ion) M/z 506.3[ M + H ]]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.58–7.24(m,5H),5.14(t,J＝12.2Hz,2H),4.58(s,1H),4.21(dd,J＝10.7,4.9Hz,1H),4.10–3.86(m,2H),3.84–3.56(m,4H),3.18–2.76(m,7H),2.59(s,2H),2.32(s,3H),2.15(dd,J＝17.0,8.6Hz,1H),1.95–1.83(m,1H),1.73–1.49(m,3H)。

Sixth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a reaction flask were added in this order (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (700.0mg,1.38mmol), 1-bromo-8-methyl-naphthalene (460.0mg,2.08mmol), tris (dibenzylideneacetone) dipalladium (63.0mg,0.07mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (60.0mg,0.10mmol), cesium carbonate (902.0mg,2.77mmol), and toluene (10.0mL), with nitrogen protection, warmed to 110 deg.C, stirred overnight, cooled to room temperature, ethyl acetate (20mL) was added, the resulting mixture was filtered and concentrated, column chromatography purification (DCM/MeOH (v/v) ═ 30/1) then afforded the title compound as a light brown solid (809.0mg, 90%).

MS(ESI,pos.ion)m/z:646.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.77–7.62(m,2H),7.50–7.27(m,8H),7.23(t,J＝7.6Hz,1H),5.07(q,J＝12.6Hz,2H),4.51(d,J＝25.2Hz,1H),4.26(td,J＝10.4,5.0Hz,1H),4.05(ddd,J＝21.8,14.5,7.4Hz,1H),3.94–3.63(m,5H),3.47–3.37(m,1H),3.28–2.65(m,12H),2.54(s,1H),2.35(s,3H),2.18(dd,J＝16.6,8.3Hz,1H),1.97–1.87(m,1H),1.73–1.52(m,3H)。

Seventh step Synthesis of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added in this order benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate (200.0mg,0.31mmol), MeOH (10mL) and palladium on charcoal (27.0mg,10 mass%), the mixture was stirred at room temperature overnight after hydrogen substitution, filtered, the filtrate was concentrated, and then purified by column chromatography (DCM/MeOH (v/v) ═ 20/1), and the resulting product was isolated again on a thick preparative plate to give the title compound (120.0mg, 76%).

MS(ESI,pos.ion)m/z:512.3[M+H]⁺。

Eighth step Synthesis of 2- ((S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridine [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyridin [4,3-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (120.0mg,0.23mmol), dichloromethane (3.0mL) and N, N-diisopropylethylamine (60.0mg,0.46mmol) in this order, cooled to-5 ℃, followed by dropwise addition of acryloyl chloride (25.0mg,0.28mmol), after completion of dropwise addition, stirring at constant temperature for 20min, washing with DCM (20mL) and saturated saline (20mL), drying, filtering, concentrating, and then purifying by column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a pale yellow solid (65.0mg, 49%).

MS(ESI,pos.ion)m/z:566.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.77–7.63(m,2H),7.51–7.30(m,3H),7.23(t,J＝7.5Hz,1H),6.77(ddd,J＝32.0,21.8,11.5Hz,1H),6.12(d,J＝16.3Hz,1H),5.72(d,J＝9.5Hz,1H),4.80(d,J＝66.3Hz,1H),4.26(td,J＝10.3,5.0Hz,1H),4.06(ddd,J＝26.4,13.5,6.7Hz,1H),3.87(s,3H),3.74(t,J＝15.8Hz,2H),3.42(dd,J＝11.6,7.2Hz,1H),3.32–2.76(m,9H),2.71(d,J＝12.2Hz,3H),2.55(s,1H),2.36(s,3H),2.19(q,J＝8.6Hz,1H),1.94(dd,J＝7.9,3.7Hz,1H),1.64(ddd,J＝19.0,13.1,7.3Hz,3H)。

Example 32- ((S) -1-acryloyl-4- ((6R,9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First step Synthesis of 1-tert-butyl 2-methyl (R) -4-oxopyrrolidine-1, 2-dicarboxylic acid ester

To a reaction flask were added 1- (tert-butyl) 2-methyl (2R,4R) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester (5.00g,20.40mmol), dichloromethane (60.0mL) and dessimutan oxidizer (10.4g,24.50mmol) in this order, the reaction was stirred at room temperature for 4 hours, filtered, a saturated aqueous sodium sulfite solution (50mL) was added to the filtrate, stirred for 10 minutes, separated, washed with an organic phase saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 4/1) to give the title compound as a colorless transparent oil (2.75g, 56%).¹H NMR(400MHz,CDCl₃):δ(ppm)4.76(dd,J＝40.0,9.8Hz,1H),3.89(d,J＝11.8Hz,2H),3.76(s,3H),2.93(dd,J＝27.6,17.1Hz,1H),2.58(d,J＝18.8Hz,1H),1.46(d,J＝7.1Hz,9H)。

Second step Synthesis of 1- (tert-butyl) 2-methyl (R) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate

Tetrahydrofuran (1mL) and sodium bis (trimethylsilyl) amide (0.3mL,0.60mmol) were added to a reaction flask, under nitrogen protection, the temperature was reduced to-78 ℃, then a tetrahydrofuran (1mL) solution of 1-tert-butyl 2-methyl (R) -4-oxopyrrolidine-1, 2-dicarboxylate (120.0mg,0.49mmol) was added dropwise, after completion of dropping, the reaction was stirred for 30min, then a tetrahydrofuran (2mL) solution of N-phenylbis (trifluoromethanesulfonyl) imide (200.0mg,0.56mmol) was added dropwise, after completion of dropping, stirring was carried out at room temperature for 2h, ethyl acetate (20mL) and water (20mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phase was combined, saturated brine (50mL) was washed, anhydrous sodium sulfate was dried, the filtrate was filtered, the filtrate was concentrated to dryness, then column chromatography (PE/EA (v/v) ═ 20/1) was purified to obtain the title compound as a colorless oil (100.0mg, 54%).

MS(ESI,pos.ion)m/z:376.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)5.72(dd,J＝18.9,1.9Hz,1H),5.09–4.96(m,1H),4.43–4.22(m,2H),3.77(s,3H),1.45(d,J＝22.2Hz,9H)。

Step three, synthesis of 1- (tert-butyl) 2-methyl (R, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylic acid ester

1- (tert-butyl) 2-methyl (R) -4- (((trifluoromethyl) sulfonyl) oxy) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate (100.0mg,0.27mmol), methyl acrylate (45.0mg,0.52mmol), triethylamine (0.2mL,1mmol), bis (triphenylphosphine) palladium dichloride (18.0mg,0.03mmol) and N, N-dimethylformamide (2mL) were added to a reaction flask, nitrogen was protected, the reaction was stirred at 70 ℃ overnight, ethyl acetate (20mL) and water (20mL) were added, liquid separation was performed, aqueous ethyl acetate (10mL) was extracted, the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) ═ 10/1) to give the title compound (32.6mg, 39%).

MS(ESI,pos.ion)m/z:256.1[M-55]⁺。

Step four Synthesis of 1- (tert-butyl) 2-methyl (2R) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester

To a reaction flask were added 1- (tert-butyl) 2-methyl (R, E) -4- (3-methoxy-3-oxoprop-1-en-1-yl) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate (240.0mg,0.77mmol), ethyl acetate (30mL) and 10% palladium on charcoal (200mg) in this order, hydrogen substitution was performed, stirring was performed at room temperature for 48 hours, palladium on charcoal was removed by filtration, silica gel was added to the filtrate, and then column chromatography purification (PE/EA (v/v) ═ 3/1) was performed to give the title compound as a colorless transparent oil (90.0mg, 37%).

MS(ESI,pos.ion)m/z:216.2[M-Boc+H]⁺。

Fifth step Synthesis of 6- (tert-butyl) 3-methyl (1R,5R) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylate

To a reaction flask were added 1- (tert-butyl) 2-methyl (2R) -4- (3-methoxy-3-oxopropyl) pyrrolidine-1, 2-dicarboxylic acid ester (270.0mg,0.86mmol) and tetrahydrofuran (20mL) in this order, the mixture was cooled to-78 ℃, KHMDS (2.0mL,2.0mmol) was added dropwise, the mixture was stirred under constant temperature for 3 hours, ethyl acetate (10mL) and 10% aqueous citric acid solution (10mL) were added, the aqueous phase after separation was extracted with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA (v/v) ═ 3/1) to give the title compound as a colorless oil (90.0mg, 37%).

MS(ESI,pos.ion)m/z:284.1[M+H]⁺。

Sixthly, synthesizing (6R,9R) -4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester

To a reaction flask were added 6- (tert-butyl) 3-methyl (1R,5R) -4-oxo-6-azabicyclo [3.2.1] octane-3, 6-dicarboxylate (90.0mg,0.32mmol), 2-methylthiourea sulfate (77.0mg,0.41mmol), sodium methoxide (85.0mg,1.57mmol), and methanol (2mL) in this order, and the mixture was stirred at room temperature overnight, water (10mL) and ethyl acetate (10mL) were added to the mixture, followed by liquid separation, extraction with aqueous ethyl acetate (10mL), and the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) ═ 1/1) to give the title compound as a white solid (36.9mg, 36%).

MS(ESI,pos.ion)m/z:324.1[M+H]⁺。

Seventh step Synthesis of tert-butyl (6R,9R) -2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

To a reaction flask were added N-phenylbis (trifluoromethanesulfonyl) imide (1.73g,4.84mmol), (6R,9R) -4-hydroxy-2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (1.044g,3.23mmol), N-lutidine (19.0mg,0.16mmol), triethylamine (0.9mL,6.00mmol) and dichloromethane (10mL) in this order, and the mixture was stirred at 40 ℃ for 20min, followed by addition of water (20mL) and dichloromethane (10mL) in this order, liquid separation, extraction of the aqueous phase with dichloromethane (20mL), combination of the organic phases, washing with saturated brine (30mL), drying with anhydrous sodium sulfate, filtration, concentration, and purification of column chromatography (PE/EA (v/v) ═ 10/1) to give the title compound as a colorless oil Substance (1.2g, 82%).

Eighth step Synthesis of tert-butyl (6R,9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

To a reaction flask were added benzyl (2S) -2- (cyanomethyl) piperazine-1-carboxylate (717.0mg,2.76mmol), N-dimethylformamide (12mL), N-diisopropylethylamine (0.7mL,4.00mmol) and tert-butyl (1.20g,2.63mmol) of (6R,9R) -2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate in that order (1.20g,2.63mmol), warmed to 60 ℃ and stirred for reaction for 2H, cooled to room temperature, added ethyl acetate (20mL) and water (20mL) in that order, separated, extracted with ethyl acetate in the aqueous phase (20mL), the organic phases combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound (1.14g, 77%).

MS(ESI,pos.ion)m/z:565.2[M+H]⁺。

Ninth step Synthesis of tert-butyl (6R,9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate

To a reaction flask were added successively tert-butyl (1.14g,2.02mmol) of synthetic (6R,9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylate and dichloromethane (15mL), cooled to-20 ℃, 93% m-chloroperoxybenzoic acid (382.0mg,2.06mmol) was added in portions, stirred for 30min with complete incubation, filtered, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified (DCM/MeOH (v) ═ 20/1) to give the title compound as a light brown solid (1.10g, 94%).

MS(ESI,pos.ion)m/z:581.2[M+H]⁺。

The reaction bottle is sequentially added with (6R,9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylsulfinyl) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (1.10g,1.89mmol), [ (2S) -1-methylpyrrole-2-yl ] methanol (240.0mg,2.08mmol) and toluene (15mL), nitrogen protection is carried out, the temperature is reduced to 0 ℃, sodium tert-butoxide (273.0mg,2.84mmol) is added, the mixture is kept warm and stirred for 0.5H after the addition is finished, ethyl acetate (20mL) and water (30mL) are added, liquid separation is carried out, aqueous phase ethyl acetate (20mL multiplied by 2) is extracted, the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, followed by column chromatography purification (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a light brown solid (680.0mg, 57%).

MS(ESI,pos.ion)m/z:632.3[M+H]⁺。

To a reaction flask were added (6R,9R) -4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 9-tetrahydro-8H-6, 9-methanopyrimido [4,5-c ] azepine-8-carboxylic acid tert-butyl ester (680.0mg,1.08mmol), ethyl acetate (6.0mL) and aqueous hydrochloric acid (2.0mL,8mmol,4.00mol/L) in this order, stirred at room temperature for 3H, sodium carbonate solid was added to adjust pH to 9-10, water (10mL) was added, mixed solvent (20mL × 3, dichloromethane/methanol ═ 10/1) was extracted, the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (DCM/MeOH (v/v) ═ 8/1) to give the title compound as a light brown solid (550.0mg, 96%).

MS(ESI,pos.ion)m/z:532.3[M+H]⁺。

Synthesis of the twelfth step benzyl (S) -2- (cyanomethyl) -4- ((6R,9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added in this order (S) -2- (cyanomethyl) -4- ((6R,9R) -2- (((S) -1-methylpyrrolidinyl-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (500.0mg,0.94mmol), 1-bromo-8-methyl-naphthalene (365.0mg,1.65mmol), tris (dibenzylideneacetone) dipalladium (43.0mg,0.05mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (40.0mg,0.07mmol), cesium carbonate (612.0mg,1.88mmol) and toluene (8mL), with nitrogen protection, the reaction was stirred at 110 ℃ overnight, cool to room temperature, add ethyl acetate (20mL), filter through celite, concentrate, and purify by column chromatography (DCM/MeOH (v/v) ═ 30/1) to give the title compound as a light brown solid (97.5mg, 43%).

MS(ESI,pos.ion)m/z:672.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.69–7.59(m,1H),7.51–7.20(m,8H),7.07(dd,J＝14.5,7.4Hz,1H),6.61(dd,J＝26.6,7.4Hz,1H),5.14(q,J＝12.4Hz,2H),4.57(s,1H),4.06–3.78(m,4H),3.67–3.37(m,3H),3.27–3.09(m,3H),3.08–2.59(m,10H),2.44–1.86(m,8H),1.72–1.44(m,3H)。

Thirteenth step Synthesis of 2- ((S) -4- ((6R,9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added in this order (S) -2- (cyanomethyl) -4- ((6R,9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (130.0mg,0.19mmol), methanol (4mL) and 10% palladium on charcoal (28.0mg), hydrogen protected, stirred at room temperature for 8H, supplemented with 10% palladium on charcoal (10.0mg), stirred at room temperature overnight, the above mixture was filtered off the palladium on charcoal, the filtrate was concentrated and purified by column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a pale yellow solid (86.0mg, 77%).

