WO2021027943A1

WO2021027943A1 - Pyrimidinopyridazinone derivative and medical use thereof

Info

Publication number: WO2021027943A1
Application number: PCT/CN2020/109333
Authority: WO
Inventors: 魏国平; 阳华; 付宁; 邴铁军; 高倩; 郭东满; 闻培洋; 赵谈封; 杨玲; 王含建; 杨霞
Original assignee: 正大天晴药业集团南京顺欣制药有限公司; 正大天晴药业集团股份有限公司
Priority date: 2019-08-14
Filing date: 2020-08-14
Publication date: 2021-02-18
Also published as: CN114174298B; CN114174298A

Abstract

A pyrimidinopyridazinone derivative and a medical use thereof. The derivative has a structure represented by general formula (I). The present invention also relates to a preparation method for the compound of general formula (I), a pharmaceutical composition of same, and a use thereof as a KRas G12C inhibitor in treating cancer.

Description

Pyridazinone and pyrimidine derivatives and their medical uses

Cross references to related applications

This application requires the Chinese patent application No. 201910749791.0 filed with the State Intellectual Property Office of the People's Republic of China on August 14, 2019, and the Chinese patent application No. 201910928635.0 filed with the State Intellectual Property Office of the People's Republic of China on September 28, 2019. The rights and interests of the Chinese patent application No. 202010060070.1 filed with the State Intellectual Property Office of the People's Republic of China on January 19, the entire content of which is hereby incorporated into this article by reference.

Technical field

This application relates to pyridazinone and pyrimidine derivatives, their preparation methods, pharmaceutical compositions containing these compounds, and their use as KRas G12C inhibitors in the treatment of cancer.

Background technique

Ras gene is an important proto-oncogene. It is named after it is found in rat sarcoma virus. The Ras protein encoded by it is located on the inner side of the cell membrane. It can bind to GTP/GDP and can be hydrolyzed with the assistance of GTPase activating protein (GAP) GTP. By transforming between the active (GTP-binding) and inactive (GDP-binding) conformations, the Ras protein controls the "on" and "off" in the signal transmission process of growth factors and cytokines, and promotes cell proliferation and differentiation. It plays an important role in life processes such as aging and apoptosis (Bos J L et al., Cell, 2007,129(5):865-877). The human Ras gene family has three members: Harvey rat sarcoma virus carcinogenic homolog (HRas), neuroblastoma rat sarcoma virus oncogene homolog (NRas) and Kirsten rat sarcoma virus oncogene Source material (KRas), of which KRas is mainly expressed in the intestine, lung and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8): 1177-1195).

Studies have shown that more than 30% of human tumors have Ras gene mutations, of which KRas mutations account for about 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2): 201-205). For KRas mutations, mutations at position 12 glycine (G12) account for about 80%, while mutations in G12C (mutation of glycine at position 12 to cysteine) account for about 14% of all mutations in G12 (Prior I A et al., Cancer Res, 2012, 72(10): 2457-2467; Hobbs G A et al. Cancer Cell, 2016, 29(3): 251-253). Mutations in G12 will reduce the catalytic activity of GAP, and ultimately promote the continuous activation of Ras, making it unable to effectively regulate cell signal transduction, thereby promoting the occurrence and development of tumors.

In recent years, people have made certain progress in drug research and development using the allosteric sites of KRas G12C mutants. Currently, the KRas G12C inhibitors under study include ARS-853, ARS-1620, MRTX-1257, AMG-510 and MRTX-849, and some of the structures are as follows. Among them, AMG-510 and MRTX-849 have entered clinical trials.

Detailed description of the invention

This application relates to a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers,

among them,

Part A is selected from

Wherein R is selected from H or C _1-6 alkyl;

Or, the AR ² part is jointly selected from

Is a 4-10 membered heterocycloalkyl containing at least two N atoms,

Is a 4-7 membered heterocycloalkyl containing at least one N atom;

Each R ^{1 is} substituted on the ring, which is independently selected from halogen, oxo, -OH, -NH ₂ , -CN or the following groups optionally substituted with 1, 2 or 3 R ⁰ : C _{1- 6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino or di-C _1-6 alkylamino;

Each R ^{0 is} independently selected from halogen, -OH, -NH ₂ , -CN, C _1-4 alkoxy, C _1-4 alkylamino or di-C _1-4 alkylamino;

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

Each R ^{2 is} independently selected from C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, -C(O)C≡CR ^b , -SO ₂ C≡CR ^b , -C(O)C(R ^a )=C(R ^b ) ₂ or -SO ₂ C(R ^a )=C(R ^b ) ₂ ;

Each R ^a is independently selected from H, deuterium, halo, C _1-4 alkyl or halogenated C _1-4 alkyl;

Each R ^{b is} independently selected from H, deuterium or the following groups optionally substituted with 1, 2, or 3 R ^c : C _1-6 alkyl, C _1-4 alkoxy C _1-3 alkyl , C _1-4 alkylamino C _1-3 alkyl, di C _1-4 alkylamino C _1-3 alkyl, 3-7 membered cycloalkyl C _1-3 alkyl, 4-7 membered heterocyclic ring Alkyl C _1-3 alkyl, phenyl C _1-3 alkyl or 5-6 membered heteroaryl C _1-3 alkyl;

Each R ^{c is} independently selected from halogen, -OH, -NH ₂ , -CN, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, or halogenated C _1-6 Alkoxy;

X is selected from a single bond, -S-, -O-, -NH- or -N(C _1-3 alkyl)-;

R ^{3 is} selected from H or the following groups optionally substituted with 1, 2 or 3 R ^d : C _1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, phenyl , Benzo 4-6 membered heterocyclyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl C _1-3 alkyl, Phenyl C _1-3 alkyl, benzo 4-6 membered heterocyclyl C _1-3 alkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclic C _1-3 alkyl or 5-10 Member heteroaryl C _1-3 alkyl;

Each R ^{d is} independently selected from deuterium, halogen, -OH, oxo, -NH ₂ , -CN, deuterated C _1-4 alkylamino, deuterated di C _1-4 alkylamino, or optionally The following groups substituted by 1, 2 or 3 R ^d1 : C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _{1 -4} alkylamino, C _1-4 alkylaminomethyl, di-C _1-4 alkylaminomethyl, C _1-3 alkoxyimino, 3-7 membered cycloalkyl, 4-7 membered hetero Cycloalkyl, 4-7 membered heterocycloalkyl C _1-3 alkyl, phenyl or 5-6 membered heteroaryl;

Each R ^{d1 is} independently selected from halogen, -OH, oxo, -NH ₂ , -CN, C _1-4 alkyl, or halo C _1-4 alkyl;

Y is selected from a single bond or -CH ₂ -;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, halogen, -CN, -OH, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, di-C _1-6 alkylamino, C _2-6 alkenyl amido or 3-7 membered cycloalkyl ；

Alternatively, R ⁴ and R ^{5 are} joined together to form ring B; or, R ⁵ and R ^{6 are} joined together to form ring B;

Ring B is selected from the following groups optionally substituted with 1, 2, 3 or 4 R ^e : phenyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl base;

Each R ^{e is} independently selected from halogen, -CN, -OH, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 Alkoxy, C _1-6 alkylamino, di-C _1-6 alkylamino or 3-7 membered cycloalkyl;

R ^{9 is} independently selected from H, halogen, C _1-6 alkyl or halo C _1-6 alkyl.

In this application,

Any one of the two connection points in can be connected to R ² , and

Any one of the two connection points in can be connected to R ² . Therefore, in this application, the AR ² part can be selected from

In some embodiments, in the compound of formula (I), moiety A is selected from

Wherein, R is selected from H or C _1-6 alkyl; or, AR ² part is jointly selected from

among them,

Is a 4-10 membered heterocycloalkyl containing at least two N atoms,

Is a 4-7 membered heterocycloalkyl containing at least one N atom;

Each R ^{1 is} substituted on the ring, which is independently selected from halogen, oxo, -OH, -NH ₂ , -CN, or the following groups optionally substituted with 1, 2 or 3 R ⁰ : C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, or di-C _1-6 alkylamino;

Each R ^{0 is} independently selected from halogen, -OH, -NH ₂ , -CN, C _1-4 alkoxy, C _1-4 alkylamino, or di-C _1-4 alkylamino;

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

Each R ^{2 is} independently selected from C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, -C(O)C≡CR ^b , -SO ₂ C≡CR ^b , -C(O)C(R ^a )=C(R ^b ) ₂ , or -SO ₂ C(R ^a )=C(R ^b ) ₂ ;

Each R ^a is independently selected from H, halo, or C _1-4 alkyl;

Each R ^{b is} independently selected from H or the following groups optionally substituted with 1, 2 or 3 R ^c : C _1-6 alkyl, C _1-4 alkoxy C _1-3 alkyl, C _1-4 alkylamino C _1-3 alkyl, di-C _1-4 alkylamino C _1-3 alkyl, 3-7 membered cycloalkyl C _1-3 alkyl, 4-7 membered heterocycloalkyl C _1-3 alkyl, phenyl C _1-3 alkyl, or 5-6 membered heteroaryl C _1-3 alkyl;

Each R ^{c is} independently selected from halogen, -OH, -NH ₂ , -CN, C _1-6 alkyl, C _1-6 alkoxy, or halo C _1-6 alkyl;

X is selected from a single bond, -S-, -O-, -NH-, or -N(C _1-3 alkyl)-;

R ^{3 is} selected from H or the following groups optionally substituted with 1, 2 or 3 R ^d : C _1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, phenyl , Benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl C _1-3 alkyl, phenyl C _1-3 alkyl, benzo 4-6 membered hetero Cyclic C _1-3 alkyl, or 5-10 membered heteroaryl C _1-3 alkyl;

Each R ^{d is} independently selected from halogen, -OH, oxo, -NH ₂ , -CN, or the following groups optionally substituted with 1, 2 or 3 R ^d1 : C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl C _1-3 alkyl, phenyl, or 5-6 membered heteroaryl;

Each R ^{d1 is} independently selected from halogen, -OH, oxo, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino;

Y is selected from a single bond or -CH ₂ -;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, halogen, -CN, -OH, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di-C _1-6 alkylamino, or 3-7 membered cycloalkyl;

Ring B is selected from the following groups optionally substituted with 1, 2, 3 or 4 R ^e : phenyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl base;

Each R ^{e is} independently selected from halogen, -CN, -OH, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl Amino, di-C _1-6 alkylamino, or 3-7 membered cycloalkyl;

R ^{9 is} independently selected from H, halogen, C _1-6 alkyl, or halogenated C _1-6 alkyl.

In some embodiments,

Is a 4-10 or 4-9 membered heterocycloalkyl containing two Ns,

It is a 4-7 membered or 4-6 heterocycloalkyl group containing one N, and the heterocycloalkyl group is a monocyclic heterocycle or spiro heterocycle.

In some embodiments, Part A is selected from

Wherein R is selected from H or C _1-6 alkyl; or, AR ² part is jointly selected from

In some embodiments, the AR ² part is collectively

In some embodiments, Part A is selected from

Wherein R is selected from H or C _1-6 alkyl. In some embodiments, Part A is selected from

In some embodiments, Part A is selected from

In some embodiments, the AR ² moiety is collectively selected from

Wherein, R is selected from H or C _1-6 alkyl.

In some embodiments, R is H. In some embodiments, R is C _1-4 alkyl. In some embodiments, R is selected from methyl or ethyl.

In some embodiments, each R ^{1 is} independently selected from halogen, oxo, -OH, -NH ₂ , -CN, or the following groups optionally substituted with 1, 2, or 3 R ⁰ : C _{1- 4} alkyl, C _1-4 alkoxy, C _1-4 alkylamino or di-C _1-4 alkylamino. In some embodiments, each R ^{1 is} independently C _1-4 alkyl optionally substituted with 1, 2, or 3 R ⁰ .

In some embodiments, each R ^{0 is} independently selected from halogen, -OH, -NH ₂ , -CN, C _1-3 alkoxy, C _1-3 alkylamino, or di-C _1-3 alkylamino . In some embodiments, each R ^{0 is} independently selected from -CN or C _1-3 alkoxy.

In some embodiments, each R ^{1 is} independently selected from C _1-4 alkyl, cyano C _1-3 alkyl, or C _1-3 alkoxy C _1-3 alkyl. In some embodiments, each R ^{1 is} independently selected from methyl, cyanomethyl, or methoxymethyl, particularly selected from methyl and cyanomethyl. In some embodiments, each R ^{1 is} independently cyanomethyl.

In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1, especially 1.

In some embodiments, the AR ² moiety is collectively selected from

In some embodiments, the AR ² moiety is collectively selected from

In some embodiments, the AR ² moiety is collectively selected from

In some embodiments, the AR ² moiety is collectively selected from

In some embodiments, the AR ² moiety is collectively selected from

In some embodiments, the AR ² part is collectively

In some embodiments, each R ^{2 is} independently selected from C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, or C _1-4 alkylsulfonyl. In some embodiments, each R ^{2 is} independently selected from -C(O)C≡CR ^b , -SO ₂ C≡CR ^b , -C(O)C(R ^a )=C(R ^b ) ₂ or -SO ₂ C(R ^a )=C(R ^b ) ₂ . In some embodiments, each R ^{2 is} independently selected from -C(O)C≡CR ^b , -C(O)CH=CH(R ^b ), or -SO ₂ CH=CH(R ^b ). In some embodiments, each R ^{2 is} independently selected from C _1-4 alkoxycarbonyl or -C(O)C(R ^a )=C(R ^b ) ₂ . In some embodiments, each R ^{2 is} independently -C(O)C(R ^a )=C(R ^b ) ₂ .

In some embodiments, each R ^a is independently selected from H, deuterium, fluoro, chloro, methyl, ethyl or halomethyl. In some embodiments, each R ^a is independently selected from H, deuterium, fluoro, chloro or trifluoromethyl. In some embodiments, each R ^a is independently selected from H or fluoro.

In some embodiments, each R ^a is independently selected from H, fluoro, chloro, methyl or ethyl. In some embodiments, R ^a is independently selected from H.

In some embodiments, each R ^{b is} independently selected from H, deuterium, or the following groups optionally substituted with 1, 2, or 3 R ^c : C _1-4 alkyl, di-C _1-3 alkyl Amino C _1-2 alkyl or 4-6 membered heterocycloalkyl C _1-2 alkyl. In some embodiments, each R ^{b is} independently selected from H, deuterium, or the following groups optionally substituted with 1, 2, or 3 R ^c : methyl, dimethylaminomethyl, morpholinomethyl Group, piperidinylmethyl, tetrahydropyrrolylmethyl or azetidinylmethyl. In some embodiments, each R ^{b is} independently selected from H or deuterium. In some embodiments, each R ^{b is} independently H.

In some embodiments, each R ^{b is} independently selected from H or the following groups optionally substituted with 1, 2, or 3 R ^c : C _1-4 alkyl, di-C _1-3 alkylamino C _1-2 alkyl or 4-6 membered heterocycloalkyl C _1-2 alkyl. In some embodiments, each R ^{b is} independently selected from H or the following groups optionally substituted with 1, 2, or 3 R ^c : methyl, dimethylaminomethyl, morpholinomethyl, Piperidinyl methyl, tetrahydropyrrolyl methyl or azetidinyl methyl.

In some embodiments, each R ² is independently ^{-C (O) C (R a} ) = C (R b) 2, wherein R ^a is independently selected from H, deuterium, fluoro, chloro or trifluoromethyl , Especially H or fluorine, and R ^{b is} selected from H or deuterium, especially H.

In some embodiments, each R ^{c is} independently selected from fluorine, chlorine, -OH, -NH ₂ , -CN, C _1-3 alkyl, C _1-3 alkoxy, or fluoro C _1-3 alkane base. In some embodiments, each R ^{c is} independently selected from fluorine, chlorine, methyl, ethyl, or trifluoromethyl.

In some embodiments, each R ^{2 is} independently selected from the following groups:

In some embodiments, each R ^{2 is} independently selected from

In some embodiments, each R ² is

In some embodiments, X is selected from a single bond, -S-, -O-, or -NH-. In some embodiments, X is selected from a single bond, -S-, -NH-, or -N(C _1-3 alkyl)-. In some embodiments, X is selected from a single bond, -O- or -NH-. In some embodiments, X is selected from a single bond.

In some embodiments, R ^{3 is} selected from H.

In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2 or 3 R ^d : C _1-4 alkyl, 3-7 membered cycloalkyl, 4-9 membered heterocycloalkane Group, phenyl, benzo4-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 4-9 membered heterocycloalkyl C _{1- 3} alkyl group, phenyl C _1-3 alkyl group, benzo 4-6 membered heterocyclic group C _1-3 alkyl group, 5-6 membered heteroaryl group C _1-3 alkyl group or 5-6 membered heteroaryl group And 4-6 membered heterocyclic group C _1-3 alkyl.

In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 R ^d : C _1-4 alkyl, 4-9 membered heterocycloalkyl, phenyl, benzo5 -6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 4-9 membered heterocycloalkyl C _1-3 alkyl or 5-6 membered Heteroaryl C _1-3 alkyl. In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2 or 3 R ^d : C _1-4 alkyl, 4-9 membered heterocycloalkyl, benzo 5-6 membered Heterocyclyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 5-6 membered heteroaryl or 4-9 membered heterocycloalkyl C _1-3 alkyl.

In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 R ^d : 4-9 membered heterocycloalkyl, phenyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 4-9 membered heterocycloalkyl C _1-3 alkyl or 5-6 membered heteroaryl C _1-3 alkyl. In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 R ^d : 4-9 membered heterocycloalkyl, benzo 5-6 membered heterocyclyl, 5-6 Member heteroaryl and 4-6 membered heterocyclyl, 5-6 membered heteroaryl or 4-9 membered heterocycloalkyl C _1-3 alkyl. In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 R ^d : 4-9 membered heterocycloalkyl or 4-9 membered heterocycloalkyl C _1-3 alkane base.

In some embodiments, R ^{3 is} selected from C _1-4 alkyl optionally substituted with 1, 2, or 3 R ^d .

In some embodiments, R ^{3 is} selected from H or the following groups optionally substituted with 1, 2 or 3 ^Rd : C _1-6 alkyl, 3-10 membered heterocycloalkyl, benzo4- 6-membered heterocyclyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl C _1-3 alkyl or 5-10 membered hetero Aryl C _1-3 alkyl.

In some embodiments, R ^{3 is} selected from H or the following groups optionally substituted with 1, 2, or 3 R ^d : C _1-6 alkyl, 3-7 membered cycloalkyl, 4-7 membered hetero Cycloalkyl, phenyl, benzo 4-6 membered heterocyclic group, 5-6 membered heteroaryl group, 4-7 membered heterocycloalkyl C _1-3 alkyl, phenyl C _1-3 alkyl, benzene And 4-6 membered heterocyclic C _1-3 alkyl group or 5-6 membered heteroaryl C _1-3 alkyl group.

In some embodiments, R ^{3 is} selected from H or the following groups optionally substituted with 1, 2, or 3 R ^d : C _1-4 alkyl, 4-7 membered heterocycloalkyl, phenyl, benzene And 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, 4-7 membered heterocycloalkyl C _1-3 alkyl group or 5-6 membered heteroaryl C _1-3 alkyl group. In some embodiments, R ^{3 is} selected from H or the following groups optionally substituted with 1, 2 or 3 R ^d : C _1-4 alkyl, 4-7 membered heterocycloalkyl, or 4-7 membered Heterocycloalkyl C _1-3 alkyl. In some embodiments, R ^{3 is} selected from H or the following groups optionally substituted with 1, 2, or 3 R ^d : methyl, ethyl, propyl, phenyl, 1,2,3,4- Tetrahydroisoquinolinyl, azetidinyl, tetrahydropyrrole methyl, morpholinyl, piperidinyl, piperidinyl, piperidinyl, morpholinyl, pyrimidinyl, pyrimidine methyl,

In some embodiments, R ^{3 is} selected from piperazinyl optionally substituted with 1, 2, or 3 ^Rd .

In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 R ^d : 4-8 membered heterocycloalkyl or 4-8 membered heterocycloalkyl C _1-3 alkane base. In some embodiments, R ^{3 is} selected from those optionally substituted with 1, 2, or 3 R ^d

In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 ^Rd : methyl, ethyl, isopropyl, or n-propyl.

In some embodiments, R ^{3 is} selected from the following groups optionally substituted with 1, 2, or 3 R ^d : phenyl, 1,2,3,4-tetrahydroisoquinolinyl, azetidine Group, tetrahydropyrrolyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, 1,3-diazepanyl, 1,4-diazepanyl, piper Pyridinyl, piperidinyl, morpholinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrimidine methyl,

In some embodiments, R ^{3 is} selected from tetrahydropyrrolyl, tetrahydropyrrolyl, piperidinyl, or azetidinyl optionally substituted with 1, 2, or 3 ^Rd . In some embodiments, R ^{3 is} selected from azetidinyl optionally substituted with 1, 2, or 3 ^Rd .

In some embodiments, each R ^{d is} independently selected from deuterium, halogen, -OH, oxo, -NH ₂ , -CN, deuterated di-C _1-4 alkylamino or optionally substituted by 1, 2 or The following groups substituted by 3 R ^d1 : C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino , C _1-4 alkylaminomethyl, two C _1-4 alkylaminomethyl, C _1-3 alkoxyimino, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl C _1-3 alkyl, or 5-6 membered heteroaryl. In some embodiments, each R ^{d is} independently selected from deuterium, halogen, oxo, -CN, or the following groups optionally substituted with 1, 2, or 3 R ^d1 : C _1-4 alkyl, Halogenated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino.

In some embodiments, each R ^{d is} independently selected from deuterium, halogen, oxo, -NH ₂ , -CN, deuterated dimethylamino, deuterated diethylamino, or optionally substituted by 1, 2 Or the following groups substituted by 3 R ^d1 : methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, dimethylaminomethyl, ethoxy Amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methyl tert-butylamino, azetidinyl, Tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrazolyl, tetrahydropyrrolylmethyl or piperidinylmethyl.

In some embodiments, each R ^{d is} independently selected from deuterium, fluorine, -NH ₂ , -CN, cyanomethyl, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethyl Oxy, dimethylaminomethyl, dimethylaminocarbonyl, diethylaminomethyl, diethylaminocarbonyl, ethoxyimino, ethylamino, isopropylamino, dimethylamino, two Ethylamino, di-n-propylamino, diisopropylamino, methyl tert-butylamino,

In some embodiments, each R ^{d is} independently selected from halogen, -OH, oxo, -NH ₂ , -CN, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl Amino, di-C _1-4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl C _1-3 alkyl, phenyl or 5-6 membered Heteroaryl.

In some embodiments, each R ^{d is} independently selected from halogen, oxo, -NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, di-C _1-4 alkylamino, 4-7 Member heterocycloalkyl or 4-7 membered heterocycloalkyl C _1-3 alkyl. In some embodiments, each R ^{d is} independently selected from fluoro, oxo, -NH ₂ , methyl, ethyl, isopropyl, methoxy, dimethylamino, diethylamino, morpholinyl , Tetrahydropyranyl, tetrahydropyrrolylmethyl or piperidine methyl. In some embodiments, each ^{Rd is} independently diisopropylamino.

In some embodiments, each R ^{d is} independently selected from fluorine, oxo, -NH ₂ or the following groups optionally substituted with 1, 2, or 3 R ^d1 : methyl, ethyl, isopropyl , Methoxy, dimethylamino, diethylamino, azetidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydropyrrolylmethyl or piperidinylmethyl. In some embodiments, each ^{Rd is} independently a diisopropylamino group optionally substituted with 1, 2, or 3 ^Rd1 .

In some embodiments, each R ^{d is} independently selected from the following groups optionally substituted with halogen: di-C _1-4 alkylamino or 4-7 membered heterocycloalkyl. In some embodiments, each R ^{d is} independently selected from the following groups optionally substituted with 1, 2, or 3 halogens: di-C _1-4 alkylamino or 4-7 membered heterocycloalkyl. In some embodiments, R ^{d is} independently selected from

In some embodiments, each R ^{d1 is} independently selected from halogen, -OH, oxo, -NH ₂ , -CN, C _1-4 alkyl, or halo C _1-4 alkyl.

In some embodiments, each R ^{d1 is} independently selected from fluorine, chlorine, bromine, -OH, oxo, -NH ₂ , -CN, methyl, ethyl, halomethyl, or haloethyl. In some embodiments, each R ^{d1 is} independently selected from fluorine, chlorine, -OH, oxo, -CN, methyl, ethyl, or trifluoromethyl.

In some embodiments, each R ^{d1 is} independently selected from fluorine.

In some embodiments, the R ^{3 is} selected from H, methyl,

In some embodiments, the R ^{3 is} selected from

In some embodiments, the R ^{3 is} selected from

In some embodiments, the R ^{3 is} selected from H, methyl,

In some embodiments, the R ^{3 is} selected from

In some embodiments, the R ^{3 is} selected from

In some embodiments, the R ^{3 is} selected from H, methyl,

In some embodiments, Y is selected from single bonds.

In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, halogen, -CN, -OH, -NH ₂ , C _1-4 alkyl, halo C _{1 -4} alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, C _2-4 alkenyl amido or 3 -6 membered cycloalkyl. In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are each independently selected from H, halogen, -OH, -NH ₂ , C _1-4 alkyl, halo C _1-4 alkane Group, C _1-4 alkoxy, halogenated C _1-4 alkoxy or C _2-4 alkenyl amido. In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, fluorine, chlorine, bromine, iodine, -CN, -OH, -NH ₂ , methyl, ethyl , N-propyl, isopropyl, trifluoromethyl, difluoromethyl,

Methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, methylamino, dimethylamino, or acrylamido. In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, fluorine, chlorine, bromine, iodine, -OH, -NH ₂ , methyl, trifluoromethyl, Difluoromethyl,

Methoxy, trifluoromethoxy, difluoromethoxy, methylamino, dimethylamino, or acrylamido. In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, fluorine, chlorine, bromine, iodine, -OH, -NH ₂ , methyl, isopropyl, tri Fluoromethyl, difluoromethyl,

Methoxy, trifluoromethoxy, difluoromethoxy or acrylamido, especially selected from H, fluorine, chlorine, bromine, -OH, -NH ₂ , methyl, isopropyl, trifluoromethyl, Difluoromethyl, or methoxy, more particularly selected from H, fluorine, chlorine, methyl and trifluoromethyl.

In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, halogen, -CN, -OH, -NH ₂ , C _1-4 alkyl, halo C _{1 -4} alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino or 3-6 membered cycloalkyl. In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, fluorine, chlorine, bromine, iodine, -OH, -NH ₂ , -CN, methyl, ethyl , Trifluoromethyl, difluoromethyl,

Methoxy, methylamino or dimethylamino. In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently selected from H, fluorine, chlorine, bromine, iodine, -OH, -NH ₂ , methyl,

Trifluoromethyl, difluoromethyl, methylamino or dimethylamino.

In some embodiments, R ⁴ and R ^{5 are} joined together to form ring B. In some embodiments, R ⁵ and R ^{6 are} joined together to form ring B.

In some embodiments, Ring B is selected from optionally substituted 2, 3 or 4 substituents R ^e of the following groups: phenyl, 5-6 membered cycloalkenyl or a 5-6 membered heteroaryl.

In some embodiments, ring B is selected from the following groups optionally substituted with 1, 2, 3, or 4 R ^e : pyrazolyl, imidazolyl, pyrrolyl, thienyl, furyl, triazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, cyclopentenyl or cyclohexenyl. In some embodiments, the ring B is selected from the following groups optionally substituted with 1, 2, 3, or 4 R ^e : phenyl, pyrazolyl, or cyclopentenyl. In some embodiments, the ring B is selected from optionally substituted 2, 3 or 4 R ^e is phenyl. In some embodiments, the ring B is selected from pyrazolyl optionally substituted with 1, 2, or 3 R ^e .

In some embodiments, the ring B is selected from optionally substituted 2, 3 or 4, or R ^e cyclopentenyl phenyl. In some embodiments, the ring B is selected from cyclopentenyl optionally substituted with 1, 2, 3, or 4 R ^e .

In some embodiments, each R ^{e is} independently selected from halogen, -CN, -OH, -NH ₂ , C _1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino or 3-6 membered cycloalkyl, especially selected from halogen, -OH, C _1-4 alkyl or C _1-4 alkoxy. In some embodiments, each R ^{e is} independently selected from fluorine, chlorine, bromine, iodine, -OH, -NH ₂ , -CN, methyl, ethyl, trifluoromethyl, difluoromethyl,

Methoxy, ethoxy, methylamino or dimethylamino. In some embodiments, each R ^{e is} independently selected from fluorine, chlorine, -OH, -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl, particularly from fluorine, Chlorine, -OH, methyl or methoxy.

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, R ^{9 is} selected from H, halogen, C _1-4 alkyl, or fluoro C _1-4 alkyl. In some embodiments, R ^{9 is} selected from H, fluorine, chlorine, methyl, or trifluoromethyl. In some embodiments, R ⁹ is H.

In some embodiments, the C _1-6 alkyl group is selected from C _1-4 alkyl groups. In some embodiments, the C _1-4 alkyl group is selected from C _1-3 alkyl group or C _1-2 alkyl group. In some embodiments, the C _1-6 alkyl group is selected from C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, or C ₆ alkyl. In some embodiments, the C _1-6 alkoxy group is selected from C _1-4 alkyl groups. In some embodiments, the C _1-4 alkoxy group is selected from C _1-3 alkoxy group or C _1-2 alkoxy group. In some embodiments, the C _1-6 alkoxy group is selected from C ₁ alkoxy, C ₂ alkoxy, C ₃ alkoxy, C ₄ alkoxy, C ₅ alkoxy, or C ₆ alkoxy. Oxy.