MS(ESI,pos.ion)m/z:538.3[M+H]⁺。

Fourteenth step Synthesis of 2- ((S) -1-acryloyl-4- ((6R,9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methylpyrimidinyl [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

2- ((S) -4- ((6R,9R) -8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-6, 9-methanopyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (80.0mg,0.15mmol), dichloromethane (2mL) and triethylamine (30.0mg,0.30mmol) were added in this order to a reaction flask, the temperature was reduced to 0 ℃, acryloyl chloride (16.0mg,0.18mmol) was then added dropwise, the mixture was stirred at room temperature for 30min, methanol (2mL), water (2mL) and dichloromethane (10mL) were added, liquid separation was carried out, the aqueous phase was extracted with dichloromethane (10 mL. times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and then purified by column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a pale yellow solid (62.7mg, 71%).

MS(ESI,pos.ion)m/z:592.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.65(s,1H),7.47(d,J＝7.2Hz,1H),7.31(dd,J＝19.7,12.2Hz,2H),7.16–7.02(m,1H),6.86(s,1H),6.72–6.53(m,1H),6.18(d,J＝16.5Hz,1H),5.77(d,J＝9.7Hz,1H),4.84(d,J＝81.3Hz,1H),4.41(s,1H),4.12–3.76(m,4H),3.57(d,J＝78.6Hz,4H),3.27–3.17(m,2H),3.12–2.64(m,12H),2.22(dt,J＝53.6,17.6Hz,8H),1.63(s,4H)。

Example 42- ((S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First Synthesis of 1-tert-butyl 3-ethyl 4-oxoazadecane-1, 3-dicarboxylic acid ester

Adding N-tert-butoxycarbonyl-3-piperidone (15.20g,76.29mmol) and diethyl ether (150mL) into a reaction flask in sequence, reducing the temperature to-30 ℃ under the protection of nitrogen, dropwise adding boron trifluoride diethyl etherate solution (12.5mL,99.50mmol), stirring at constant temperature for 30min after dropwise addition, dropwise adding 95% ethyl diazoacetate (10.5mL,94.90mmol), stirring at room temperature for 1h after dropwise addition, adding saturated aqueous sodium bicarbonate solution (200mL), stirring at room temperature for 60min, separating liquid, extracting aqueous phase ethyl acetate (50mL multiplied by 2), combining organic phases, washing with saturated saline (100mL), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the title compound as a bright yellow transparent oily substance (21.76g, 100%).

Second step synthesis of tert-butyl 4-hydroxy-2- (methylthio) -5,7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepine-6-carboxylate

To a single neck flask were added 1-tert-butyl 3-ethyl 4-oxoazaalkane-1, 3-dicarboxylic acid ester (21.00g,73.61mmol), S-methylisothiourea sulfate (20.78g,110.40mmol), methanol (200mL) and sodium methoxide (19.87g,368.00mmol) in this order, the mixture was stirred at room temperature overnight, after dilution with ethyl acetate (100mL), saturated aqueous citric acid was added to adjust the pH to neutral, ethyl acetate (200mL × 3) was extracted, the organic phases were combined, washed with saturated brine (400mL), dried over anhydrous sodium sulfate, filtered, concentrated and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as an off-white solid (11.77g, 51%).

MS(ESI,pos.ion)m/z:312.1[M+H]⁺。

Step three, synthesizing 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) tert-butyl-5, 7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepine-6-carboxylic acid tert-butyl ester

To a reaction flask were added tert-butyl 4-hydroxy-2- (methylthio) -5,7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepine-6-carboxylate (100.0mg,0.32mmol), dichloromethane (3mL) and triethylamine (64.0mg,0.63mmol) in this order under nitrogen, cooled to 0 ℃, followed by dropwise addition of trifluoromethanesulfonic anhydride (108.0mg,0.38mmol), transfer of the mixture to room temperature and stirring for 30min, addition of water (10mL), liquid separation, extraction of the aqueous phase with dichloromethane (10mL × 2), combination of the organic phases, washing with saturated saline (20mL), drying over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (PE/EA (v/v) ═ 10/1) to give the title compound as a light-colored solid (48.50mg, 34%).

MS(ESI,pos.ion)m/z:444.1[M+H]⁺。

Fourth step Synthesis of tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,7,8, 9-tetrahydro-6H-pyrimidinyl [5,4-c ] azepine 6-carboxylate

To a reaction flask were added tert-butyl 2- (methylthio) -4- (((trifluoromethyl) sulfonyl) oxy) tert-butyl-5, 7,8, 9-tetrahydro-6H-pyrimido [5,4-c ] azepine-6-carboxylate (3.90g,8.79mmol), (S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (2.51g,9.68mmol), N-dimethylacetamide (50mL) and N, N-diisopropylethylamine (3.0mL,17.00mmol) in this order, nitrogen protected, the reaction was stirred at 100 ℃ for 1H, cooled to room temperature, dichloromethane (50mL) and water (100mL) were added for separation, the aqueous phase was extracted with dichloromethane (50 mL. times.2), the organic phases were combined, washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate, filtration, concentration of the filtrate to dryness, followed by column chromatography purification (PE/EA (v/v) ═ 3/1) gave the title compound (900.00mg, 82%).

MS(ESI,pos.ion)m/z:553.2[M+H]⁺。

Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added in this order (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -5,7,8, 9-tetrahydro-6H-pyrimidinyl [5,4-c ] azepine 6-carboxylic acid tert-butyl ester (773.7mg,1.40mmol), dichloromethane (12mL) and TFA (3mL), the reaction was stirred at room temperature for 1H, and the reaction was evaporated to dryness to afford the title compound as a clear oil (633.6mg, 100%).

Sixth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added in this order benzyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate (2.34g,5.17mmol), 1-bromo-8-methylnaphthalene (1.37g,6.20mmol), tris (dibenzylideneacetone) dipalladium (237.0mg,0.26mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (239.0mg,0.41mmol), cesium carbonate (3.37g,10.30mmol) and toluene (25mL), under nitrogen protection, warmed to 110 ℃ and stirred for 24H, cooled to room temperature, diluted with ethyl acetate (20mL), filtered, the filtrate concentrated, then purified by column chromatography (PE/EA (v/v) ═ 3/1) to give the title compound as a tan solid (900.0mg, 29%).

MS(ESI,pos.ion)m/z:593.3[M+H]⁺。

Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (methylsulfonyl) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added in this order (S) -benzyl 2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate (100.0mg,0.17mmol) and dichloromethane (10mL), cooled to 0 deg.C, then added m-chloroperoxybenzoic acid (34.0mg,0.17mmol,85 mass%), stirred at an incubation time for 20min, added dichloromethane (10mL) diluted and water (10mL), separated, the aqueous phase extracted with dichloromethane (10mL), the organic phases combined, washed with saturated aqueous sodium bicarbonate (20mL), washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a yellow solid (83.0mg, 81%).

MS(ESI,pos.ion)m/z:625.3[M+H]⁺。

Eighth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylate

Sequentially adding (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (methylsulfonyl) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (660.0mg,1.08mmol), N-methyl-L-prolinol (139.0mg,1.21mmol) and toluene (20mL) into a reaction bottle, cooling to 0 ℃, then adding sodium tert-butoxide (211.0mg,2.20mmol), reacting for 30min under heat preservation, adding ethyl acetate (20mL) and water (20mL), separating, extracting the aqueous phase with ethyl acetate (20mL), combining the organic phases, washing with saturated water, drying with anhydrous sodium sulfate, filtering, concentrating, column chromatography purification (DCM/MeOH (v/v) ═ 20/1) then afforded the title compound as a light yellow solid (500.0mg, 70%).

MS(ESI,pos.ion)m/z:660.3[M+H]⁺。

Ninth step Synthesis of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added in this order (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (100.0mg,0.15mmol), palladium on carbon (10.0mg,10 mass%) and methanol (4mL), hydrogen protected, stirred overnight at room temperature, palladium on carbon filtered off, and the resulting filtrate was concentrated and then isolated on a thick plate (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a light yellow solid (79.7mg, 100%).

MS(ESI,pos.ion)m/z:526.3[M+H]⁺。

Tenth step Synthesis of 2- ((S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (80.0mg,0.152mmol), dichloromethane (4.0mL) and N, N-diisopropylethylamine (39.0mg,0.30mmol) in that order, cooled to-10 ℃, followed by acryloyl chloride (16.0mg,0.18mmol), stirred for 10min after completion of dropping, warmed to room temperature, and the mixture was concentrated and then isolated on a thick plate (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a light yellow solid (30.3mg, 34%).

MS(ESI,pos.ion)m/z:580.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.81–7.65(m,2H),7.46(d,J＝13.6Hz,2H),7.36(dd,J＝15.2,7.9Hz,1H),7.25(t,J＝6.2Hz,1H),6.81–6.39(m,1H),6.03(d,J＝16.6Hz,1H),5.66(dd,J＝10.4,2.2Hz,1H),4.69(d,J＝67.9Hz,1H),4.23(d,J＝52.0Hz,4H),3.57(s,2H),3.43(d,J＝13.4Hz,2H),3.11(dd,J＝30.9,19.9Hz,4H),2.97–2.72(m,7H),2.67(s,2H),2.44(s,3H),2.33(s,1H),2.02–1.89(m,4H),1.68(d,J＝36.3Hz,3H)。

Example 52- ((S) -1-acryloyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First step Synthesis of ethyl 4- ((8-chloronaphthalen-1-yl) amino) -3-oxobutyrate

To an acetonitrile (200mL) solution of 8-chloronaphthalen-1-amine (8.00g,45.0mmol), potassium iodide (14.98g,90.0mmol), and sodium carbonate (7.58g,90.1mmol) was added ethyl 4-chloro-3-oxobutyrate (14.85g,90.2mmol), the reaction was heated under reflux for 10 hours, cooled to room temperature, the reaction solution was concentrated, saturated sodium sulfite (100mL) and water (100mL) were added, ethyl acetate (200mL × 3) was extracted, the organic phases were combined, washed successively with saturated sodium sulfite (100mL), water (100mL × 2) and saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v) ═ 1/4) to give the title compound as a brownish red solid (7.57g, 55%).

MS(ESI,pos.ion)m/z:306.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.67(dd,J＝8.1,0.5Hz,1H),7.70-7.65(m,1H),7.53(s,1H),7.42(dd,J＝7.4,1.0Hz,1H),7.33(t,J＝7.9Hz,1H),7.28(t,J＝7.8Hz,1H),7.21(d,J＝8.0Hz,1H),6.41(d,J＝7.7Hz,1H),4.28-4.23(m,4H),3.61(s,2H),1.32(t,J＝7.1Hz,3H)。

Second step Synthesis of ethyl 4- (3-chloro-N- (8-chloronaphthalen-1-yl) propionamide) -3-oxobutyrate

To a solution of ethyl 4- ((8-chloronaphthalen-1-yl) amino) -3-oxobutanoate (7.00g,22.9mmol) and sodium carbonate (4.87g,46.0mmol) in dichloromethane (120mL) was added dropwise a solution of 3-chloropropionyl chloride (4.37g,33.4mmol) in anhydrous dichloromethane (5.0mL) at 0 ℃, the reaction was stirred at room temperature for 2h, water (150mL) was added to quench the reaction, the aqueous phase was extracted with dichloromethane (100mL × 2), the organic phases were combined, then washed with water (200mL) and saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and then purified (PE/EA (v/v) ═ 3/1) to give the title compound as a brownish red liquid (8.90g, 98%).

MS(ESI,pos.ion)m/z:396.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)7.96(d,J＝8.2Hz,1H),7.91-7.85(m,2H),7.67(dd,J＝7.5,0.7Hz,1H),7.56(t,J＝7.8Hz,1H),7.47(t,J＝7.8Hz,1H),5.20(d,J＝17.8Hz,1H),4.15(q,J＝7.1Hz,1H),3.86(t,J＝12.7Hz,1H),3.81-3.68(m,2H),3.61(d,J＝15.9Hz,1H),3.53(d,J＝15.9Hz,1H),2.61(ddd,J＝16.7,7.8,6.7Hz,1H),2.39(ddd,J＝16.7,7.9,6.3Hz,1H),1.22(t,J＝7.1Hz,3H)。

Step three, synthesizing 1- (8-chloronaphthalene-1-yl) -3, 7-dioxoazepine-4-ethyl formate

To a solution of ethyl 4- (3-chloro-N- (8-chloronaphthalen-1-yl) propionamide) -3-oxobutyrate (0.71g,1.79mmol) in acetone (10.0mL) were added potassium carbonate (0.51g,3.66mmol) and potassium iodide (0.45g,2.70mmol), heated to reflux for 10h, dried under reduced pressure, dichloromethane (10mL) and water (10mL) were added, then 3M HCl was added to adjust the pH to 5, liquid separation was performed, the aqueous phase was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried under reduced pressure, and then column chromatography purification (PE/EA (v/v) ═ 1/1) gave the title compound as a viscous pale yellow liquid (0.27g, 42%).

MS(ESI,pos.ion)m/z:360.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)7.89(d,J＝8.1Hz,1H),7.84(d,J＝8.1Hz,1H),7.67(d,J＝6.7Hz,0.5H),7.64-7.58(m,1H),7.57-7.49(m,1H),7.48-7.43(m,0.5H),7.40(t,J＝7.8Hz,1H),4.94(d,J＝7.9Hz,0.5H),4.87(s,0.5H),4.46-4.40(m,0.5H),4.25-4.08(m,1.5H),3.98(q,J＝7.1Hz,1H),3.41(q,J＝15.7Hz,1H),2.97-2.85(m,0.5H),2.76-2.57(m,2.5H),2.39-2.29(m,0.5H),2.25-2.16(m,0.5H),1.25(t,J＝7.1Hz,1.5H),1.03(t,J＝7.1Hz,1.5H)。

The fourth step of synthesis of 8- (8-chloronaphthalen-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepine-4, 7-dione

To ethyl 1- (8-chloronaphthalen-1-yl) -3, 7-dioxaazepine-4-carboxylate (3.60g,10.0mmol) and S-methylisothiourea sulfate (2.79g,10.0mmol) were added potassium carbonate (5.58g,40.4mmol) and water (100mL), the reaction was stirred vigorously overnight, then 2M HCl was added to adjust the pH to 5, dichloromethane (100mL × 6) was extracted, the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a white solid (2.30g, 60%). MS (ESI, pos.ion) M/z 386.1[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)12.77(s,1H),7.84(t,J＝7.6Hz,2H),7.64(d,J＝6.9Hz,1H),7.40(dt,J＝11.2,7.9Hz,2H),7.06-6.98(m,1H),5.79(s,1H),4.76(d,J＝6.9Hz,1H),3.08-2.91(m,1H),2.83-2.66(m,2H),2.64(s,3H),2.37-2.21(m,1H)。

Fifth step Synthesis of benzyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a solution of 8- (8-chloronaphthalen-1-yl) -2- (methylthio) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepine-4, 7-dione (1.10g,2.86mmol) in acetonitrile (20.0mL) were added BOP (1.64g,3.71mmol) and DBU (0.90g,5.88mmol), stirred at room temperature for 30min, added benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (0.83g,3.19mmol), heated to 60 ℃ for reaction overnight, the heating was stopped, the flask was dried under reduced pressure, dichloromethane (100mL) was added, washed successively with water (50mL × 2) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography purification (PE/EA (v/v) ═ 1/2) gave the title compound as a yellow solid (1.0g, 56%).