In some embodiments, the halogen is selected from fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is selected from fluorine. In some embodiments, the halo refers to substitution with one or more halogens. In some embodiments, the halo refers to substitution with one or more halogens selected from fluorine, chlorine, and bromine. In some embodiments, the halo refers to substitution with one or more fluorines. In some embodiments, the one or more includes 1, 2, 3, 4, 5, 6, 7, 8, or 9.

In some embodiments, the deuteration refers to substitution with at least one deuterium. In some embodiments, the deuteration refers to substitution with at least three deuteriums. In some embodiments, the deuteration means that all hydrogens in the group are replaced by deuterium.

In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

In some embodiments, the heterocycloalkyl group contains 1 or 2 N atoms.

In some embodiments, the heterocycloalkyl group contains 1 O atom.

In some embodiments, the heterocycloalkyl group contains 1 N atom and 1 O atom.

In some embodiments, the heterocyclic group contains 1 or 2 heteroatoms selected from N or O.

In some embodiments, the heterocyclic group contains 1 N atom.

In some embodiments, the heterocycloalkyl group includes a monocyclic ring, a spiro ring or a bridged ring. In some embodiments, the heterocycloalkyl group includes a monocyclic ring or a spiro ring. In some embodiments, the heterocycloalkyl group includes monocyclic or bridged rings.

This application relates to compounds of general formula (Ia) or general formula (Ib) or general formula (Ic) or general formula (Id) or general formula (Ie) or a pharmaceutically acceptable salt, stereoisomer or stereoisomer Body mixture:

Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, Y, m, A and B are as defined above.

This application also relates to the following compounds or their pharmaceutically acceptable salts, stereoisomers or mixtures of stereoisomers:

On the other hand, this application relates to a pharmaceutical composition, which comprises the general formula (I), general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id) or general formula (Ie) of the present application ) A compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers. In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.

On the other hand, this application relates to a method for treating KRas G12C-mediated diseases in mammals, including administering a therapeutically effective amount of general formula (I), general formula (Ia), and A compound of formula (Ib), general formula (Ic), general formula (Id) or general formula (Ie) or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers or a pharmaceutical composition thereof.

On the other hand, this application relates to a compound of general formula (I), general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id) or general formula (Ie) or a pharmaceutically acceptable compound thereof The use of a salt, a stereoisomer or a mixture of stereoisomers or a pharmaceutical composition thereof in the preparation of a medicine for treating diseases related to KRas G12C.

On the other hand, this application relates to a compound of general formula (I), general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id) or general formula (Ie) or a pharmaceutically acceptable compound thereof Use of salts, stereoisomers or mixtures of stereoisomers or pharmaceutical compositions thereof in the treatment of diseases related to KRas G12C.

On the other hand, this application relates to general formula (I), general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id), or general formula (I) for treating KRas G12C-mediated diseases Ie) A compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers or a pharmaceutical composition thereof.

In some embodiments of the present application, the disease related to KRas G12C or KRas G12C-mediated disease is preferably cancer.

In some embodiments of the application, the cancer includes lung cancer and pancreatic cancer.

In some embodiments of the application, the cancer is lung cancer, preferably non-small cell lung cancer.

definition

Unless otherwise stated, the following terms used in this application have the following meanings. A specific term should not be regarded as uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.

The term "optional" or "optionally" means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation. For example, the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH ₂ CH ₃ ), monosubstituted (such as CH ₂ CH ₂ F), or polysubstituted (such as CHFCH ₂ F, CH ₂ CHF ₂ etc.) or completely substituted (CF ₂ CF ₃ ). Those skilled in the art can understand that for any group containing one or more substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.

C _mn in this context means that the part has an integer number of carbon atoms in a given range. For example, "C _1-6 "means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

When any variable (such as R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, each R has independent options.

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a covalent bond.

When one of the variables is selected from a covalent bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a covalent bond, it means that the structure is actually A-Z.

When the linking group listed does not indicate its linking direction, the linking direction is arbitrary. For example, in A-L-Z, the linking group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.

When the bond of a substituent is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, structural unit

It means that it can be substituted at any position on cyclohexyl or cyclohexadiene.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxy" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "mercapto" refers to the -SH group.

The term "amino" refers to the -NH ₂ group.

The term "nitro" refers to the -NO ₂ group.

The term "imino" refers to the =NH group.

The term "alkyl" refers to a hydrocarbon group of the general formula C _n H _2n+1 . The alkyl group may be linear or branched. For example, the term "C _1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, such as C ₁ , C ₂ , C ₃ , C ₄ , C ₅ or C ₆ alkyl (eg methyl, ethyl , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, Neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moiety (ie, alkyl) in the alkoxy group, alkylamino group, dialkylamino group, alkylsulfonyl group, alkylcarbonyl group and alkylthio group has the same definition as described above.

The term "alkoxy" refers to -O-alkyl.

The term "alkylamino" refers to -NH-alkyl.

The term "dialkylamino" refers to -N(alkyl) ₂ .

The term "alkylsulfonyl" refers to -SO ₂ -alkyl.

The term "alkylcarbonyl" refers to -CO-alkyl.

The term "alkylthio" refers to -S-alkyl.

The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group with at least one double bond composed of carbon atoms and hydrogen atoms, such as a C _2-6 alkenyl group. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms, such as C _2-6 alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH ₃ ), 2-propynyl (-CH ₂ -C≡CH), 1,3-Butadiynyl (-C≡CC≡CH) and so on.

The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring, such as a 3, 4, 5, 6, 7, 8, 9 or 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantane Alkyl and so on.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring containing at least one carbon-carbon double bond that is not fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 5- to 8-membered ring, such as a 5-, 6, 7, or 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

The term "heterocyclyl" refers to a non-aromatic ring containing heteroatoms that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocyclic ring is usually 3 to 3 heteroatoms containing 1 to 4 heteroatoms (preferably 1 to 3 heteroatoms, more preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. A 7-membered ring, such as a 3, 4, 5, 6 or 7-membered ring. Non-limiting examples of heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuran, dihydrofuran, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , Pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

The term "heterocycloalkyl" refers to a heteroatom-containing cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycloalkyl group is usually a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring. Preferred heterocycloalkyl groups have a single 4 to 7 membered ring, or multiple fused rings containing 6 to 10, especially 6 to 8 ring atoms. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfiethane, and azathione groups. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane Examples of cyclic groups, thiabutanyl, and 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine Examples of 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxepanyl, and thiepanyl.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated π-electron system. For example, the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.

The term "heteroaryl" refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, and S, the remaining ring atoms are C, and have at least one aromatic ring. The preferred heteroaryl group refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C, and all have an aromatic ring system. Preferred heteroaryl groups have a single 4 to 8 membered ring (e.g. 4, 5, 6, 7 or 8 membered ring), especially a 5 to 8 membered ring, or contain 6 to 14 (e.g. 6, 7, 8, 9 , 10, 11, 12, 13, or 14), especially multiple fused rings of 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

The term "treatment" means administering the compounds or formulations described in this application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, which includes but is not limited to:

(i) Suppress the disease or disease state, that is, curb its development;

(ii) Alleviate the disease or disease state, even if the disease or disease state subsides. In US patent practice, prevention is not allowed in the definition of treatment.

The term "therapeutically effective amount" means (i) treating a specific disease, condition or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specific disease, condition, or disorder, or (iii) delaying what is described herein The dosage of the compound of the present application for the onset of one or more symptoms of a specific disease, condition or disorder. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .

The term "pharmaceutical composition" refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound of the application to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound. Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood as an open, non-exclusive meaning, that is, "including but not limited to".

The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energy that can interconvert via a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where protons can migrate between two ring nitrogens. Valence tautomers include interconversion through the recombination of some bonding electrons.

The present application also includes compounds of the present application that are the same as those described herein, but with one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from those generally found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc.

Certain isotope-labeled compounds of the application (such as those labeled with ³ H and ¹⁴ C) can be used in the analysis of compound and/or substrate tissue distribution. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotope-labeled compounds of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.

In addition, substitution with heavier isotopes (such as deuterium (ie ² H)) can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations The following may be preferred, where the deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium.

For example, when R ^{9 is} selected from methyl, the partial deuterium substitution of the compound of formula (I) may be:

The compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

The compounds of the present application may have one or more atropisomers, unless otherwise specified, the atropisomers refer to photoactive isomers produced due to hindered free rotation between single bonds. The compound containing a chiral axis of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of atropisomers include, but are not limited to:

The pharmaceutical composition of the application can be prepared by combining the compound of the application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

Typical routes for administering the compound of the application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, gels, slurries, suspensions, etc., for oral administration to patients.

The solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and processing the mixture into granules to obtain tablets Or the core of the dragee. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

The pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.

In all the methods of administration of the compounds described herein, the daily dose is 0.01 mg/kg body weight to 200 mg/kg body weight.

The compound of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.

The chemical reaction in the specific embodiment of the application is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the application and the reagents and materials required. In order to obtain the compound of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

When Y is a single bond and R ⁹ is hydrogen, the compound of general formula (I) can be synthesized as follows, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X , M and A are as defined above.

Under suitable conditions, raw material 1 undergoes a coupling reaction to obtain Intermediate 2, and Intermediate 2 is deprotected to obtain Intermediate 3, followed by a substitution reaction with Intermediate 4 to obtain Intermediate 5. Intermediate 5 is substituted with the corresponding ring A compound to obtain intermediate 6, and then the N atom of ring A is protected to obtain compound 7, and compound 7 is coupled to obtain intermediate 8, which is then intramolecularly cyclized to obtain intermediate 9. Intermediate 9 is deprotected to obtain intermediate 10, and finally reacts with the corresponding acid halide compound of R ² to obtain 11.

When Y is a single bond and R ⁹ is hydrogen, the compound of general formula (I) can also be synthesized according to the following method, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Parts X, m and A are as defined above.

Under suitable conditions, raw material 1 undergoes a coupling reaction to obtain intermediate 2, and intermediate 2 is deprotected to obtain intermediate 3, followed by a substitution reaction with intermediate 4'to obtain intermediate 5'. Intermediate 5'and the corresponding ring A compound undergo substitution reaction to obtain intermediate 6', then the N atom of ring A is protected to obtain compound 7', compound 7'is coupled to obtain intermediate 8', and then intramolecular Cyclization gives intermediate 9'. The intermediate 9'is oxidized to obtain the intermediate 10' or 11', and then reacted with the corresponding XR ³ fragment compound to obtain the intermediate 9. Intermediate 9 is deprotected to obtain intermediate 10, and finally reacts with the corresponding acid halide compound of R ² to obtain 11.

Each product obtained from the reaction in the above route can be obtained by traditional separation techniques, such traditional techniques including but not limited to filtration, distillation, crystallization, chromatographic separation and the like. The starting materials can be synthesized by oneself or purchased from commercial institutions (for example, but not limited to Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this application can be synthesized into a single isomer or a mixture of isomers.

Abbreviations:

aq stands for water-containing; atm stands for atmospheric pressure; SEMCl stands for (2-(chloromethoxy)ethyl)trimethylsilane; eq stands for equivalent weight; 1,3-DPPP stands for 1,3-bis(diphenylphosphino) Propane; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; THF stands for tetrahydrofuran ; BPO represents benzoyl peroxide; Tol represents toluene; Bn represents benzyl; Boc represents tert-butoxycarbonyl; DIEA is N,N-diisopropylethylamine; IPA is isopropanol; AcOH is acetic acid; ACN is Acetonitrile; m-CPBA is m-chloroperoxybenzoic acid; NaCNBH ₃ is sodium cyanoborohydride; NaBH ₃ CN is sodium cyanoborohydride; LAH is lithium aluminum hydride; 9-BBN is 9-borobicyclononane; MsCl is methanesulfonyl chloride; rt is room temperature; rt is room temperature; (Boc) ₂ O is di-tert-butyl dicarbonate; Boc ₂ O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; TFAA is trifluoro Acetic anhydride; TEA is triethylamine; Et ₃ N is triethylamine; DMAP is 4-dimethylaminopyridine; DIBAL-H is diisobutyl aluminum hydride; NBS is bromosuccinamide; dppf is 1,1 '-Bis(diphenylphosphino)ferrocene; Ph ₃ P is triphenylphosphine; Pd(OAc) ₂ is palladium acetate; Pd(PPh ₃ P) ₂ Cl ₂ is bis(triphenylphosphine) chloride Palladium; Pd ₂ (dba) ₃ is tris(benzylideneacetone) two palladium; XPhos stands for 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl; XANTPHOS is 4,5 -Bis(diphenylphosphino)-9,9-dimethylxanthene; t-BuONa is sodium tert-butoxide; XPhos-Pd-G3 is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate; Pd(dppf)Cl ₂ is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; HATU is 2-(7-azabenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate. Ms represents methanesulfonyl; Tf is trifluoromethanesulfonyl; Ts is p-toluenesulfonyl; Cbz is benzyloxycarbonyl.

The compound is artificially or

The software is named, and the commercially available compounds use the supplier catalog name.

Example

For the sake of clarity, examples are further used to illustrate the present invention, but the examples do not limit the scope of the application. This article has described the application in detail and disclosed its specific embodiments. For those skilled in the art, various changes and improvements will be made to the embodiments of the application without departing from the spirit and scope of the application. Obvious.

All reagents used in this application are commercially available and can be used without further purification.

Preparation Example 1

step 1:

Dissolve dipropylamine hydrochloride (2.39g) in 1,2-dichloroethane (100ml) at room temperature, add compound 1-1 (1.00g) and stir the reaction for 10 minutes, then add triacetoxyboron Sodium hydride (4.91 g) was reacted at room temperature for 2 hours. It was quenched by adding water (200 mL), extracted with dichloromethane (3×200 mL), the organic phases were combined and washed with saturated brine (200 mL), and concentrated under reduced pressure to obtain crude product 1-2 (968 mg).

LC-MS: m/z 257(M+H) ⁺ .

Step 2:

Compound 1-2 (968 mg) was dissolved in hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (675.3 mg).

LC-MS: m/z 157(M+H) ⁺ .

Preparation Example 2

Synthesis of Preparation Example 2 Referring to Preparation Example 1, bis(2-chloroethyl)amine hydrochloride was used instead of dipropylamine hydrochloride to obtain a crude product (59.2 mg).

LC-MS: m/z 197(M+H) ⁺ .

Preparation Example 3

step 1:

Compound 3-1 (800 mg) was dissolved in dichloromethane (30 mL) at room temperature, triethylamine (1.35 g) and acetyl chloride (789.8 mg) were added at 0 degrees Celsius, and reacted at room temperature for 2 hours. It was quenched by adding water (80 mL), extracted with dichloromethane (3×80 mL), the organic phases were combined and washed with saturated brine (80 mL), and concentrated under reduced pressure to obtain crude product 3-2 (614 mg).

LC-MS: m/z 290(M+H) ⁺ .

Step 2:

Compound 3-2 (614 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (10 mL) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 3-3 (694 mg).

LC-MS: m/z 190(M+H)+.

Step 3:

Compound 3-3 (694 mg) was dissolved in 1,2-dichloroethane (20 ml) at room temperature, and the raw material tert-butyl 3-oxoazetidine-1-carboxylate (175 mg ) After stirring and reacting for 10 minutes, sodium triacetoxyborohydride (865 mg) was added and reacted at room temperature for 2 hours. Add water (50 mL) to quench, extract with dichloromethane (3×50 mL), wash with saturated brine (50 mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure and purify by silica gel column chromatography (Methanol/dichloromethane=3%-10%), product 3-4 (264 mg) was obtained.

LC-MS: m/z 345(M+H) ⁺ .

Step 4:

Compound 3-4 (80.0 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (5 mL) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (61.8 mg).

LC-MS: m/z 245(M+H) ⁺ .

Preparation Example 4

step 1:

At room temperature, compound 4-1 (1 g) was suspended in dichloromethane (30 ml), and at 0 degrees Celsius, triethylamine (1.50 g) and methanesulfonyl chloride (850 mg) were sequentially added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (50 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 4-2 (800 mg).

LC-MS: m/z 280(M+H) ⁺ .

Step 2:

Compound 4-2 (800 mg) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, potassium thioacetate (1.63 g) was added, and the reaction was stirred at 65 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (50 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-20%) to obtain product 4-3 (390 mg).

LC-MS: m/z 260(M+H) ⁺ .

Step 3:

At room temperature, lithium tetrahydroaluminum (2.5 moles per liter, 3.12 ml) was dissolved in tetrahydrofuran (10 ml), compound 4-3 (390 mg) was slowly added dropwise, and the reaction was stirred at 65 degrees Celsius for 3 hours. After the reaction was completed, sodium sulfate decahydrate (30 mL) was added for quenching, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (120 mg).

LC-MS: m/z 132(M+H) ⁺

Preparation Example 5

step 1:

At room temperature, compound 5-1 (50.0 mg) was dissolved in methanol (3 mL). Add 2,2-difluoroethane (28.4 mg) and sodium cyanoborohydride (36.7 mg) sequentially. The reaction was overnight at room temperature, quenched by slowly adding water (10 mL), and extracted with ethyl acetate (3×20 mL). The organic phases were combined and washed with saturated brine (20 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 5-2 (69.1 mg).

LC-MS: m/z 237(M+H) ⁺

Step 2:

At room temperature, compound 5-2 (67.1 mg) was dissolved in 1,2-dichloroethane (5 mL). Acetaldehyde (37.5 mg) and sodium triacetoxyborohydride (36.7 mg) were sequentially added. After reacting at room temperature for 1 hour, it was quenched by slowly adding water (10 mL), and extracted with dichloromethane (3×15 mL). The organic phases were combined and washed with saturated brine (20 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 5-3 (35.0 mg).

LC-MS: m/z 265(M+H) ⁺

Step 3:

Compound 5-3 (35.0 mg) was dissolved in hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and reacted at room temperature for 20 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (30.5 mg).

LC-MS: m/z 165(M+H) ⁺

Preparation Example 6

step 1:

At room temperature, compound 6-1 (2 g) was dissolved in 1,4 dioxane solution (25 ml), and 5 ml of water was added. Add isopropenyl boronic acid pinacol ester (2.32 mg), potassium carbonate (3.18 g), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.94 g) in sequence. The reaction solution was reacted at 60 degrees Celsius for 16 hours under the protection of nitrogen. After the reaction, it was quenched with water and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 6-2 (1.27 g).

LC-MS: m/z 136(M+H) ⁺

Step 2:

At room temperature, compound 6-2 (1.27 g) was dissolved in methanol (20 mL). Palladium on carbon (0.8 g) was added. The reaction system was reacted at room temperature for 16 hours in a hydrogen environment. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain crude product 6-3 (1.15 g).

LC-MS: m/z 138(M+H) ⁺

Step 3:

Compound 6-3 (1.15 g) was dissolved in dichloromethane (30 ml) at room temperature, and triethylamine (2.71 g) and trifluoromethanesulfonic anhydride (5.2 g) were added in sequence, and reacted at 0 degrees Celsius for 2 hours. After the reaction was completed, it was quenched by adding water (30 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=40%-55%) to obtain product 6-4 (1.4 g).

LC-MS: m/z 270(M+H) ⁺

Step 4:

Compound 6-4 (500 mg) was dissolved in 1,4 dioxane solution (10 ml) at room temperature, and pinacol diborate (566 mg), potassium acetate (364 mg), [1 ,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (151 mg). The reaction system was reacted at 80°C for 16 hours under the protection of nitrogen. After the reaction is complete, add water (10 mL) to quench. Extract with ethyl acetate (3×80 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 55%-65%) to obtain the title compound (341 mg).

LC-MS: m/z 248(M+H) ⁺

Preparation Example 7

step 1:

Dissolve compound 7-1 (5.00 g) in N,N-dimethylformamide (70 ml) at room temperature, add cyclo(propylene) malonate (3.55 g), and then continue under ice bath conditions. Add formic acid (3.4 g), triethylamine (3.24 g), and react at 80 degrees Celsius for 14 hours. After the reaction, the reaction solution was cooled in an ice bath, quenched by adding water (150 ml), the pH of the system was adjusted to 1-2 with concentrated hydrochloric acid, stirred at room temperature for 30 minutes, the reaction system was filtered, the filter cake was retained, and concentrated under reduced pressure The crude product 7-2 (4.80 g) was obtained.

LC-MS: m/z 247(M+H) ⁺ .

Step 2:

Compound 7-2 (4.80 g) was dissolved in chlorosulfonic acid (40 ml) under ice bath, and reacted at room temperature for 3 hours. After the completion of the reaction, the reaction solution was cooled in an ice bath, and water (100 ml) was added under the ice bath to quench. It was extracted with ethyl acetate (3×150 mL), and the organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 7-3 (4.20 g).

LC-MS: m/z 229(M+H) ⁺ .

Step 3:

Compound 7-3 (4.20 g) was dissolved in trifluoroacetic acid (30 ml) under ice bath conditions, sodium borohydride (3.47 g) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, under ice bath conditions, the reaction solution (50 mL) was quenched, and the pH of the reaction solution was adjusted to 7 with sodium carbonate. It was extracted with ethyl acetate (3×150 mL), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 8%-12%) to obtain the title compound (2.20 g).

LC-MS: m/z 215(M+H) ⁺ .

Preparation Example 8

Synthesis of Preparation Example 8 Referring to Preparation Example 7, 2-bromo-3-chlorobenzaldehyde was substituted for compound 7-1 to obtain the title compound (2.20 g).

LC-MS: m/z 231(M+H) ⁺ .

Preparation Example 9

step 1:

Take the titanium tetrachloride solution (50 ml, 1 mol/L) at room temperature, cool to -40 degrees Celsius, slowly add the dimethyl zinc solution (71.4 ml, 1 mol/L), and stir at -40 degrees Celsius for 30 minutes. Compound 9-1 (5 g) was dissolved in dichloromethane (20 mL) at room temperature and slowly added to the reaction solution. The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was quenched with methanol (40 mL). It was extracted with dichloromethane (3×150 mL), and the organic phases were combined and washed with water (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=7%-11%) to obtain the title compound (3.7 g).

LC-MS: m/z 225(M+H) ⁺ .

Preparation Example 10

step 1

Compound 10-1 (300 mg) was dissolved in acetonitrile (10 ml), diisopropylethylamine (244.32 mg), 3-methylpyrazole (155.21 mg) were added, and the resulting reaction solution was reacted at 70 degrees Celsius. hour. After the reaction was completed, it was quenched by adding water (20 mL). It was extracted with ethyl acetate (20 mL×3). After the organic phases were combined, they were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The crude product 10-2 (250 mg) was obtained.

LC-MS: m/z 304(M+H) ⁺

Step 2

Compound 10-2 (250 mg) was dissolved in anhydrous methanol (30 mL), and palladium on carbon (10%) (125 mg) was sequentially added under nitrogen protection. The resulting reaction solution was replaced with hydrogen three times, and reacted at room temperature for 2 hours (10 atmospheres). After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain the title compound (150 mg).

LC-MS: m/z 138(M+H) ⁺

Preparation Example 11

Synthesis of Preparation Example 11 Referring to Preparation Example 10, pyrazole was used instead of 3-methylpyrazole to obtain the title compound (80 mg).

LC-MS: m/z 124(M+H) ⁺

Preparation Example 12

Synthesis of Preparation Example 12 Referring to Preparation Example 10, 3-(trifluoromethyl)pyrazole was used instead of 3-methylpyrazole to obtain the title compound (100 mg).

LC-MS: m/z 192(M+H) ⁺

Preparation Example 13

step 1

Under a nitrogen atmosphere, compound 13-1 (10 g) was dissolved in tetrahydrofuran solution (30 ml). After the temperature of the reaction system dropped to -78 degrees Celsius and stabilized, a tetrahydrofuran solution of lithium diisopropylamide (16.31) was added dropwise. Milliliters, 2 moles per liter). After reacting the reaction system for 3 hours, 1,2-dibromotetrachloroethane (35.86 g) was added. The final reaction system reacted for 12 hours.

After LCMS monitoring showed that the raw material disappeared, it was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain product 13-2 (11.27 g).

LC-MS: m/z 253(M+H) ⁺

Step 2

Under a nitrogen atmosphere, compound 13-2 (11.27 g) was dissolved in tetrahydrofuran solution (30 ml). After the temperature of the reaction system dropped to 0 degrees Celsius and stabilized, a tetrahydrofuran solution of borane dimethyl sulfide (21.09 ml) was added dropwise. , 10 moles per liter). After the reaction system was reacted at 50 degrees Celsius for 2 hours, after the reaction was over, the reaction solution was cooled in an ice bath, quenched by adding water (150 ml), the pH of the system was adjusted to 1-2 with concentrated hydrochloric acid, and the mixture was mixed with ethyl acetate ( 50 ml × 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (20 ml × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. Get crude product 13-3 (10 grams).

LC-MS: m/z 239(M+H) ⁺

Step 3

Under a nitrogen atmosphere, compound 13-3 (10 g) was dissolved in a dichloromethane solution (30 mL), and after the temperature of the reaction system dropped to 0 degrees Celsius and stabilized, Des Martin (21.25 g) was added. After the reaction system was reacted at room temperature for 2 hours, after the reaction was completed, the reaction solution was extracted with ethyl acetate (50 ml × 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (20 ml × 3 times) , Then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product 13-4 (9.12 g) was obtained.

LC-MS: m/z 237(MH) ⁺

Step 4:

Dissolve compound 13-4 (9.12g) in N,N-dimethylformamide (70ml) at room temperature, add cyclo(propylene) malonate (5.54g), and then in order under ice bath Add formic acid (2.3 g) and triethylamine (11.66 g), and react at 100 degrees Celsius for 14 hours. After the reaction, the reaction solution was cooled in an ice bath, quenched by adding water (150 ml), the pH of the system was adjusted to 1-2 with concentrated hydrochloric acid, stirred at room temperature for 30 minutes, the reaction system was filtered, the filter cake was retained, and concentrated under reduced pressure Get crude product. Get product 13-5 (6 grams).

LC-MS: m/z 281(M+H)+.

Step 5:

Compound 13-5 (6 g) was dissolved in chlorosulfonic acid (40 ml) under ice bath, and reacted at room temperature for 3 hours. After the completion of the reaction, the reaction solution was cooled in an ice bath, and water (100 ml) was added under the ice bath to quench. It was extracted with ethyl acetate (3×150 mL), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 13-6 (4 g).

LC-MS: m/z 263(M+H) ⁺ .

Step 6:

Compound 13-6 (4 g) was dissolved in trifluoroacetic acid (30 ml) under ice bath conditions, sodium borohydride (2.87 g) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, under ice bath conditions, the reaction solution (50 mL) was quenched, and the pH of the reaction solution was adjusted to 7 with sodium carbonate. It was extracted with ethyl acetate (3×150 mL), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=8%-12%) to obtain the title compound (1.7 g).

LC-MS: m/z 249(M+H) ⁺ .

Preparation Example 14

Synthesis of Preparation Example 14 Referring to Preparation Example 13, 3-chloro-4-fluorobenzoic acid was used instead of compound 13-1 to obtain the product (1.70 g).

LC-MS: m/z 249(M+H) ⁺ .

Preparation Example 15

step 1:

At room temperature, compound 15-1 (300 mg) was dissolved in methanol (8 mL). Add acetaldehyde (354 mg) and sodium cyanoborohydride (609 mg) sequentially. After reacting overnight at room temperature, it was quenched by slowly adding water (100 mL) and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 15-2 (250 mg).

LC-MS: m/z 243(M+H) ⁺

Step 2:

Compound 15-2 (250 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (200 mg).

LC-MS: m/z 143(M+H) ⁺

Preparation Example 16

step 1:

At room temperature, compound 16-1 (300 mg) was dissolved in N,N-dimethylformamide (20 mL). Iodoisopropane (1.48 g) and N,N-diisopropylethylamine (1.35 g) were sequentially added. After reacting overnight at 100 degrees Celsius, it was quenched by slowly adding water (100 mL), and extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 16-2 (150 mg).

LC-MS: m/z 257(M+H) ⁺

Step 2:

Compound 16-2 (150 mg) was dissolved in hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) solution at room temperature, and reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (80 mg).

LC-MS: m/z 157(M+H) ⁺

Preparation Example 17

Synthesis of Preparation Example 17 Referring to Preparation Example 1, N-methyl-N-tert-butylamine was used instead of dipropylamine hydrochloride to obtain the crude title compound (110 mg).

LC-MS: m/z 143(M+H) ⁺

Preparation Example 18

step 1:

At room temperature, compound 18-1 (300 mg) was dissolved in 1,2-dichloroethane (10 mL). Acetaldehyde (334 mg) and sodium acetate borohydride (0.967 g) were sequentially added. Reacted overnight at room temperature, quenched by slowly adding water (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 18-2 (210 mg).

LC-MS: m/z 227(M+H) ⁺

Step 2:

Compound 18-2 (210 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (140 mg).

LC-MS: m/z 127(M+H) ⁺

Preparation Example 19

Synthesis of Preparation Example 19 Referring to Preparation Example 18, acetone was used instead of acetaldehyde to obtain the crude title compound (150 mg).

LC-MS: m/z 141(M+H) ⁺ .

Preparation Example 20

step 1:

At room temperature, compound 20-1 (300 mg) was dissolved in 1,2-dichloroethane (10 mL). Acetone (302.8 mg) and sodium acetate borohydride (1.107 g) were sequentially added. The reaction was carried out overnight at room temperature, quenched by slowly adding water (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 20-2 (240 mg).

LC-MS: m/z 215(M+H) ⁺

Step 2:

At room temperature, compound 20-2 (240 mg) was dissolved in dichloromethane (10 mL). Triethylamine (339.4 mg) and trifluoroacetic anhydride (352.8 mg) were sequentially added. Reacted overnight at room temperature, quenched by slowly adding water (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 20-3 (315 mg).

LC-MS: m/z 311(M+H) ⁺

Step 3:

Compound 20-3 (310 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (230 mg).

LC-MS: m/z 211(M+H) ⁺

Preparation Example 21

step 1:

At room temperature, compound 21-1 (300 mg) was dissolved in N,N-dimethylformamide (10 mL). HATU (849.3 mg), diethylamine (170.8 mg), and N,N-diisopropylethylamine (301.9 mg) were sequentially added. React at room temperature for 3 hours, slowly add water (100 mL) to quench, and extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 21-2 (150 mg).

LC-MS: m/z 257(M+H) ⁺

Step 2:

Compound 21-2 (150 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (100 mg).

LC-MS: m/z 157(M+H) ⁺

Preparation Example 22

Synthesis of Preparation Example 22 Refer to Preparation Example 1, using tert-butyl 3-formylazetidine-1-carboxylate instead of compound 1-1 , and diethylamine instead of dipropylamine hydrochloride to obtain a crude product (190 mg) .

LC-MS: m/z 143(M+H) ⁺

Preparation Example 23

step 1:

At room temperature, compound 23-1 (300 mg) was dissolved in methanol (10 mL). Add diethylamine (383.3 mg) and sodium cyanoborodeuteride (345.8 mg) sequentially. React at room temperature for 2 hours, slowly add water (100 mL) to quench, and extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 23-2 (240 mg).

LC-MS: m/z 230(M+H) ⁺

Step 2:

Compound 23-2 (240 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (160 mg).

LC-MS: m/z 130(M+H) ⁺

Preparation Example 24

step 1:

At room temperature, compound 24-1 (300 mg) was dissolved in N,N-dimethylformamide (10 mL). Deuterated iodoethane (840.4 mg) and N,N-diisopropylethylamine (673.4 mg) were sequentially added. The reaction was kept at 100 degrees Celsius overnight, quenched by slowly adding water (100 mL), and extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 24-2 (150 mg).

LC-MS: m/z 239(M+H) ⁺

Step 2:

Compound 24-2 (150 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (90 mg).

LC-MS: m/z 139(M+H) ⁺

Preparation Example 25

Synthesis of Preparation Example 25 Referring to Preparation Example 1, N-ethyltrifluoroethylamine hydrochloride was used instead of dipropylamine hydrochloride to obtain a crude product (350 mg).

LC-MS: m/z 183(M+H) ⁺

Preparation Example 26

step 1:

At room temperature, compound 26-1 (3 g) was dissolved in 1,2-dichloroethane (50 mL). Ethylamine hydrochloride (1.43 g) and sodium acetate borohydride (11.1 g) were sequentially added. After reacting for 4 hours at room temperature, it was quenched by slowly adding water (200 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (2×100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 26-2 (1.55 g).

LC-MS: m/z 201(M+H) ⁺

Step 2:

At 0 degrees Celsius, compound 26-2 (500 mg) was dissolved in dichloromethane (30 mL). Triethylamine (0.52 mL) and trifluoroacetic anhydride (629 mg) were sequentially added. After reacting for 2 hours at 0 degrees Celsius, it was quenched by slowly adding water (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (2×80 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 26-3 (618 mg).

LC-MS: m/z 297(M+H) ⁺

Step 3:

Compound 26-3 (618 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (497 mg).

LC-MS: m/z 197(M+H) ⁺

Preparation Example 27

Synthesis of Preparation Example 27 Referring to Preparation Example 18, azetidine-3-carbamic acid tert-butyl ester hydrochloride was used instead of compound 18-1 to obtain a crude product (412 mg).

LC-MS: m/z 101(M+H) ⁺

Preparation Example 28

step 1:

At -40°C, compound 28-1 (300 mg) was dissolved in N,N-dimethylformamide (15 mL). Deuterated methyl iodide (505 mg) and N,N-diisopropylethylamine (0.91 ml) were sequentially added. After reacting at -40 degrees Celsius for 2 hours, it was quenched by slowly adding water (100 mL), and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (2×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 28-2 (45.7 mg).

LC-MS: m/z 207(M+H) ⁺

Step 2:

Compound 28-2 (45.7 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (5 mL) at room temperature, and reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude title compound (30.2 mg).

LC-MS: m/z 107(M+H) ⁺

Preparation Example 29

Synthesis of Preparation Example 29 Referring to Preparation Example 1, morpholine was used instead of dipropylamine hydrochloride to obtain a crude product (295 mg).

LC-MS: m/z 143(M+H) ⁺ .

Preparation Example 30

Synthesis of Preparation Example 30 Referring to Preparation Example 1, 4-fluoropiperidine hydrochloride was used instead of dipropylamine hydrochloride to obtain a crude product (370 mg).

LC-MS: m/z 159(M+H) ⁺ .

Preparation Example 31

Synthesis of Preparation Example 31 Referring to Preparation Example 1, 4,4-difluoropiperidine was used instead of dipropylamine hydrochloride to obtain a crude product (295 mg).

LC-MS: m/z 177(M+H) ⁺

Example 1

step 1:

Dissolve raw material 1a (3.90 g) in toluene (30 ml) at room temperature, add tert-butyl carbazate (2.80 g), cesium carbonate (11.6 g), and XPhos-Pd-G3 (3.0 g) in sequence. Under nitrogen protection, the reaction solution was reacted at 100°C for 2 hours. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-25%) to obtain product 1b as a purple solid (1.70 g).

LC-MS: m/z 273(M+H) ⁺ .

Step 2:

Dissolve the raw material 1b in a hydrochloric acid/1,4-dioxane (4 mol/L) (30 ml) solution at room temperature, and react for 15 minutes at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the purple crude product 1c (1.08 g). No purification is required and it is directly used in the next step.

LC-MS: m/z 173(M+H) ⁺ .

Step 3:

At room temperature, the raw material 1c (1.08 g) was dissolved in N,N-dimethylformamide (30 mL). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (1.4 g). After reacting at room temperature for 4 hours, a saturated aqueous sodium bicarbonate solution (100 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated aqueous sodium bicarbonate solution (100 ml) and dried to obtain crude product 1d as a black solid (2.4 g). No purification is required and it is directly used in the next step.

LC-MS: m/z 377(M+H) ⁺ .

Step 4:

At room temperature, the raw material 1d (2.4 g) was dissolved in dry isopropanol (100 ml). Add 2-cyanomethylpiperazine hydrochloride (1.5 g) and N,N-diisopropylethylamine (5.2 ml) sequentially. After reacting overnight at room temperature, water (200 mL) was slowly added to quench. Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 1e as a black solid (2.21 g). No purification is required and it is directly used in the next step.

LC-MS: m/z 466(M+H) ⁺ .

Step 5:

At room temperature, the raw material 1e (2.21 g) was dissolved in tetrahydrofuran (100 ml), and triethylamine (0.70 ml) and di-tert-butyl dicarbonate (1.04 g) were added. The reaction solution was reacted at 30°C for 4 hours. After the reaction was completed, it was quenched by adding water (200 mL). Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-25%) to obtain product 1f as a brown solid (500 mg).

LC-MS: m/z 566(M+H) ⁺ .

Step 6:

At room temperature, dissolve the raw material 1f (500mg) in methanol (20ml), add triethylamine (0.12ml), Pd(dppf)Cl ₂ (72.3mg), and then fill with carbon monoxide gas (20 atm) The reaction solution was reacted at 100°C for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-40%) to obtain 1 g of the product as a yellow solid (120 mg).

LC-MS: m/z 590(M+H) ⁺ .

Step 7:

At room temperature, 1 g (120 mg) of the raw material was dissolved in acetic acid (20 ml), and the reaction solution was reacted at 110°C for 15 minutes. After the reaction is complete, slowly add saturated sodium carbonate solution until no bubbles are generated, and extract with ethyl acetate (3×100 ml). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=60%-80%) to obtain the product for 1 h as a pale yellow solid (93 mg).

LC-MS: m/z 558(M+H) ⁺ .

Step 8:

At 0°C, the raw material was dissolved in dichloromethane (20 ml) for 1 h (93 mg), and m-chloroperoxybenzoic acid (40 mg) was added. The reaction solution was reacted at 0°C for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 1i as a pale yellow solid (112 mg).

LC-MS: m/z 574(M+H) ⁺ .

Step 9:

At room temperature, (S)-N-methylprolinol (45 mg) was dissolved in tetrahydrofuran (10 ml), and sodium hydride (16 mg) was added at 0°C. After reacting at room temperature for 30 minutes, raw material 1i (112 mg) was added. The reaction solution was reacted at room temperature for 15 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a C18 reverse column (acetonitrile/water (0.1% ammonium bicarbonate) = 45%-60%) to obtain product 1j as a pale yellow solid (67.2 mg).

LC-MS: m/z 625(M+H) ⁺ .

Step 10:

The raw material 1j (67.2 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 1k (52.4 mg).

LC-MS: m/z 525(M+H) ⁺ .

Step 11:

At room temperature, the raw material 1k (52.4 mg) was suspended in dichloromethane (20 mL), and at -40 degrees Celsius, triethylamine (0.08 mL) and acryloyl chloride (14.5 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate : 25 ml/min; gradient: 23-45%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 1 (2.4 mg).

LC-MS: m/z 579(M+H) ⁺

¹ H-NMR(CD ₃ OD)δ:8.66(s,1H), 8.10(d,J=8.4Hz,1H), 7.91(d,J=8.4Hz,1H), 7.67-7.60(m,1H) ,7.52-7.43(m,2H),7.36(d,J=8.7Hz,1H),6.94-6.74(m,1H),6.34(d,J=15.6Hz,1H),5.88(d,J=10.5 Hz, 1H), 5.05-4.96 (m, 1H), 4.77-4.40 (m, 4H), 4.21-4.00 (m, 1H), 3.98-3.64 (m, 4H), 3.27-3.15 (m, 1H), 3.08(s,3H),3.07-2.92(m,2H),2.45-2.35(m,1H),2.28(s,3H),2.20-2.01(m,4H)

Example 2

step 1:

At room temperature, the starting material 2a (2 g) was dissolved in N,N-dimethylformamide (50 mL). Add 1-naphthylhydrazine hydrochloride (1.75 g). After reacting at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution (100 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (100 mL) and dried to obtain crude product 2b as a brown solid (3.75 g). No purification is required and it is directly used in the next step.

LC-MS: m/z 363(M+H) ⁺ .

Step 2:

At room temperature, raw material 2b (3.75 g) was dissolved in dry isopropanol (100 ml). Add 2-cyanomethylpiperazine hydrochloride (4.10g) and N,N-diisopropylethylamine (8.99ml) sequentially. After reacting overnight at room temperature, water (200 mL) was slowly added to quench. Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (200 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 2c as a brown solid (7.28 g). No purification is required and it is directly used in the next step.

LC-MS: m/z 452(M+H) ⁺ .

Step 3:

At room temperature, raw material 2c (7.28 g) was dissolved in tetrahydrofuran (100 ml), and triethylamine (2.24 ml) and di-tert-butyl dicarbonate (3.7 ml) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (200 mL). Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=25%-45%) to obtain product 2d as a yellow solid (2.55 g).

LC-MS: m/z 552(M+H) ⁺ .

Step 4:

At room temperature, dissolve the raw material 2d (2.55 g) in methanol (150 ml), add triethylamine (0.66 ml), [1,1'-bis(diphenylphosphino)ferrocene] dichloride in turn Palladium (390 mg) was filled with carbon monoxide gas (20 atm), and the reaction solution was reacted at 100°C for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=25%-45%) to obtain product 2e as a yellow solid (800 mg).

LC-MS: m/z 576(M+H) ⁺ .

Step 5:

At room temperature, the raw material 2e (800 mg) was dissolved in acetic acid (30 ml), and the reaction solution was reacted at 110°C for 15 minutes. After the reaction is complete, slowly add saturated sodium carbonate solution until no bubbles are generated, and extract with ethyl acetate (3×100 ml). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=40%-60%) to obtain product 2f as a white solid (450 mg).

LC-MS: m/z 544(M+H) ⁺ .

Step 6:

At 0°C, the raw material 2f (450 mg) was dissolved in dichloromethane (20 ml), m-chloroperoxybenzoic acid (170 mg) was added, and the reaction solution was reacted at 0°C for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 2 g of crude product as a white solid (390 mg).

LC-MS: m/z 560(M+H) ⁺ .

Step 7:

Dissolve 2 g (190 mg) of the raw material in tetrahydrofuran (20 ml) at room temperature, add (S)-N-methylprolinol (80 mg), sodium tert-butoxide (65 mg), and react at room temperature. 15 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 2h (200 ml).

LC-MS: m/z 611(M+H) ⁺ .

Step 8:

The raw material was dissolved in a 1,4-dioxane (4 mol/L) (10 ml) solution of hydrochloric acid for 2 h (200 ml) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 2i (300 mg). No purification is required and it is directly used in the next step.

LC-MS: m/z 511(M+H) ⁺ .

Step 9:

At room temperature, the raw material 2i (300 mg) was suspended in dichloromethane (20 mL), and at -40 degrees Celsius, triethylamine (0.41 mL) and acryloyl chloride (65 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; Gradient: 29-41%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 2 (17.4 mg).

LC-MS: m/z 565(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.63 (s, 1H), 8.55 (s, 1H), 8.15-8.03 (m, 2H), 7.73-7.49 (m, 5H), 6.93-6.75 (m, 1H) ), 6.34 (d, J = 16.8 Hz, 1H), 5.87 (d, J = 10.2 Hz, 1H), 5.10-4.96 (m, 1H), 4.84-4.37 (m, 4H), 4.27-3.98 (m, 2H),3.95-3.70(m,2H),3.52-3.38(m,2H),3.12-2.96(m,2H),2.91-2.85(m,1H),2.83(s,3H),2.37-2.20( m.1H),2.10-1.87(m,3H)

Example 3

step 1:

The raw material 3a (10g) was dissolved in N,N-dimethylformamide (150ml) at room temperature, and benzyl bromide (13g) and potassium carbonate (17g) were added in sequence, kept at room temperature and reacted overnight. After the reaction, water (600 mL) was slowly added to quench. Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 3b as a brown solid (14.3 g).

LC-MS: m/z 255(M+H) ⁺ .

Step 2:

At room temperature, the raw material 3b (9.2 g) was dissolved in N,N-dimethylformamide (150 ml), and sodium iodide (8.22 g) was added. After reacting overnight at 140°C, it was quenched by slowly adding water (600 mL). Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 25%-40%) to obtain product 3c as a brown solid (3.7 g).

LC-MS: m/z 347(M+H) ⁺ .

Step 3:

At room temperature, dissolve the raw material 3c (3.7g) in methanol (150ml), add triethylamine (1.5ml), Pd(dppf)Cl ₂ (436.8mg), and then fill with carbon monoxide gas (5 atm) The reaction solution was reacted at 50°C for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-45%) to obtain the product 3d as a yellow solid (2.36 g).

LC-MS: m/z 279(M+H) ⁺ .

Step 4:

At room temperature, the raw material 3d (1.7 g) was dissolved in ethanol (50 ml), potassium carbonate (2.53 g) and formamidine acetate (954 mg) were added. The reaction solution was reacted at 80°C for 3 hours. After the reaction was completed, water (100 mL) was added to quench, the solid was retained after filtration, and water (100 mL) was added for washing. After drying, crude product 3e was obtained as a white solid (1.53 g).

LC-MS: m/z 255(M+H) ⁺ .

Step 5:

At room temperature, the raw material 3e (1.53 g) was dissolved in thionyl chloride (20 ml), and two drops of N,N-dimethylformamide were added dropwise. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 3f as a yellow solid (1.1 g).

LC-MS: m/z 273(M+H) ⁺ .

Step 6:

At room temperature, the raw material 3f (400 mg) was dissolved in isopropanol (30 ml), and N-tert-butoxycarbonyl-piperazine (273.5 mg), N,N-diisopropylethylamine (1.21 Ml), the reaction solution was reacted at 50°C for 2 hours. After the reaction was completed, it was quenched by slowly adding water (100 mL), and extracted with ethyl acetate (3×60 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 50%-65%) to obtain 3 g of the product as a yellow solid (396.6 mg).

LC-MS: m/z 423(M+H) ⁺ .

Step 7:

3 g (50 mg) of the raw material was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (42.4 mg) for 3 hours .

LC-MS: m/z 323(M+H) ⁺ .

Step 8:

At room temperature, the raw material was suspended in dichloromethane (10 mL) for 3 h (42.4 mg), and at -40 degrees Celsius, triethylamine (0.084 mL) and acryloyl chloride (21.6 mg) were added sequentially. The reaction solution was reacted at -40°C for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate : 25 ml/min; gradient: 17%-22%; time 2 minutes; detector wavelength 254/220 nm) to obtain product 3 (8.4 mg).

LC-MS: m/z 377(M+H) ⁺

¹ H-NMR (DMSO) δ: 8.81 (s, 1H), 8.41 (s, 1H), 7.38-7.27 (m, 5H), 6.85-6.76 (m, 1H), 6.17 (dd, J ₁ = 2Hz, J ₂ = 16.4 Hz, 1H), 5.74 (dd, J ₁ = 2.4 Hz, J ₂ = 10.4 Hz, 1H), 5.32 (s, 2H), 3.95-3.88 (m, 4H), 3.83-3.76 (m, 2H),3.75-3.69(m,2H)

Example 4

step 1:

Dissolve sodium nitrite (3.75g) in water (50ml) at room temperature and dissolve raw material 4a (7.66g) in a mixed solution of hydrochloric acid (4mol/L 100ml)/ethanol (50ml), and add dropwise to the solution A good sodium nitrite aqueous solution, stir for 45 minutes at -5°C, dissolve stannous chloride dihydrate (19.6 g) in hydrochloric acid (6 mol/L 50 ml), perform pre-cooling, and add dropwise to the reaction solution after 45 minutes The reaction solution was reacted at -5°C for 3 hours. After the reaction was completed, sodium carbonate was slowly added to adjust the pH to alkaline and quenched by adding water (500 mL). Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 4b as a brown oil (5.75 g).

LC-MS: m/z 157(M+H) ⁺ .

Step 2:

At room temperature, the raw material 4b (5.75 g) was dissolved in N,N-dimethylformamide (150 ml). After adding hydrochloric acid (12 mol/L 2 ml) dropwise, 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (8.22 g) was added. After reacting for 4 hours at room temperature, saturated aqueous sodium bicarbonate solution (200 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated aqueous sodium bicarbonate solution (200 ml) and dried to obtain crude product 4c as a brown solid (13.4 g).

LC-MS: m/z 361(M+H) ⁺ .

Step 3:

At room temperature, raw material 4c (13.4 g) was dissolved in dry isopropanol (200 ml). Add 2-cyanomethylpiperazine hydrochloride (7.3 g) and N,N-diisopropylethylamine (31 ml) sequentially. After reacting at room temperature for 16 hours, it was quenched by slowly adding water (500 mL). Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 4d as a brown solid (15.2 g).

LC-MS: m/z 450(M+H) ⁺ .

Step 4:

At room temperature, the raw material 4d (15.2 g) was dissolved in tetrahydrofuran (150 ml), and triethylamine (4.75 ml) and di-tert-butyl dicarbonate (7.38 g) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain product 4e as a yellow solid (9 g).

LC-MS: m/z 550(M+H) ⁺ .

Step 5:

At room temperature, dissolve raw material 4e (9g) in methanol (200ml), add triethylamine (2.3ml), Pd(dppf)Cl ₂ (1.34g) in sequence, and then fill with carbon monoxide gas (20 atm) The reaction solution was reacted at 100°C for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=35%-50%) to obtain the product 4f as a yellow solid (3.2 g).

LC-MS: m/z 574(M+H) ⁺ .

Step 6:

At room temperature, the raw material 4f (3.2 g) was dissolved in acetic acid (50 ml), and the reaction solution was reacted at 110°C for 15 minutes. After the reaction was completed, water (500 mL) was slowly added for quenching, the pH was adjusted to alkaline with sodium carbonate, and extraction was performed with ethyl acetate (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=60%-80%) to obtain product 4 (2 g).

LC-MS: m/z 542(M+H) ⁺ .

¹ H-NMR (CD ₃ OD)δ: 8.41 (s, 1H), 7.59-7.49 (m, 1H), 7.13-6.99 (m, 2H), 4.63-4.50 (m, 1H), 4.50-4.37 (m ,1H),4.25-4.12(m,1H),3.94-3.83(m,1H),3.80(s,3H),3.64-3.52(m,2H),3.47-3.37(m,1H),3.11-2.98 (m, 1H), 2.98-2.87 (m, 1H), 2.57 (s, 3H), 1.46 (s, 9H)

Example 5

step 1:

The raw material 5a (20 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 5b .

LC-MS: m/z 442(M+H) ⁺ .

Step 2:

At room temperature, the raw material 5b was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.025 mL) and acryloyl chloride (5 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate : 25 ml/min; gradient: 55-75%; time 10 minutes; detector wavelength 254/220 nm) to obtain product 5 (8.4 mg).

LC-MS: m/z 496(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.49 (s, 1H), 7.58-7.46 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 9.0 Hz, 1H) ,6.90-6.74(m,1H),6.32(d,J=17.1Hz,1H),5.86(d,J=11.1Hz,1H),5.12-4.56(m,2H),4.45-4.33(m,1H ),4.22-4.05(m,1H),3.99-3.86(m,1H),3.84(s,3H),3.83-3.66(m,2H),3.07-2.96(m,2H),2.65(s,3H) )

Example 6

step 1:

At 0°C, the raw material 6a (1.98 g) was dissolved in dichloromethane (50 ml), m-chloroperoxybenzoic acid (748.1 mg) was added, and the reaction solution was reacted at 0°C for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (200 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 6b as a pale yellow solid (2.61 g).

LC-MS: m/z 558(M+H) ⁺ .

Step 2:

Dissolve raw material 6b (900 mg) in tetrahydrofuran (50 ml) at room temperature, add (S)-N-methylprolinol (372 mg), sodium tert-butoxide (310 mg), and react at room temperature. 10 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a C18 reverse column (acetonitrile/water (0.1% ammonium bicarbonate) = 45%-60%) to obtain product 6c as a pale yellow solid (279.6 mg).

LC-MS: m/z 609(M+H) ⁺ .

Step 3:

The raw material 6c (279.6 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/liter) (20 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 6d (233.6 mg).

LC-MS: m/z 509(M+H) ⁺ .

Step 4:

At room temperature, the raw material 6d (233.6 mg) was suspended in dichloromethane (20 mL), and at -40 degrees Celsius, triethylamine (0.065 mL) and acryloyl chloride (62.1 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reversed phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25 ml/min; Gradient: 15-30%; time 7 minutes; detector wavelength 254/220 nm) to obtain product 6 (56 mg).

LC-MS: m/z 563(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.51 (s, 1H), 7.58-7.47 (m, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.99-6.91 (m, 1H), 6.91 6.72(m,1H), 6.34(d,J=17.1Hz,1H), 5.86(d,J=10.5Hz,1H), 5.13-4.99(m,1H), 4.69-4.50(m,3H), 4.47 -4.34(m,1H),4.22-4.06(m,1H),3.99-3.86(m,1H),3.84(s,3H),3.82-3.55(m,2H),3.26-3.15(m,1H) ,3.14-2.87(m,3H), 2.63(s,3H), 2.57-2.46(m,1H), 2.24-2.10(m,1H),1.97-1.77(m,3H)

Example 7

step 1:

Dissolve raw material 7a (10.5g) in toluene (150ml) at room temperature, add tert-butyl carbazate (7g), cesium carbonate (29g), 2-dicyclohexylphosphorus-2',4' in sequence After 6'-triisopropylbiphenyl (4.2g) and tris(dibenzylideneacetone)dipalladium (4g), the reaction solution was reacted at 100°C for 2 hours under nitrogen protection. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-25%) to obtain product 7b as a yellow solid (9.9 g).

LC-MS: m/z 291(M+H) ⁺ .

Step 2:

The raw material 7b (9.9 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (100 ml) solution at room temperature, and reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the yellow crude product 7c (7.7 g).

LC-MS: m/z 191(M+H) ⁺ .

Step 3:

At room temperature, the starting material 7c (7.7 g) was dissolved in N,N-dimethylformamide (100 ml). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (7.6 g). After reacting for 4 hours at room temperature, saturated aqueous sodium bicarbonate solution (200 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (200 mL) and dried to obtain crude product 7d as a brown solid (13.4 g).

LC-MS: m/z 395(M+H) ⁺ .

Step 4:

At room temperature, the raw material 7d (13.4 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-cyanomethylpiperazine hydrochloride (10.1 g) and N,N-diisopropylethylamine (34 ml) sequentially. After reacting overnight at room temperature, it was quenched by slowly adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 7e as a brown oil (20.9 g).

LC-MS: m/z 484(M+H) ⁺ .

Step 5:

At room temperature, the starting material 7e (20.9 g) was dissolved in tetrahydrofuran (150 ml), and triethylamine (6 ml) and di-tert-butyl dicarbonate (9.9 ml) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-30%) to obtain the product 7f as a brown solid (16.1 g).

LC-MS: m/z 584(M+H) ⁺ .

Step 6:

At room temperature, dissolve the raw material 7f (16.1g) in methanol (300ml), add triethylamine (3.88ml), Pd(dppf)Cl ₂ (2.25g), and then fill with carbon monoxide gas (20 atm). The reaction solution was reacted at 100°C for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-30%) to obtain 7 g of the product as a yellow solid (11.4 g).

LC-MS: m/z 608(M+H) ⁺ .

Step 7:

At room temperature, 7 g (6.9 g) of the raw material was dissolved in acetic acid (100 ml), and the reaction solution was reacted at 110°C for 15 minutes. After the reaction was completed, water (500 mL) was slowly added for quenching, and sodium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=35%-50%) to obtain the product 7h as a yellow solid (3.18 g).

LC-MS: m/z 576(M+H) ⁺ .

Step 8:

At 0°C, the raw material was dissolved in methylene chloride (50 ml) for 7h (3.18 g), m-chloroperoxybenzoic acid (1.12 g) was added, and the reaction solution was reacted at 0°C for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (300 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 7i as a brown solid (4.08 g).

LC-MS: m/z 592(M+H) ⁺ .

Step 9:

Dissolve the raw material 7i (4.08g) in tetrahydrofuran (100ml) at room temperature, add (S)-N-methylprolinol (1.6g) and sodium tert-butoxide (1.32g) in sequence, and react at room temperature 10 minutes. After the reaction was completed, it was quenched by adding water (300 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-15%) to obtain the product 7j as a pale yellow solid (48.4 mg).

LC-MS: m/z 643(M+H) ⁺ .

Step 10:

The raw material 7j (48.4 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 7k (40.8 mg).

LC-MS: m/z 543(M+H) ⁺ .

Step 11:

At room temperature, the raw material 7k (40.8 mg) was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.05 mL) and acryloyl chloride (10.2 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate : 25 ml/min; gradient: 40-63%; time 6 minutes; detector wavelength 254/220 nm) to obtain product 7 (3.1 mg).

LC-MS: m/z 597(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.55 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.67-7.54 (m, 2H), 6.83 (s, 1H), 6.33 (d, J = 16.8Hz, 1H), 5.86 (d, J = 10.4Hz, 1H), 5.10-5.00 (m, 1H), 4.70-4.39 (m, 4H), 4.23-4.10 (m, 1H), 4.04-3.93 (m,1H),3.88-3.77(m,1H),3.74-3.64(m,1H),3.20-3.11(m,1H),3.08-2.95(m,2H),2.93-2.83(m,1H) ,2.58(s,3H),2.51-2.40(m,1H),2.27(s,3H),2.20-2.11(m,1H),1.98-1.74(m,3H)

Example 8

step 1:

Dissolve raw material 8a (5g) in toluene (150ml) at room temperature, add tert-butyl carbazate (4.3g), cesium carbonate (17.7g), 2-dicyclohexylphosphorus-2',4' in sequence After 6'-triisopropylbiphenyl (4.2g) and tris(dibenzylideneacetone)dipalladium (4g), the reaction solution was reacted at 100°C for 2 hours under nitrogen protection. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%-15%) to obtain product 8b in the form of brown oil (5.1 g).

LC-MS: m/z 237(M+H) ⁺ .

Step 2:

The raw material 8b (5.1 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (100 ml) solution at room temperature, and reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a brown crude product 8c (3.72 g).

LC-MS: m/z 137(M+H) ⁺ .

Step 3:

At room temperature, the raw material 8c (3.72 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (4.82 g). After reacting for 4 hours at room temperature, saturated aqueous sodium bicarbonate solution (200 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated aqueous sodium bicarbonate solution (200 ml), and dried to obtain a crude product 8d as a brown solid (7.8 g).

LC-MS: m/z 341(M+H) ⁺ .

Step 4:

At room temperature, the raw material 8d (3.55 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-cyanomethylpiperazine hydrochloride (3.10 g) and N,N-diisopropylethylamine (8.6 ml) sequentially. After reacting overnight at room temperature, it was quenched by slowly adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 8e as a brown solid (7.5 g).

LC-MS: m/z 430(M+H) ⁺ .

Step 5:

At room temperature, the raw material 8e (7.5 g) was dissolved in tetrahydrofuran (150 ml), and triethylamine (2.5 ml) and di-tert-butyl dicarbonate (4.0 ml) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain the product 8f as a yellow solid (5 g).

LC-MS: m/z 530(M+H) ⁺ .

Step 6:

At room temperature, dissolve raw material 8f (5g) in methanol (150ml), add triethylamine (1.33ml), Pd(dppf)Cl ₂ (772mg), and then fill with carbon monoxide gas (20 atm) The reaction solution was reacted at 100°C for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain 8 g of the product as a yellow solid (1 g).

LC-MS: m/z 554(M+H) ⁺ .