MS(ESI,pos.ion)m/z:627.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.87-7.76(m,2H),7.67-7.60(m,1H),7.46-7.32(m,7H),7.12(dd,J＝12.9,6.8Hz,1H),5.81(d,J＝7.1Hz,1H),5.18(s,2H),4.88-4.78(m,1H),4.60-4.48(m,1H),4.38-4.19(m,1H),4.10-3.80(m,2H),3.49-3.31(m,1H),3.29-2.93(m,3H),2.80-2.61(m,3H),2.59(s,3H),2.53-2.44(m,1H),2.36-2.19(m,1H)。

Sixth step Synthesis of benzyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfinyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4, 5-c) at 0 deg.C]To a solution of benzyl azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.50g,0.80mmol) in dichloromethane (20.0mL) was added m-chloroperoxybenzoic acid (0.17g,0.90mmol), stirred at rt for 30min, dichloromethane (50mL) was added, washed successively with saturated sodium carbonate (30mL × 2), water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to dryness to give the title compound as an off-white solid (0.50g, 97%). MS (ESI, pos. ion) M/z 643.3[ M + H ]]⁺。

Seventh step Synthesis of benzyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a solution of benzyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylsulfonyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.50g,0.78mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (0.10g,0.89mmol) in dichloromethane (20.0mL) at 0 ℃ was added sodium tert-butoxide (0.16g,1.66mmol), stirred for 1H with incubation, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a yellow solid (0.45g, 83%). 200mg of the crude product was collected and purified over a thick prep. plate (DCM/MeOH (v/v) ═ 15/1) to give 0.17g of a pale yellow solid.

MS(ESI,pos.ion)m/z:694.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.86-7.76(m,2H),7.67-7.59(m,1H),7.47-7.30(m,7H),7.14(dd,J＝10.4,7.4Hz,1H),5.81(d,J＝4.2Hz,1H),5.18(s,2H),4.90-4.81(m,1H),4.57-4.41(m,2H),4.36-4.26(m,1H),4.14-3.85(m,5H),3.57-3.38(m,2H),3.36-3.25(m,1H),3.24-2.95(m,4H),2.79-2.65(m,3H),2.58-2.44(m,4H),2.40-2.28(m,2H),2.13-2.01(m,1H)。

Eighth step Synthesis of 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a solution of (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (0.15g,0.22mmol) in methanol (10.0mL) was added palladium on charcoal (0.15g, 10%), the reaction was stirred at room temperature for 30min under hydrogen atmosphere, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 7/1) to give the title compound as a yellow solid (97mg, 80%).

MS(ESI,pos.ion)m/z:560.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.81(dd,J＝8.1,3.4Hz,2H),7.65-7.60(m,1H),7.44-7.32(m,2H),7.18-7.13(m,1H),5.82(d,J＝1.4Hz,1H),4.89-4.79(m,1H),4.63-4.48(m,1H),4.40-4.18(m,2H),4.00-3.77(m,1H),3.34-3.16(m,1H),3.08-2.95(m,4H),2.92-2.84(m,1H),2.78-2.72(m,2H),2.72-2.65(m,2H),2.64-2.56(m,3H),2.49-2.41(m,2H),2.37-2.28(m,2H),2.18-2.07(m,2H),1.91-1.78(m,3H)。

Ninth step Synthesis of 2- ((S) -1-acryloyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a solution of 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (87.0mg,0.16mmol) and triethylamine (33.6mg,0.33mmol) in dichloromethane (10.0mL) at 0 ℃ was slowly added dropwise a solution of acryloyl chloride (22.3mg,0.25mmol) in anhydrous dichloromethane (0.5mL), warmed to room temperature and stirred for 30min, quenched with water (10mL), separated, the aqueous phase extracted with DCM (10 mL. times.4), the organic phases combined, washed with saturated saline (20mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, then purify by column chromatography (DCM/MeOH (v/v) ═ 15/1) to give the title compound as an off-white solid (43.4mg, 46%).

MS(ESI,pos.ion)m/z:614.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.86-7.74(m,2H),7.61(d,J＝6.7Hz,1H),7.44-7.30(m,2H),7.10(dd,J＝20.4,7.3Hz,1H),6.61-6.45(m,1H),6.39-6.29(m,1H),5.85-5.74(m,1H),4.91-4.80(m,1H),4.70-4.57(m,1H),4.48-4.35(m,1H),4.32-4.10(m,1H),4.05-3.83(m,1H),3.13-2.90(m,3H),2.84-2.45(m,8H),2.25-2.07(m,4H),2.05-1.96(m,1H),1.95-1.82(m,2H),1.34-1.18(m,4H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm)177.4,170.0,165.1,164.0,136.9,132.0,131.0,130.8,130.3,130.2,129.5,128.8,128.1,127.1,126.5,126.3,126.2,126.0,115.3,95.7,67.8,57.4,45.8,41.3,31.5,30.3,30.1,29.7,28.2,25.1,22.5,22.5,8.6。

Example 6(S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-1-yl) prop-2-en-1-one

First step Synthesis of tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate

To a reaction flask were added 4-tert-butyl 7-ethyl 6-oxo-1, 4-oxazepan-4, 7-dicarboxylate (3.0g,10.1mmol) and methanol (50mL), stirred at room temperature, followed by addition of sodium methoxide (2.82g,50.6mmol) and S-methylisothiourea sulfate (3.5g,18.2mmol), reacted overnight at room temperature, adjusted to pH 3 with 1N hydrochloric acid, concentrated to remove methanol, added water (50mL), stirred for 20min, and filtered to give the title compound as a white solid (2.78g, 88%).

MS(ESI,pos.ion)m/z:314.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)11.76(s,1H),4.52(d,J＝38.2Hz,2H),4.18(d,J＝19.1Hz,2H),3.86(m,2H),2.55(s,3H),1.44(s,9H)。

Second step Synthesis of tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate

To a reaction flask were added tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (500mg,1.6mmol), BOP (936mg, 2.1mmol), DBU (0.4mL,3mmol) and acetonitrile (7mL), reacted at room temperature for 20min, benzyl piperazine-1-carboxylate (0.5mL,3mmol) was added, reacted at 40 ℃ for 5H, cooled to room temperature, the solvent was removed by concentration, and then purified by column chromatography (PE/EA (v/v) ═ 3/1) to give the title compound as a yellow solid (576mg, 70%).

MS(ESI,pos.ion)m/z:516.2[M+H]⁺。

Third step Synthesis of tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methanesulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate

To a reaction flask was added 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester (550mg,1.1mmol) and ethyl acetate (5mL), stirred at 0 ℃, m-chloroperoxybenzoic acid (238mg,1.2mmol) was added, reacted at 0 ℃ for 1H, diluted with ethyl acetate (200mL), washed with saturated aqueous sodium bicarbonate (16mL), the organic phase was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (480mg, 85%).

MS(ESI,pos.ion)m/z:532.1[M+H]⁺。

Fourth step Synthesis of (S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester

To a reaction flask was added tert-butyl 4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methanesulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (1.054g,2.0mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (433mg, 3.6mmol) and toluene (10mL), cooled to 0 ℃, added sodium tert-butoxide (385mg,4.0mmol), reacted further at 0 ℃ for 1H, added ethyl acetate (200mL), then washed with water (20mL), the organic phase concentrated to dryness and purified by column chromatography (dichloromethane: 1.1M aminomethanol (v/v) ═ 100/1) to give a yellow solid (1.06g, 92%).

MS(ESI,pos.ion)m/z:583.3[M+H]⁺。

Fifth step Synthesis of benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate

The reaction flask was charged with (S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester (480mg,0.82mmol), trifluoroacetic acid (4mL) and dichloromethane (8mL), reacted at room temperature for 2H, the solvent was removed by concentration, and the concentrate was used directly in the next reaction (417mg, 100%).

Sixth step Synthesis of benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate

Adding (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4, 5-f) into a bottle][1,4]Oxazacycloheptan-4-yl) piperazine-1-carboxylic acid benzyl ester (410mg,0.85mmol), 1-bromonaphthalene (0.4mL,3mmol), Pd₂(dba)₃(79mg,0.085mmol), xanthphos (100mg,0.17mmol), cesium carbonate (847mg,2.6mmol) and toluene (5mL) were reacted overnight at 100 ℃ under nitrogen, cooled to room temperature, the reaction was concentrated to dryness and purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (417.0mg, 81%). MS (ESI, pos. ion) M/z 609.3[ M + H ]]⁺。

Seventh step Synthesis of (S) -2- ((1-Methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] Oxazacycloheptane

A reaction flask was charged with benzyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (140mg,0.23mmol), palladium on charcoal (70mg,0.066mmol), 7M ammonia in methanol (4mL) and methanol (4mL), reacted overnight at room temperature under hydrogen protection, filtered through celite, the filtrate was concentrated to dryness and the concentrate was used directly in the next reaction (113mg, 100%).

MS(ESI,pos.ion)m/z:475.3[M+H]⁺。

Eighth step Synthesis of (S) -1- (4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-1-yl) prop-2-en-1-one

To a reaction flask were added (S) -2- ((1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan (60mg,0.13mmol), DIPEA (40mg,0.31mmol) and dichloromethane (2mL), cooled to 0 ℃, acryloyl chloride (20mg,0.22mmol) was slowly added dropwise, EtOAc was stirred at room temperature for 2h, the reaction was concentrated to dryness and then purified by column chromatography (MeOH/v) ═ 90/10) to give the title compound as a yellow solid (25mg, 37%).

MS(ESI,pos.ion)m/z:529.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)8.27(m,1H),7.89(m,1H),7.56(d,J＝8.1Hz,1H),7.46(m,2H),7.37(t,J＝7.7Hz,1H),7.16(d,J＝7.3Hz,1H),6.60(m,1H),6.34(d,J＝16.7Hz,1H),5.75(d,J＝10.6Hz,1H),4.36(s,2H),4.17(s,2H),3.89(s,4H),3.80(s,2H),3.66(m,4H),3.15(t,J＝7.4Hz,1H),2.76(s,1H),2.52(s,1H),2.33(m,1H),2.14(m,1H),2.00(s,3H),1.86(m,1H),1.78(s,2H),0.87(m,1H)。

Example 7(S) -1- (4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-1-yl) prop-2-en-1-one

Synthesis of benzyl (S) -4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate in the first step

Adding (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxyl) -6,7,8, 9-tetrahydropyrimidine [4, 5-f) into a reaction bottle][1,4]OxazacyclesHeptane-4-yl) piperazine-1-carboxylic acid benzyl ester (934mg,1.9mmol), 1-bromo-8-methylnaphthalene (771mg,2.9mmol), Pd₂(dba)₃(181mg,0.19mmol), XantPhos (231mg,0.39mmol), cesium carbonate (1.93g,5.8mmol) and toluene (10mL) were reacted overnight at 100 ℃ under nitrogen, cooled to room temperature, the reaction was concentrated to dryness and purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (0.84g, 70%).

MS(ESI,pos.ion)m/z:623.4[M+H]⁺。

Second step Synthesis of (S) -8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan

To a bottle was added benzyl (S) -4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (420mg,0.67mmol), palladium on charcoal (210mg,0.2mmol), 7M ammonia in methanol (4mL) and methanol (4mL), reacted overnight at room temperature under hydrogen protection, filtered through celite, the filtrate was concentrated to dryness and the concentrate was used directly in the next reaction (331mg, 100%).

MS(ESI,pos.ion)m/z:489.3[M+H]⁺。

Third step Synthesis of benzyl (S) -4- (8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate

To a reaction flask were added (S) -8- (8-methylnaphthalen-1-yl) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan (100mg,0.20mmol), DIPEA (60mg,0.46mmol) and dichloromethane (3mL), cooled to 0 ℃, acryloyl chloride (30mg,0.33mmol) was added slowly, stirred at room temperature for 2h, the reaction was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (6mg, 5%).

MS(ESI,pos.ion)m/z:543.3[M+H]⁺。

Example 82- ((S) -1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile

Synthesis of a first step tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate

To a reaction flask were added tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate (1.2g,3.8mmol), BOP (2.25g, 5.0mmol), DBU (0.9mL,6.0mmol) and acetonitrile (20mL), reacted at room temperature for 30min, added benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.12g,4.2mmol), reacted at 40 ℃ for 5H, allowed to cool to room temperature, concentrated to remove the solvent, and purified by column chromatography (PE/EA (v/v) ═ 3/1) to give the title compound as a yellow solid (1.35g, 64%).

MS(ESI,pos.ion)m/z:555.2[M+H]⁺。

Second step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methanesulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate

To a reaction flask were added (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester (1.3g,2.3mmol) and ethyl acetate (12mL), stirred at 0 ℃, added m-chloroperoxybenzoic acid (523mg,2.6mmol), reacted at 0 ℃ for 2H, diluted with ethyl acetate (200mL), washed with saturated aqueous sodium bicarbonate (20mL), the organic phase concentrated to dryness, and purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (0.84g, 63%).