Step 7:

At room temperature, 8 g (1 g) of the raw material was dissolved in acetic acid (100 ml), and the reaction solution was reacted at 110° C. for 15 minutes. After the reaction was completed, water (300 mL) was slowly added to quench, and sodium carbonate was added until no bubbles were generated, and it was extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-60%) to obtain the product for 8h as an off-white solid (167 mg).

LC-MS: m/z 522(M+H) ⁺ .

Step 8:

At 0°C, the raw material was dissolved in dichloromethane (20 ml) for 8h (167 mg), m-chloroperoxybenzoic acid (65 mg) was added, and the reaction solution was reacted at 0°C for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 8i as a white solid (205.7 mg).

LC-MS: m/z 538(M+H) ⁺ .

Step 9:

Dissolve raw material 8i (205.7 mg) in tetrahydrofuran (20 ml) at room temperature, add (S)-N-methylprolinol (66 mg), sodium tert-butoxide (73 mg), and react at room temperature. 10 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 8j as a white solid (31 mg).

LC-MS: m/z 589(M+H) ⁺ .

Step 10:

The raw material 8j (31 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 8k (27.6 mg).

LC-MS: m/z 489(M+H) ⁺ .

Step 11:

At room temperature, the raw material 8k (27.6 mg) was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.04 mL) and acryloyl chloride (9.5 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 25-40%; time 6 minutes; detector wavelength 254/220 nm) to obtain product 8 (3.9 mg).

LC-MS: m/z 543(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.50 (s, 1H), 7.36-7.23 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.94-6.76 (m, 1H), 6.33 ( d, J = 16.8Hz, 1H), 5.86 (d, J = 10.4Hz, 1H), 5.11-5.00 (m, 1H), 4.67-4.37 (m, 4H), 4.20-4.09 (m, 1H), 4.00 -3.90(m,1H),3.88-3.73(m,2H),3.17-3.10(m,1H),3.07-2.92(m,2H),2.87-2.78(m,1H),2.55(s,3H) ,2.46-2.34(m,4H),2.17-2.10(m,1H),2.05(s,3H),1.90-1.74(m,3H)

Example 9

step 1:

Dissolve raw material 9a (3g) in toluene (100ml) at room temperature, add tert-butyl carbazate (1.99g), cesium carbonate (8.18g), 2-dicyclohexylphosphorus-2',4' in sequence After 6'-triisopropylbiphenyl (1.2g) and tris(dibenzylideneacetone)dipalladium (1.15g), the reaction solution was reacted at 100°C for 2 hours under nitrogen protection. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%-20%) to obtain product 9b (3.63 g).

LC-MS: m/z 291(M+H) ⁺ .

Step 2:

The raw material 9b (3.63 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/liter) (100 ml) solution at room temperature, and reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 9c (2.83 g).

LC-MS: m/z 191(M+H) ⁺ .

Step 3:

At room temperature, the raw material 9c (2.83 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (2.79 g). After reacting for 4 hours at room temperature, saturated aqueous sodium bicarbonate solution (200 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (200 mL) and dried to obtain crude product 9d (5.47 g).

LC-MS: m/z 395(M+H) ⁺ .

Step 4:

At room temperature, the raw material 9d (5.47 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-cyanomethylpiperazine hydrochloride (4.11 g) and N,N-diisopropylethylamine (12.1 ml) sequentially. After reacting overnight at room temperature, it was quenched by slowly adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 9e (7.02 g).

LC-MS: m/z 484(M+H) ⁺ .

Step 5:

At room temperature, the raw material 9e (7.02 g) was dissolved in tetrahydrofuran (150 ml), and triethylamine (2.22 ml) and di-tert-butyl dicarbonate (3.41 ml) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-30%) to obtain product 9f (4.2 g).

LC-MS: m/z 584(M+H) ⁺ .

Step 6:

At room temperature, dissolve the raw material 9f (4.2g) in methanol (150ml), add triethylamine (1.00ml), Pd(dppf)Cl ₂ (587mg), and then fill with carbon monoxide gas (20 atm) , The reaction solution was reacted at 100 degrees Celsius for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain 9 g (2.13 g) of the product.

LC-MS: m/z 608(M+H) ⁺ .

Step 7:

At room temperature, 9 g (2.13 g) of the raw material was dissolved in acetic acid (100 ml), and the reaction solution was reacted at 110 degrees Celsius for 15 minutes. After the reaction was completed, water (300 mL) was slowly added to quench, and sodium carbonate was added until no bubbles were generated, and it was extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-60%) to obtain the product 9h (1.05 g).

LC-MS: m/z 576(M+H) ⁺ .

Step 8:

At 0 degrees Celsius, the material 9h (1.05 g) was dissolved in dichloromethane (20 ml), m-chloroperbenzoic acid (85%) (370 mg), the reaction liquid under the reaction conditions of 0 ° C for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 9i (1.45 g).

LC-MS: m/z 592(M+H) ⁺ .

Step 9:

Dissolve raw material 9i (500 mg) in tetrahydrofuran (20 ml) at room temperature, add (S)-N-methylprolinol (194 mg), sodium tert-butoxide (162 mg), and react at room temperature 10 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 9j (50.7 mg).

LC-MS: m/z 643(M+H) ⁺ .

Step 10:

The raw material 9j (50.7 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 9k (46 mg).

LC-MS: m/z 543(M+H) ⁺ .

Step 11:

At room temperature, the raw material 9k (46 mg) was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.06 mL) and acryloyl chloride (14.4 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 25-45%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 9 (6.7 mg).

LC-MS: m/z 597(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.51 (s, 1H), 7.72-7.64 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H) ,6.93-6.76(m,1H),6.32(d,J=20Hz,1H), 5.86(d,J=8Hz,1H), 5.12-4.99(m,1H), 4.69-4.61(m,2H), 4.59-4.54 (m, 1H), 4.47-4.33 (m, 1H), 4.21-4.09 (m, 1H), 4.01-3.89 (m, 1H), 3.88-3.64 (m, 2H), 3.30-3.23 (m ,1H), 3.15-2.96(m,3H), 2.67(s,3H), 2.61(s,3H), 2.25-2.13(m,1H), 1.94-1.78(m,3H).

Example 10

step 1:

The raw material 10a (2 g) was dissolved in acetonitrile (50 ml) at room temperature, and triethylamine (1.34 ml) and benzyl bromide (1.51 g) were sequentially added, and the reaction solution was reacted at room temperature overnight. After the reaction, the reaction solution was spin-dried under reduced pressure, then water (250 mL) was slowly added for quenching, and the mixture was extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). After the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%-20%) to obtain product 10b (2.7 g).

LC-MS: m/z 340(M+H) ⁺ .

Step 2:

The raw material 10b (2.7 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (100 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 10c (2.2 g).

LC-MS: m/z 240(M+H) ⁺ .

Step 3:

At room temperature, the raw material 10c (2.2 g) was dissolved in methanol (80 ml). Sodium cyanoborohydride (1.0 g) and formaldehyde solution (37%) (970 mg) were sequentially added. After reacting at room temperature for 2 hours, it was quenched by slowly adding water (250 mL), and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). After the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-60%) to obtain product 10d (1.24 g).

LC-MS: m/z 254(M+H) ⁺ .

Step 4:

At room temperature, the raw material 10d (1.24 g) was dissolved in methanol (50 ml). After adding palladium on carbon (10%) (124 mg), the reaction was carried out at room temperature for 2 hours in a hydrogen environment. After the reaction was completed, filtration was performed, and the filtrate was spin-dried and dried to obtain crude product 10e (855 mg).

LC-MS: m/z 164(M+H) ⁺ .

Step 5:

Intermediate 9i (500 mg) was dissolved in tetrahydrofuran (20 mL) at room temperature, and raw material 10e (277 mg) and sodium tert-butoxide (162 mg) were added in sequence, and reacted at room temperature for 10 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 10f (75 mg).

LC-MS: m/z 691(M+H) ⁺ .

Step 6:

The raw material 10f (75 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 10 g (69 mg) of crude product.

LC-MS: m/z 591(M+H) ⁺ .

Step 7:

At room temperature, 10 g (69 mg) of the raw material was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.08 mL) and acryloyl chloride (19.9 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 30-55%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 10 (5.5 mg).

LC-MS: m/z 645(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.46 (s, 1H), 7.72-7.65 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.38-7.28 (m, 2H), 7.14 7.04(m,2H),6.84-6.71(m,1H), 6.28(d,J=16.8Hz,1H), 5.83(d,J=8Hz,1H), 5.27-4.69(m,1H),4.66- 4.57 (m, 1H), 4.32-4.21 (m, 1H), 4.19-4.02 (m, 2H), 3.83-3.58 (m, 5H), 2.89-2.69 (m, 5H), 2.61 (s, 3H), 2.51(s,3H).

Example 11

step 1:

Intermediate 9i (450 mg) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and 3-diethylaminoazetidine (198 mg), N,N-bis Isopropylethylamine (0.63 ml) was reacted overnight at room temperature. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 11a (271 mg).

LC-MS: m/z 656(M+H) ⁺ .

Step 2:

The raw material 11a (271 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/liter) (20 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 11b (243 mg).

LC-MS: m/z 556(M+H) ⁺ .

Step 3:

At room temperature, the raw material 11b (244.3 mg) was suspended in dichloromethane (20 mL), and at 0 degrees Celsius, triethylamine (0.29 mL) and acryloyl chloride (73.8 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 47-53%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 11 (47 mg).

LC-MS: m/z 610(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.32 (s, 1H), 7.70-7.64 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H) ,6.87-6.76(m,1H),6.32(d,J=16.8Hz,1H), 5.85(d,J=9.6Hz,1H),5.11-4.67(m,1H),4.59-4.53(m,1H ), 4.47-4.38 (m, 2H), 4.33-4.27 (m, 1H), 4.26-4.08 (m, 3H), 3.99-3.90 (m, 1H), 3.77-3.52 (m, 3H), 3.05-2.92 (m,2H),2.91-2.79(m,4H),2.64-2.57(m,3H),1.17(t,J=8.0Hz,6H).

Example 12 and Example 13

The compound racemate 11 was subjected to chiral resolution (column type: Chiralpak IC, 2*25cm, 5um; mobile phase A: methyl tert-butyl ether (10 mmol/L ammonia in methanol), mobile phase B: Methanol, flow rate: 20 ml/min; gradient: 30%; time: 16 minutes) to obtain monomers 12 and 13 .

Analysis conditions of monomer 12 (peak 1) :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol; gradient: 70:30; flow rate: 1 ml/min; retention time: 1.886 minutes

¹ H-NMR (CD ₃ OD) δ: 8.32 (s, 1H), 7.70-7.64 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H) ,6.90-6.74(m,1H),6.31(d,J=16.8Hz,1H),5.85(d,J=9.6Hz,1H),5.11-4.67(m,1H),4.59-4.51(m,1H ), 4.47-4.36(m,2H),4.34-4.07(m,4H),3.96-3.88(m,1H),3.77-3.49(m,3H),3.06-2.93(m,2H),2.89-2.77 (m,4H),2.63-2.56(m,3H),1.16(t,J=8.0Hz,6H)

Analysis conditions of monomer 13 (peak 2) :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol; gradient: 70:30; flow rate: 1 ml/min; retention time: 2.945 minutes

¹ H-NMR(CD ₃ OD)δ: 8.33(s,1H),7.71-7.64(m,1H),7.57(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H) ,6.92-6.73(m,1H),6.32(d,J=16.8Hz,1H),5.85(d,J=9.6Hz,1H),5.11-4.63(m,1H),4.61-4.50(m,1H ), 4.49-4.37 (m, 2H), 4.35-4.06 (m, 4H), 4.04-3.90 (m, 1H), 3.79-3.51 (m, 3H), 3.06-2.94 (m, 2H), 2.93-2.79 (m,4H),2.65-2.56(m,3H),1.18(t,J=8.0Hz,6H)

Example 14

step 1:

Dissolve 14a (3.0g) in toluene (100ml) at room temperature, add tert-butyl carbazate (2.5g), cesium carbonate (10.4g), 2-dicyclohexylphosphorus-2',4' in sequence After 6'-triisopropylbiphenyl (1.5g), tris(dibenzylideneacetone)dipalladium (1.5g), the reaction solution was reacted at 100°C for 2 hours under the protection of nitrogen. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%-15%) to obtain product 14b (2.5 g). LC-MS: m/z 241(M+H) ⁺ .

Step 2:

The raw material 14b (2.5 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (50 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 14c (1.8 g). LC-MS: m/z 141(M+H) ⁺ .

Step 3:

At room temperature, the starting material 14c (1.8 g) was dissolved in N,N-dimethylformamide (100 ml). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (2.66 g). After reacting at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution (100 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (100 ml) and dried to obtain crude product 14d (4.7 g). LC-MS: m/z 345(M+H) ⁺ .

Step 4:

At room temperature, the starting material 14d (4.7 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-cyanomethylpiperazine hydrochloride (3.48g) and N,N-diisopropylethylamine (11.2ml) successively. After reacting overnight at room temperature, water (300 mL) was slowly added to quench. Extract with ethyl acetate (3×250 mL). The organic phases after extraction were combined and washed twice with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 14e (8.6 g). LC-MS: m/z 434(M+H) ⁺ .

Step 5:

At room temperature, the starting material 14e (8.6 g) was dissolved in tetrahydrofuran (150 ml), and triethylamine (4.1 ml) and di-tert-butyl dicarbonate (5.9 ml) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (500 mL). It was extracted with ethyl acetate (3×250 mL), and the extracted organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain the product 14f (3.9 g).

LC-MS: m/z 534(M+H) ⁺ .

Step 6:

At room temperature, the raw material 14f (1.9g) was dissolved in methanol (150ml), and then triethylamine (0.52ml), Pd(dppf)Cl ₂ (294mg) were added in sequence, and carbon monoxide gas (20 atm) was added. , The reaction solution was reacted at 100 degrees Celsius for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain 14 g (376 mg) of the product.

LC-MS: m/z 558(M+H) ⁺ .

Step 7:

At room temperature, 14 g (376 mg) of raw materials were dissolved in acetic acid (100 ml), and the reaction solution was reacted at 60 degrees Celsius for 30 minutes. After the reaction was completed, water (300 mL) was slowly added to quench, and sodium carbonate was added until no bubbles were generated, and it was extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-60%) to obtain the product 14h (197 mg). LC-MS: m/z 526(M+H) ⁺ .

Step 8:

At 0 degrees Celsius, the material 14h (197 mg) was dissolved in dichloromethane (20 ml), m-chloroperbenzoic acid (76 mg), the reaction solution was reacted for 1 hour at 0 degrees Celsius. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 14i (281 mg). LC-MS: m/z 542(M+H) ⁺ .

Step 9:

Dissolve 14i (281.0 mg) in tetrahydrofuran (20 ml) at room temperature, add (S)-N-methylprolinol (89 mg), sodium tert-butoxide (100 mg), and react at room temperature. 30 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain the product 14j (35 mg).

LC-MS: m/z 593(M+H) ⁺ .

Step 10:

The raw material 14j (35 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 14k (30 mg). LC-MS: m/z 493(M+H) ⁺ .

Step 11:

At room temperature, the raw material 14k (30 mg) was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.04 mL) and acryloyl chloride (7.7 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 25-40%; time 6 minutes; detector wavelength 254/220 nm) to obtain product 14 (7.5 mg). LC-MS: m/z 547(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.51 (s, 1H), 7.45-7.32 (m, 1H), 7.30-7.17 (m, 2H), 6.98-6.74 (m, 1H), 6.33 (d, J = 16.8Hz, 1H), 5.86 (d, J = 9.9Hz, 1H), 5.12-4.99 (m, 1H), 4.66-4.40 (m, 4H), 4.28-4.03 (m, 1H), 3.98-3.65 ( m, 3H), 3.20-2.85 (m, 4H), 2.58 (s, 3H), 2.52-2.39 (m, 1H), 2.23-2.11 (m, 1H), 2.08 (m, 3H), 1.93-1.75 ( m,3H).

Example 15

step 1:

At room temperature, the raw material 15a (70.0 g) was dissolved in toluene (2000 ml), and t-butyl carbazate (46.0 g), cesium carbonate (189 g), 4,5-bis(diphenylphosphine)- After 9,9-dimethylxanthene (34g), tris(dibenzylideneacetone)dipalladium (26.5g), the reaction solution was reacted at 70°C for 3 hours under the protection of nitrogen. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=3%-15%) to obtain product 15b (83.0 g). LC-MS: m/z 293(M+H) ⁺ .

Step 2:

The raw material 15b (83.0 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (500 ml) solution at room temperature, and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 15c (60.0 g). LC-MS: m/z 193(M+H) ⁺ .

Step 3:

At room temperature, the starting material 15c (60.0 g) was dissolved in N,N-dimethylformamide (500 ml). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (49.7 g). After reacting at room temperature for 3 hours, a saturated aqueous sodium bicarbonate solution (400 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (400 ml) and dried to obtain crude product 15d (87.0 g). LC-MS: m/z 397(M+H) ⁺ .

Step 4:

At room temperature, the raw material 15d (87.0 g) was dissolved in N,N-dimethylformamide (800 ml). Add 2-cyanomethylpiperazine hydrochloride (29.1 g) and N,N-diisopropylethylamine (216 ml) sequentially. Reacted at room temperature for 3 hours, and quenched by slowly adding water (2000 mL). Extract with ethyl acetate (3 x 1500 mL). The organic phases were combined and washed with saturated brine (500 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 15e (82.0 g). LC-MS: m/z 486(M+H) ⁺ .

Step 5:

At room temperature, dissolve raw material 15e (82.0g) in N,N-dimethylformamide (800ml), add N,N-diisopropylethylamine (65.4g) and di-tert-butyl dicarbonate (108 ml). React at 35 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (1000 mL). Extract with ethyl acetate (3×800 mL). The organic phases were combined and washed with saturated brine (500 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 15f (89.0 g). LC-MS: m/z 586(M+H) ⁺ .

Step 6:

At room temperature, the raw material 15f (89.0g) was dissolved in N,N-dimethylformamide (800ml), and N,N-diisopropylethylamine (139ml), 4-dimethylaminopyridine was added (0.93 g) and di-tert-butyl dicarbonate (108 ml). React at 35 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (1000 mL). Extract with ethyl acetate (3×800 mL). The organic phases were combined and washed with saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain 15 g (80.0 g) of the product. LC-MS: m/z 686(M+H) ⁺ .

Step 7:

At room temperature, dissolve 15g (80.0g) of raw material in methanol (3000ml), add triethylamine (16.2ml), [1,1'-bis(diphenylphosphino)ferrocene]dichloride in turn Palladium (8.52 g) was filled with carbon monoxide gas (20 atmospheres), and the reaction solution was reacted at 80 degrees Celsius for 6 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain the product 15h (30.0 g). LC-MS: m/z 710(M+H) ⁺ .

Step 8:

At room temperature the starting material 15h (30 g) was dissolved in hydrochloric acid / 1,4-dioxane (4 mol / l) (150 mL), reacted for 1 hour at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 15i (21 g). LC-MS: m/z 510(M+H) ⁺ .

Step 9:

At room temperature, the raw material 15i (21.0 g) was dissolved in acetic acid (600 ml), and the reaction solution was reacted at 100 degrees Celsius for 1 hour. After the reaction was completed, water (2500 mL) was slowly added for quenching, and sodium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (3×2000 mL). The organic phases were combined and washed with saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 15j (18.0 g). LC-MS: m/z 478(M+H) ⁺ .

Step 10:

At room temperature, dissolve raw material 15j (18.0g) in N,N-dimethylformamide (200ml), add N,N-diisopropylethylamine (24.2g), di-tert-butyl dicarbonate (24.2 mL). React at 35 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×500 mL). The organic phases were combined and washed with saturated brine (500 mL). After the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-70%) to obtain the product 15k (8.5 g). LC-MS: m/z 578(M+H) ⁺ .

Step 11:

At 0 degrees Celsius, the raw material 15k (8.5 g) was dissolved in dichloromethane (100 ml), m-chloroperoxybenzoic acid (85%) (8.8 g) was added, and the reaction solution was reacted at 0 degrees Celsius for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 15 l (12.5 g) of crude product. LC-MS: m/z 610(M+H) ⁺ .

Step 12:

At room temperature, 15l (12.5g) of the raw material was dissolved in N,N-dimethylformamide (120ml), and 3-diethylaminoazetidine dihydrochloride (9.85g) was added successively, N, N-Diisopropylethylamine (20.3ml) was reacted for 2 hours at room temperature. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×500 mL). The organic phases were combined and washed with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=3%-10%) to obtain the product 15m (13.0 g). LC-MS: m/z 658(M+H) ⁺ .

Step 13:

The raw material 15m (13.0 g) was dissolved in hydrochloric acid/1,4-dioxane (4 mol/L) (150 ml) solution at room temperature, and reacted at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 15n (7.50 g). LC-MS: m/z 558(M+H) ⁺ .

Step 13:

At room temperature, the raw material 15n (7.5 g) was suspended in dichloromethane (200 ml), and at -40 degrees Celsius, triethylamine (8.8 ml) and acryloyl chloride (1.37 g) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 40 minutes. After the reaction was completed, it was quenched by adding water (200 mL). Extract with dichloromethane (3×200 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 80 ml/min; gradient: 40-80%; time 25 minutes; detector wavelength 254/220 nm) to obtain product 15 (4.9 g).

LC-MS: m/z 612(M+H) ⁺ .

¹ H-NMR(CD ₃ OD)δ: 8.35(s,1H), 8.14(d,J=8.4Hz,1H),8.00(d,J=8.4Hz,1H),7.72-7.67(m,1H) ,7.60(d,J=7.4Hz,2H),7.50(t,J=7.8Hz,1H),6.72-6.88(m,1H),6.29(d,J=16.6Hz,1H),5.83(d, J = 10.8Hz, 1H), 4.96-5.12 (m, 1H), 4.57-4.48 (m, 1H), 4.42-4.26 (m, 3H), 4.22-4.05 (m, 3H), 3.79-3.90 (m, 1H), 3.78-3.54 (m, 3H), 3.04-2.90 (m, 2H), 2.77 (d, J = 6.8 Hz, 4H), 1.12 (t, J = 7.2 Hz, 6H).

Example 16 and Example 17

The racemate compound 15 is split into monomers 16 and 17 by chiral high pressure preparation. Column type: CHIRALPAK IA: 2*25cm, 5um; mobile phase: methyl tert-butyl ether (0.1% diethylamine), mobile phase: methanol; flow rate: 20 ml/min; gradient: 40%, time 40 minutes; The detector wavelength is 254/220 nm). The first and fourth peaks are compound 16 , and the second and third peaks are compound 17 .

Compound 16 :

LC-MS: m/z 612(M+H) ⁺ .

¹ H-NMR(CD ₃ OD)δ: 8.32(s,1H), 8.15(d,J=7.8Hz,1H), 8.02(d,J=8.1Hz,1H), 7.71(t,J=7.8Hz ,1H),7.63-7.57(m,2H),7.51(t,J=7.8Hz,1H),6.95-6.68(m,1H),6.30(d,J=16.5Hz,1H),5.83(d, J = 10.5Hz, 1H), 5.09-4.96 (m, 1H), 4.51-4.42 (m, 1H), 4.40-4.21 (m, 3H), 4.19-3.98 (m, 3H), 3.78-3.45 (m, 4H), 3.03-2.90 (m, 2H), 2.65 (q, J = 7.2Hz, 4H), 1.08 (t, J = 7.2Hz, 6H).

Compound 17 :

LC-MS: m/z 612(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.31 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.72-7.65 (m, 1H) ,7.61-7.55(m,2H),7.52-7.45(m,1H),6.90-6.69(m,1H),6.28(d,J=18.0Hz,1H),5.87-5.75(m,1H),5.10 -4.95(m,1H),4.52-4.41(m,1H),4.38-4.20(m,3H),4.17-3.97(m,3H),3.76-3.49(m,4H),3.02-2.87(m, 2H), 2.68-2.58(q,J=7.2Hz,4H),1.06(t,J=7.2Hz,6H).

Example 18

step 1:

Dissolve raw material 18a (50.0g) in toluene (500ml) at room temperature, add tert-butyl carbazate (7.14g), cesium carbonate (126.4g), 2-dicyclohexylphosphorus-2',4' in sequence After 6'-triisopropylbiphenyl (18.4g) and tris(dibenzylideneacetone)dipalladium (17.7g), the reaction solution was reacted at 70°C for 2 hours under the protection of nitrogen. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (500 mL×3). The organic phases were combined and washed with saturated brine (200 mL). After the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%-15%) to obtain product 18b (36.2 g). LC-MS: m/z 311(M+H) ⁺ .

Step 2:

Raw material 18b (36.2 g) was dissolved in a 1,4-dioxane solution (4 mol/liter, 300 ml) of hydrogen chloride. React at room temperature for 30 minutes. After the reaction is complete, concentrate under reduced pressure to obtain crude product 18c . No purification is required and it is directly used in the next step. LC-MS: m/z 211(M+H) ⁺ .

Step 3:

Raw material 18c (28.5 g) was dissolved in N,N-dimethylformamide (200 mL), and 4,6-dichloro-2-methylthiopyrimidine-5-carbaldehyde (25.6 g) was added. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was quenched by adding water (500 mL). The precipitated solid was filtered and washed with saturated sodium bicarbonate solution to obtain crude product 18d (45.5 g). No purification is required and it is directly used in the next step. LC-MS: m/z 415(M+H) ⁺

Step 4:

Dissolve raw material 18d (45.5g) in N,N-dimethylformamide (200ml), then add N,N-diisopropylethylamine (71.0g), 2-cyanomethylpiperazine dihydrochloride Salt (26.1 g). The resulting mixture was reacted at room temperature for 16 hours. After the reaction was completed, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (500 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain crude product 18e (45.1 g). No purification is required and it is directly used in the next step. LC-MS: m/z 504(M+H) ⁺

Step 5:

Raw material 18e (45.1 g) was dissolved in N,N-dimethylformamide (500 ml), and di-tert-butyl dicarbonate (29.3 g) and triethylamine (27.18 g) were added in sequence. The resulting solution was reacted at room temperature for 2 hours. After the reaction was completed, it was diluted with water (500 mL), and extracted with ethyl acetate (500 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-30%) to obtain product 18f (41.5 g). LC-MS: m/z 604(M+H) ⁺

Step 6:

At room temperature, dissolve raw material 18f (41.5g) and triethylamine (6.95g) in methanol (500ml), add [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium (5.0341 g). The reaction solution was placed in a CO atmosphere (10 atmospheres) and reacted at 100 degrees Celsius for 2 hours. After the reaction is complete, it is concentrated to dryness and diluted with water (500 ml). Extract with ethyl acetate (500 mL×3). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-40%) to obtain 18 g (13.7 g) of the product. LC-MS: m/z 628(M+H) ⁺

Step 7:

At room temperature, 18 g (13.7 g) of the raw material was dissolved in acetic acid (300 ml). The reaction solution was placed at 110 degrees Celsius to react for 40 minutes. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (500 mL×3). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50%-70%) to obtain the product 18h (6.95 g). LC-MS: m/z 596(M+H) ⁺

Step 8:

At room temperature, the raw material was dissolved in dichloromethane (200 ml) for 18 h (6.95 g), m-chloroperoxybenzoic acid (6.03 g) was added, and the reaction was carried out for 1 hour. After the reaction was completed, it was quenched by adding a saturated aqueous solution of sodium thiosulfate (500 mL), and then extracted with ethyl acetate (500 mL×3). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 18i (6.10 g). No purification is required and it is directly used in the next step. LC-MS: m/z 628(M+H) ⁺

Step 9:

At room temperature, dissolve raw material 18i (6.27g) in N,N-dimethylformamide (100ml), add N,N-diisopropylethylamine (3.75g) and 3-diethylamino nitrogen Etidine hydrochloride (2.92 g), react for 1 hour. After the reaction was completed, it was quenched by adding water (100 mL), and then extracted with ethyl acetate (200 mL×3). The organic phases were combined and washed with saturated brine (50 mL). After the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude product 18j (6.55 g). LC-MS: m/z 676(M+H) ⁺

Step 10:

At room temperature, the raw material 18j (6.55 g) was dissolved in a 1,4-dioxane solution (4 mol/L, 50 ml) of hydrogen chloride and reacted for 30 minutes. After the reaction, the crude product 18k (5.79 g) was obtained by concentration under reduced pressure. No purification is required and it is directly used in the next step. LC-MS: m/z 576(M+H) ⁺

Step 11:

The raw material 18k (5.52 g) was dissolved in dichloromethane (50 ml), and after cooling to -40 degrees Celsius, triethylamine (2.79 g) and acryloyl chloride (1.24 g) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 20 minutes. After the reaction is complete, add water (50 mL) to quench and concentrate to dryness. The crude product obtained was purified by preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 25 ml/min ; Gradient: 30-40%; detector wavelength 254/220 nm), product 18 (3.21 g) is obtained. LC-MS: m/z 630(M+H) ⁺

¹ H NMR (300MHz, CD ₃ OD) δ 8.30 (s, 1H), 7.78-7.73 (m, 2H), 7.48 (d, J = 6.6 Hz, 1H), 6.69-6.66 (m, 1H), 6.29 (d,J=15.6Hz,1H),5.83(d,J=9.6Hz,1H),5.04-5.00(m,1H),4.58-4.49(m,2H),4.35-4.23(m,3H), 4.18-4.05(m,2H),3.78-3.45(m,4H),3.05-2.92(m,2H),2.67(q,J=7.2Hz,4H),1.08(t,J=7.2Hz,6H) .

Example 19 and Example 20

The racemate compound 18 was prepared and resolved by chiral high pressure (column type: CHIRALPAK AD-H, 2.0cm ID*25cm L; mobile phase A: carbon dioxide; mobile phase B: isopropanol (2 mmol/L ammonia-methanol solution) ); Flow rate: 40 ml/min; Gradient: 45%, time 20 minutes; Detector wavelength 254/220 nm). Compounds 19 and 20 were obtained .

Compound 19 :

LC-MS: m/z 630(M+H) ⁺

¹ H NMR(300MHz,CD ₃ OD)δ8.27(s,1H),7.79-7.72(m,2H),7.47(d,J=5.7Hz,1H),6.82-6.75(m,1H),6.27 (d, J = 12.6Hz, 1H), 5.81 (d, J = 7.2 Hz, 1H), 5.10-5.00 (m, 1H), 4.48 (t, J = 9.3 Hz, 1H), 4.45-4.33 (m, 2H), 4.24(d,J=8.1Hz,1H),4.23-4.10(m,3H),3.82-3.33(m,4H),3.05-2.92(m,2H),2.69(q,J=5.4Hz ,4H),1.08(t,J=5.4Hz,6H).

Retention time: 1.976min

Compound 20 :

LC-MS: m/z 630(M+H) ⁺

¹ H NMR (300MHz, CD ₃ OD) δ 8.20 (s, 1H), 7.78-7.62 (m, 2H), 7.48 (d, J = 5.4 Hz, 1H), 6.92-6.75 (m, 1H), 6.28 (d,J=12.6Hz,1H),5.82(d,J=7.8Hz,1H),5.05-5.01(m,1H),4.55-4.40(m,3H),4.32-4.21(m,3H), 4.10-4.05(m,2H), 3.78-3.45(m,3H), 3.10-2.88(m,6H), 1.18(t,J=5.4Hz,6H).

Retention time 3.163min

Example 21

step 1:

At room temperature, the raw material 21a (5.00 g) was dissolved in N,N-dimethylformamide (80 ml). Add N,N-diisopropylethylamine (15.0 g) and iodoisopropane (14.8 g) sequentially. The reaction was carried out at a temperature of 100° C. for 16 hours, quenched by slowly adding water (100 mL), and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%). Obtained product 21b (700 mg). LC-MS: m/z 257(M+H) ⁺

Step 2:

The raw material 21b (100 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 21c (55.0 mg). LC-MS: m/z 157(M+H) ⁺

Step 3:

At 0 degrees Celsius, the (100 ml), m-chloroperbenzoic acid (85%) (5.3 g) for 2 hours at room temperature, the reaction solution feed member 9h (5.0 g) was dissolved in methylene chloride. After the reaction, it was quenched by adding saturated sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 9i' (4.8 g). LC-MS: m/z 608(M+H) ⁺ .

Step 4:

Intermediate 9i' (50.0 mg) was dissolved in N,N-dimethylformamide (3 mL) at room temperature, and 21c (31.7 mg), N,N-diisopropylethylamine (53.1 Mg), react overnight at room temperature. After the reaction was completed, it was quenched by adding water (30 mL). Extract with ethyl acetate (3×30 mL). The organic phases were combined and washed with saturated brine (30 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 21d (45.0 mg). LC-MS: m/z 684(M+H) ⁺ .

Step 5:

The raw material 21d (45.0 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 mL) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 21e (38 mg). LC-MS: m/z 584(M+H) ⁺

Step 6:

At room temperature, the raw material 21e (35 mg) was suspended in dichloromethane (5 mL), and at -40 degrees Celsius, triethylamine (28.5 mg) and acryloyl chloride (8.09 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (30 mL). Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 35-80%; time 10 minutes; detector wavelength 254/220 nm) to obtain product 21 (7.8 mg). LC-MS: m/z 638(M+H) ⁺ .

¹ H-NMR(CD ₃ OD)δ: 8.36(s,1H), 7.74(t,J=7.8Hz,1H), 7.63(d,J=7.8Hz,1H), 7.39(d,J=7.8Hz ,1H), 7.09-6.74(m,1H), 6.38(d,J=16.8Hz,1H), 5.92(d,J=10.8Hz,1H), 5.28-5.00(m,1H),4.64-4.52( m,1H),4.50-4.10(m,7H),3.89-3.49(m,3H),3.34-3.21(m,2H),3.18-2.99(m,2H),2.68(s,3H),1.18( d, J=6.6Hz, 12H).

Example 22

step 1:

At room temperature, the raw material 22a (11.0 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-cyanomethylpiperazine hydrochloride (10.7 g) and N,N-diisopropylethylamine (42.9 ml) sequentially. After reacting overnight at room temperature, it was quenched by slowly adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 22b (15.1 g). LC-MS: m/z 312(M+H) ⁺ .

Step 2:

At room temperature, the raw material 22b (15.1 g) was dissolved in tetrahydrofuran (150 ml), and triethylamine (8.44 ml) and di-tert-butyl dicarbonate (10.5 ml) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=35%-50%) to obtain product 22c (15.7 g).

LC-MS: m/z 412(M+H) ⁺ .

Step 3:

At room temperature, dissolve raw material 22c (15.7g) in methanol (150ml), add triethylamine (5.3ml), Pd(dppf)Cl ₂ (3.11g) in sequence, and fill with carbon monoxide gas (5 atm) , The reaction solution was reacted at 80 degrees Celsius for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=35%-50%) to obtain the product 22d (12.5 g).

LC-MS: m/z 436(M+H) ⁺ .

Step 4:

At 0 degrees Celsius, the raw material 22d (12.5 g) was dissolved in dichloromethane (20 ml), and m-chloroperoxybenzoic acid (85%) (5.81 g) was added. The reaction solution was reacted at 0 degrees Celsius for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (500 mL), and extracted with dichloromethane (3×250 mL). The organic phases were combined and washed with saturated brine (200 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 22e (12.8 g). LC-MS: m/z 452(M+H) ⁺ .

Step 5:

Dissolve raw material 22e (12.8g) in N,N-dimethylformamide (50ml) at room temperature, add 3-diethylaminoazetidine (7.61g), N,N-diiso Propylethylamine (25.3 ml) was reacted overnight at room temperature. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (3×250 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=0%-10%) to obtain the product 22f (6.3 g). LC-MS: m/z 516(M+H) ⁺ .

Step 6:

Dissolve 22f (6.3 g) in ethanol at room temperature, add hydrazine hydrate (0.89 ml), and react overnight at 80 degrees Celsius. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified with a reverse phase chromatography column (acetonitrile/water (10 mmol/L, ammonium bicarbonate) = 35%-50%) to obtain 22 g (3.8 g) ). LC-MS: m/z 498(M+H) ⁺ .

Step 7:

Dissolve 22 g (50 mg) of the raw material in N,N-dimethylformamide (5 ml) at room temperature, add 2,3-dichlorophenylboronic acid (28.7 mg), copper acetate (18.2 mg), and pyridine in sequence (11.9 mg), the reaction was stirred for 24 hours. It was quenched by adding water (20 mL). Extract with ethyl acetate (3×20 mL). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=5%-10%) to obtain the product 22h (10 mg). LC-MS: m/z 642(M+H) ⁺ .

Step 8:

The raw material was dissolved in hydrochloric acid/1,4-dioxane (4 mol/L) (5 mL) solution for 22 h (10 mg) at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 22i (7.5 mg). LC-MS: m/z 542(M+H) ⁺ .

Step 9:

At room temperature, the raw material 22i (7.5 mg) was suspended in dichloromethane (5 ml), and at -40 degrees Celsius, triethylamine (6.53 mg) and acryloyl chloride (2.34 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×10 mL). The organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column to obtain product 22 (3.2 mg).

LC-MS: m/z 596(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.33 (s, 1H), 7.72 (t, J = 6.0 Hz, 1H), 7.51-7.50 (m, 2H), 6.84 (s, 1H), 6.32 (d, J = 16.8Hz, 1H), 5.85 (d, J = 9.9Hz, 1H), 5.15-4.99 (m, 1H), 4.58-4.50 (m, 1H), 4.39-4.28 (m, 3H), 4.17-4.09 (m,2H),3.79-3.62(m,5H),3.08-2.96(m,2H),2.67(q,J ₁ =7.2Hz,J ₂ =7.5Hz,4H),1.09(t,J=7.2 Hz, 6H).

Example 23

step 1:

Dissolve 22 g (30.0 mg) of the intermediate in N,N-dimethylformamide (3 mL) at room temperature, add 3,5-dichlorophenylboronic acid (11.5 mg), pyridine (6.36 mg), and oxidize in sequence. Cuprous (5.75 mg), reacted overnight at 90 degrees Celsius. After the reaction was completed, it was quenched by adding water (30 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (2×30 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 23a (27.0 mg). LC-MS: m/z 642(M+H) ⁺

Step 2:

The raw material 23a (27 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 23b (25.0 mg). LC-MS: m/z 542(M+H) ⁺

Step 3:

At room temperature, raw material 23b (25.0 mg) was suspended in dichloromethane (5 mL), and at -40 degrees Celsius, triethylamine (0.03 mL, 0.216 mmol), acryloyl chloride (3.91 mg, 0.043 mmol) were added in sequence. Mole). The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (30 mL). Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 23 (3.0 mg).

LC-MS: m/z 596(M+H) ⁺

¹ H-NMR (CD ₃ OD)δ: 8.31 (s, 1H), 7.75 (d, J=1.92 Hz, 2H), 7.53-7.47 (m, 1H), 6.90-6.75 (m, 1H), 6.29 ( d,J=16.5Hz,1H),5.83(d,J=11.5Hz,1H),5.10-4.96(m,1H),4.54-4.45(m,1H),4.39-4.03(m,6H),3.79 -3.49(m,4H),3.06-2.90(m,2H),2.75-2.59(m,4H),1.09(t,J=7.2Hz,6H).

Example 24

Synthesis of Example 24 With reference to Example 23, 2,5-dichlorophenylboronic acid was used instead of 3,5-dichlorophenylboronic acid, and purified by preparative reverse phase chromatography to obtain product 24 (4.2 mg).

LC-MS: m/z 596(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.31 (s, 1H), 7.63-7.58 (m, 2H), 7.55-7.50 (m, 1H), 6.89-6.73 (m, 1H), 6.29 (d, J = 16.5Hz, 1H), 5.83 (d, J = 9.6Hz, 1H), 5.09-5.00 (m, 1H), 4.54-4.46 (m, 1H), 4.39-4.03 (m, 6H), 3.76-3.48 ( m,4H),3.06-2.88(m,2H),2.69-2.58(m,4H),1.07(t,J=7.2Hz,6H).

Example 25

Synthesis of Example 25 With reference to Example 23, 2-trifluoromethoxy-3-chlorophenylboronic acid was used instead of 3,5-dichlorophenylboronic acid, and purified by preparative reverse phase chromatography to obtain product 25 (1.3 mg).

LC-MS: m/z 646(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.32 (s, 1H), 7.64-7.54 (m, 3H), 6.84-6.74 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.83 ( d, J = 11.5Hz, 1H), 5.09-4.99 (m, 1H), 4.54-4.47 (m, 1H), 4.38-4.25 (m, 3H), 4.18-4.02 (m, 3H), 3.81-3.59 ( m,4H),3.03-2.91(m,2H),2.91-2.59(m,4H),1.08(t,J=7.2Hz,6H).

Example 26

Preparation of Example 26 With reference to Example 23, 3,5-ditrifluoromethyl-phenylboronic acid was used instead of 3,5-dichlorophenylboronic acid, and purified by preparative reverse phase chromatography to obtain product 26 (7.2 mg).

LC-MS: m/z 664(M+H) ⁺

¹ H-NMR(CD ₃ OD)δ: 8.45(s,2H), 8.38(s,1H), 8.03(s,1H), 6.97-6.71(m,1H), 6.31(d,J=16.8Hz, 1H), 5.86 (d, J = 10.5Hz, 1H), 5.14-4.96 (m, 1H), 4.57-4.46 (m, 1H), 4.30-4.25 (m, 3H), 4.21-4.03 (m, 3H) ,3.84-3.47(m,4H),3.08-2.91(m,2H), 2.67(q,J=7.2Hz,4H), 1.09(t,J=7.2Hz,6H).

Example 27

step 1:

At room temperature, the raw material 9i (66.1 mg) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (114 mg) and the compound of Preparation Example 3 (61.8 Mg), the reaction was stirred overnight. After the reaction was completed, water (30 mL) was added for quenching, and then extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (methanol/dichloromethane=3%-10%) to obtain product 27a (50.9 mg).

LC-MS: m/z 772(M+H) ⁺

Step 2:

The raw material 27a (50.9 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 27b (43.2 mg).

LC-MS: m/z 672(M+H) ⁺ .

Step 3:

At room temperature, the raw material 27b (43.2 mg) was suspended in dichloromethane (5 ml), and at -40 degrees Celsius, triethylamine (31.0 mg, 0.30 mmol), acryloyl chloride (10.9 mg, 0.012 mmol) were added sequentially. Mole). The reaction solution was reacted at room temperature for 15 minutes. After the reaction is complete, add water (10 mL) to quench. Extract with dichloromethane (3×10 mL). The organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 27c (37.9 mg).

LC-MS: m/z 726(M+H) ⁺ .

Step 4:

The raw material 27c (37.9 mg) was dissolved in a tetrahydrofuran/water (volume ratio 1:1, 5 ml) solution at room temperature, and sodium bicarbonate (13.1 mg) was added to react for 30 minutes at room temperature. After the reaction was completed, diluted hydrochloric acid was added to adjust the pH to about 7-8, and the mixture was extracted with ethyl acetate (30 ml×3). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column to obtain product 27 (8.9 mg).

LC-MS: m/z 642(M+H) ⁺ .

¹ H-NMR (CD ₃ OD)δ: 8.28 (s, 1H), 7.69-7.64 (m, 1H), 7.57-7.54 (m, 1H), 7.31 (d, J = 7.5Hz, 1H), 6.91 6.76(m,1H),6.31(d,J=18.6Hz,1H), 5.84(d,J=9.0Hz,1H), 5.12-5.00(m,1H),4.50-4.46(m,1H), 4.37 -4.26(m,3H),4.18-4.13(m,3H),3.94-3.86(m,1H), 3.67-3.64(m,7H),3.03-2.94(m,2H), 2.76(t,J= 5.7Hz, 4H), 2.61-2.58 (m, 3H).

Example 28

step 1:

Under the protection of nitrogen, the raw material 28a (3.00 g) was dissolved in dry N,N-dimethylformamide (30 mL), the temperature of the mixed solution was cooled to 0 degrees Celsius, sodium hydride (1.25 g) was added and the reaction was stirred at this temperature 1 After hours, iodomethane (14.1 g) was added and reacted at room temperature for 2 hours. After the reaction was completed, water (60 mL) was added for quenching. It was extracted with ethyl acetate (3×60 mL), the organic phases were combined and washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 5%-20%) to obtain product 28b (2.30 g).

LC-MS: m/z 239(M+H) ⁺ .

Step 2:

Raw material 28b (2.30 g) was dissolved in trifluoroacetic acid (100 ml) at room temperature, sodium borohydride (1.78 g) was added at 0 degrees Celsius, and the reaction was carried out at room temperature for 16 hours. After the reaction is over, add water (20mL) for quenching, adjust the pH of the reaction solution to about 7-8 with saturated sodium carbonate solution, then extract with ethyl acetate (3×20mL), combine the organic phases and use saturated brine (20mL) After washing, drying with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/petroleum ether=8%-25%) to obtain product 28c (1.37 g).

LC-MS: m/z 225(M+H) ⁺ .

Step 3:

Raw material 28c (1.37g) was dissolved in toluene (100ml) at room temperature, and t-butyl carbazate (967.5mg), cesium carbonate (5.98g), methanesulfonic acid (2-dicyclohexylphosphino- 2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (569.2 mg) Then, the reaction solution was reacted at 100 degrees Celsius for 2 hours under the protection of nitrogen. After the reaction, the reaction solution was filtered, the filtrate was retained and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-30%) to obtain product 28d (1.45 g).

LC-MS: m/z 277(M+H) ⁺ .

Step 4:

Raw material 28d (1.45g) was dissolved in hydrochloric acid/1,4-dioxane (4mol/L) (100ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 28e (1.10 g). LC-MS: m/z 177(M+H) ⁺ .

Step 5:

At room temperature, raw material 28e (1.10 g) was dissolved in N,N-dimethylformamide (50 mL). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (1.04 g). After reacting at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution (100 mL) was slowly added to allow solids to precipitate out. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (100 ml) and dried to obtain crude product 28f (1.98 g).

LC-MS: m/z 381(M+H) ⁺ .

Step 6:

At room temperature, the starting material 28f (1.98 g) was dissolved in N,N-dimethylformamide (50 mL). Add 2-cyanomethylpiperazine hydrochloride (1.34g) and N,N-diisopropylethylamine (3.35g) sequentially. After reacting overnight at room temperature, it was quenched by slowly adding water (100 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 28 g (1.92 g) of crude product. LC-MS: m/z 470(M+H) ⁺ .

Step 7:

At room temperature, 28 g (1.92 g) of the raw material was dissolved in N,N-dimethylformamide (50 mL), and triethylamine (1.23 g) and di-tert-butyl dicarbonate (2.67 g) were added. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-30%) to obtain the product 28h (1.86 g).

LC-MS: m/z 570(M+H) ⁺ .

Step 8:

At room temperature, dissolve the raw materials for 28h (500 mg) in methanol (10 ml), add triethylamine (87.8 mg), Pd(dppf)Cl ₂ (71.08 mg), and fill with carbon monoxide gas (20 atm). , The reaction solution was reacted at 100 degrees Celsius for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain product 28i (258 mg). LC-MS: m/z 594(M+H) ⁺ .

Step 9:

At room temperature, the raw material 28i (258 mg) was dissolved in acetic acid (10 ml), and the reaction solution was reacted at 110 degrees Celsius for 15 minutes. After the reaction was completed, water (30 mL) was slowly added for quenching, and sodium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-60%) to obtain product 28j (126 mg). LC-MS: m/z 562(M+H) ⁺ .

Step 10:

At 0 degrees Celsius, the raw material 28j (50.0 mg) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (85%) (63.1 mg) was added. The reaction solution was reacted at 0 degrees Celsius for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (10 mL), and extracted with dichloromethane (3×10 mL). The organic phases were combined and washed with saturated brine (10 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 28k (44.2 mg). LC-MS: m/z 578(M+H) ⁺ .

Step 11:

At room temperature, the raw material 28k (44.2 mg) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (49.3 mg) and N,N-diethyl were added. Azetidine-3-amine dihydrochloride (24.6 mg), the reaction was stirred for 12 hours. After the reaction was completed, it was quenched by adding water (10 mL), and then extracted with ethyl acetate (10×3 mL). The organic phases were combined and washed with saturated brine (10 mL). After the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, the crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-15%) to obtain 28 l (35.4 mg) of the product. LC-MS: m/z 642(M+H) ⁺ .

Step 12:

At room temperature the starting material 28l (35.4 mg) was dissolved in hydrochloric acid / 1,4-dioxane (4 mol / l) (5 ml), reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 28m (28.3 mg). LC-MS: m/z 542(M+H) ⁺ .

Step 13:

At room temperature, the raw material 28m (28.3 mg) was suspended in dichloromethane (5 ml), and at -40 degrees Celsius, triethylamine (25.1 mg) and acryloyl chloride (8.82 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction is complete, add water (10 mL) to quench. Extract with dichloromethane (3×10 mL). The organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 28 (4.7 mg).

LC-MS: m/z 596(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.31 (s, 1H), 7.30-7.28 (m, 2H), 7.23-7.19 (m, 1H), 6.92-6.76 (m, 1H), 6.31 (d, J = 16.5Hz, 1H), 5.85 (d, J = 11.4Hz, 1H), 5.12-5.03 (m, 1H), 4.56-4.51 (m, 1H), 4.39-4.29 (m, 3H), 4.17-4.08 ( m, 3H), 3.79-3.59 (m, 4H), 3.04-2.96 (m, 2H), 2.85 (s, 2H), 2.70-2.61 (m, 6H), 1.15 (s, 6H), 1.09 (d, J=6.6Hz, 6H).

Example 29

step 1:

Intermediate 9i (1.00 g) was dissolved in tetrahydrofuran (10 mL) at room temperature, sodium hydroxide solution (10 mL, 3 mol/L) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, it was extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (2×30 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 29a (768 mg).

LC-MS: m/z 546(M+H) ⁺ .

Step 2:

Dissolve 29a (768 mg) in dichloromethane (10 ml) at room temperature, add triethylamine (455.8 mg) and trifluoromethanesulfonic anhydride (873.8 mg) in order under ice bath conditions, and react at 0 degrees Celsius 2 hours. After the reaction is complete, add water (10 mL) to quench. Extract with ethyl acetate (3×80 mL). The organic phases were combined and washed with saturated brine (2×40 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=75%-80%) to obtain a yellow solid 29b (660 mg). LC-MS: m/z 678(M+H)+.

Step 3:

At room temperature, the raw material 29b (50.0 mg) was dissolved in 1,4 dioxane/water solution (3/0.6 ml), and the compound of Preparation Example 6 (36.5 mg), potassium carbonate (20.4 mg), [1, 1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (6.01 mg). The reaction system was reacted at 80 degrees Celsius for 16 hours under the protection of nitrogen. After the reaction was completed, water (4 mL) was added for quenching. Extract with ethyl acetate (3×30 mL). The organic phases were combined and washed with saturated brine (2×20 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/petroleum ether = 8%-12%) to obtain product 29c (37.0 mg).

LC-MS: m/z 649(M+H) ⁺

Step 4:

Raw material 29c (37.0 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and reacted for 30 minutes at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 29d (32.0 mg, 95.9%).

LC-MS: m/z 549(M+H) ⁺ .

Step 5:

At room temperature, the raw material 29d (32.0 mg) was suspended in dichloromethane (10 ml), and at -40 degrees Celsius, triethylamine (27.6 mg) and acryloyl chloride (5.94 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 30 minutes. After the reaction was completed, it was quenched by adding water (20 mL). Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column to obtain product 29 (5.3 mg).

LC-MS: m/z 603(M+H) ⁺

¹ H NMR(CD ₃ OD)δ:8.63-8.59(m,2H), 8.25-8.17(m,1H), 7.69(t,J=7.8Hz,1H), 7.60(d,J=7.8Hz,1H ),7.42-7.34(m,2H),6.95-6.76(m,1H),6.32(d,J=16.8Hz,1H), 5.86(d,J=10.8Hz,1H),5.11-4.96(s, 1H),4.68-4.54(s,1H),4.52-4.40(s,1H),4.26-3.64(m,5H),3.10-2.93(m,2H),2.62(d,J=2.4Hz,3H) ,1.35-1.30(m,6H).

Example 30

step 1:

Raw material 30a (2 g) was dissolved in tetrahydrofuran (20 ml) at room temperature, and borane-dimethyl sulfide solution (3 ml) (10 mol/L) was added under ice bath conditions, and reacted at 70 degrees Celsius for 3 hours. After the reaction, it was quenched by adding saturated aqueous ammonium chloride solution (20 mL) at room temperature, and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=29%-32%) to obtain product 30b (1.39 g). LC-MS: m/z 213(M+H) ⁺ .

Step 2:

Dissolve sodium hydride (188 mg) in tetrahydrofuran (30 mL) at room temperature, add raw material 30b (1.39 g) under ice bath, stir at room temperature for 30 minutes, and add methyl iodide (1.11 g). React overnight at room temperature. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added at room temperature to quench. It was extracted with ethyl acetate (3×150 mL), and the organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 30c (1.32 g). LC-MS: m/z 227(M+H) ⁺ .

Step 3:

Dissolve raw material 30c (1.32g) in toluene (30ml) at room temperature, add tert-butyl carbazate (0.92g), cesium carbonate (3.79g), 4,5bis(diphenylphosphine)-9 in sequence After 9-dimethylxanthene (554 mg) and tris(dibenzylidene indeneacetone) dipalladium (532 mg), the reaction solution was reacted at 90 degrees Celsius for 3 hours under the protection of nitrogen. After the reaction, the reaction solution was quenched with water (100 mL) at room temperature. Extract with ethyl acetate (3×150 mL). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 12%-16%) to obtain the product 30d (1.45 g). LC-MS: m/z 279(M+H) ⁺ .

Step 4:

The raw material 30d (1.45 g) was dissolved in hydrochloric acid/1,4-dioxane (4 mol/L) (30 ml) solution at room temperature, and reacted at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 30e (1.09 g). LC-MS: m/z 179(M+H) ⁺ .

Step 5:

At room temperature, the raw material 30e (1.09 g) was dissolved in N,N-dimethylformamide (20 mL). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (1.02 g). After reacting at room temperature for 3 hours, it was quenched by slowly adding water (50 mL). Extract with ethyl acetate (3×150 mL). The organic phases were combined and washed with saturated brine (150 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 30f (1.58 g). LC-MS: m/z 383(M+H) ⁺ .

Step 6:

At room temperature, the raw material 30f (1.58 g) was dissolved in N,N-dimethylformamide (20 mL). Add 2-cyanomethylpiperazine hydrochloride (0.98g) and N,N-diisopropylethylamine (2.66g) sequentially. The reaction was carried out at room temperature for 3 hours, and water (100 mL) was slowly added to quench. Extract with ethyl acetate (3×150 mL). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 30 g (1.89 g) of crude product. LC-MS: m/z 472(M+H) ⁺ .

Step 7:

At room temperature, dissolve 30g (1.89g) of raw material in N,N-dimethylformamide (20ml), add N,N-diisopropylethylamine (2.59g) and di-tert-butyl dicarbonate (1.75g). React at 35 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-25%) to obtain the product 30h (1.27 g). LC-MS: m/z 572(M+H) ⁺ .

Step 8:

At room temperature, the raw material was dissolved in methanol (120 ml) for 30h (1.27 mg), and then triethylamine (220 mg), [1,1'-bis(diphenylphosphino)ferrocene] dichloride After palladium (180.8 mg) was charged with carbon monoxide gas (20 atm), the reaction solution 100 was reacted for 3 hours at degrees Celsius. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=22%-28%) to obtain product 30i (494 mg). LC-MS: m/z 596(M+H) ⁺ .

Step 9:

At room temperature, the raw material 30i (494 mg) was dissolved in acetic acid (15 ml), and the reaction solution was reacted overnight at 50 degrees Celsius. After the reaction was completed, water (100 mL) was slowly added to quench, sodium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (3×80 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=52%-58%) to obtain product 30j (194 mg). LC-MS: m/z 564(M+H) ⁺ .

Step 10:

At room temperature, the raw material 30j (194 mg) was dissolved in dichloromethane (10 ml), m-chloroperoxybenzoic acid (85%) (208 mg) was added, and the reaction solution was reacted at room temperature for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (20 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 30k (285 mg). LC-MS: m/z 596(M+H) ⁺ .

Step 11:

At room temperature, the raw material 30k (285 mg) was dissolved in N,N-dimethylformamide (20 ml), and 3-diethylaminoazetidine dihydrochloride (192 mg) was added successively, N, N-Diisopropylethylamine (371 mg) was reacted for 2 hours at room temperature. After the reaction was completed, it was quenched by adding water (3 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 30 l (216 mg) of crude product. LC-MS: m/z 644(M+H) ⁺ .

Step 12:

30 l (100 mg) of the raw material was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/l) (8 ml) solution at room temperature, and reacted for 30 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of 30m (69 mg). LC-MS: m/z 544(M+H) ⁺ .

Step 13:

At room temperature, the raw material 30m (69.0 mg) was suspended in dichloromethane (10 ml), and at -40 degrees Celsius, triethylamine (38.5 mg) and acryloyl chloride (14.9 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 30 minutes. After the reaction is complete, add water (10 mL) to quench. Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 30 (8.2 mg).

LC-MS: m/z 598(M+H) ⁺ .

¹ H-NMR(CD ₃ OD)δ: 8.19(s,1H), 7.25-7.19(m,2H), 7.14(s,1H), 6.79-6.62(m,1H), 6.19(d,J=16.8 Hz,1H), 5.73(d,J=10.4Hz,1H),5.00-4.89(m,1H),4.44-4.35(m,1H),4.29-4.13(m,4H),4.07-3.92(m, 3H), 3.67-3.52 (m, 4H), 3.20-3.18 (m, 3H), 3.16-3.12 (m, 1H), 2.99-2.81 (m, 4H), 2.77-2.65 (m, 1H), 2.56 ( q, J = 7.2Hz, 4H), 0.98 (t, J = 7.2Hz, 6H).

Example 31

step 1:

The intermediate 30l (160 mg) was dissolved in dichloromethane (20 ml) at room temperature, and boron tribromide (194 mg) was slowly added under nitrogen protection. React at room temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added at room temperature to quench. It was extracted with dichloromethane (3×100 mL), and the organic phases were combined and washed with water (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 31a (43 mg). LC-MS: m/z 530(M+H) ⁺ .

Step 2:

At room temperature, the raw material 31a (43 mg) was suspended in dichloromethane (10 ml), and at -40 degrees Celsius, triethylamine (24.6 mg) and acryloyl chloride (14.9 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 30 minutes. After the reaction is complete, add water (10 mL) to quench. Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 31 (1.5 mg).

LC-MS: m/z 584(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.17 (s, 1H), 7.32-7.18 (m, 2H), 7.12 (d, J = 7.2Hz, 1H), 6.82-6.62 (m, 1H), 6.19 ( d,J=16.8Hz,1H),5.73(d,J=10.4Hz,1H),5.00-4.88(m,1H),4.55-4.47(m,1H),4.43-4.36(m,1H),4.29 -4.12(m,3H),4.09-3.89(m,3H),3.71-3.31(m,4H),3.17-3.10(m,1H),3.01-2.91(m,1H),2.90-2.70(m, 3H), 2.64-2.52 (m, 5H), 0.98 (t, J = 7.2Hz, 6H).