MS(ESI,pos.ion)m/z:571.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.36(m,5H),5.19(s,2H),4.72(m,5H),4.24(m,2H),4.12(m,1H),3.98(m,1H),3.78(m,1H),3.34(m,3H),2.88(s,4H),2.62(d,J＝16.1Hz,1H),1.42(s,9H)。

Third step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylate

To a reaction flask was added 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methanesulfinyl) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester (840mg,1.5mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (321mg, 2.7mmol) and toluene (10mL), cooled to 0 ℃, sodium tert-butoxide (286mg,3.0mmol) was added, reaction was continued at 0 ℃ for 1H, ethyl acetate (200mL) was added, then water (20mL) was washed, the organic phase was concentrated to dryness, then column chromatography (dichloromethane/methanol (v/v) ═ 100/1) gave the title compound as a yellow solid (933mg, 100%).

MS(ESI,pos.ion)m/z:622.5[M+H]⁺。

Fourth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate

The reaction flask was charged with 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydropyrimido [4,5-f ] [1,4] oxazepan-8 (9H) -carboxylic acid tert-butyl ester (833mg,1.3mmol), trifluoroacetic acid (4mL) and dichloromethane (8mL), reacted at room temperature for 2H, dichloromethane (200mL) was added, washed with saturated aqueous sodium bicarbonate solution (15mL), and the organic phase was concentrated to give the title compound as a yellow solid (740mg, 100%).

MS(ESI,pos.ion)m/z:522.3[M+H]⁺。

Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate

Adding (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4, 5-f) into the bottle][1,4]Oxazacycloheptan-4-yl) piperazine-1-carboxylic acid benzyl ester (740mg,1.4mmol), 1-bromo-8-methylnaphthalene (480mg,2.1mmol), Pd₂(dba)₃(133mg,0.14mmol), XantPhos (169mg,0.28mmol), Cesium carbonate (1.42g,4.3mmol) and formazanBenzene (10mL), under nitrogen, at 100 ℃ overnight, was allowed to cool to rt, the reaction was concentrated to dryness and purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (670.0mg, 71%).

MS(ESI,pos.ion)m/z:662.3[M+H]⁺。

Sixth step Synthesis of 2- ((S) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimido [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile

The reaction flask was charged with (S) -benzyl 2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidio [4,5-f ] [1,4] oxazepan-4-yl) piperazine-1-carboxylate (330mg,0.50mmol), palladium on charcoal (165mg,0.16mmol), 7M ammonia in methanol (6mL) and methanol (6mL), reacted overnight at room temperature under hydrogen protection, filtered through celite, the filtrate was concentrated to dryness and the concentrate was used directly in the next reaction (281mg, 100%).

MS(ESI,pos.ion)m/z:528.3[M+H]⁺。

Seventh step Synthesis of 2- ((S) -1-acryloyl-4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask was added 2- ((S) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydropyrimidino [4,5-f ] [1,4] oxazepan-4-yl) piperazin-2-yl) acetonitrile (281mg,0.53mmol), DIPEA (0.2mL,1.0mmol) and dichloromethane (4mL), cooled to 0 ℃, acryloyl chloride (60mg,0.65mmol) was slowly added dropwise, stirred at room temperature for 3h, the reaction was concentrated to dryness, and then column chromatography (DCM/MeOH (v/v) ═ 100/1) gave the title compound as a yellow solid (65mg, 21%).

MS(ESI,pos.ion)m/z:582.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.66(d,J＝8.0Hz,1H),7.62(d,J＝7.9Hz,1H),7.33(m,3H),7.22(d,J＝6.9Hz,1H),6.68(m,1H),6.39(d,J＝16.1Hz,1H),5.82(d,J＝10.4Hz,1H),5.05(s,1H),4.75(m,1H),4.68(m,2H),4.45(m,4H),4.14(m,1H),3.96(s,1H),3.65(m,5H),3.21(m,3H),2.87(s,3H),2.69(m,4H),2.55(s,1H),2.16(m,1H),2.02(m,1H),1.89(m,2H)。

Example 92- ((S) -1-acryloyl-4-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First Synthesis of Ethyl 5- (naphthalen-1-ylamino) pentanoate

The reaction flask was charged with 1-aminonaphthalene (3.5g,24.2mmol), ethyl 5-bromovalerate (5.16g,24.2mmol), sodium acetate (2.1g,25mmol) and absolute ethanol (50mL), refluxed overnight, cooled to room temperature, diluted with ethyl acetate (200mL), washed once with water (25mL), the organic phase concentrated to dryness, and purified by column chromatography (PE/EA (v/v) ═ 10/1) to afford the title compound as a yellow solid (5.92g, 90%).

MS(ESI,pos.ion)m/z:272.2[M+H]⁺。

Second step Synthesis of ethyl 5- (2-ethoxy-N- (naphthalen-1-yl) -2-oxoacetylamino) pentanoate

Ethyl 5- (naphthalen-1-ylamino) pentanoate (2.12g,7.8mmol), sodium carbonate (996mg,9.4mmol) and toluene (16mL) were added to a reaction flask, stirred at 0 ℃, added with oxalyl chloride monoethyl ester (523mg,2.6mmol), reacted at room temperature for 2h, the reaction was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 5/1) to give the title compound as a yellow solid (2.05g, 71%).

MS(ESI,pos.ion)m/z:372.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.89(m,3H),7.64(m,2H),7.44(t,J＝7.7Hz,1H),7.37(dd,J＝7.1,0.7Hz,1H),4.35(m,1H),4.08(q,J＝7.1Hz,2H),3.87(m,2H),3.46(m,1H),2.30(t,J＝7.0Hz,1H),1.81(m,2H),1.66(m,1H),1.20(t,J＝7.1Hz,3H),0.57(t,J＝7.1Hz,3H)。

Step three, synthesizing 3-hydroxy-1- (naphthalene-1-yl) -2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-ethyl formate

To a reaction flask were added ethyl 5- (2-ethoxy-N- (naphthalen-1-yl) -2-oxoacetylamino) pentanoate (1.01g,5.5mmol) and tetrahydrofuran (25mL), cooled to 0 ℃, added 60% sodium hydride (331mg,8.3mmol), reacted at room temperature for 2h, diluted with ethyl acetate (200mL), washed once with saturated aqueous ammonium chloride (12mL), the organic phase concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 3/1) to give the title compound as a yellow solid (1.01g, 56%).

MS(ESI,pos.ion)m/z:326.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)12.29(s,1H),8.01(m,2H),7.84(m,1H),7.65(m,3H),7.36(m,1H),4.50(m,2H),3.98(m,1H),3.60(m,1H),2.94(m,1H),2.63(m,1H),2.27(m,1H),1.93(m,1H),1.39(t,J＝7.1Hz,3H)。

The fourth step of synthesis of 4-hydroxy-2- (methylthio) -8- (naphthalen-1-yl) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one

To a microwave tube were added ethyl 3-hydroxy-1- (naphthalen-1-yl) -2-oxo-2, 5,6, 7-tetrahydro-1H-azepin-4-carboxylate (657mg,2.0mmol), S-methylisothiourea sulfate (700mg,3.7mmol), sodium carbonate (1.072g,10.1mmol), and toluene (10mL), reacted at 110 ℃ in a microwave for 6H, cooled to room temperature, diluted with ethyl acetate (100mL), adjusted to pH 4 with 1N aqueous hydrochloric acid, separated, the organic phase concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a yellow solid (104mg, 15%).

MS(ESI,pos.ion)m/z:352.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)11.61(s,1H),8.01(m,3H),7.64(m,3H),7.45(d,J＝6.9Hz,1H),4.01(m,1H),3.76(m,1H),3.31(m,1H),2.87(m,1H),2.68(s,3H),2.29(m,1H),2.12(m,1H)。

Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask was added 4-hydroxy-2- (methylthio) -8- (naphthalen-1-yl) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one (185mg,0.53mmol), BOP (320mg,0.71mmol), triethylamine (0.15mL,1.1mmol), and acetonitrile (3mL), reacted at room temperature for 30min, added (S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (155mg,0.59mmol), reacted at 80 ℃ overnight, cooled to room temperature, the reaction solution was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a yellow solid (151mg, 48%).

MS(ESI,pos.ion)m/z:593.2[M+H]⁺。

Sixth step Synthesis of benzyl (2S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask were added benzyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (142mg,0.24mmol) and ethyl acetate (3mL), stirred at 0 ℃, added m-chloroperoxybenzoic acid (55mg,0.27mmol), reacted at 0 ℃ for 2H, diluted with ethyl acetate (100mL), washed with saturated aqueous sodium bicarbonate (8mL), the organic phase concentrated to dryness, and purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (184mg, 100%).

MS(ESI,pos.ion)m/z:609.4[M+H]⁺。

Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a reaction flask was added benzyl (2S) -2- (cyanomethyl) -4- (2- (methylsulfinyl) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (184mg,0.30mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (70mg, 0.58mmol), and toluene (4mL), cooled to 0 ℃, sodium tert-butoxide (60mg,0.62mmol) was added, reacted at 0 ℃ for 1H, diluted with ethyl acetate (100mL), washed once with water (10mL), the organic phase was concentrated to dryness, and then column chromatography purification (DCM/MeOH (v/v) ═ 100/1) gave the title compound as a yellow solid (84mg, 42%).

MS(ESI,pos.ion)m/z:660.5[M+H]⁺。

Eighth step Synthesis of 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask was added (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylic acid benzyl ester (84mg,0.13mmol), palladium on charcoal (42mg,0.039mmol), 7M ammonia in methanol (6mL) and methanol (6mL), hydrogen protected, reacted overnight at room temperature, the reaction was filtered over celite, the filtrate was concentrated, and the concentrate was used directly in the next reaction (84mg, 100%).

Ninth step Synthesis of 2- ((S) -1-acryloyl-4-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask was added 2- ((S) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8- (naphthalen-1-yl) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (50mg,0.095mmol), DIPEA (30mg,0.23mmol) and dichloromethane (2mL), cooled to 0 ℃, acryloyl chloride (15mg,0.16mmol) was slowly added dropwise, stirred at room temperature for 2H, the reaction was concentrated to dryness, and then column chromatography purification (DCM/MeOH (v/v): 100/1) gave the title compound as a yellow solid (3mg, 5%).

MS(ESI,pos.ion)m/z:580.3[M+H]⁺。

Example 102- ((S) -1-acryloyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First step Synthesis of Ethyl 5- ((8-chloronaphthalen-1-yl) amino) pentanoate

To a reaction flask were added 8-chloro-1-aminonaphthalene (5.0g,27.7mmol), ethyl 5-bromovalerate (11.8g,55.3mmol), sodium bicarbonate (4.68g,55.4mmol) and acetonitrile (60mL), refluxed overnight, cooled to room temperature, diluted with ethyl acetate (200mL), washed once with water (25mL), the organic phase concentrated to dryness, and purified by column chromatography (PE/EA (v/v) ═ 50/1) to give the title compound as a yellow solid (9.55g,100％)。MS(ESI,pos.ion)m/z:306.1[M+H]⁺。

second step Synthesis of ethyl 5- (N- (8-chloronaphthalen-1-yl) -2-ethoxy-2-oxoacetylamino) pentanoate

To a reaction flask was added ethyl 5- ((8-chloronaphthalen-1-yl) amino) pentanoate (9.55g,31.2mmol), sodium carbonate (3.98g,37.5mmol) and toluene (70mL), stirred at 0 ℃, then added oxalyl chloride monoethyl ester (5.0mL,44mmol), reacted at room temperature for 4h, the reaction was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 5/1) to give the title compound as a yellow solid (8.09g, 64%).

MS(ESI,pos.ion)m/z:406.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.92(dd,J＝8.3,0.9Hz,1H),7.82(dd,J＝8.1,0.7Hz,1H),7.67(dd,J＝7.5,1.1Hz,1H),7.45(m,2H),7.36(dd,J＝7.2,1.2Hz,1H),4.43(m,1H),4.09(q,J＝7.1Hz,2H),3.84(m,2H),3.06(m,1H),2.32(m,2H),1.84(m,2H),1.67(m,2H),1.22(t,J＝7.1Hz,3H),0.68(t,J＝7.1Hz,3H)。

Step three, synthesizing 1- (8-chloronaphthalene-1-yl) -3-hydroxy-2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-ethyl formate

The reaction flask was charged with ethyl 5- (N- (8-chloronaphthalen-1-yl) -2-ethoxy-2-oxoacetylamino) pentanoate (8.09g,19.9mmol) and tetrahydrofuran (100mL), cooled to 0 ℃, added with 60% sodium hydride (1.2g,30mmol), reacted at room temperature for 5h, diluted with ethyl acetate (400mL), washed once with saturated aqueous ammonium chloride (40mL), the organic phase concentrated to dryness, and purified by column chromatography (PE/EA (v/v) ═ 3/1) to give the title compound as a yellow solid (4.14g, 58%).

MS(ESI,pos.ion)m/z:360.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)12.16(s,1H),7.90(d,J＝7.9Hz,1H),7.82(d,J＝8.1Hz,1H),7.60(d,J＝7.4Hz,1H),7.56(m,1H),7.40(t,J＝7.8Hz,1H),7.35(d,J＝7.2Hz,1H),4.46(m,2H),4.07(m,1H),3.41(dd,J＝15.0,6.0Hz,1H),2.99(dd,J＝14.9,6.4Hz,1H),2.49(m,1H),2.26(m,1H),1.94(m,1H),1.38(t,J＝7.1Hz,3H)。

The fourth step of synthesis of 8- (8-chloronaphthalen-1-yl) -4-hydroxy-2- (methylthio) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one

To a reaction flask was added ethyl 1- (8-chloronaphthalen-1-yl) -3-hydroxy-2-oxo-2, 5,6, 7-tetrahydro-1H-azepine-4-carboxylate (2.1g,5.8mmol), S-methylisothiourea sulfate (1.24g,8.7mmol), sodium acetate (2.42g,17.5mmol) and toluene (35mL), reacted overnight at 110 ℃, cooled to room temperature, diluted with ethyl acetate (400mL), adjusted to pH 4 with 1N aqueous hydrochloric acid, separated, the organic phase concentrated to dryness, and purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a yellow solid (480mg, 21%).

MS(ESI,pos.ion)m/z:386.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.93(d,J＝8.0Hz,1H),7.84(d,J＝8.1Hz,1H),7.65(m,2H),7.45(d,J＝7.1Hz,1H),7.41(t,J＝7.8Hz,1H),4.12(m,1H),4.00(m,1H),3.53(m,2H),2.64(s,3H),2.51(m,1H),1.95(s,1H)。

Fifth step Synthesis of tert-butyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a reaction flask were added 8- (8-chloronaphthalen-1-yl) -4-hydroxy-2- (methylthio) -5,6,7, 8-tetrahydro-9H-pyrimido [4,5-c ] azepin-9-one (400mg,1.0mmol), BOP (608mg,1.4mmol), triethylamine (0.25mL,1.8mmol), and acetonitrile (5mL), reacted at room temperature for 30min, added (S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (280mg,1.2mmol), reacted at 80 ℃ overnight, cooled to room temperature, the reaction solution was concentrated to dryness, and purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a yellow solid (259mg, 42%).