Example 32

step 1

The raw material 32a (15.0 g) was dissolved in dimethyl sulfoxide (150 ml), and hydrazine hydrate solution (98%) (30 ml) was added at 0 degrees Celsius. The resulting mixture was heated to room temperature and stirred for 36 hours. After the reaction was completed, water (100 mL) was added and the pH was adjusted to 8 with anhydrous sodium carbonate solution. The mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The crude product 32b (14.0 g) was obtained.

LC-MS: m/z 255(M+H) ⁺

Step 2

The raw material 32b (14.0 g) was dissolved in N,N-dimethylformamide (100 ml), and triethylamine (8.33 g) and di-tert-butyl dicarbonate (13.2 g) were added at 0 degrees Celsius. The resulting mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was added to water (100 ml) and the pH was adjusted to 8 with anhydrous sodium carbonate solution. The mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-30%) to obtain product 32c (14.0 g). LC-MS: m/z 355(M+H) ⁺

Step 3

Dissolve raw material 32c (14.0 g) in 1,4-dioxane (100 ml), add vinyl borate pinacol ester (7.30 g), [1,1'-bis(diphenylphosphine) Ferrocene] Palladium dichloride (3.20 g), anhydrous potassium carbonate (13.6 g). Under a nitrogen atmosphere, the resulting mixture was reacted at 80 degrees Celsius for 2 hours. After the reaction was completed, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-30%) to obtain product 32d (9.00 g). LC-MS: m/z 317(M+H) ⁺

Step 4

The raw material 32d (9.00 g) was dissolved in anhydrous methanol (100 ml), and palladium on carbon (10%) (0.9 g) was added under the protection of nitrogen. The resulting reaction solution was replaced with hydrogen three times and reacted at 60 degrees Celsius for 2 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain crude product 32e (9.00 g) as a pale yellow solid. LC-MS: m/z 319(M+H) ⁺

Step 5

A 1,4-dioxane solution (100 ml) of hydrogen chloride was added to the raw material 32e (9.00 g). The resulting solution was stirred at room temperature for 1 hour. After the reaction, the product was concentrated to dryness to obtain product 32f (5.00 g). No purification is required and it is directly used in the next step. LC-MS: m/z 219(M+H) ⁺

Step 6

The starting material 32f (5.00 g) was dissolved in N,N-dimethylformamide (20 ml), and 2-(methylthio)-4,6-dichloro-5-pyrimidinecarbaldehyde (4.60 g) was added. The resulting reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to precipitate a solid. The mixture was filtered, and the resulting solid was washed with water (3x200 mL) and dried. 32 g (6.00 g) of crude product was obtained. LC-MS: m/z 423(M+H) ⁺

Step 7

Dissolve 32g (6.00g) of the raw material in N,N-dimethylformamide (20ml), add N,N-diisopropylethylamine (9.16g), 2-cyanomethylpiperazine di salt The resulting mixture of acid salt (3.60 g) was reacted at room temperature for 2 hours. After the reaction is complete, add water (200 mL) to dilute. It was extracted with ethyl acetate (3x200 mL). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain the product 32h (6.00 g). LC-MS: m/z 512(M+H) ⁺

Step 8

The raw material 32h (6.00 g) was dissolved in N,N-dimethylformamide (20 ml), and di-tert-butyl dicarbonate (3.80 g) and diisopropylethylamine (4.50 g) were added in sequence. The resulting solution was reacted at room temperature for 2 hours. After the reaction was completed, water (150 mL) was added to dilute, and the mixture was extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-40%) to obtain product 32i (4.23 g). LC-MS: m/z 612(M+H) ⁺

Step 9

The raw material 32i ( 4.23g ) was dissolved in anhydrous methanol (100ml), triethylamine (699mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (506 Mg), the resulting reaction solution was replaced with carbon monoxide three times. The resulting solution was reacted at 100 degrees Celsius and 20 standard atmospheres for 3 hours. After the reaction was completed, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain product 32j (1.20 g). LC-MS: m/z 636(M+H) ⁺

Step 10

The raw material 32j (1.2 g) was dissolved in glacial acetic acid (20 ml), and the resulting solution was reacted at 110 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding a saturated aqueous solution of sodium bicarbonate (200 mL). It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=40%-60%) to obtain the product 32k (390 mg). LC-MS: m/z 604(M+H) ⁺

Step 11

The raw material 32k (390 mg) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (334.46 mg) was added at 0 degrees Celsius. The resulting reaction liquid was reacted at room temperature for 1 hour. After the reaction was completed, a saturated aqueous solution of sodium thiosulfate (20 mL) was added for quenching. It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The resulting crude product 32l (350 mg). LC-MS: m/z 636(M+H) ⁺

Step 12

Dissolve 32 l (350 mg) of raw material in N,N-dimethylformamide (5 mL), add diisopropylethylamine (213.49 mg), 3-(diethylamino)azetidine hydrochloric acid Salt (84.72 mg), the resulting reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is 32m (300 mg). LC-MS: m/z 684(M+H) ⁺

Step 13

A 1,4-dioxane solution (20 ml) of hydrogen chloride was added to the raw material 32m (300 mg). The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness to obtain product 32n (150 mg). No purification is required and it is directly used in the next step.

LC-MS: m/z 584(M+H) ⁺

Step 14

The raw material 32n (150 mg) was dissolved in dichloromethane (5 ml), and after cooling to -20 degrees Celsius, triethylamine (130.03 mg) and acryloyl chloride (27.91 mg) were sequentially added. The resulting solution was reacted at -20 degrees Celsius for 1 hour. After the reaction is complete, add water (5 mL) to quench and concentrate to dryness. The obtained crude product was purified with a preparative chromatography column to obtain product 32 (30 mg).

LC-MS: m/z 638(M+H) ⁺

¹ H NMR (CD ₃ OD) δ: 8.28 (s, 1H), 7.80-7.65 (m, 2H), 7.28 (d, J = 7.2Hz, 1H), 6.93-6.70 (s, 1H), 6.29 (d ,J=16.8Hz,1H),5.83(d,J=10.4Hz,1H),5.13-4.97(s,1H),4.56-4.45(m,1H),4.38-4.23(m,3H),4.18- 4.00(m,3H),3.80-3.37(m,5H),3.11-2.83(m,2H),2.71-2.53(m,4H),1.33(dd,J ₁ =10.0Hz, J ₂ ＝6.8Hz, 6H),1.07(t,J=7.2Hz,6H).

Example 33

step 1:

At room temperature, the raw material 18i (2837 mg) was dissolved in N,N-dimethylformamide (100 ml), and N,N-diisopropylethylamine (2918 mg) and N,N-diethyl were added. Azetidine hydrochloride (1357 mg), reacted for 1 hour. After the reaction was completed, it was quenched by adding water (100 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined and washed with saturated brine (500 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 33a (2629 mg).

LC-MS: m/z 676(M+H) ⁺

Step 2:

At room temperature, the raw material 33a (2629 mg) was dissolved in a 1,4-dioxane solution (4 mol/L, 100 ml) of hydrogen chloride and reacted for 30 minutes. After the reaction, the crude product 33b (2214 mg) was obtained by concentration under reduced pressure. No purification is required and it is directly used in the next step.

LC-MS: m/z 576(M+H) ⁺

Step 3:

The raw material 33b (2214 mg) was dissolved in NN-dimethylformamide (100 ml), and triethylamine (1098 mg), HATU (275.4 mg), and 2-fluoroacrylic acid (358 mg) were added in sequence to obtain The solution was reacted at room temperature for 2 hours. After the reaction was completed, it was quenched by adding water (50 mL), and then extracted with ethyl acetate (50 mL×3). The organic phases were combined and washed with saturated brine (20 mL). The organic phases were dried with anhydrous sodium sulfate and reduced The crude product obtained by pressure concentration was purified with a preparative chromatography column to obtain product 33 (835 mg).

LC-MS: m/z 648(M+H)

¹ H NMR (300MHz, CD ₃ OD-d ₄ ) δ 8.29 (s, 1H), 7.78-7.66 (m, 2H), 7.45-7.40 (m, 1H), 5.37-5.20 (m, 2H), 4.80 (m,1H),4.59-4.31(m,6H), 4.25(d,J=8.4Hz,1H),4.08(s,1H),3.63(s,3H),3.27-3.18(m,4H), 2.97(d,J=5.4Hz,2H), 1.28(t,J=5.4Hz,6H).

Example 34 and Example 35

The racemate compound 33 was chiral resolution (column type: (CHIRAL ART Cellulose-SC, 2*25cm, 5um; mobile phase A: methyl tert-butyl ether (0.1% diethylamine)), mobile phase B: ethanol (30%); flow rate: 15 mL/min) to obtain products 34 (315 mg, retention time t=1.86 minutes) and 35 (300 mg, retention time t=3.07 minutes).

Product 34

LC-MS: m/z 648(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.31 (s, 1H), 7.79 (dd, J ₁ = 8.1 Hz, J ₂ = 16.2 Hz, 2H), 7.51-7.46 (m, 1H), 5.44-5.25 ( m, 2H), 4.56 (d J = 12.3 Hz, 1H), 4.47-4.37 (m, 2H), 4.32-4.15 (m, 2H), 4.02-3.95 (m, 1H), 3.73-3.55 (m, 3H) ),3.34-3.29(m,2H),3.34-3.29(m,2H),3.04(d,J=8.1Hz,1H),2.94-2.89(m,4H),1.18(t,J=7.2Hz, 6H).

Product 35

LC-MS: m/z 648(M+H) ⁺

¹ H-NMR (CD ₃ OD)δ: 8.37 (s, 1H), 7.81 (dd, J ₁ = 8.1 Hz, J ₂ =18.6 Hz, 2H), 7.48 (d, J = 7.5 Hz, 1H), 5.46 -5.24(m,2H),4.69-4.53(m,3H),4.49-4.38(m,3H),4.31(d,J=10.8Hz,1H),4.23-4.06(m,1H),3.77-3.63 (m, 3H), 3.39-3.32 (m, 3H), 3.30-3.26 (m, 2H), 3.03 (d, J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz, 6H).

Example 36

Synthesis of Example 36 With reference to Example 33, compound 9i was used instead of compound 18i , and purified by preparative reverse phase chromatography to obtain product 36 (5.2 mg).

LC-MS: m/z 628(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.29 (s, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz ,1H),5.47-5.23(m,2H),4.55(d,J=14.4Hz,1H),4.41-4.05(m,6H),3.85-3.41(m,5H),3.14-3.00(m,2H) ), 2.68(q,J=7.2Hz,4H), 2.60(q,J=2.5Hz,3H), 1.10(t,J=7.2Hz,6H).

Example 37

step 1:

At room temperature, the raw material 18i (28.4 mg) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (30.2 mg) and (R)-1 were added. 4-azabicyclo[4.3.0]nonane (10.7 mg), react for 1 hour. After the reaction was completed, water (20 mL) was added for quenching, and then extracted with ethyl acetate (20×3 mL). The organic phases were combined and washed with saturated brine (20 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 37a (27.5 mg).

LC-MS: m/z 674(M+H) ⁺

Step 2:

At room temperature, the raw material 37a (27.5 mg) was dissolved in a 1,4-dioxane solution (4 mol/L, 10 mL) of hydrogen chloride and reacted for 30 minutes. After the reaction was completed, it was concentrated under reduced pressure to obtain crude product 37b (23.7 mg). No purification is required and it is directly used in the next step.

LC-MS: m/z 574(M+H) ⁺

Step 3:

The raw material 37b (24.9 mg) was dissolved in dichloromethane (20 ml), and after cooling to -40 degrees Celsius, triethylamine (12.4 mg) and acryloyl chloride (4.1 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 20 minutes. After the reaction is complete, add water (20 mL) to quench and concentrate to dryness. The obtained crude product was purified with a preparative chromatography column to obtain product 37 (2.1 mg).

LC-MS: m/z 628(M+H) ⁺

¹ H NMR(CD ₃ OD)δ: 8.32(s,1H),7.84-7.73(m,2H),7.50(d,J=7.2Hz,1H),6.94-6.73(m,1H),6.31(d ,J=16.5Hz,1H), 5.84(d,J=10.8Hz,1H), 5.27-4.96(m,3H), 4.47(d,J=14.1Hz,1H), 4.28(d,J=12.0Hz ,1H),4.17-4.04(m,1H),3.86-3.47(m,3H),3.22-2.94(m,5H), 2.82(t,J=1.20Hz,1H),2.34-2.18(m,2H) ), 2.14-1.77 (m, 4H), 1.59-1.44 (m, 1H).

Example 38 and Example 39

The racemate compound 37 was subjected to chiral resolution (column type: (R, R) WHELK-O1, 4.6*100mm 3.0μm; mobile phase A: n-hexane: methyl tert-butyl ether = 1:1 (0.1% Ethylenediamine)), mobile phase B: ethanol (70:30); flow rate: 40 ml/min; gradient: 30%) to obtain products 38 (5.1 mg, retention time t = 6.27 minutes) and 39 (5.2 mg, Retention time t = 7.09 minutes).

Product 38

LC-MS: m/z 628(M+H) ⁺

¹ H-NMR(CDCl ₃ )δ: 8.01(s,1H),7.66-7.53(m,2H),7.32(d,J=7.8Hz,1H),6.64-6.50(m,1H),6.45-6.34 (m, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.28-4.74 (m, 3H), 4.48-4.03 (m, 3H), 3.75-3.39 (m, 3H), 3.22-3.05 (m ,4H),3.01-2.66(m,3H),2.36-2.09(m,2H),2.02-1.87(m,4H).

Product 39

LC-MS: m/z 628(M+H) ⁺

¹ H-NMR(CDCl ₃ )δ: 8.02(s,1H), 7.67-7.55(m,2H), 7.32(d,J=7.8Hz,1H), 6.64-6.54(m,1H), 6.45-6.39 (m,1H),5.87(d,J=10.5Hz,1H),5.26-4.73(m,3H),4.46-4.03(m,3H),3.72-3.42(m,3H),3.22-3.05(m ,4H),3.01-2.76(m,3H),2.36-2.09(m,2H),2.02-1.88(m,4H).

Example 40

Synthesis of Example 40 Refer to Example 37, using N,N-dipropyl-azetidine hydrochloride instead of (R)-1,4-azabicyclo[4.3.0]nonane, preparative chromatography Column purification, product 40 (2.3 mg) was obtained.

LC-MS: m/z 658(M+H) ⁺

¹ H NMR(CD ₃ OD)δ: 8.31(s,1H),7.84-7.73(m,2H),7.50(d,J=8.1Hz,1H),6.92-6.78(s,1H),6.30(d ,J=16.8Hz,1H),5.85(d,J=10.5Hz,1H),5.12-5.07(m,1H),4.58-4.53(m,1H),4.38-4.23(m,3H),4.20- 4.05(m,2H),3.81-3.59(m,5H),3.05-2.93(m,2H),2.56-2.46(m,4H),1.64-1.41(m,4H),0.94(t,J=7.2 Hz, 6H).

Referring to the synthesis method of Example 37, compound 9i' was used instead of compound 18i , and (R)-1,4-azabicyclo[4.3.0]nonane was replaced with a suitable nitrogen-containing heterocyclic compound or preparation example compound to obtain The following compounds:

Example 50

step 1:

Dissolve raw material 50a (22.0g) in toluene (500ml) at room temperature, add tert-butyl carbazate (15.84g), cesium carbonate (65.2g), 2-dicyclohexylphosphorus-2',4' in sequence After 6'-triisopropylbiphenyl (9.52g), tris(dibenzylideneacetone)dipalladium (9.15g), the reaction solution was reacted at 70°C for 2 hours under nitrogen protection. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (500x3 mL). The organic phases were combined and washed with saturated brine (200 mL). After the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=5%-15%) to obtain product 50b (19.4 g).

LC-MS: m/z 272(M+H) ⁺ .

Step 2:

The raw material 50b (19.4 g) was dissolved in a 1,4-dioxane solution (4 mol/liter, 300 ml) of hydrogen chloride. React at room temperature for 30 minutes. After the reaction is complete, concentrate under reduced pressure to obtain crude product 50c . No purification is required and it is directly used in the next step. LC-MS: m/z 172(M+H) ⁺ .

Step 3:

The raw material 50c (14.5 g) was dissolved in N,N-dimethylformamide (200 ml), and 4,6-dichloro-2-methylthiopyrimidine-5-carbaldehyde (12.5 g) was added. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (500x3 mL). The organic phases were combined and washed with saturated brine (200 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 50d (17.24 g). No purification is required and it is directly used in the next step. LC-MS: m/z 376(M+H) ⁺

Step 4:

Dissolve raw material 50d (17.2g) in N,N-dimethylformamide (200ml), then add N,N-diisopropylethylamine (29.6g), 2-cyanomethylpiperazine dihydrochloride Salt (10.9 g). The resulting mixture was reacted at room temperature for 2 hours. After the reaction was completed, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (500 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain crude product 50e (16.7 g). No purification is required and it is directly used in the next step. LC-MS: m/z 465(M+H) ⁺

Step 5:

The raw material 50e (16.7 g) was dissolved in N,N-dimethylformamide (500 ml), and di-tert-butyl dicarbonate (9.43 g) and triethylamine (11.1 g) were sequentially added. The resulting solution was reacted at room temperature for 2 hours. After the reaction was completed, water (500 mL) was added for dilution, and extracted with ethyl acetate (500×3 mL). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-30%) to obtain product 50f (14.3 g). LC-MS: m/z 565(M+H) ⁺

Step 6:

The raw material 50f (14.3 g) was dissolved in 500 ml of ethanol: ammonium chloride (10:1), and iron powder (6.39 g) was sequentially added, and the resulting solution was reacted at room temperature for 16 hours. After the completion of the reaction, it was diluted with water (500 ml) and extracted with ethyl acetate (500×3 ml). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=40%-60%) to obtain 50 g (8.26 g) of the product.

LC-MS: m/z 535(M+H) ⁺

Step 7:

50 g (8.26 g) of the raw material was dissolved in N,N-dimethylformamide (300 ml), and di-tert-butyl dicarbonate (4.04 g) and triethylamine (4.68 g) were sequentially added. The resulting solution was reacted at room temperature for 2 hours. After the reaction was completed, it was diluted with water (200 mL) and extracted with ethyl acetate (300×3 mL). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-40%) to obtain the product 50h (5.51 g). LC-MS: m/z 635(M+H) ⁺

Step 8:

At room temperature, dissolve the raw materials for 50h (5.51g) and triethylamine (877.7mg) in methanol (300ml), add [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium (709.9 mg). The reaction solution was placed in a CO atmosphere (10 atmospheres) and reacted at 100 degrees Celsius for 2 hours. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (100x3 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-40%) to obtain the product 50i (1.915 g). LC-MS: m/z 659(M+H) ⁺

Step 9:

At room temperature, the raw material 50i (1.92 g) was dissolved in acetic acid (100 ml). The reaction solution was placed at 50 degrees Celsius to react for 16 hours. After the reaction was completed, it was quenched by adding water (500 mL). Extract with ethyl acetate (500x3 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50%-70%) to obtain the product 50j (244 mg). LC-MS: m/z 627(M+H) ⁺

Step 10:

At room temperature, the material 50j (244.1 mg) was dissolved in dichloromethane (30 ml), m-chloroperbenzoic acid (201.1 mg) was reacted for 1 hour. After the reaction was completed, a saturated aqueous solution of sodium thiosulfate (50 mL) was added for quenching, and then extracted with ethyl acetate (50×3 mL). The organic phases were combined and washed with saturated brine (10 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a crude product of 50k (229.8 mg). No purification is required and it is directly used in the next step. LC-MS: m/z 659(M+H) ⁺

Step 11:

At room temperature, dissolve raw material 50k (229.8 mg) in N,N-dimethylformamide (20 mL), add N,N-diisopropylethylamine (225.1 mg) and N,N-diethyl Azetidine hydrochloride (83.8 mg), reacted for 1 hour. After the reaction was completed, water (30 mL) was added for quenching, and then extracted with ethyl acetate (30x3 mL). The organic phases were combined and washed with saturated brine (20 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 50 l (202.4 mg) of crude product. LC-MS: m/z 707(M+H) ⁺

Step 12:

At room temperature, the material 50l (202.4 mg) was dissolved in hydrogen chloride in 1,4-dioxane (4 mol / l, 50 ml) was stirred for 30 minutes. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product of 50m (156.4 mg). No purification is required and it is directly used in the next step.

LC-MS: m/z 507(M+H) ⁺

Step 12:

The raw material 50m (156.4 mg) was dissolved in dichloromethane (50 ml), and after cooling to -40 degrees Celsius, triethylamine (81.9 mg) and acryloyl chloride (19.8 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 30 minutes. After the reaction is complete, add water (30 mL) to quench and concentrate to dryness. The obtained crude product was purified with a preparative chromatography column to obtain product 50 (52.3 mg).

LC-MS: m/z 561(M+H) ⁺

¹ H NMR (CD ₃ OD) δ: 8.31 (s, 1H), 7.20-7.12 (m, 1H), 6.94-6.74 (m, 1H), 6.71-6.65 (m, 1H), 6.52-6.43 (m, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.8 Hz, 1H), 5.09-5.01 (m, 1H), 4.60-4.47 (m, 2H), 4.38-4.24 (m ,3H),4.18-4.02(m,2H),3.78-3.56(m,4H),3.08-2.87(m,2H), 2.65(dd,J ₁ =6.6Hz,J ₂ =14.4Hz,4H), 1.08(t,J=7.2Hz,6H).

Example 51

Intermediate 50m (30 mg, 0.05 mmol) was dissolved in dichloromethane (20 mL), and after cooling to -40 degrees Celsius, triethylamine (15.2 mg) and acryloyl chloride (9.0 mg, 0.1 mmol) were added sequentially . The resulting solution was reacted at -40 degrees Celsius for 30 minutes. After the reaction is complete, add water (30 mL) to quench and concentrate to dryness. The obtained crude product was purified by a preparative chromatography column to obtain product 51 (2.3 mg).

LC-MS: m/z 615(M+H) ⁺

¹ H NMR (CD ₃ OD) δ: 8.33 (s, 1H), 8.05-7.96 (m, 1H), 7.57-7.46 (m, 1H), 7.13 (t, J = 9.6Hz, 1H), 6.95-6.71 (m, 1H), 6.49-6.25 (m, 3H), 5.85 (d, J = 10.8 Hz, 1H), 5.75-5.69 (m, 1H), 4.64-4.41 (m, 1H), 4.39-4.22 (m ,3H),4.18-4.06(m,2H),3.83-3.59(m,6H),3.07-2.87(m,2H), 2.67(dd,J ₁ ＝7.2Hz,J ₂ ＝14.4Hz,4H), 1.09(t,J=7.8Hz,6H).

Example 52

Compound 50 (156 mg) was dissolved in acetonitrile (20 mL), N-chlorosuccinimide (185.2 mg) was added, and the resulting solution was reacted at 80 degrees Celsius for 16 hours. After the reaction is complete, add water (30 mL) to quench and concentrate to dryness. The obtained crude product was purified with a preparative chromatography column to obtain product 52 (20.0 mg).

LC-MS: m/z 629(M+H) ⁺

¹ H NMR (CD ₃ OD) δ: 8.34 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 6.86-6.72 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.83(d,J=10.8Hz,1H),5.09-4.97(m,1H),4.65-4.47(m,3H),4.37-4.25(m,2H),4.17-4.03(m,2H),3.78- 3.51 (m, 4H), 3.28-2.91 (m, 2H), 2.65 (dd, J ₁ = 7.5 Hz, J ₂ = 14.4 Hz, 4H), 1.07 (t, J = 7.2 Hz, 6H).

Example 53

step 1:

Intermediate 9i (50 mg) was dissolved in 1,4-dioxane (5 ml) at room temperature, and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (35.4 mg) was added sequentially , 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (12.4 mg), potassium carbonate (35.2 mg), react at 80 degrees Celsius for 2 hours. After the reaction was completed, it was quenched by adding water (30 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (2×30 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 53a (20 mg).

LC-MS: m/z 610(M+H) ⁺

Step 2:

The raw material 53a (20 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 53b (15 mg).

LC-MS: m/z 510(M+H) ⁺ .

Step 3:

At room temperature, the raw material 53b (15.0 mg) was suspended in dichloromethane (5 ml), and at -40 degrees Celsius, triethylamine (14.1 mg) and acryloyl chloride (3.04 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding water (30 mL). Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 53 (3.1 mg).

LC-MS: m/z 564(M+H) ⁺

1H-NMR(CD ₃ OD)δ: 8.55(s,1H),8.50(s,1H),8.37(s,1H),7.70(t,J=7.6Hz,1H),7.64-7.56(m,1H) ), 7.38 (d, J = 8.0 Hz, 1H), 6.95-6.77 (m, 1H), 6.33 (d, J = 16.8 Hz, 1H), 5.86 (d, J = 10.4 Hz, 1H), 5.20-5.06 (m,1H),4.81-4.72(m,1H),4.67-4.55(m,1H),4.46-4.34(m,1H),4.22-4.10(m,1H),3.99(s,3H), 3.87 -3.70(m,2H),3.18-2.96(m,2H),2.62(s,3H).

Example 54

step 1:

The raw material 54a (5.0 g) was dissolved in ethanol (90 ml) at room temperature, hydrazine hydrate (30 ml) was added, and the mixture was placed at 80 degrees Celsius to react overnight. After the reaction was completed, after reacting overnight at room temperature, water (300 mL) was slowly added for quenching. Extract with ethyl acetate (3×250 mL). The organic phases after extraction were combined and washed twice with saturated brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 54b (5.2 g). LC-MS: m/z 202(M+H) ⁺ .

Step 2:

At room temperature, the raw material 54b (5.2g) was dissolved in N,N-dimethylformamide (100ml), and N,N-diisopropylethylamine (10.0g), di-tert-butyl dicarbonate ( 11.2g), placed at room temperature to react for 2 hours. After the reaction was over, water (300 mL) was slowly added to quench. Extract with ethyl acetate (3×250 mL). The organic phases after extraction were combined and washed twice with saturated brine (250 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-35%) to obtain the product 54c (7.5 g). LC-MS: m/z 302(M+H) ⁺ .

Step 3:

The raw material 54c (7.5 g) was dissolved in dichloromethane (150 ml) at room temperature, added to a solution of trifluoroacetic acid (30 ml), and reacted overnight at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 54d (7.6 g). LC-MS: m/z 202(M+H) ⁺ .

Step 4:

At room temperature, the raw material 54d (7.6 g) was dissolved in N,N-dimethylformamide (100 mL). Add 2-methylthio-4,6-dichloro-5-pyrimidinecarbaldehyde (4.82 g). After reacting for 2 hours at room temperature, a saturated aqueous sodium hydrogen carbonate solution (100 mL) was slowly added to precipitate a solid. The filtered solid was washed with saturated sodium bicarbonate aqueous solution (100 mL) and dried to obtain crude product 54e (8.5 g).

LC-MS: m/z 406(M+H) ⁺ .

Step 5:

At room temperature, the starting material 54e (8.5 g) was dissolved in dichloromethane (100 ml). At -78 degrees Celsius, diisobutylaluminum hydride (5.96 g) was added. After reacting at -78 degrees Celsius for 8 hours, an aqueous hydrochloric acid solution (adjusted to pH = 1) was slowly added. Extract with ethyl acetate (3×250 mL). The organic phases after extraction were combined and washed twice with saturated brine (250 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-35%) to obtain the product 54f (4.5 g).

LC-MS: m/z 409(M+H) ⁺ .

Step 6:

At room temperature, the raw material 54f (4.5 g) was dissolved in toluene (60 ml). Add p-toluenesulfonic acid (1.89 g) and ethylene glycol (1.36 g) in sequence. After reacting at 100 degrees Celsius for 4 hours, it was quenched by adding water. Extract with ethyl acetate (3×150 mL). The organic phases after extraction were combined and washed twice with saturated brine (150 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 15%-25%) to obtain 54 g (4.6 g) of the product.

LC-MS: m/z 453(M+H) ⁺ .

Step 7:

At room temperature, 54 g (4.6 g) of the raw material was dissolved in N,N-dimethylformamide (80 mL). Add 2-cyanomethylpiperazine hydrochloride (2.42g) and N,N-diisopropylethylamine (6.58g) sequentially. After reacting at room temperature for 2 hours, it was quenched by slowly adding water (200 mL). Extract with ethyl acetate (3×150 mL). The organic phases after extraction were combined and washed twice with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of 54h (4.8 g).

LC-MS: m/z 542(M+H) ⁺ .

Step 8:

At room temperature, the raw material 54h (4.8g) was dissolved in N,N-dimethylformamide (80ml), and N,N-diisopropylethylamine (3.43g) and di-tert-butyl dicarbonate were added. (3.83g). After reacting at room temperature for 2 hours, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (3×200 mL), and the extracted organic phases were combined and washed with saturated brine (250 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-40%) to obtain product 54i (5.1 g).

LC-MS: m/z 642(M+H) ⁺ .

Step 9:

At room temperature, dissolve raw material 54i (5.1g) in methanol (200ml), add triethylamine (8043mg), Pd(dppf)Cl ₂ (562mg), and then fill with carbon monoxide gas (20 atm) , The reaction solution was reacted at 100 degrees Celsius for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-35%) to obtain the product 54j (2.4 g).

LC-MS: m/z 666(M+H) ⁺ .

Step 10:

At room temperature, the raw material 54j (2.4 g) was dissolved in acetic acid (50 ml), and the reaction solution was reacted overnight at 50 degrees Celsius. After the reaction was completed, water (100 mL) was slowly added for quenching, and sodium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=45%-60%) to obtain the product 54k (800 mg).

LC-MS: m/z 634(M+H) ⁺ .

Step 11:

At room temperature, the raw material 54k (800 mg) was dissolved in dichloromethane (20 ml), m-chloroperoxybenzoic acid (650 mg) was added, and the reaction was carried out at room temperature for 45 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 54 l (820 mg) of crude product.

LC-MS: m/z 666(M+H) ⁺

Step 12:

At room temperature, the raw materials, 54l (820 mg) were dissolved in N,N-dimethylformamide (20 ml), and 3-diethylaminoazetidine hydrochloride (494 mg) was added successively, N, N-Diisopropylethylamine (793 mg) was reacted for 2 hours at room temperature. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-10%) to obtain the product 54m (450 mg).

LC-MS: m/z 714(M+H) ⁺

Step 13:

The raw material 54m (450 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 ml) solution at room temperature, and reacted at room temperature for 1 hour. After the reaction was completed, sodium carbonate aqueous solution was added to adjust the pH=8, and the mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product 54n (300 mg) was obtained.

LC-MS: m/z 570(M+H) ⁺ .

Step 14:

At room temperature, the raw material 54n (300 mg) was dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (204 mg) and di-tert-butyl dicarbonate were added. (227 mg). After reacting at room temperature for 2 hours, it was quenched by adding water (100 mL). It was extracted with ethyl acetate (3×100 mL), the extracted organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=5%-10%) to obtain the product 54o (310 mg).

LC-MS: m/z 670(M+H) ⁺ .

Step 15:

At room temperature, the raw material 54o (100 mg) was dissolved in dichloromethane (20 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (165 mg) was added. Reacted overnight at room temperature and quenched by adding water (30 mL). It was extracted with dichloromethane (3×30 mL), and the extracted organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=5%-10%) to obtain the product 54p (40 mg).

LC-MS: m/z 692(M+H) ⁺ .

Step 16:

The raw material 54p (40 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the reaction, the crude product 54q (30 mg) was obtained by concentration under reduced pressure.

LC-MS: m/z 592(M+H) ⁺ .

Step 17:

At room temperature, the raw material 54q (30 mg) was suspended in dichloromethane (5 ml), and at -40 degrees Celsius, triethylamine (24.2 mg) and acryloyl chloride (5.2 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 15 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column to obtain product 54 (9.8 mg).

LC-MS: m/z 646(M+H) ⁺

¹ H-NMR(CD ₃ OD)δ: 8.31(s,1H), 8.08(d,J=8.0Hz,1H), 7.96(t,J=8.0Hz,1H), 7.71(d,J=8.0Hz ,1H),7.16(t,J=54.0Hz,1H),6.91-6.72(m,1H),6.29(d,J=16.8Hz,1H),5.83(d,J=10.4Hz,1H),5.13 -4.99 (m, 1H), 4.57-4.45 (m, 1H), 4.39-4.21 (m, 3H), 4.19-4.00 (m, 3H), 3.78-3.43 (m, 4H), 3.04-2.89 (m, 2H), 2.64(q,J=7.2Hz,4H), 1.07(t,J=7.2Hz,6H).

Example 55 and Example 56

step 1:

At room temperature, the raw material 55a (1 g) was dissolved in ethanol (20 ml). Diethylamine (451 mg) was added. After reacting overnight at room temperature, it was quenched by slowly adding water (100 mL), and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (2×100 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a dark yellow solid crude mixture 55b and 56a (1:10) (1.00 g).

55b , LC-MS: m/z 268(M+H) ⁺

56a , LC-MS: m/z 241(M+H) ⁺

Step 2:

The raw material mixture 55b and 56a (1.00 g) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 ml) solution at room temperature, and reacted at room temperature for 15 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude red mixture 55c and 56b (800 mg).

55c , LC-MS: m/z 168(M+H) ⁺

56b , LC-MS: m/z 141(M+H) ⁺

Step 3:

Intermediate 9i' (250 mg) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and crude mixtures 55c and 56b (87.6 mg) were added successively, N,N-diisopropylethyl Amine (0.36 mL), react overnight at room temperature. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=0%-12%) to obtain products 55d (16 mg) and 56c (142 mg).

LC-MS: m/z 695(M+H) ⁺

LC-MS: m/z 668(M+H) ⁺

Step 4:

The raw material 55d (16 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 55e (13 mg).

LC-MS: m/z 595(M+H) ⁺

Step 5:

At room temperature, the raw material 55e (13 mg) was suspended in dichloromethane (5 mL), and at -40 degrees Celsius, triethylamine (0.02 mL) and acryloyl chloride (2.1 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 20-40%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 55 (2.3 mg).

LC-MS: m/z 649(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.29 (s, 1H), 7.71-7.52 (m, 2H), 7.36-7.26 (m, 1H), 6.95-6.72 (m, 1H), 6.29 (d, J = 16.8Hz, 1H), 5.83 (d, J = 9.6Hz, 1H), 5.14-5.01 (m, 1H), 4.64-4.46 (m, 2H), 4.34-4.13 (m, 4H), 3.79-3.45 ( m,4H),3.06-2.87(m,4H),2.66-2.47(m,7H),1.13(t,J=6.8Hz,6H).

Step 6:

The raw material 56c (142 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (5 ml) solution at room temperature, and the reaction was carried out at room temperature for 15 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 56d (127.6 mg).

LC-MS: m/z 568(M+H) ⁺

Step 7:

At room temperature, the raw material 56d (127.6 mg) was suspended in dichloromethane (5 mL), and at -40 degrees Celsius, triethylamine (0.15 mL) and acryloyl chloride (19.2 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×30 mL). The organic phases were combined and washed with saturated brine (2×30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 56 (40 mg).

LC-MS: m/z 622(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.30 (s, 1H), 7.69-7.49 (m, 2H), 7.33-7.25 (m, 1H), 6.90-6.72 (m, 1H), 6.29 (d, J = 16.8Hz, 1H), 5.83 (d, J = 9.6Hz, 1H), 5.11-4.99 (m, 1H), 4.59-4.44 (m, 2H), 4.35-4.14 (m, 5H), 3.79-3.46 ( m,5H),3.19-2.91(m,4H),2.58(s,3H),1.25(t,J=7.2Hz,3H).

Example 57

step 1:

At room temperature, the material 57a (20 g) was dissolved in dichloromethane (400 ml). Add L-alanine methyl ester hydrochloride (11.6g), N,N-diisopropylethylamine (50.9ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodi Imine hydrochloride (19.2 g). After nitrogen replacement 3 times, the reaction was carried out at room temperature for 16 hours. After the reaction was completed, it was quenched by slowly adding water (500 mL), and extracted with dichloromethane (3×200 mL). The organic phases were combined and washed with saturated brine (300 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 57b (17 g). LC-MS: m/z 325(M+H) ⁺ .

Step 2:

At room temperature, the raw material 57b (17 g) was dissolved in methanol (300 ml)/cyclohexane (50 ml). Palladium/carbon (560 mg, water content 40%) was added and then 5 atmospheres of hydrogen was charged. React at 70 degrees Celsius for 3 hours. After the reaction is completed, filter, the filter residue was washed with methanol (2×100 ml), and the filtrate was combined and concentrated under reduced pressure to obtain crude product 57c (9.8 g).

LC-MS: m/z 191(M+H) ⁺ .

Step 3:

At room temperature, the raw material 57c (9.8 g) was dissolved in methanol (100 ml). Triethylamine (14.3 ml) was added, and after nitrogen replacement 3 times, the reaction was carried out overnight at 60 degrees Celsius. After the reaction is complete, concentrate under reduced pressure, add 2-butanone (50 ml)/petroleum ether (50 ml) and stir for 30 minutes, then filter, and filter cake with 2-butanone/petroleum ether (1:2, 2 ×100ml) was washed and dried to obtain crude product 57d ( 4.3g ). LC-MS: m/z 159(M+H) ⁺ .

Step 4:

The raw material 57d (4.3 g) was dissolved in a borane/tetrahydrofuran (1 mol/L) (20 ml) solution at room temperature, and reacted at 70 degrees Celsius for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 57e (3.5 g). LC-MS: m/z 131(M+H) ⁺ .

Step 5:

At 0 degrees Celsius, the raw material 57e (3.50 g) was dissolved in tetrahydrofuran (80 ml), and triethylamine (3.73 ml) and di-tert-butyl dicarbonate (5.79 ml) were added. The reaction solution was reacted for 2 hours at 0 degrees Celsius. After the reaction was completed, it was quenched by adding water (200 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (150 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 57f (1.55 g). LC-MS: m/z 231(M+H) ⁺ .

Step 6:

At room temperature, the raw material 57f (1.55 g) was dissolved in ethyl acetate (30 ml)/water (30 ml), and sodium bicarbonate (1.7 g) and benzyl chloroformate (1.49 g) were added. The reaction solution was reacted overnight at room temperature. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×80 mL). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=40%-50%) to obtain 57 g (968 mg) of the product.

LC-MS: m/z 365(M+H) ⁺ .

Step 7:

At room temperature, 57 g (968 mg) of the raw material was dissolved in dichloromethane (30 mL), and triethylamine (805 mg) and methanesulfonyl chloride (365 mg) were sequentially added. The reaction solution was reacted for 2 hours at room temperature. After the reaction was completed, it was quenched by adding water (200 mL). Extract with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=35%-50%) to obtain the product 57h (826 mg).

LC-MS: m/z 443(M+H) ⁺ .

Step 8:

At room temperature, the raw material 57h (826 mg) was dissolved in N,N-dimethylacetamide (30 mL), and sodium cyanide (366 mg) was added. The reaction solution was reacted overnight at 60 degrees Celsius. After the reaction is complete, add water (200 mL) and ferrous sulfate (1.5 g, 10 mmol) to quench. After quenching, it was filtered, the filter residue was washed with ethyl acetate (3×50 ml), and the filtrate was extracted with ethyl acetate (3×100 ml). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-50%) to obtain the product 57i (457 mg). LC-MS: m/z 374(M+H) ⁺ .

Step 9:

The raw material 57i (457 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (20 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 57j (374 mg). LC-MS: m/z 274(M+H) ⁺ .

Step 10:

Intermediate 18d (460 mg) was dissolved in N,N-dimethylformamide (15 mL) at room temperature. The raw material 57j (374 mg) and N,N-diisopropylethylamine (0.97 ml) were sequentially added. After reacting overnight at room temperature, it was quenched by slowly adding water (150 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=20%-40%) to obtain the product 57k (141 mg). LC-MS: m/z 652(M+H) ⁺ .

Step 11:

At room temperature, dissolve the raw material 57k (141 mg) in methanol (15 ml), add triethylamine (0.03 ml), Pd(dppf)Cl ₂ (17.6 mg), and then fill with carbon monoxide gas (20 atm). , The reaction solution was reacted at 100 degrees Celsius for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=25%-40%) to obtain 57l (100 mg) of the product.

LC-MS: m/z 676(M+H) ⁺ .

Step 12:

At room temperature, 57 l (100 mg) of the raw material was dissolved in acetic acid (20 ml), and the reaction solution was reacted at 110 degrees Celsius for 20 minutes. After the reaction was completed, water (150 mL) was slowly added for quenching, and sodium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=50%-70%) to obtain the product 57m (80.2 mg). LC-MS: m/z 644(M+H) ⁺ .

Step 13:

At room temperature, the raw material 57m (80.2 mg) was dissolved in dichloromethane (20 ml), m-chloroperoxybenzoic acid (85%) (50.5 mg) was added, and the reaction solution was reacted at room temperature for 40 minutes. After the reaction, it was quenched by adding sodium thiosulfate aqueous solution (100 mL), and extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 57n (72.0 mg). LC-MS: m/z 676(M+H) ⁺ .

Step 14:

At room temperature, the raw material 57n (72.0 mg) was dissolved in N,N-dimethylformamide (10 ml), and 3-diethylaminoazetidine (64.2 mg) and triethylamine (32.3 mg) were added sequentially. ), react overnight at room temperature. After the reaction was completed, it was quenched by adding water (50 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 57o (60.2 mg). LC-MS: m/z 724(M+H) ⁺ .

Step 15:

Dissolve the raw material 57o (60.2 mg) in dichloromethane (10 ml) at 0 degrees Celsius, add hydrogen bromide/acetic acid (1 mol/L) (1 ml), and react at 0 degrees Celsius for 4 hours. After the completion of the reaction, it was quenched by adding water (100 mL), the pH of the reaction solution was adjusted to 8 with sodium carbonate, and then extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (100 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 57p (20.0 mg). LC-MS: m/z 590(M+H) ⁺ .

Step 16:

At room temperature, the raw material 57p (20.0 mg) was suspended in dichloromethane (20 ml), and at -40 degrees Celsius, triethylamine (17.1 mg) and acryloyl chloride (3.07 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (50 mL). Extract with dichloromethane (3×20 mL). The organic phases were combined and washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 57 (3.0 mg).

LC-MS: m/z 644(M+H) ⁺ .

¹ H-NMR (CD ₃ OD)δ: 8.22 (s, 1H), 7.88-7.73 (m, 2H), 7.56-7.43 (m, 1H), 6.85-6.70 (m, 1H), 6.34 (d, J = 16.2 Hz, 1H), 5.86 (d, J = 10.5 Hz, 1H), 5.26-5.13 (m, 1H), 4.73-4.58 (m, 2H), 4.53-4.27 (m, 3H), 4.22-4.01 ( m,2H),3.82-3.62(m,3H),3.02-2.86(m,2H),2.75-2.58(m,4H),1.50-1.37(m,3H),1.09(t,J=7.2Hz, 6H).

Example 58

step 1

The raw material 58a (10.0 g) was dissolved in absolute ethanol (150 ml), and hydrazine hydrate (10.3 g) was added at room temperature. The resulting mixture was heated to 80 degrees Celsius and stirred for 8 hours. After the completion of the reaction, the reaction solution was cooled to room temperature and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-50%) to obtain product 58b (5.3 g). LC-MS: m/z 255(M+H) ⁺

Step 2

The starting material 58b (5.3 g) was dissolved in NN-dimethylformamide (15 ml), and 2-(methylthio)-4,6-dichloro-5-pyrimidinecarbaldehyde (4.17 g) was added. The resulting mixture was reacted at room temperature for 2 hours. After the reaction is completed, no treatment is required, and the next reaction is directly carried out.

LC-MS: m/z 459(M+H) ⁺

Step 3

Add N,N-diisopropylethylamine (7.02 g) and 2-cyanomethylpiperazine dihydrochloride (2.37 g) to the reaction solution in the previous step. React at room temperature for 2 hours. After the reaction is completed, no treatment is required, and the next reaction is directly carried out. LC-MS: m/z 548(M+H)

Step 4

Add N,N-diisopropylethylamine (1.77 g) and di-tert-butyl dicarbonate (2.98 g) to the reaction solution in the previous step. React at room temperature for 2 hours. After the reaction, it was extracted with ethyl acetate (200 ml x 3), and the extract was concentrated to dryness. The crude product obtained was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 30%-60%) to obtain product 58e (5.1 g) . LC-MS: m/z 648(M+H)

Step 5

The raw material 58e (5.10 g) was dissolved in anhydrous methanol (50 ml), and triethylamine (0.80 g), [1,1'-bis(diphenylphosphino)ferrocene] two were added in sequence at room temperature. Palladium chloride (0.58 g) was injected with CO gas to 20 atmospheres and reacted at 100 degrees Celsius for 2 hours. After the reaction is complete, cool to room temperature. The organic phase is concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 58f (1.2 g). LC-MS: m/z 672(M+H) ⁺

Step 6

The raw material 58f (1.2 g) was dissolved in acetic acid (15 ml) and reacted at 110 degrees Celsius for 30 minutes. After the reaction is completed, the pH of the reaction solution is adjusted to neutral with anhydrous sodium carbonate. It was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined and concentrated to dryness. The filtrate was concentrated to dryness to obtain 58 g (400 mg) of the product. LC-MS: m/z 640(M+H) ⁺

Step 7

58 g (400 mg, 0.625 mmol) of the raw material was dissolved in dichloromethane (10 mL), then m-chloroperoxybenzoic acid (173 mg, 1.87 mmol) was added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, solid ammonium chloride was added to quench, 15 mL of water was added and extraction was performed with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness to obtain the product 58h (300 mg).

LC-MS: m/z 672(M+H) ⁺

Step 8

The raw material 58h (300 mg) was dissolved in N,N-dimethylformamide solution (10 mL). N,N-diisopropylethylamine (288 mg) and N,N-diethylazetidine-3-amine hydrochloride (68.6 mg) were sequentially added, and the resulting solution was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with 10 ml of water and extracted with ethyl acetate (15 ml×3). The organic phases were combined and concentrated to dryness to obtain crude product 58i (100 mg).

LC-MS: m/z 720(M+H) ⁺

Step 9

1,4-Dioxane solution (10 mL) was added to the raw material 58i (100 mg), and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, it was directly concentrated to dryness to obtain crude product 58j (50 mg) for the next reaction. LC-MS: m/z 620(M+H) ⁺

Step 10

The raw material 58j (50 mg) was dissolved in a dichloromethane solution (10 ml), and triethylamine (40.77 mg) and acryloyl chloride (8.75 mg) were sequentially added under ice bath. The reaction was carried out under ice bath for 30 minutes. After the reaction was completed, it was diluted with 10 ml of water and extracted with dichloromethane (15 ml×3). The organic phases were combined and concentrated to dryness to give a crude product 58 . Purified by a preparative chromatography column, product 58 (2 mg) was obtained.

LC-MS: m/z 674(M+H) ⁺

¹ H NMR (300MHz, CD ₃ OD-d ₄ ) δ 8.31 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.73-7.49 (m, 2H), 6.83 (m, 1H), 6.31(m,1H), 5.85(m,1H), 5.07(m,1H), 4.63–4.00(m,7H), 3.75(m,4H), 2.99(d,J=7.2Hz,2H), 2.67 (q,J=7.2Hz,4H), 1.09(t,J=7.2Hz,6H).

Example 59 and Example 60

Chiral resolution of the racemate compound 58 (column type: Chiralpak IC, 2*25cm, 5um; mobile phase A: methyl tert-butyl ether (10 mmol/L ammonia in methanol), mobile phase B: ethanol , Flow rate: 20 ml/min; gradient: 50%; time: 18 minutes) to obtain monomer 59 , 60 .

Splitting conditions of monomer 59 :

Column type: CHIPALPAK IC-3; mobile phase A: n-hexane: methyl tert-butyl ether (0.1% diethylamine) = 1:1, mobile phase B: ethanol; gradient: 60: 40; flow rate: 1 ml/ Minutes; retention time: 2.68 minutes

¹ H-NMR (300MHz, CD ₃ OD-d4) δ 8.31 (s, 1H), 8.01 (m, 1H), 7.73-7.49 (m, 2H), 6.96-6.69 (m, 1H), 6.37-6.24 (m,1H),5.92-5.78(m,1H),5.17-4.98(m,1H),4.63-4.00(m,7H),3.75-3.42(m,4H),3.00(d,J=7.2Hz ,2H), 2.67(q,J=7.2Hz,4H),1.08(t,J=7.2Hz,6H).

Splitting conditions of monomer 60 :

Column type: CHIPALPAK IC-3; mobile phase A: n-hexane: methyl tert-butyl ether (0.1% diethylamine) = 1:1, mobile phase B: ethanol; gradient: 70:30; flow rate: 1 ml/ Minutes; retention time: 3.54 minutes

¹ H-NMR (300MHz, CD ₃ OD-d4) δ 8.31 (s, 1H), 8.01 (m, 1H), 7.74-7.49 (m, 2H), 6.99-6.68 (m, 1H), 6.35-6.25 (m,1H),5.91-5.77(m,1H),5.16-5.00(m,1H),4.62-4.98(m,7H),3.75-3.41(m,4H),3.00(d,J=7.2Hz ,2H), 2.67(q,J=7.2Hz,4H),1.08(t,J=7.2Hz,6H).

Example 61

step 1:

At room temperature, HATU (227 mg), triethylamine (0.21 mL), 2-fluoroacrylic acid (40.3 mg) were stirred in N,N-dimethylformamide (5 mL) for 30 minutes, and then the intermediate 58j (196 mg) was dissolved in N,N-dimethylformamide (2 ml) and added to the above reaction solution, and reacted at room temperature for 2 hours. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 61 (76 mg).

LC-MS: m/z 692(M+H) ⁺ .

¹ H-NMR (CD ₃ OD)δ: 8.31 (s, 1H), 8.07-7.95 (m, 1H), 7.74-7.60 (m, 1H), 7.57-7.48 (m, 1H), 5.47-5.23 (m ,2H),4.85-4.80(m,1H),4.62-4.49(m,1H),4.44-4.01(m,6H),3.83-3.51(m,4H),3.14-2.99(m,2H),2.75 -2.56(m,4H),1.10(t,J=7.5Hz,6H).

Example 62 and Example 63

The compound racemate 61 was subjected to chiral resolution (column type: Chiralpak IC, 2*25cm, 5um; mobile phase A: methyl tert-butyl ether (10 mmol/L ammonia in methanol), mobile phase B: Ethanol, flow rate: 20 ml/min; gradient: 50%; time: 18 minutes) to obtain monomers 62 , 63 .

Analysis conditions of monomer 62 :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; gradient: 60: 40; flow rate: 1 ml/min; retention time: 1.750 minutes

¹ H-NMR (CD ₃ OD) δ: 8.28 (s, 1H), 8.02-7.97 (m, 1H), 7.69-7.62 (m, 1H), 7.53-7.48 (m, 1H), 5.44-5.24 (m ,2H),4.62-4.45(m,2H),4.39-4.00(m,6H),3.77-3.51(m,4H),3.11-2.96(m,2H),2.71-2.58(m,4H),1.06 (t,J=7.2Hz,6H).

Analysis conditions of monomer 63 :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; gradient: 60: 40; flow rate: 1 ml/min; retention time: 2.648 minutes

¹ H-NMR (CD ₃ OD) δ: 8.29 (s, 1H), 8.02-7.98 (m, 1H), 7.70-7.63 (m, 1H), 7.54-7.49 (m, 1H), 5.43-5.25 (m ,2H),4.62-4.49(m,2H),4.40-4.02(m,6H),3.77-3.52(m,4H),3.09-3.00(m,2H),2.71-2.60(m,4H),1.07 (t,J=7.2Hz,6H).

Example 64

Synthesis of Example 64 With reference to Example 33, compound 58h was used instead of compound 18i , and 3-dipropylaminoazetidine was used instead of NN-diethylazetidine hydrochloride. Purification by preparative reversed-phase chromatography column , Get product 64 (93 mg). LC-MS: m/z 720(M+H) ⁺ .

¹ H-NMR (CD ₃ OD) δ: 8.28 (s, 1H), 8.02-7.98 (m, 1H), 7.69-7.63 (m, 1H), 7.53-7.48 (m, 1H), 5.42-5.24 (m ,2H),4.59-4.46(m,2H),4.37-3.99(m,6H),3.78-3.53(m,4H),3.11-2.97(m,2H),2.56-2.43(m,4H),1.59 -1.42(m,4H),0.91(t,J=7.6Hz,6H).

Example 65 and Example 66

The compound racemate 64 was subjected to chiral resolution (column type: Chiralpak IC, 2*25cm, 5um; mobile phase A: methyl tert-butyl ether (10 mmol/L ammonia in methanol), mobile phase B: Ethanol, flow rate: 18 ml/min; gradient: 30%; time: 22 minutes) to obtain monomers 65 , 66 .

Analysis conditions of monomer 65 :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; gradient: 70:30; flow rate: 1 ml/min; retention time: 1.989 minutes

¹ H-NMR (CD ₃ OD) δ: 8.27 (s, 1H), 8.02-7.97 (m, 1H), 7.69-7.63 (m, 1H), 7.54-7.49 (m, 1H), 5.42-5.24 (m ,2H),4.62-4.45(m,2H),4.37-4.02(m,6H),3.77-3.51(m,4H),3.09-2.95(m,2H),2.53-2.43(m,4H),1.56 -1.45(m,4H),0.92(t,J=7.2Hz,6H).

Analysis conditions of monomer 66 :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol; gradient: 70:30; flow rate: 1 ml/min; retention time: 3.359 minutes

¹ H-NMR (CD ₃ OD) δ: 8.27 (s, 1H), 8.01-7.97 (m, 1H), 7.69-7.63 (m, 1H), 7.53-7.48 (m, 1H), 5.44-5.24 (m ,2H),4.65-4.46(m,2H),4.38-4.00(m,6H),3.78-3.51(m,4H),3.11-2.96(m,2H),2.54-2.43(m,4H),1.56 -1.44(m,4H),0.91(t,J=7.2Hz,6H).

Example 67

step 1

The raw material 67a (10.0 g) was dissolved in anhydrous acetonitrile (200 ml), and p-methoxybenzyl chloride (9.02 g) and potassium carbonate (21.7 g) were added at room temperature. The resulting mixture was stirred at room temperature for 6 hours. After the reaction is completed, the mixture is filtered and the filtrate is concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-50%) to obtain product 67b (8.0 g).

LC-MS: m/z 311(M+H) ⁺

Step 2

Dissolve raw material 67b (8.0 g) in dry toluene (150 ml), add tert-butoxycarbonyl hydrazine (4.08 g), tridibenzylidene acetone dipalladium (2.35 g), 2-dicyclohexyl at room temperature Phosphorus-3,6-dimethoxy-2,4,6-tris│propyl-1,1-biphenyl (2.76g), cesium carbonate (16.8g). The resulting mixture was heated to 70 degrees Celsius and stirred for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature. The mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-50%) to obtain product 67c (3 g). LC-MS: m/z 363(M+H) ⁺

Step 3

The raw material 67c (3 g) was added to a 1,4-dioxane solution of HCl (50 mL, 4 mol/L), and stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was concentrated to dryness to obtain crude product 67d (2.0 g). LC-MS: m/z 143(M+H) ⁺

Step 4

The raw material 67d (2.0 g) was dissolved in NN-dimethylformamide (20 mL), and 2-(methylthio)-4,6-dichloro-5-pyrimidinecarbaldehyde (2.83 g) was added. The resulting mixture was reacted at room temperature for 2 hours. LC-MS: m/z 347(M+H) ⁺

Step 5

Add N,N-diisopropylethylamine (2.05 g) and 2-cyanomethylpiperazine dihydrochloride (0.722) to the reaction solution in the previous step. React at room temperature for 2 hours. LC-MS: m/z 436(M+H)

Step 6

Add tert-butyldimethylsilane (0.5 g) and imidazole (0.22 g) to the reaction solution in the previous step. React at room temperature for 2 hours.

LC-MS: m/z 550(M+H)

Step 7

Add di-tert-butyl dicarbonate (1.11 g) and N,N-diisopropylethylamine (1.64 g) to the reaction solution in the previous step. React at room temperature for 2 hours. After the reaction was completed, it was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. The filtrate was concentrated to dryness to obtain the product 67h (1.4 g). LC-MS: m/z 650(M+H) ⁺

Step 8

The raw material 67h (1.4 g) was dissolved in anhydrous methanol (100 ml), and triethylamine (0.22 g), [1,1'-bis(diphenylphosphino)ferrocene] two were added in sequence at room temperature. Palladium chloride (0.18 g) was injected with CO gas to 20 atmospheres and reacted at 100 degrees Celsius for 2 hours. After the reaction is complete, cool to room temperature. The organic phase is concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 30%-60%) to obtain product 67i (0.3 g). LC-MS: m/z 674(M+H) ⁺

Step 9

The raw material 67i (0.3 g) was dissolved in acetic acid (10 ml) and reacted at 50 degrees Celsius for 8 hours. After the reaction is completed, the pH of the reaction solution is adjusted to neutral with anhydrous sodium carbonate. It was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. The filtrate was concentrated to dryness to obtain the product 67j (150 mg). LC-MS: m/z 642(M+H) ⁺

Step 10

The raw material 67j (150 mg) was dissolved in dichloromethane (10 mL), and then m-chloroperoxybenzoic acid (173 mg) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, solid ammonium chloride was added to quench, 15 mL of water was added and extraction was performed with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness to obtain a crude product of 67k (100 mg). LC-MS: m/z 674(M+H) ⁺

Step 11

The raw material 67k (100 mg) was dissolved in N,N-dimethylformamide solution (5 mL). N,N-diisopropylethylamine (96.0 mg) and N,N-diethylazetidine-3-amine hydrochloride (22.8 mg) were sequentially added, and the resulting solution was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with 10 ml of water and extracted with ethyl acetate (15 ml×3). The organic phases were combined and concentrated to dryness to obtain 67 l (50 mg) of crude product.

LC-MS: m/z 722(M+H) ⁺

Step 12

A 1,4-dioxane solution of HCl (10 mL, 4 mol/L) was added to the raw material 67k (50 mg), and the reaction was carried out at room temperature for 30 minutes. After the reaction is completed, no treatment is required, and it is directly concentrated to dryness to obtain a crude product of 67m (15 mg) for the next reaction. LC-MS: m/z 508(M+H) ⁺

Step 13

The raw material 67m (15.0 mg) was dissolved in a dichloromethane solution (3 ml), and triethylamine (15.0 mg) and acryloyl chloride (2.67 mg) were sequentially added under ice bath. The reaction was carried out under ice bath for 30 minutes. After the reaction was completed, it was diluted with 10 ml of water and extracted with dichloromethane (15 ml×3). The organic phases were combined and concentrated to dryness. The crude product was purified with a preparative chromatography column to obtain product 67 (1.0 mg).

LC-MS: m/z 562(M+H) ⁺

¹ H NMR(DMSO)δ: 8.23(s,1H), 7.20-7.38(m,1H), 6.70-6.92(m,3H), 6.11-6.27(m,1H), 5.79(d,J=10.8Hz) ,1H),4.71-5.06(m,2H),3.81-4.42(m,9H),3.53-3.78(m,4H),3.01(q,J=7.2Hz,4H),0.96(t,J=7.2 Hz, 6H).

Example 68

step 1

Raw material 68a (2.0g) was dissolved in N,N-dimethylformamide (150ml), and 2-(methylthio)-4,6-dichloro-5-pyrimidinecarbaldehyde (2.27g) was added at room temperature ). The resulting mixture was stirred at room temperature for 2 hours. After the reaction is completed, the reaction does not need to be treated and is directly used in the next step.