MS(ESI,pos.ion)m/z:593.2[M+H]⁺。

Sixth step Synthesis of tert-butyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a reaction flask were added tert-butyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (259mg,0.44mmol) and ethyl acetate (4mL), stirred at 0 ℃, m-chloroperoxybenzoic acid (100mg,0.49mmol) was added, reacted at 0 ℃ for 2H, diluted with ethyl acetate (100mL), washed with saturated aqueous sodium bicarbonate (8mL), the organic phase was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (277mg, 100%).

MS(ESI,pos.ion)m/z:609.2[M+H]⁺。

Seventh step Synthesis of tert-butyl (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a reaction flask was added tert-butyl (2S) -4- (8- (8-chloronaphthalen-1-yl) -2- (methylthio) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (277mg,0.45mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (100mg,0.83mmol) and toluene (4mL), cooled to 0 ℃, added sodium tert-butoxide (100mg,0.83mmol), reacted at 0 ℃ for 2H, diluted with ethyl acetate (100mL), washed once with water (10mL), the organic phase concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (121mg, 40%).

MS(ESI,pos.ion)m/z:660.2[M+H]⁺。

Eighth step Synthesis of 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimidinoo [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask was added (S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (120mg,0.18mmol), trifluoroacetic acid (2mL) and dichloromethane (4mL), reacted at room temperature for 2H, the reaction was concentrated, and the concentrate was used directly in the next reaction (241mg, 100%).

MS(ESI,pos.ion)m/z:526.3[M+H]⁺。

Ninth step Synthesis of 2- ((S) -1-acryloyl-4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added 2- ((S) -4- (8- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -9-oxo-6, 7,8, 9-tetrahydro-5H-pyrimidino [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (241mg,0.31mmol), DIPEA (0.25mL,1.4mmol) and dichloromethane (4mL), cooled to 0 ℃, acryloyl chloride (40mg,0.43mmol) was slowly added dropwise, stirred at room temperature for 2H, the reaction was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (10mg, 5%).

MS(ESI,pos.ion)m/z:614.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.93(d,J＝8.2Hz,1H),7.83(d,J＝8.2Hz,1H),7.68(m,2H),7.50(m,2H),6.58(m,1H),6.40(d,J＝16.6Hz,1H),5.84(d,J＝10.4Hz,1H),4.66(m,1H),4.47(m,1H),3.97(m,2H),3.58(m,2H),3.38(m,1H),3.17(m,1H),3.01(m,2H),2.88(m,1H),2.76(s,1H),2.62(d,J＝5.0Hz,3H),2.58(m,2H),2.39(m,5H),2.20(m,2H),2.07(m,3H)。

Example 112- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -1-acryloylpiperazin-2-yl) acetonitrile

First step synthesis of 1, 4-di-tert-butyl-5-ethyl-6-oxo-1, 4-diazepine-1, 4, 5-tricarboxylate

LiHMDS (23mL,23mmol) was added to a reaction flask, stirred at-78 deg.C, di-tert-butyl 6-oxo-1, 4-diazepine-1, 4-dicarboxylate (5.0g,15.4mmol) and tetrahydrofuran (30mL) were added dropwise, reaction was completed at-40 deg.C for 1h, then ethyl cyanoformate (2.4mL, 23mmol) was added dropwise, reaction was completed at room temperature for 5h, ethyl acetate (400mL) was added for dilution, washing was performed with saturated ammonium chloride (30mL), the organic phase was concentrated to dryness, and then purification by column chromatography (PE/EA (v/v) ═ 5/1) gave the title compound as a yellow solid (3.57g, 60%).

MS(ESI,pos.ion)m/z:231.1[M-Boc-55+H]⁺。

Second step Synthesis of di-tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylate

To a reaction flask were added 1, 4-di-tert-butyl 5-ethyl 6-oxo-1, 4-diazepine-1, 4, 5-tricarboxylate (1.1g,2.9mmol), S-methylisothiourea sulfate (1.01g,7.1mmol), sodium acetate (1.18g,14.2mmol) and toluene (8mL), reacted overnight at 110 ℃, cooled to room temperature, diluted with ethyl acetate (200mL), the aqueous phase was adjusted to pH 3 with 1N aqueous hydrochloric acid, the organic phase was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a yellow solid (0.43g, 37%).

MS(ESI,pos.ion)m/z:413.2[M+H]⁺。

Third step Synthesis of di-tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylate

To a microwave tube were added di-tert-butyl 4-hydroxy-2- (methylthio) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylate (420mg,1.0mmol), BOP (600mg,1.3mmol), triethylamine (0.25mL,1.8mmol), and acetonitrile (5mL), reacted at room temperature for 30min, followed by addition of tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (300mg,1.1mmol), reacted at microwave 90 ℃ for 12H, cooled to room temperature, the reaction solution was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v): 3/1) to give the title compound as a yellow solid (390mg, 59%).

MS(ESI,pos.ion)m/z:654.2[M+H]⁺。

Synthesis of 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methanesulfinyl) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylic acid di-tert-butyl ester

To a reaction flask were added (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methylthio) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylic acid di-tert-butyl ester (740mg,1.1mmol) and ethyl acetate (6mL), stirred at 0 ℃, then m-CPBA (253mg,1.3mmol) was added, reacted at 0 ℃ for 1H, diluted with ethyl acetate (200mL), washed with saturated aqueous sodium bicarbonate solution (12mL), the organic phase was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v) ═ 100/1) to give the title compound as a yellow solid (603mg, 80%).

MS(ESI,pos.ion)m/z:670.1[M+H]⁺。

Fifth step Synthesis of di-tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylate

To a reaction flask was added 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (methanesulfinyl) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylic acid di-tert-butyl ester (600mg,0.90mmol), (S) -2-hydroxymethyl-1-methylpyrrolidine (195mg,1.6mmol) and toluene (6mL), cooled to 0 ℃, sodium tert-butoxide (174mg,1.8mmol) was added, reacted at 0 ℃ for 1H, diluted with ethyl acetate (100mL), washed with water (10mL), the organic phase was concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (569mg, 86%).

MS(ESI,pos.ion)m/z:721.4[M+H]⁺。

Sixth step Synthesis of 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5-carboxylic acid

The reaction flask was charged with 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrimido [5,4-e ] [1,4] diazepine-5, 8(9H) -dicarboxylic acid di-tert-butyl ester (510mg,0.71mmol), trifluoroacetic acid (3mL) and dichloromethane (6mL), stirred at room temperature for 5H, the reaction was concentrated and the concentrate was used directly in the next reaction (439mg, 100%).

MS(ESI,pos.ion)m/z:565.2[M+H]⁺。

Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazine-1-carboxylate

The reaction flask was charged with 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e][1,4]Diazepine-5-carboxylic acid (378mg,0.73mmol), 1-bromo-8-methylnaphthalene (197mg,0.87mmol), Pd₂(dba)₃(68mg,0.073mmol), XantPhos (87mg,0.15mmol), cesium carbonate (483g,1.5mmol) and DMSO (4mL) under nitrogen at 100 ℃ overnight, cooled to room temperature, the reaction concentrated to dryness and purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (105g, 22%).

MS(ESI,pos.ion)m/z:661.2[M+H]⁺。

Eighth step Synthesis of benzyl (S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate

To a reaction flask was added (S) -benzyl 2- (cyanomethyl) -4- (8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazine-1-carboxylate (105mg,0.16mmol), DIPEA (50mg,0.38mmol) and dichloromethane (2mL), stirred at room temperature, acetyl chloride (20mg,0.25mmol) was added dropwise, stirred at room temperature for 4H, the reaction was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (110mg, 99%).

MS(ESI,pos.ion)m/z:703.2[M+H]⁺。

Ninth step Synthesis of 2- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added (S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (416mg,0.59mmol), palladium on charcoal (200mg,0.19mmol), 7M ammonia in methanol (6mL) and methanol (6mL), hydrogen protected, reacted overnight at room temperature, the reaction was filtered through celite, the filtrate was concentrated, and the concentrate was used directly in the next reaction (300mg, 100%).

MS(ESI,pos.ion)m/z:569.3[M+H]⁺。

Tenth step Synthesis of 2- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) -1-acryloylpiperazin-2-yl) acetonitrile

To a reaction flask was added 2- ((S) -4- (5-acetyl-8- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6,7,8, 9-tetrahydro-5H-pyrimido [5,4-e ] [1,4] diazepin-4-yl) piperazin-2-yl) acetonitrile (300mg,0.53mmol), DIPEA (140mg,1.1mmol) and dichloromethane (4mL), cooled to 0 ℃, acryloyl chloride (60mg,0.65mmol) was slowly added dropwise, stirred at room temperature for 2H, the reaction was concentrated to dryness, followed by column chromatography purification (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (6mg, 2%).

MS(ESI,pos.ion)m/z:623.2[M+H]⁺。

Example 121- ((S) -4- (6- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one

First step Synthesis of 3- (benzyloxy) -1-bromonaphthalene

In a reaction flask were charged 4-bromonaphthalene-2-hydroxy (1.0g,4.5mmol), tetrahydrofuran (25mL) and (bromomethyl) benzene (782.0mg,4.6mmol), warmed to 75 ℃ for 18h, added water (20mL), extracted with ethyl acetate (50mL × 3), the organic phases combined, washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate of the organic phase, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 100/10) to give the title compound as a white solid (1.1g, 76%).

¹H NMR(400MHz,DMSO-d₆):δ(ppm)8.03(d,J＝8.2Hz,1H),7.87(d,J＝7.8Hz,1H),7.66(d,J＝2.3Hz,1H),7.57–7.48(m,5H),7.42(t,J＝7.3Hz,2H),7.36(d,J＝7.2Hz,1H),5.24(s,2H)。

Second step Synthesis of benzyl (S) -4- (6- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate

Adding (S) -3-methyl-4- (2- (((S) -1-methylpyrrole-2-yl) methoxyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d) into a reaction bottle]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (450mg,0.76mmol), 3- (benzyloxy) -1-bromonaphthalene (390mg,1.2mmol), Pd₂(dba)₃(182mg,0.2mmol), xanthphos (178mg,0.3mmol), cesium carbonate (946mg,2.9mmol) and toluene (20mL) under nitrogen, warming to 105 ℃ for 23h, adding water (10mL), extracting with ethyl acetate (70mL × 3), combining the organic phases, washing with saturated brine (10mL × 2), concentrating the organic phase to dryness, and purifying by column chromatography (DCM/MeOH (v/v) ═ 100/5) to give the title compound (330mg, 49%).

MS(ESI,pos.ion)m/z:699.4[M+H]⁺。

Third step Synthesis of 4- (4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-1-methylpyrrolidin-2-yl) methoxy) -5H-pyrrolo [3,4-d ] pyrimidin-6 (7H) -yl) naphthalen-2-ol

To a reaction flask were added (S) -benzyl 4- (6- (3- (benzyloxy) naphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (300mg,0.43mmol), a methanol solution of ammonia (10mL,7mol/L), and 10% palladium on carbon (220mg, 5%), followed by stirring at room temperature for 5.5H under a hydrogen atmosphere, filtration over celite, and concentration of the filtrate to dryness to give the title compound (180mg, 88%).

MS(ESI,pos.ion)m/z:475.3[M+H]⁺。

Fourth step Synthesis of 1- ((S) -4- (6- (3-hydroxynaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one

A reaction flask was charged with 4- (4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-1-methylpyrrolidin-2-yl) methoxy) -5H-pyrrolo [3,4-d ] pyrimidin-6 (7H) -yl) naphthalen-2-ol (70mg,0.15mmol), DIPEA (40.2mg,0.3mmol) and dichloromethane (5ml), cooled to-30 ℃, acryloyl chloride (10mg,0.11mmol) was added dropwise, stirred at rt for 0.5H, the reaction was concentrated to dryness, then purified by column chromatography (EtOAc (v/v) ═ 100/10) to give the title compound (30mg, 38%).

MS(ESI,pos.ion)m/z:529.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.73–7.69(m,2H),7.49(d,J＝7.7Hz,1H),7.23–7.14(m,3H),6.57–6.46(m,1H),6.34(t,J＝14Hz,1H),5.73(d,J＝10.3Hz,1H),4.90–4.71(m,2H),4.66–4.58(m,1H),4.47(s,3H),4.34(d,J＝11.1Hz,1H),4.01-3.90(m,1H),3.74–3.66(m,2H),3.52(s,1H),3.45(d,J＝12.0Hz,1H),3.17–3.31(m,2H),2.89(s,3H),2.29–2.16m,2H),2.03(s,2H),1.27(s,3H),1.15(d,J＝6.4Hz,3H)。

Example 132- ((S) -1-acryloyl-4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Synthesis of benzyl (S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate in the first step

Adding (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d) into a reaction bottle]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (500.0mg,1.02mmol), 1-bromo-8 chloronaphthalene (365.4mg,1.51mmol), Pd₂(dba)₃(193.5mg,0.2mmol)、XantPhos(185.2mg,0.31mmol)、Cs₂CO₃(1.0g,3.01mmol) and toluene (30.0mL), stirred at 105 ℃ for 18h under nitrogen, the reaction was filtered through celite, and purified by column chromatography (DCM/MeOH (v/v) ═ 100/10) to give the title compound as a light brown solid (370.00mg, 56%).

MS(ESI,pos.ion)m/z:652.2[M+H]⁺。

Second step Synthesis of 2- ((S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Palladium on carbon (100.0mg, 10%) was added to (S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (120.0mg,0.18mmol) in NH₃In a solution of MeOH (40ml,7mol/L), the reaction was stirred at room temperature under hydrogen for 5h, filtered through celite, and the filtrate was concentrated to dryness to give the title compound as a yellowish solid (80.0mg, 84%).

MS(ESI,pos.ion)m/z:518.2[M+H]⁺。

Third step Synthesis of 2- ((S) -1-acryloyl-4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Acryloyl chloride (16.5mg,0.18mmol) was added to a solution of 2- ((S) -4- (6- (8-chloronaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (80.0mg,0.15mmol) in DCM (20.0mL) at 10 ℃, followed by triethylamine (25.2mg,0.25mmol), the reaction was stirred at 10 ℃ for 30min, the reaction was evaporated to dryness under reduced pressure, a saturated sodium bicarbonate solution (15mL) was added, dichloromethane (50mL × 2) was extracted, the organic phase was concentrated to dryness, and then column chromatography purification (DCM/MeOH (v/v) ═ 10/1) gave the title compound as a white solid (24.8mg, 24%).

MS(ESI,pos.ion)m/z:572.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃):δ(ppm)7.77(d,J＝7.5Hz,1H),7.68–7.63(m,1H),7.54(dd,J＝7.4,0.9Hz,1H),7.51–7.46(m,2H),7.36(t,J＝7.8Hz,1H),6.61–6.51(m,1H),6.38(d,J＝16.6Hz,1H),5.82(d,J＝10.4Hz,1H),5.07-4.84(m,2H),4.60–4.40(m,5H),4.28-4.22(m,2H),3.48-3.25(m,3H),3.14(t,J＝7.6Hz,1H),2.80-2.72(m,2H),2.53(s,3H),2.37-2.30(m,2H),2.11-2.08(m,1H),1.90-1.77(m,3H),1.30-1.27(m,1H)。

Example 142- ((S) -1-acryloyl-4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate in the first step

Adding (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d) into a reaction bottle]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (430.0mg,0.87mmol), 2 bromo-3-fluoro-anisole (260.5mg,1.27mmol), Pd₂(dba)₃(168.0mg,0.18mmol)、XantPhos(160.2mg,0.27mmol)、Cs₂CO₃(868.1mg,2.66mmol) and toluene (25.0mL), stirred at 105 ℃ for 20h under nitrogen, the reaction was filtered through celite, and purified by column chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a brown solid (160.00mg, 30%).

MS(ESI,pos.ion)m/z:616.4[M+H]⁺。

Second step Synthesis of 2- ((S) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Palladium on carbon (120.0mg, 10%) was added to (S) -2- (cyanomethyl) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (160.0mg,0.26mmol) in NH₃In a solution of MeOH (25ml,7mol/L), the reaction was stirred at room temperature under hydrogen for 2h, filtered through celite, and the filtrate was concentrated to dryness to give the title compound as a light brown solid (110.0mg, 88%).

MS(ESI,pos.ion)m/z:482.4[M+H]⁺。

Third step Synthesis of 2- ((S) -1-acryloyl-4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Acryloyl chloride (19.0mg,0.2mmol) was added to a solution of 2- ((S) -4- (6- (2-fluoro-6-methoxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (100.0mg,0.2mmol) in DCM (20.0mL) at 10 ℃, followed by triethylamine (243.5mg,2.4mmol), stirring at 0 ℃ for reaction for 30min, the reaction solution was evaporated under reduced pressure, saturated brine (15mL), dichloromethane (40mL × 2) was added, the organic phase was concentrated to dryness, and then column chromatography purification (DCM/MeOH (v/v) ═ 10/1) gave the title compound as a white solid (13.5mg, 12.1%).

MS(ESI,pos.ion)m/z:536.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.09(dd,J＝14.6,8.3Hz,1H),6.77-6.72(m,2H),6.57(s,1H),6.39(d,J＝16.7Hz,1H),5.83(d,J＝9.9Hz,1H),4.78-4.71(m,2H),4.53(s,1H),4.46(dd,J＝10.7,5.5Hz,1H),4.26(dd,J＝10.7,6.1Hz,1H),3.87(s,3H),3.44(s,1H),3.20-3.18(m,2H),2.83-2.79(m,2H),2.74-2.66(m,1H),2.55(s,3H),2.36-2.22(m,4H),2.12-2.08(m,1H),1.92–1.87(m,1H),1.82-1.77(m,2H),1.29-1.27(m,2H),0.89-0.92(m,1H)。

Example 152- ((S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Synthesis of first step tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

To a solution of benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.35g,5.21mmol) in n-butanol (30.0mL) was added tert-butyl 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (1.50g,5.17mmol) and DIPEA (1.38g,10.64mmol) in that order, warmed to 100 ℃ for 6H, allowed to cool to room temperature, the reaction was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a pale yellow solid (2.58g, 97%).

MS(ESI,pos.ion)m/z:513.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.45-7.35(m,5H),5.21(s,2H),4.85-4.69(m,2H),4.68-4.58(m,1H),4.58-4.30(m,3H),4.25-4.06(m,2H),3.64-3.46(m,1H),3.43-3.25(m,2H),2.87-2.70(m,1H),2.69-2.58(m,1H),1.52(s,9H)。

Second step Synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

To a reaction flask were added tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (2.10g,4.09mmol), (S) - (1-methylpyrrole-2-yl) methanol (0.61g,5.33mmol), palladium acetate (0.094g,0.42mmol), BINAP (0.26g,0.42mmol), cesium carbonate (2.68g,8.22mmol) and anhydrous toluene (60.0mL) in this order, with nitrogen protection, warmed to reflux for 10H, cooled to room temperature, the reaction was concentrated under reduced pressure, DCM (50mL) and methanol (10mL) were added to the residue, stirred at room temperature for 10min, filtered, DCM/MeOH (10/1 v/v), 50mL × 2) the filter cake was rinsed off, the filtrate was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a dark brown solid (0.88g, 36%).

MS(ESI,pos.ion)m/z:592.3[M+H]⁺。

Third step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

To a solution of 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (0.88g,1.50mmol) in DCM (5.0mL) at 0 ℃, a dioxane solution of hydrogen chloride (20.0mL,80.00mmol,4.0mol/L) was added dropwise, stirring was carried out for 10min after completion of the incubation, then the reaction was stirred at room temperature for 2H, the reaction was concentrated under reduced pressure, an methanolic ammonia solution (20.0mL,7.0mol/L) was added to the residue, stirring was carried out for 10min, the reaction was concentrated to dryness, and then column chromatography purification (DCM/MeOH (v/v) ═ 20/1) was carried out to give the title compound as a pale black solid (0.42g, 58%).

MS(ESI,pos.ion)m/z:492.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)7.48-7.31(m,5H),5.20(s,2H),4.62(s,1H),4.47(d,J＝13.9Hz,1H),4.44-4.35(m,2H),4.35-4.29(m,1H),4.24-4.14(m,2H),4.11-4.00(m,2H),3.38(s,1H),3.28-3.08(m,3H),2.80-2.66(m,2H),2.62(dd,J＝16.6,5.2Hz,1H),2.54-2.45(m,3H),2.34-2.29(m,1H),2.10-1.99(m,1H),1.91-1.81(m,1H),1.81-1.70(m,2H)。

Fourth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Sequentially adding (S) -2- (cyanomethyl) -4- (2- (((S) -1-methylpyrrole-2-yl) methoxyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d) into a reaction bottle]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (0.40g,0.81mmol), 1-bromo-8-methylnaphthalene (0.27g,1.24mmol), Pd₂(dba)₃(0.15g,0.17mmol), Xantphos (0.15g,0.26mmol), sodium tert-butoxide (0.18g,1.85mmol) and anhydrous toluene (20.0mL) under nitrogen, warmed to reflux for 10h, cooled to room temperature, the reaction was concentrated to dryness and then purified by column chromatography (DCM/MeOH (v/v) ═ 25/1) to give the title compound as a grey black solid which was then purified by thick prep plates (DCM/MeOH ═ 10/1, v/v) to give a grey black solid (0.14g, 27%).

Fifth step Synthesis of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of benzyl (S) -2- (cyanomethyl) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (0.53g,0.84mmol) in methanoamine (20.0mL,7.0mol/L) was added 10% palladium on charcoal (0.53g), protected with hydrogen, stirred at room temperature for 30min, filtered, the filtrate concentrated to dryness, then purified by column chromatography (DCM/MeOH (v/v) ═ 20/1) to give the title compound as a light yellow semi-solid (0.14g, 34%).

MS(ESI,pos.ion)m/z:498.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.76-7.68(m,2H),7.55-7.49(m,1H),7.46(t,J＝7.6Hz,1H),7.37(t,J＝7.5Hz,1H),7.33-7.28(m,1H),4.69-4.56(m,1H),4.55-4.30(m,5H),4.28-4.16(m,1H),3.99(dd,J＝23.1,12.7Hz,1H),3.27-3.02(m,4H),3.01-2.82(m,5H),2.77-2.65(m,1H),2.61-2.44(m,5H),2.36-2.27(m,1H),2.14-2.05(m,1H),1.81-1.71(m,3H)。

Sixth step Synthesis of 2- ((S) -1-acryloyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a solution of 2- ((S) -4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (60.4mg,0.12mmol), triethylamine (29.4mg,0.29mmol) in anhydrous DCM (10.0mL) was added dropwise acryloyl chloride (11.7mg,013mmol), stirred at 0 ℃ for 30min, water (20mL) was added to quench the reaction, the solution was separated, the aqueous phase was extracted with DCM (20mL × 2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography purification (DCM/MeOH (MeOH/v) ═ 50/1) gave the title compound as pale yellow color Solid (39.1mg, 58.4%).

MS(ESI,pos.ion)m/z:552.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.78-7.65(m,2H),7.56-7.48(m,1H),7.45(t,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,1H),7.29(d,J＝7.4Hz,1H),6.65-6.47(m,1H),6.38(d,J＝16.7Hz,1H),5.82(d,J＝10.2Hz,1H),4.97(s,1H),4.78-4.53(m,2H),4.52-4.36(m,4H),4.29-4.09(m,2H),3.64-3.40(m,1H),3.36-3.19(m,1H),3.13(t,J＝7.6Hz,1H),2.92(s,3H),2.87-2.61(m,3H),2.52(s,3H),2.39-2.27(m,1H),2.24-1.97(m,3H),1.91-1.70(m,3H)；

¹³C NMR(151MHz,CDCl₃):δ(ppm)172.6,167.7,166.1,164.9,159.3,148.1,136.2,134.7,134.7,131.3,130.9,129.8,129.7,128.8,127.1,126.9,126.6,125.7,122.1,122.0,105.5,105.3,70.1,65.6,64.1,60.4,60.3,60.1,59.9,57.7,45.1,41.8,29.7,29.0,23.2,23.0。

Example 162- ((S) -1-acryloyl-4- (6- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

First step Synthesis of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

A reaction flask was charged with 4-bromo-5-methyl-1H-indazole (3.0g,14mmol), dichloromethane (30mL) and p-toluenesulfonic acid (272.6mg,1.504mmol), cooled to 15 ℃,3, 4-dihydro-2H-pyran (2.4g,29mmol) was added dropwise, the reaction was stirred overnight, the reaction was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 1/1) to give the title compound as a white solid (1.2g, 29%).

MS(ESI,pos.ion)m/z:295.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.98(s,1H),7.44(d,J＝8.5Hz,1H),7.24(d,J＝8.5Hz,1H),5.68(dd,J＝9.1,2.7Hz,1H),4.04–3.95(m,1H),3.79–3.67(m,1H),2.60–2.50(m,1H),2.49(s,3H),2.11(ddd,J＝13.0,9.6,6.2Hz,2H),1.83–1.62(m,3H)。

Synthesis of the second benzyl (2S) -2- (cyanomethyl) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Toluene (15.0mL), 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (259.1mg,0.8777mmol), (2S) -2- (cyanomethyl) -4- [2- [ [ (2S) -1-methylpyrrolidin-2-yl) are added to the reaction flask]Methoxy radical]-6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidin-4-yl]Piperazine-1-carboxylic acid benzyl ester (280.0mg,0.5696mmol), XantPhos (103.2mg,0.1730mmol), cesium carbonate (561.0mg,1.72mmol) and Pd₂(dba)₃(108.2mg,0.1146mmol), reaction at 105 ℃ for 22h, filtration through celite, addition of silica gel powder to the filtrate, and purification by column chromatography (DCM/MeOH (v/v) ═ 5/1) gave the title compound as a light brown solid (165.0mg, 41%).

MS(ESI,pos.ion)m/z:706.3[M+H]⁺。

Third step Synthesis of 2- ((2S) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

The reaction vial was charged with benzyl (2S) -2- (cyanomethyl) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (160.0mg,0.2267mmol), 7M ammonia in methanol (15.0mL,105mmol), and 10% palladium on charcoal (160.0mg), respectively, reacted at room temperature for 3H and the reaction was concentrated to dryness to give the title compound as a slightly yellow solid (105.0mg, 81%).

MS(ESI,pos.ion)m/z:572.3[M+H]⁺。

Fourth step Synthesis of 2- ((2S) -1-acryloyl-4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask were added 2- ((2S) -4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (105.0mg,0.1837mmol), dichloromethane (10.0mL), acryloyl chloride (19.5mg,0.215mmol) and triethylamine (32.1mg,0.317mmol), the reaction was stirred at room temperature for 30min, the reaction solution was evaporated under reduced pressure, dichloromethane was added, plate separation (DCM/MeOH (v/v) ═ 10/1) was performed to obtain the title compound (70.0mg, 61%).

MS(ESI,pos.ion)m/z:626.3[M+H]⁺。

Fifth step Synthesis of 2- ((S) -1-acryloyl-4- (6- (5-methyl-1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

To a reaction flask, 2- ((2S) -1-acryloyl-4- (6- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (150.0mg,0.2397mmol), dichloromethane (15.0mL) and trifluoroacetic acid (3.0mL) were added at-5 ℃, the reaction was stirred for 30min, a saturated sodium bicarbonate solution was added until no bubbles were formed in the system, dichloromethane (60mL × 2) was extracted, the organic phases were combined and silica gel powder was added to the organic phase and purified by column chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a light brown solid (150.0mg, 28%).

MS(ESI,pos.ion)m/z:542.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.95(s,1H),7.29(s,3H),6.56(s,1H),6.39(d,J＝16.2Hz,1H),5.83(d,J＝8.0Hz,1H),4.87–4.85(m,2H),4.79–4.76(s,1H),4.59(s,2H),4.53–4.50(m,1H),3.55–3.46(m,2H),3.28(s,2H),2.82(s,3H),2.71–2.68(m,2H),2.46(s,3H),2.27-2.22(m,1H),2.02(s,2H),1.69–1.64(m,1H),1.39–1.27(s,6H)。

Example 172- ((S) -1-acryloyl-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

First step Synthesis of ethyl 4- ((2-fluorophenyl) amino) -3-oxobutyrate

To a solution of 2-fluoroaniline (2.00g,18.01mmol), potassium iodide (5.99g,36.08mmol) and sodium carbonate (3.03g,36.0mmol) in acetonitrile (40.0mL) was added ethyl 4-chloro-3-oxobutyrate (5.98g,36.36mmol), heated to reflux overnight, the solvent was removed by reduced pressure rotary evaporation, then dichloromethane (200mL) was added, washed successively with water (100mL × 2) and saturated brine (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE/EA (v/v) ═ 2/1) to give the title compound as a light brown liquid (3.10g, 72%).

MS(ESI,pos.ion)m/z:240.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.06-6.97(m,2H),6.74-6.66(m,1H),6.62-6.55(m,1H),4.23(q,J＝7.1Hz,2H),4.18(s,2H),3.56(s,2H),1.31(t,J＝7.2Hz,3H)。

Second step Synthesis of ethyl 4- (3-chloro-N- (2-fluorophenyl) propionamide) -3-oxobutyrate

To a solution of ethyl 4- ((2-fluorophenyl) amino) -3-oxobutanoate (3.00g,12.56mmol) and sodium carbonate (1.99g,18.81mmol) in anhydrous dichloromethane (25.0mL) was slowly added dropwise 3-chloropropionyl chloride (2.07g,16.30mmol) at 0 ℃, reaction was completed overnight at room temperature, dichloromethane (100mL) was added, washed successively with water (50mL × 2) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography purification (PE/EA (v/v) ═ 2/1) gave the title compound as a light brown liquid (3.20g, 77%).

MS(ESI,pos.ion)m/z:330.1[M+H]⁺。

Step three, synthesizing 1- (2-fluorophenyl) -3, 7-dioxoazepine-4-ethyl formate

To a solution of ethyl 4- (3-chloro-N- (2-fluorophenyl) propionamide) -3-oxobutyrate (1.51g,4.58mmol) in acetone (60.0mL) were added potassium carbonate (1.28g,9.29mmol) and potassium iodide (1.14g,6.84mmol), the mixture was heated to reflux overnight, cooled to room temperature, evaporated to dryness under reduced pressure, dichloromethane and methanol (50mL, v/v. 10/1) and water (50mL) were added, the liquid was separated, the aqueous phase was extracted with dichloromethane (50 mL. times.3), the organic phases were combined, evaporated to dryness under reduced pressure, and then purified by column chromatography (PE/EA (v/v. times. 1/1) to give the title compound as a yellow solid (0.44g, 33%).

MS(ESI,pos.ion)m/z:294.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.51(td,J＝8.0,1.7Hz,1H),7.44-7.36(m,1H),7.27-7.17(m,2H),5.03(d,J＝17.6Hz,1H),4.18(q,J＝7.1Hz,2H),4.09(d,J＝17.7Hz,1H),3.79-3.72(m,2H),3.63-3.45(m,2H),2.73-2.51(m,2H),1.25(dd,J＝9.5,4.7Hz,3H)。

The fourth step of synthesis of 8- (2-fluorophenyl) -2- (methylthio) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepine-4, 7-dione

To ethyl 1- (2-fluorophenyl) -3, 7-dioxoazepine-4-carboxylate (1.20g,4.09mmol) and S-methylisothiourea sulfate (1.15g,4.14mmol) were added potassium carbonate (2.26g,16.4mmol) and water (60mL), stirred at room temperature overnight, 2M hydrochloric acid was added to adjust the system pH to 5-6, dichloromethane (100mL × 6) was extracted, the organic phases were combined, the organic phase was concentrated to dryness, and column chromatography purification (PE/EA (v/v) ═ 1/4) gave the title compound as a white solid (1.20g, 92%).

MS(ESI,pos.ion)m/z:320.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)12.43(s,1H),7.28-7.19(m,2H),7.16-7.06(m,2H),6.02(s,1H),5.00-4.90(m,1H),2.93-2.78(m,1H),2.70-2.60(m,2H),2.58(s,3H),2.30-2.17(m,1H)。

Fifth step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a solution of 8- (2-fluorophenyl) -2- (methylthio) -5,6,8, 9-tetrahydro-3H-pyrimido [4,5-c ] azepine-4, 7-dione (1.20g,3.76mmol) in acetonitrile (35.0mL) were added BOP (2.16g,4.89mmol) and DBU (1.16g,7.63mmol), stirred at room temperature for 0.5H, added benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.08g,4.17mmol), heated to 40 ℃ for overnight reaction, rotary-dried under reduced pressure, added dichloromethane (100mL), washed successively with water (50mL × 2) and saturated brine (50mL), dried over anhydrous sodium sulfate of the organic phase, filtered, the filtrate concentrated to dryness, and then purified (PE/EA (v/v) ═ 1/2) to give the title compound as a white solid (1.54g, 73%).

MS(ESI,pos.ion)m/z:561.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)7.44-7.19(m,8H),7.19-7.10(m,1H),6.48-6.38(m,1H),5.76(s,1H),5.19-5.07(m,2H),5.06-4.97(m,1H),4.59-4.47(m,1H),3.98-3.87(m,1H),3.30-3.15(m,2H),3.09-2.92(m,1H),2.86-2.74(m,2H),2.72-2.54(m,2H),2.40(s,3H)。

Sixth step Synthesis of benzyl (2S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylsulfonyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a solution of (S) -benzyl 2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylthio) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (0.19g,0.34mmol) in dichloromethane (10.0mL) at 0 ℃ was added m-chloroperoxybenzoic acid (70.3mg,0.38mmol), stirred at rt for 0.5H, dichloromethane (20mL) added, washed successively with saturated sodium carbonate (20mL × 2), water (20mL) and saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound as an off-white semisolid (0.17g, 87%).

MS(ESI,pos.ion)m/z:577.2[M+H]⁺。

Seventh step Synthesis of benzyl (S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate

To a solution of benzyl (2S) -2- (cyanomethyl) -4- (8- (2-fluorophenyl) -2- (methylsulfonyl) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (0.62g,1.10mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (0.14g,1.23mmol) in dichloromethane at 0 ℃, sodium tert-butoxide (0.22g,2.45mmol) was added, the reaction was stirred at constant temperature for 1H, water (50mL) and dichloromethane (30mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (50mL × 3), the organic phases were combined, the organic phase was concentrated to dryness, and column chromatography purification (DCM/MeOH (v/v) ═ 10/1) gave the title compound as a yellow solid (0.55g, 81%).

MS(ESI,pos.ion)m/z:628.3[M+H]⁺。

Eighth step Synthesis of 2- ((S) -4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a solution of benzyl (S) -2- (cyanomethyl) -4-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazine-1-carboxylate (0.25g,0.40mmol) in methanol (10.0mL) was added 10% palladium on charcoal (0.25g), the reaction was stirred at room temperature for 0.5H under hydrogen atmosphere, filtered through a filter, the filtrate was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 15/1) to give the title compound as an off-white solid (0.14g, 71%).

MS(ESI,pos.ion)m/z:494.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)7.33-7.29(m,1H),7.26-7.21(m,1H),7.16-7.10(m,2H),6.12(d,J＝5.1Hz,1H),5.09-5.02(m,1H),4.48(br,1H),4.25-4.16(m,1H),4.00-3.83(m,1H),3.25(br,1H),3.14-3.00(m,3H),2.89-2.75(m,4H),2.73-2.38(m,9H),2.26-2.06(m,3H),1.99-1.88(m,2H)。

Ninth step Synthesis of 2- ((S) -1-acryloyl-4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile

To a solution of 2- ((S) -4- (8- (2-fluorophenyl) -2- (((S) -1-methylpyrrol-2-yl) methoxy) -7-oxo-6, 7,8, 9-tetrahydro-5H-pyrimido [4,5-c ] azepin-4-yl) piperazin-2-yl) acetonitrile (0.10g,0.20mmol) and triethylamine (46.1mg,0.46mmol) in dichloromethane (10.0mL) at 0 ℃, a solution of acryloyl chloride (21.7mg,0.24mmol) in anhydrous dichloromethane (0.5mL) was added dropwise, the mixture was stirred for 30min under incubation, water (20mL) was added to quench the reaction, extraction was performed with dichloromethane (20mL × 3), the organic phases were combined, the organic phase was concentrated to dryness, and then purified (DCM/MeOH (v/v) ═ 10/1) to give a light yellow solid, the solid was further purified by preparative TLC (DCM/MeOH (v/v) ═ 10/1) to give an off-white solid (42mg, 38%).

MS(ESI,pos.ion)m/z:548.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)7.34-7.29(m,1H),7.27-7.20(m,1H),7.16-7.09(m,2H),6.64-6.53(m,1H),6.40(d,J＝16.7Hz,1H),6.14(d,J＝5.0Hz,1H),5.84(d,J＝10.5Hz,1H),5.08(dt,J＝8.1,4.0Hz,1H),5.01-4.84(m,1H),4.64-4.53(m,1H),4.38-4.21(m,2H),4.03-3.90(m,1H),3.65-3.52(m,1H),3.41-3.29(m,1H),3.26-3.11(m,1H),3.04-2.91(m,1H),2.84-2.55(m,8H),2.55-2.42(m,1H),2.26-2.08(m,3H),2.06-1.93(m,2H),1.91-1.81(m,2H)；

¹³C NMR(151MHz,CDCl₃):δ(ppm)175.1,170.5,166.3,165.0,164.3,164.2,157.4,130.0,128.8,128.3,126.6,125.1,124.7,116.7,93.0,65.9,64.9,57.4,41.3,30.3,30.1,29.7,28.5,28.4,26.7,26.5,22.6,15.3,14.1。

Example 181- ((S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Synthesis of a first step tert-butyl (S) -4- (4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

DIPEA (5.6g,42mmol) and benzyl (S) -3-methylpiperazine-1-carboxylate (6.5g,28mmol) were added to a DMF (25mL) solution of 2, 4-dichloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (8.0g,28mmol), the reaction was stirred at 90 ℃ for 3.5H, water (50mL) was added to the reaction solution, ethyl acetate (80mL × 3) was added for extraction, the organic phases were combined and washed with saturated brine (10mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then column chromatography purification was performed (PE/EA (v/v) ═ 90/10) to obtain the title compound as a white solid (10.4g, 77%).

MS(ESI,pos.ion)m/z:488.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.42–7.32(m,5H),5.23–5.14(m,2H),4.80–4.62(m,2H),4.49(d,J＝22.5Hz,2H),4.30–4.09(m,2H),4.01(s,1H),3.39–3.12(m,2H),3.03(s,1H),1.78(s,1H),1.51(s,9H),1.25(s,3H)。

Second step Synthesis of (S) - (1-methylpyrrolidin-2-yl) methanol

Tert-butyl (S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (3.4mg,17mmol) was added to a solution of dry tetrahydrofuran (80mL) at 0 ℃, followed by the slow addition of lithium aluminum hydride (1.0g,26mmol), stirring at 0 ℃ for 10min, then heating at reflux with stirring for 2.5h, cooling to 0 ℃, followed by the slow addition of methanol (15mL), then addition of water (15mL), after no bubble generation, addition of sodium hydroxide solution (10mL), filtration of the reaction through celite, concentration of the filtrate to dryness, and purification by column chromatography (DCM/MeOH (v/v) ═ 80/10) to give the title compound as a brown oil (1.5g, 77%).

MS(ESI,pos.ion)m/z:166.1[M+H]⁺。

Third step synthesis of tert-butyl 4- ((S) -4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate

Under the protection of nitrogen, (S) -4- (4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2-chloro-5, 7-dihydro-6H-pyrrolo [3, 4-d)]Pyrimidine-6-carboxylic acid tert-butyl ester (1.25g,2.5mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (400mg,3.5mmol), Pd (OAc)₂(63.5mg,0.27mmol)、BINAP(339.2mg,0.52mmol)、Cs₂CO₃(1.78g,5.2mmol) and toluene (25mL) were added to a reaction flask, the reaction was stirred at 105 ℃ for 12h, the reaction mixture was filtered through celite, and silica was added to the filtrateThe gum powder was concentrated to dryness and then purified by column chromatography (DCM/MeOH (v/v) ═ 97/3) to give the title compound as a brown solid (550mg, 38%).

MS(ESI,pos.ion)m/z:567.5[M+H]⁺。

Fourth step Synthesis of benzyl (S) -3-methyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Trifluoroacetic acid (3.0mL) was added to 4- ((S) -4- ((benzyloxy) carbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5, 7-dihydro-6H-pyrrolo [3,4-d]Pyrimidine-6-carboxylic acid tert-butyl ester (550mg,0.97mmol) in dichloromethane (10mL) was stirred at room temperature for 4h, and saturated NaHCO was added to the reaction mixture₃The solution (10mL) and water (10mL) were added, dichloromethane (50mL × 2) was further added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound as a yellow-brown solid (450mg, 99%).

MS(ESI,pos.ion)m/z:467.5[M+H]⁺。

Fifth step Synthesis of 1-bromo-8-methylnaphthalene

Methyllithium (21mL,34 mmol; 1.6M in ether) is added to a solution of 1, 8-dibromonaphthalene (8g,28mmol) in THF (20mL) at 0 deg.C, the reaction is stirred for 30min at 0 deg.C, and CH is added dropwise₃I (20g,140mmol), warmed to room temperature and stirred for 4h, the reaction was concentrated to dryness, ethyl acetate (120mL) was added, washed with saturated brine (10mL × 3), dried over anhydrous sodium sulfate of the organic phase, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (PE) to give crude product, which was then recrystallized from IPA to give the title compound as a white solid (3.2g, 52%).

Sixth step Synthesis of benzyl (S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

Under the protection of nitrogen, (S) -3-methyl-4- (2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6, 7-dihydro-5H-pyrrolo [3, 4-d)]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (300mg,0.6mmol), 1-bromo-8-methylnaphthalene (160mg,0.7mmol), Pd₂(dba)₃(105mg,0.11mmol)、XantPhos(102mg,0.17mmol)、Cs₂CO₃(577mg,1.7mmol) and toluene (20mL) were added to a reaction flask, the reaction was stirred at 105 ℃ for 23h, the reaction was filtered through celite, the filtrate was concentrated to dryness, and then purified by column chromatography (DCM/MeOH (v/v) ═ 90/10) to give the title compound as a yellow solid (120.0mg, 30%).

MS(ESI,pos.ion)m/z:607.3[M+H]⁺。

Seventh step Synthesis of 6- (8-methylnaphthalen-1-yl) -4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine

Palladium on carbon (73.5mg, 5%, 10 wt%, 50% water) was added to (S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (70mg,0.11mmol) in NH₃To a solution of MeOH (5mL,7mol/L) was added MeOH (3mL), the reaction was stirred at room temperature under hydrogen for 3h, filtered through celite, and the filtrate was concentrated to dryness to give the title compound as a yellow solid (54mg, 99%).

MS(ESI,pos.ion)m/z:473.3[M+H]⁺。

Eighth step Synthesis of 1- ((S) -3-methyl-4- (6- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Acryloyl chloride (13.8mg,0.15mmol) was added to a solution of 6- (8-methylnaphthalen-1-yl) -4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidine (70mg,0.15mmol) in dichloromethane (5ml) at 0 ℃, followed by triethylamine (40.5mg,0.4mmol), the reaction was stirred at 0.5H, the reaction was concentrated to dryness, and then purified by column chromatography (EtOAc/MeOH (v/v) ═ 90/10) to give the title compound as a yellow solid (13mg, 13.3%).

MS(ESI,pos.ion)m/z:527.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.71(d,J＝8.0Hz,2H),7.50(d,J＝6.3Hz,1H),7.47(d,J＝7.7Hz,1H),7.36(t,J＝7.5Hz,1H),7.29(s,1H),6.66-6.48(m,1H),6.35(d,J＝16.7Hz,1H),5.75(d,J＝10.2Hz,1H),5.01–4.94(m,1H),4.69-4.64(m,1H),4.62-4.53(m,2H),4.48(d,J＝13.7Hz,1H),4.45-4.34(m,3H),4.02(s,1H),3.78-3.74(m,2H),3.57-3.48(m,2H),3.29(d,J＝7.4Hz,2H),2.36-2.25(m,3H),2.18-2.04(m,3H),1.26-1.29(m,9H)。

Biological assay

The LC/MS/MS system used for the analysis was a Waters Xevo G2-XS Qtof time-of-flight mass spectrometer. Mass spectrometry conditions are shown in table a:

TABLE A

Analysis A Waters Acquity I Class Sepax Bio-C4, 2.1X 50mm, 3. mu.M column was used to inject 10. mu.L of sample. Analysis conditions were as follows: the mobile phases were water (containing 0.1% formic acid) (a) and acetonitrile (containing 0.1% formic acid) (B). The flow rate was 0.6 mL/min. The column temperature was 65 ℃. Mobile phase gradients are shown in table B:

TABLE B

Time	Gradient of mobile phase A	Gradient of mobile phase B
			0min	95％	5％
0.75min	95％	5％
			1.0min	75％	25％
6.0min	50％	50％
			6.25min	0％	100％
7.5min	0％	100％
			7.75min	95％	5％
9min	95％	5％

Example A stability in human and rat liver microsomes

Human or rat liver microsomes were incubated in duplicate wells in polypropylene tubes. A typical incubation mixture comprises human or rat liver microsomes (0.5mg protein/mL), the compound of interest (1. mu.M) and a total volume of 15. mu.L of NADPH (2.0mM) potassium phosphate buffer (PBS,100mM, pH 7.4), and the test compound is dissolved in DMSO and diluted with PBS to give a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37 ℃ in communication with the air, and after pre-incubation for 3min, protein was added to the mixture and the reaction started. At different time points (0, NCF, 20 and 60min), the reaction was stopped by adding the same volume of ice-cold acetonitrile. The samples were stored at-80 ℃ until LC/MS/MS analysis.

The concentration of compound in the human or rat liver microsome incubation mixture was determined by the method of LC/MS.

Parallel incubation experiments were performed using denatured microsomes as negative controls, incubated at 37 ℃ and the reactions stopped at different time points (0, NCF, 20 and 60 min).

Verapamil (1 μm) was used as a positive control, incubated at 37 ℃ and the reaction terminated at different time points (0, NCF, 20 and 60 min).

Data analysis

For each reaction, the concentration of compound in human or rat liver microsome incubations (expressed as a percentage) was plotted as a percentage of the relative zero time point to infer intrinsic hepatic clearance in vivo CLint (ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.prediction of human hepatic clearance from in vivo and experimental experiments and in vitro methods students with liver microsomes from animals and distribution 2001,29:1316 1324.). Results see table 1, table 1 for experimental results of the stability of compounds provided in some examples of the invention in human and rat liver microparticles.

Table 1 experimental results for the stability of the compounds provided in some of the examples of the invention in human and rat liver microparticles

As can be seen from Table 1, the compounds of the present invention exhibited suitable stability when incubated in human and rat liver microsomes.

Example BInhibition of SOS 1-mediated guanosine exchange by the compounds of the invention

The experimental method comprises the following steps: the AlphaLISA method measures the inhibitory effect of a compound on SOS 1-mediated guanosine exchange.

The experimental steps are as follows:

1) low Mg²⁺His-KRAS G12C (aa 1-169) was incubated with GDP for 30min under solution conditions, followed by 10mM Mg²⁺The solution was terminated.

2) Desalting was then performed using a desalting column and protein concentration was measured.

3) Compound preparation and dosing treatment

a, preparing a mother solution: test compounds were dissolved in DMSO to prepare 10mM stock solutions.

b, using DMSO to dilute the compound by 3 times to obtain 11 concentration gradients of the compound, and adding 2 mu L of compound solution into 38 mu L of experiment buffer solution to obtain a compound working solution.

4) mu.L of His-KRAS G12C-GDP and 2. mu.L of compound working solution were added to the 384 test plates and preincubated at 25 ℃ for 15 min.

5) After 2h incubation with 4. mu.L of SOS1 protein and GTP, 10. mu.L of purified GST-cRAF (RBD domain, amino acids 1-149), Nickle chellate acceptor beads and Glutathione donor beads (Perkin Elmer) were added, mixed well, centrifuged at 1000rpm for 1min and incubated at 25 ℃ for 2 h.

6) Read plate detection

AlphaLISA signals were read after 2h incubation using Envision (Perkin Elmer, 2104).

7) Data analysis

IC fitting of Compounds Using GraphPad PRISM8.0 De-fitting₅₀。

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC₅₀-X)×HillSlope))

X logarithm of Compound concentration

Y is AlphaLISA signal

The experimental results show thatIn the experiments on the inhibition of SOS 1-mediated guanosine exchange,IC of the Compounds of the invention₅₀< 100. mu.M, it is understood that the compound of the present invention acts on SOS1-mediated guanosine exchange has an inhibitory effect.

EXAMPLE C inhibitory Activity of Compounds of the invention on cell proliferation

The experimental method comprises the following steps: the CTG method measures the inhibitory activity of a compound on cell proliferation.

The cell assay conditions are shown in table C:

watch C

Cell name	Cell/well	Incubation time (h)	Complete culture medium
				H358	1000	72	RPMI1640+10％FBS

1) Cell culture

The cells are cultured by adopting a proper culture medium and are placed in a 5% carbon dioxide incubator at 37 ℃. Cells were observed 1 time daily using an inverted microscope and the medium was changed every 2-4 days. The cells were collected, centrifuged at 1200rpm for 5min, the supernatant was discarded, and the cells were transferred to a new sterile petri dish at a ratio of 1:3 to 1:8 for culture.

2) Cell plating

Cells in the exponential growth phase were collected and counted using a cell counter. The cells were resuspended in the corresponding medium and adjusted to the appropriate concentration. 90 μ L of cell suspension was added to each well in a 96-well cell culture plate. The cells were cultured overnight in a 5% carbon dioxide incubator at 37 ℃.

3) Compound preparation and dosing treatment

And b, diluting the compound by 3 times by using DMSO (dimethyl sulfoxide) to obtain 9 concentration gradients of the compound, diluting the gradient diluted compound by 20 times by using a complete culture medium, and uniformly mixing to obtain a 10 multiplied by concentration drug working solution.

c, adding medicine: the cell culture plate was removed, 10. mu.L/well of the above 10 Xconcentration drug working solution was added to the corresponding well of the cell culture plate, and incubated for 72 hours in an incubator at 37 ℃.

4) Read plate detection

and (a) after the compound is treated for 72 hours, the cell morphology is observed under an inverted microscope, the cell growth state in the DMSO control hole is normal, no pollution phenomenon is seen, and whether the compound is separated out from each hole or not is judged.

b, the prepared CTG solution is placed at room temperature for balancing for 10-20 min.

c adding 50 mu L/hole of CTG solution according to the CTG operation instructions, and placing on a shaking table to shake for 20min in the dark.

d, measuring the fluorescence signal value by using a microplate reader.

5) Data analysis

Growth inhibition rate%_{Negative group}-V_{Experimental group})/(V_{Negative group}-V_{Blank group}) X 100% where V_{Negative group}Average value of solvent control group, V_{Experimental group}Reading for the drug treatment group, V_{Blank group}The readings were from the cell-free drug-free treatment group. Data were analyzed and IC counted using GraphPad Prism 5.0 software₅₀The value is obtained. The results are shown in Table 2, and Table 2 shows the results of experiments for inhibiting cell proliferation using the compounds provided in some examples of the present invention.

TABLE 2 results of experiments for inhibiting cell proliferation of compounds provided in some of the examples of the present invention

Example No. 2	IC₅₀(μM)
		Example 1	3.02
Example 2	1.96
		Example 4	3.32
Example 8	0.50
		Example 9	4.21
Example 10	2.85
		Example 13	0.72
Example 15	0.58

The experimental results show thatIn the test of inhibitory Activity on cell proliferationThe compounds of the present invention have inhibitory activity on cell proliferation.

EXAMPLE D binding of Compounds of the invention to KRAS4B-G12C protein

The experimental method comprises the following steps: the LC-MS method detects the binding of the compound and KRAS4B-G12C protein.

The experimental steps are as follows:

1) experimental buffer preparation is shown in Table D

Table D

2) Loading of GDP into KRAS-4B-G12C protein

2 times of KRAS-4B-G12C protein is diluted to 103 μ M, 2mL of protein is taken and added with 1mL of 2 XGDP loading buffer solution, the mixture is gently mixed, incubated at room temperature for 1.5h, subpackaged into 100 μ L/tube, rapidly frozen in liquid nitrogen and stored in a refrigerator at-80 ℃.

3) KRAS-4B-G12C analysis

Mixing the reagents of Table E below

TABLE E

Reagent	Dosage of
		GDP loaded KRAS-4B-G12C (20uM)	5uL
Compound (10% DMSO solution)	5uL
		10 × incubation buffer	5uL
Ultrapure water	35uL
		In total	50uL

4) Incubating at room temperature for 30min and 3h

5) The reaction was stopped by adding 5. mu.L of 5% formic acid

6) LC-MS detection

A total of 55. mu.L of the reaction mixture was centrifuged at 15000rpm for 10min before loading.

7) The Kras (G12C) binding percentage% was calculated

KRAS (G12C) binding rate ═ complex peak height/[ complex peak height + peak height not bound to KRAS G12C ] × 100

Results see table 3, table 3 for the results of the 1h protein binding experiments for the compounds provided in some of the examples of the present invention.

TABLE 3 results of protein binding experiments with compounds provided in some of the examples of the invention

Example No. 2	Protein binding Rate (%)
		Example 8	92
Example 9	89.7
		Example 13	89.9
Example 15	95.8

The experimental result shows that the compound has higher binding rate with KRAS4B-G12C protein.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

w is a bond, -O- (CR)^mRⁿ)_p-、-S-(CR^mRⁿ)_p-or-NR^d-(CR^mRⁿ)_p-；

R^m、Rⁿ、R^eand R^fEach independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, wherein, said C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy can be independently and optionally substituted by 1,2,3, 4 or 5 groups selected from deuterium, halogen atom, hydroxyl, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Of hydroxyalkoxyl groupsSubstituted by a group;

each R^xIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl; wherein, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxoAmino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

Rⁱand R^jEach independently of the others is hydrogen, deuterium, C_1-3Alkyl or C_1-3Haloalkyl, wherein, said C_1-3Alkyl and C_1-3Haloalkyl can be independently and optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

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

n is 0, 1,2,3, 4,5, 6,7 or 8;

p is 0, 1,2,3, 4,5 or 6.

2. The compound of claim 1, wherein X is

3. The compound of claim 1, wherein R^aAnd R^bEach independently hydrogen, deuterium, a halogen atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy groups may independently optionally be substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

R^cis hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl can be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH₂OH、-OCH₂CH₂OH, isopropoxy, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl;

R^dis hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein the methyl, ethyl, n-propyl, isopropyl or difluoromethyl groups may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

R^m、Rⁿ、R^eand R^fEach independently hydrogen, deuterium, a halogen atom, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are providedPropoxy may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, a halogen atom, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

4. The compound of claim 1, wherein R²Is hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_6-10Aryl, 5-10 membered heteroaryl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl or-CR^eR^f-NR^gR^hWherein, said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_6-10Aryl, 5-10 membered heteroaryl, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

5. The compound of claim 1, wherein R²Is hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CR^eR^f-NR^gR^hWherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl,Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

6. The compound of claim 1, wherein R³Is C_6-10Aryl or 5-to 10-membered heteroaryl, wherein, said C_6-10Aryl and 5-10 membered heteroaryl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_1-4The group of hydroxyalkoxy.

7. The compound of claim 1, wherein R³Is composed of

Wherein, the

8. The compound of claim 1, wherein each R^xIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted by 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3Substituted by the radical hydroxyalkoxy;

each R^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein, said C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen atomsHydroxy, oxo, amino, nitro, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_1-3The group of hydroxyalkoxy.

9. The compound of claim 1, wherein each R^xIndependently is deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxyTrifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH is substituted by a group;

each R^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl and CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups may be independently optionally substituted with 1,2,3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

10. The method of claim 1A compound of formula (I) wherein RⁱAnd R^jEach independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or difluoromethyl, wherein said methyl, ethyl, n-propyl, isopropyl and difluoromethyl groups may independently optionally be substituted with 1,2,3, 4 or 5 substituents selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH₂OH and-OCH₂CH₂OH groups.

11. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof of a compound having one of the following structures:

12. a pharmaceutical composition comprising a compound of any one of claims 1-11; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

13. Use of a compound of any one of claims 1 to 11 or a pharmaceutical composition of claim 12 in the manufacture of a medicament for preventing, treating or ameliorating a KRAS G12C mediated disease in a patient.

14. The use of claim 13, wherein the KRAS G12C mediated disease is cancer.

15. The use of claim 14, wherein the cancer is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, or melanoma.