LC-MS: m/z 381(M+H) ⁺

Step 2

Add 2-cyanomethylpiperazine dihydrochloride (1.01 g) and N,N-diisopropylethylamine (10.9 g) to the upper reaction solution. The resulting mixture was reacted at room temperature for 2 hours. After the reaction is completed, no treatment is required, and the next reaction is directly carried out. LC-MS: m/z 470(M+H) ⁺

Step 3

Add N,N-diisopropylethylamine (1.03 g) and di-tert-butyl dicarbonate (1.74 g) to the reaction solution in the previous step. React at room temperature for 2 hours. After the reaction was completed, it was diluted with water (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness to obtain a crude product 68d (2.7 g). LC-MS: m/z 570(M+H) ⁺

Step 4

The raw material 68d (2.7g) was dissolved in N,N-dimethylformamide solution (15ml), and 4-dimethylaminopyridine (0.03g), di-tert-butyl dicarbonate (3.10g), N, N-Diisopropylethylamine (1.84 g). React at room temperature for 2 hours. After the reaction was completed, it was diluted with water (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 68e (2.5 g). LC-MS: m/z 670(M+H) ⁺

Step 5

The raw material 68e (2.5g) was dissolved in anhydrous methanol (100ml), and triethylamine (0.38g), [1,1'-bis(diphenylphosphino)ferrocene] two were added in sequence at room temperature. Palladium chloride (0.27 g) was introduced into CO gas to 20 atmospheres and reacted at 100 degrees Celsius for 2 hours. After the reaction is complete, cool to room temperature. The organic phase is concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 68f (1.00 g). LC-MS: m/z 694(M+H) ⁺

Step 6

The raw material 68f (1 g) was added to a 1,4-dioxane solution of HCl (15 ml, 4 mol/L), and stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was concentrated to dryness to obtain 68 g (800 mg) of the product as a brown-yellow solid. LC-MS: m/z 494(M+H) ⁺

Step 7

68 g (800 mg) of the raw material was dissolved in acetic acid (10 ml) and reacted at 110 degrees Celsius for 30 minutes. After the reaction is completed, the pH of the reaction solution is adjusted to neutral with anhydrous sodium carbonate. It was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. The filtrate was concentrated to dryness to obtain the product 68h (300 mg). LC-MS: m/z 462(M+H) ⁺

Step 8

Dissolve raw material 68h (300 mg) in N,N-dimethylformamide solution (10ml), add N,N-diisopropylethylamine (126 mg), di-tert-butyl dicarbonate (212 mg) ). React at room temperature for 2 hours. After the reaction was completed, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness to obtain the crude product 68i (280 mg). LC-MS: m/z 562(M+H) ⁺

Step 9

The raw material 68i (280 mg) was dissolved in dichloromethane (10 mL), and then m-chloroperoxybenzoic acid (257..71 mg) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, solid ammonium chloride was added to quench, 20 mL of aqueous solution was added and extracted with ethyl acetate (30 mL×3). The organic phases were combined and concentrated to dryness to obtain crude product 68j (200 mg). LC-MS: m/z 594(M+H) ⁺

Step 10

The raw material 68j ( 200 mg) was dissolved in N,N-dimethylformamide solution (10 mL). N,N-diisopropylacetamide (217.41 mg) and N,N-diethylazetidine-3-amine hydrochloride (56.08 mg) were sequentially added, and the resulting solution was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with 10 ml of water and extracted with ethyl acetate (15 ml×3). The organic phases were combined and concentrated to dryness to obtain a crude product of 68k (100 mg). LC-MS: m/z 642(M+H) ⁺

Step 11

A 1,4-dioxane solution (10 ml, 4 mol/L) of HCl gas was added to the raw material 68k (100 mg), and the reaction was carried out at room temperature for 30 minutes. After the completion of the reaction, without treatment, it was directly concentrated to dryness to obtain 68 l (60 mg) of crude product for the next reaction. LC-MS: m/z 542(M+H) ⁺

Step 10

Dissolve 68 liters (60 mg) of raw materials in dichloromethane solution (10 mL), add triethylamine (56.0 mg) and acryloyl chloride (12.0 mg) in order under ice bath. The reaction was carried out under ice bath for 30 minutes. After the reaction was completed, it was diluted with 10 ml of water and extracted with dichloromethane (15 ml×3). The organic phases were combined and concentrated to dryness to obtain a crude product 68 .

Purified by preparative chromatography column, product 68 (5 mg) was obtained.

LC-MS: m/z 596(M+H)+

1H NMR(CD3OD)δ8.40(s,1H), 7.69-7.45(m,3H), 6.96-6.73(m,1H), 6.39-6.24(m,1H), 6.07-5.66(m,1H), 5.20-4.97(m,1H),4.45-4.04(m,7H),3.90-3.46(m,4H),3.17-2.88(m,2H),2.73(q,J=7.2Hz,4H),1.12( t,J=7.2Hz,6H).

Example 69

step 1

Raw material 69a (5.0 g) was dissolved in absolute ethanol (150 ml), and wet palladium carbon (0.5 g) was added at room temperature. Under hydrogen conditions, the mixture was heated to 60 degrees Celsius and stirred for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature. After the reaction solution was filtered, the organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-50%) to obtain product 69b (4.5 g).

LC-MS: m/z 180(M+H) ⁺

Step 2

Raw material 69b (1.5 g) was added to 6 moles per liter of hydrochloric acid aqueous solution (20 ml), and sodium nitrite (0.57 g) aqueous solution was slowly added dropwise at room temperature, and stirred at room temperature for 1 hour. Stannous chloride (2.53 g) was dissolved in 6 moles per liter of hydrochloric acid aqueous solution, cooled in an ice bath, slowly dropped into the reaction solution, and reacted at room temperature for 3 hours. After the reaction was completed, the pH was adjusted to neutral and then extracted with ethyl acetate (200 ml×3), and the extract was concentrated to dryness to obtain the product 69c (1.4 g). LC-MS: m/z 195(M+H) ⁺

Step 3

Raw material 69c (1.4 g) was dissolved in NN-dimethylformamide (15 mL), and 2-(methylthio)-4,6-dichloro-5-pyrimidinecarbaldehyde (1.44 g) was added. The resulting mixture was reacted at room temperature for 2 hours. After the reaction is completed, no treatment is required, and the next reaction is directly carried out.

LC-MS: m/z 399(M+H) ⁺

Step 4

Add N,N-diisopropylethylamine (2.91 g) and 2-cyanomethylpiperazine dihydrochloride (0.62 g) to the reaction solution in the previous step. React at room temperature for 2 hours. After the reaction is completed, no treatment is required, and the next reaction is directly carried out. LC-MS: m/z 488(M+H)

Step 5

Add N,N-diisopropylethylamine (0.71 g) and di-tert-butyl dicarbonate (1.21 g) to the reaction solution in the previous step. React for 2 hours at room temperature. After the reaction, it was extracted with ethyl acetate (200 ml x 3), and the extract was concentrated to dryness. The crude product obtained was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 30%-60%) to obtain product 69f (2 g) . LC-MS: m/z 588(M+H)

Step 6

The raw material 69f (2 g) was dissolved in anhydrous methanol (50 ml), and triethylamine (0.34 g), [1,1'-bis(diphenylphosphino)ferrocene] two were added in sequence at room temperature. Palladium chloride (0.25 g) was injected with CO gas to 20 atmospheres and reacted at 100 degrees Celsius for 2 hours. After the reaction is complete, cool to room temperature. The organic phase is concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain 69 g (0.7 g) of the product. LC-MS: m/z 612(M+H) ⁺

Step 7

69 g (0.7 g) of the raw material was dissolved in acetic acid (30 ml) and reacted at 110 degrees Celsius for 30 minutes. After the reaction is completed, the pH of the reaction solution is adjusted to neutral with anhydrous sodium carbonate. It was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined and concentrated to dryness. The filtrate was concentrated to dryness to obtain the product 69h (200 mg). LC-MS: m/z 580(M+H) ⁺

Step 8

The raw material 69h (200 mg) was dissolved in dichloromethane (5 mL), then m-chloroperoxybenzoic acid (178.38 mg, 1.034 mmol) was added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, solid ammonium chloride was added to quench, 15 mL of water was added and extraction was performed with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness to obtain product 69i (100 mg). LC-MS: m/z 612(M+H) ⁺

Step 9

The raw material 69i (100 mg) was dissolved in N,N-dimethylformamide solution (10 mL). N,N-diisopropylethylamine (105 mg) and N,N-diethylazetidine-3-amine hydrochloride (25.1 mg) were sequentially added, and the resulting solution was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with 10 ml of water and extracted with ethyl acetate (15 ml×3). The organic phases were combined and concentrated to dryness to obtain crude 69j (50 mg).

LC-MS: m/z 660(M+H) ⁺

Step 10

A 1,4-dioxane solution (10 ml, 4 mol/L) of HCl gas was added to the raw material 69j (50 mg), and the reaction was carried out at room temperature for 30 minutes. After the reaction is completed, no treatment is required, and it is directly concentrated to dryness to obtain a crude product of 69k (50 mg) for the next reaction.

LC-MS: m/z 560(M+H) ⁺

Step 11

The raw material 69k (50 mg) was dissolved in a dichloromethane solution (10 ml), and triethylamine (45.14 mg) and acryloyl chloride (9.69 mg) were sequentially added under ice bath. The reaction was carried out under ice bath for 30 minutes. After the reaction was completed, it was diluted with 10 ml of water and extracted with dichloromethane (15 ml×3). The organic phases were combined and concentrated to dryness to obtain a crude product 69 . Purified with a preparative chromatography column to obtain product 69 (2 mg).

LC-MS: m/z 614(M+H) ⁺

¹ H NMR (300MHz, CD ₃ OD-d ₄ ) δ 8.32 (s, 1H), 7.68 (m, 2H), 6.82 (m, 1H), 6.31 (m, 1H), 5.85 (m, J = 10.7 Hz,1H),5.07(m,1H),4.73-3.98(m,7H),3.74(m,4H),2.98(m,2H),2.67(q,J=7.2Hz,4H),1.09(t ,J=7.2Hz,6H).

Example 70

At room temperature, the raw material 33b (30.0 mg) was suspended in N,N-dimethylformamide (5 ml), and at room temperature, N,N-diisopropylethylamine (20.2 mg) was added successively. Phosphoric anhydride (33 mg), 2-chloroacrylic acid (8.27 mg). The reaction solution was reacted at room temperature for 30 minutes. After the reaction was completed, methanol (1 mL) was added for quenching. The crude product was purified by a preparative reverse phase chromatography column to obtain product 70 (6.00 mg). LC-MS: m/z 664(M+H) ⁺

¹ H-NMR (DMSO) δ: 8.26 (s, 1H), 8.00-7.77 (m, 2H), 7.65-7.50 (m, 1H), 5.85 (m, 2H), 4.98-4.48 (m, 1H), 4.41-4.27 (m, 1H), 4.25-4.03 (m, 3H), 4.02-3.77 (m, 3H), 3.75-3.40 (m, 4H), 3.17-2.96 (m, 2H), 2.58-2.51 (m ,4H),0.96(t,J=7.2Hz,6H).

Example 71

Synthesis of Example 71 Referring to Example 70, 2-(trifluoromethyl)acrylic acid was used instead of 2-chloroacrylic acid and purified by preparative reversed-phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 13-35%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 71 (5.60 mg ).

LC-MS: m/z 698(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.21 (s, 1H), 7.74-7.63 (m, 2H), 7.42-7.34 (m, 1H), 6.20 (s, 1H), 5.92 (s, 1H), 4.99(s, 1H), 4.33(s, 2H), 4.16(s, 3H), 3.89(s, 2H), 3.76-3.34(m, 4H), 2.95(s, 2H), 2.81(s, 4H) ,1.09(d,J=6.8Hz,6H).

Example 72

Synthesis of Example 72 Referring to Example 70, deuterated acrylic acid was used instead of 2-chloroacrylic acid, and purified by preparative reversed-phase chromatography to obtain product 72 (6.40 mg).

LC-MS: m/z 633(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.29 (s, 1H), 7.83-7.72 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 5.05 (s, 1H), 4.50 (d, J = 14.0Hz, 1H), 4.40-4.20 (m, 3H), 4.10 (s, 3H), 3.77-3.44 (m, 4H), 2.96 (s, 2H), 2.65 (q, J = 7.2Hz, 4H ),1.07(t,J=7.2Hz,6H).

Referring to the synthesis method of step 3 to 11 in Example 30, replacing compound 30c with a suitable brominated compound or preparation example compound, the following compounds were prepared:

Example 82

step 1:

Intermediate 9i' (80 mg) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and the compound of Preparation Example 26 (61.3 mg) and N,N-diisopropylethylamine were added sequentially (0.14 ml), react overnight at room temperature. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (2×80 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 82a (92 mg).

LC-MS: m/z 724(M+H) ⁺

Step 2:

The raw material 82a (92 mg) was dissolved in a hydrochloric acid/1,4-dioxane (4 mol/L) (10 ml) solution at room temperature, and reacted for 15 minutes at room temperature. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude product 82b (81 mg).

LC-MS: m/z 624(M+H) ⁺

Step 3:

At room temperature, the raw material 82b (67 mg) was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (0.09 mL) and acryloyl chloride (16.6 mg) were sequentially added. The reaction solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (100 mL). Extract with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (2×80 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain crude product 82c (80 mg).

LC-MS: m/z 678(M+H) ⁺

Step 4:

Raw material 82c (80 mg) was dissolved in tetrahydrofuran (10 mL)/water (2 mL) at room temperature, sodium hydroxide (9.44 mg) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated brine (2×80 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reverse phase chromatography column to obtain product 82 (12.1 mg).

LC-MS: m/z 582(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.27 (s, 1H), 7.67-7.60 (m, 1H), 7.57-7.50 (m, 1H), 7.33-7.26 (m, 1H), 6.88-6.73 (m ,1H), 6.28(d,J=16.8Hz,1H), 5.83(d,J=9.6Hz,1H),5.11-4.99(m,1H),4.52-4.35(m,3H),4.31-4.20( m,1H),4.14-3.91(m,3H),3.82-3.52(m,4H),3.05-2.82(m,2H),2.70-2.61(m,2H), 2.59-2.51(m,3H), 1.15(t,J=6.8Hz,3H).

Example 83

Synthesis of Example 83 With reference to Example 82, compound 9i was used instead of compound 9i' , and the compound of Preparation Example 20 was used instead of the compound of Preparation Example 26. Purification by preparative reverse phase chromatography column gave product 83 (6.2 mg).

LC-MS: m/z 596(M+H) ⁺

¹ H-NMR(CD ₃ OD)δ:8.30(s,1H), 7.67(t,J=7.8Hz,1H), 7.56(d,J=7.5Hz,1H), 7.32(d,J=8.1Hz ,1H),6.95-6.72(m,1H),6.31(d,J=16.5Hz,1H), 5.85(d,J=10.8Hz,1H), 5.16-4.95(m,1H),4.56-4.40( m,3H),4.35-4.21(m,1H),4.17-3.87(m,4H),3.81-3.46(m,3H),3.08-2.87(m,3H),2.60(d,J=2.4Hz, 3H), 1.14 (d, J=6.3Hz, 6H).

Referring to the synthesis method of steps 1 to 3 in Example 82, replacing the compound of Preparation Example 26 with a suitable nitrogen-containing heterocyclic compound or the compound of Preparation Example, the following compounds were prepared:

Referring to the synthesis method of step 1 to 3 in Example 82, using compound 9i instead of compound 9i' , and replacing the compound of Preparation Example 26 with a suitable nitrogen-containing heterocyclic compound or preparation example compound, the following compounds were prepared (the compound is in the form of formate , Its crude free base will form a salt with formic acid in the mobile phase when purified by a preparative chromatography column):

Example 126 and Example 127

The compound racemate 89 was subjected to chiral resolution (column type: NB-Lux 5um i-Cellulose-5, 2.12*25cm, 5μm; mobile phase A: methyl tert-butyl ether (10nM ammonia-methanol), mobile phase B: ethanol, flow rate: 20 ml/min; gradient: 20%; time: 29 minutes) to obtain monomers 126 and 127 .

Analysis conditions of monomer 126 :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol; gradient: 30%; flow rate: 1 ml/min; retention time: 1.861 minutes

¹ H-NMR (CD ₃ OD) δ: 8.30 (s, 1H), 7.68-7.64 (m, 1H), 7.57-7.54 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.92 6.75(m, 1H), 6.31(d,J=17.7Hz,1H), 5.85(d,J=11.7Hz,1H),5.11-5.03(m,1H),4.52(d,J=12.9Hz,1H ), 4.38-4.26(m,3H), 4.19-4.07(m,3H), 3.80-3.65(m,4H), 3.04-2.96(m,2H), 2.60(d,J=2.4Hz,3H), 2.56-2.51(m,4H), 1.58-1.50(m,4H), 0.94(t,J=7.2Hz,6H).

Analysis conditions of monomer 127 :

Column type: CHIPALPAK IC-3; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol; gradient: 30%; flow rate: 1 ml/min; retention time: 2.996 minutes

¹ H-NMR (CD ₃ OD)δ: 8.29 (s, 1H), 7.67-7.62 (m, 1H), 7.55-7.53 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 6.80- 6.78(m,1H), 6.28(d,J=16.8Hz,1H), 5.82(d,J=10.2Hz,1H), 5.06-5.03(m,1H),4.50(d,J=15.3Hz,1H ),4.33-4.28(m,3H),4.24-4.11(m,3H),3.80-3.53(m,4H),3.29-2.97(m,2H),2.58(d,J=2.4Hz,3H), 2.56-2.51(m,4H),1.59-1.47(m,4H),0.92(t,J=7.2Hz,6H).

Example 128 and Example 120

The racemate compound 93 is separated into monomers 128 and 129 by chiral high pressure preparation (column type: CHIRAL ART Cellulose-SC, 2*25cm, 5um; mobile phase: methyl tert-butyl ether (10mmol/L ammonia methanol solution) , Mobile phase: ethanol; flow rate: 20 ml/min; gradient: 50%, time 9 minutes; detector wavelength 254/220 nm). Compound 128 (retention time t=1.822 minutes) and compound 129 (retention time t=2.624 minutes) were obtained respectively

Compound 128 :

¹ H-NMR (CD ₃ OD) δ: 8.29 (s, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz ,1H), 6.94-6.71(m,1H), 6.29(d,J=16.8Hz,1H), 5.83(d,J=10.8Hz,1H), 5.35-4.90(m,3H), 4.57-4.39( m, 1H), 4.26 (d, J = 12.4 Hz, 1H), 4.17-4.02 (m, 1H), 3.83-3.41 (m, 3H), 3.20-3.08 (m, 3H), 3.03-2.91 (m, 2H), 2.82(t,J=11.6Hz,1H),2.58(d,J=2.4Hz,3H),2.35-2.19(m,2H),2.17-2.05(m,1H),2.03-1.75(m ,3H),1.57-1.44(m,1H).

Compound 129 :

¹ H NMR (CD ₃ OD) δ: 8.29 (s, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.91-6.71 (m, 1H), 6.29 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 5.30-4.90 (m, 3H), 4.51-4.39 (m ,1H),4.31-4.21(m,1H),4.16-4.04(m,1H),3.79-3.42(m,3H),3.19-3.08(m,3H),3.04-2.92(m,2H),2.87 -2.72(m,1H),2.58(q,J=2.4Hz,3H),2.32-2.19(m,2H),2.14-2.05(m,1H),2.01-1.76(m,3H),1.56-1.44 (m,1H).

Example 130

Synthesis of Example 130 Referring to steps 1 to 3 of Example 82, compound 8i was used instead of compound 9i' , and 3-diethylaminoazetidine hydrochloride was used instead of the compound of Preparation Example 26. Purification by preparative reversed-phase chromatography was performed. The product was 130 (39.5 mg).

LC-MS: m/z 556(M+H) ⁺

¹ H-NMR(CD ₃ OD)δ: 8.31(s,1H),7.34-7.20(m,2H),7.17-7.10(m,1H),6.96-6.74(m,1H),6.31(d,J = 16.8Hz, 1H), 5.85 (d, J = 10.2Hz, 1H), 5.12-4.99 (m, 1H), 4.58-4.46 (m, 1H), 4.43-4.02 (m, 6H), 3.80-3.44 ( m, 4H), 3.10-2.88 (m, 2H), 2.73-2.59 (m, 4H), 2.39 (s, 3H), 2.04 (s, 3H), 1.17 (t, J = 7.2 Hz, 6H).

Example 131

Synthesis of Example 131 With reference to steps 1 to 3 of Example 82, compound 1i was used instead of compound 9i' , and 3-(N,N-diethylamino)azetidine hydrochloride was used instead of the compound of Preparation Example 26, preparative Purified by reversed-phase chromatography to obtain product 131 (8.2 mg).

LC-MS: m/z 592(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.37 (s, 1H), 8.07 (d, J = 8.0, 1.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.8Hz,1H),7.45(t,J=8.4Hz,2H),7.33(d,J=7.2Hz,1H),6.96-6.88(m,1H),6.01(d,J=16.8Hz,1H) ,5.91-5.77(m,1H),5.05(s,1H),4.52(d,J=13.6Hz,1H),4.44-4.25(m,3H),4.20-4.00(m,3H),3.80-3.49 (m,4H),3.07-2.90(m,2H),2.68(q,J=7.2Hz,4H),2.52-2.19(m,3H),1.09(t,J=7.2Hz,6H).

Example 132

Synthesis of Example 132 Referring to Example 11, 3-(dimethylamino)azetidine dihydrochloride was used instead of 3-diethylaminoazetidine, and purified by preparative reverse phase chromatography to obtain product 132 (12 mg).

LC-MS: m/z 582(M+H) ⁺

¹ H-NMR(CD ₃ OD)δ:δ8.31(s,1H), 7.67(t,J=7.8Hz,1H), 7.57(d,J=7.8Hz,1H), 7.32(d,J= 7.8Hz, 1H), 6.96-6.72 (m, 1H), 6.31 (d, J = 16.8Hz, 1H), 5.86 (d, J = 10.5Hz, 1H), 5.13-4.98 (m, 1H), 4.67- 4.49(m,2H),4.41-4.22(m,3H),4.20-4.00(m,3H),3.79-3.46(m,3H),3.09-2.91(m,2H),2.61(d,J=2.4 Hz, 3H), 2.28 (s, 6H).

Example 133

Synthesis of Example 133 With reference to Example 11, azetidine was used instead of 3-diethylaminoazetidine and purified by preparative reverse phase chromatography to obtain product 133 (13.5 mg).

LC-MS: m/z 539(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.27 (s, 1H), 7.69-7.62 (m, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H) ,6.96-6.75(m,1H),6.31(d,J=16.8Hz,1H),5.84(d,J=10.5Hz,1H),5.11-4.80(m,1H),4.50-4.41(m,1H ), 4.34-4.21 (m, 5H), 4.18-4.05 (m, 1H), 3.79-3.39 (m, 3H), 3.05-2.93 (m, 2H), 2.63-2.57 (m, 3H), 2.48-2.35 (m,2H)

Example 134

Synthesis of Example 134 With reference to Example 11, 3-diethylaminoazetidine was replaced with 3-acridinyl acridine ditrifluoroacetate, and purified by preparative reverse phase chromatography to obtain product 134 (18 mg ).

LC-MS: m/z 594(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.30 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz ,1H), 6.98-6.72(m,1H), 6.31(d,J=16.5Hz,1H), 5.85(d,J=10.5Hz,1H), 5.14-4.99(m,1H), 4.68-4.44( m,2H),4.36-4.20(m,3H),4.17-3.89(m,3H),3.82-3.49(m,4H),3.38(t,J=7.2Hz,3H),3.08-2.89(s, 2H), 2.60(d,J=2.4Hz,3H), 2.24-2.10(m,2H).

Example 135

Synthesis of Example 135 With reference to steps 1 to 3 of Example 82, the compound of Preparation Example 31 was substituted for the compound of Preparation Example 26, and the product was purified by preparative reverse phase chromatography to obtain product 135 (12 mg).

LC-MS: m/z 658(M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 8.30 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz ,1H), 6.96-6.70(m,1H), 6.31(d,J=16.8Hz,1H), 5.85(d,J=10.5Hz,1H), 5.15-4.98(m,1H), 4.60-4.46( m,1H),4.41-4.21(m,3H),4.20-4.02(m,3H),3.79-3.44(m,3H),3.42-3.36(m,1H),3.07-2.86(m,2H), 2.68-2.46 (m, 7H), 2.13-1.93 (m, 4H).

Example 136

Synthesis of Example 136 Refer to steps 2 to 3 of Example 33, replace compound 33a with compound 15m , and purify with preparative column to obtain product 136 (4 mg).

LC-MS: m/z 630(M+H) ⁺

¹ H-NMR(CD ₃ OD): δ8.33(d,J=2.1Hz,1H), 8.15(d,J=8.2Hz,1H), 8.05-7.99(m,1H), 7.77-7.44(m ,4H),5.47-5.21(m,2H),5.01-4.90(m,1H),4.50(d,J=13.9Hz,1H),4.43-4.22(m,3H),4.21-3.91(m,3H) ), 3.66 (d, J = 40.3 Hz, 4H), 3.04 (d, J = 7.2 Hz, 2H), 2.67 (q, J = 7.2 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H).

Test Example 1 Detection of Covalent Protein Addition Reaction Products

His-KRAS-G12C protein (1-169a.a.) was expressed and purified by E. coli and incubated with GDP to prepare the inactive GDP-His-KRAS-G12C complex, which was dissolved in the reaction buffer and stored for a long time in- 80 degrees. In the experiment, 3uM test compound and 2uM GDP-His-KRAS-G12C protein complex were incubated at room temperature for 5 and 30 minutes, respectively, and the reaction was terminated with formic acid at a final concentration of 5%. The sample was centrifuged at 15,000 rpm for 10 minutes, and the supernatant was taken into the Waters Acquity I Class instrument for analysis, and the relative content of His-KRAS-G12C and His-KRAS-G12C complex covalently bound to the compound were detected.

Calculate the binding amount (POC value, percent of control) between the compound and KRAS-G12C protein after incubation for 5 and 30 minutes according to the following formula:

POC,% = the peak value of the complex after the addition reaction of the protein and the compound/(the peak value of the complex after the addition reaction of the protein and the compound + the peak value of the protein)×100

The test results of some example compounds are shown in Table 1.

Table 1: The binding capacity of the compound and KRAS-G12C protein

The test results of some example compounds are shown in Table 4:

Table 4: The binding capacity of the compound and KRAS-G12C protein

Note: + means 30%≤POC value＜50%;

++ means 50%≤POC value＜80%;

+++ means POC value ≥80%;

——Means that the POC value is not detected.

Test Example 2 KRAS-G12C inhibitory activity

1. ERK protein phosphorylation detection

Inoculate H358 cells (ATCC, CRL-5807) or MIA PaCa-2 (ATCC, CRL-1420) expressing KRAS-G12C protein in a 384-well cell culture plate coated with polylysine at 6000 cells per well , The medium components are RPMI1640 (Gibco, A10491-01), 10% FBS (Gibco, 10099141C) and 1% Pen/Strep (Gibco, 15140-122), cultured in a 5% carbon dioxide cell incubator for 16 hours; Echo550 Add the compounds in gradient dilutions to the cell culture medium, the final concentration of DMSO is 0.5%, and continue to incubate for 3 hours; add 40μL/well of 8% paraformaldehyde, incubate at room temperature for 20 minutes; wash once with PBS and add 40μL/well 100% methanol, permeate at room temperature for 10 minutes; wash with PBS and add 20μL/well of blocking solution for 1 hour at room temperature; dilute rabbit anti-phospho-p44/42MAPK(T202/Y204) antibody at 1:1000 with blocking solution, press Dilute mouse anti-GAPDH (D4C6R) antibody at 1:2000, add 20μL/well to the cells, block overnight at 4°C; wash 3 times with PBST, incubate for 2 minutes each time; dilute goat anti-rabbit 800CW antibody at 1:1000 with blocking solution And goat anti-mouse 680RD antibody, add 20μL/well to the cells, incubate for 45 minutes at room temperature; wash 3 times with PBST, incubate for 2 minutes each time, finally centrifuge the cell culture plate upside down, 1000rpm, 1 minute, read with Odyssey CLx Take the fluorescence signal value.

The data was fitted by XLFit 5.0 according to the 4-parameter formula Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) to calculate the IC ₅₀ value.

The test results of some example compounds are shown in Table 2.

Table 2: Results of phosphorylation detection of compound ERK protein

实施例化合物编号Example compound number	H358 IC ₅₀(nM) H358 IC ₅₀ (nM)	MIA PaCa-2 IC ₅₀(nM) MIA PaCa-2 IC ₅₀ (nM)
11	259259	132132
22	866.5866.5	260260
77	575575	————
88	18211821	————
99	361361	————
1010	972972	————
1111	22twenty two	1818
1212	844844	614614
1313	22twenty two	1414
1515	1818	2525
1717	2929	1313
1818	1515	2020
1919	389389	442442
2020	4.84.8	5.75.7
21twenty one	1616	1616

Note: —— means not detected.

The test results of some example compounds are shown in Table 5.

Table 5: Test results of ERK protein phosphorylation of compounds

Note: A represents IC ₅₀ ≤50nM;

B represents 50nM＜IC ₅₀ ≤150nM;

C represents 150nM＜IC ₅₀ ≤500nM;

D represents 500nM＜IC ₅₀ ≤999nM;

——It means that the IC ₅₀ value has not been tested.

2. Detection of cell proliferation inhibition

Use Echo550 to add the diluted compounds to a low-adsorption round-bottomed 384-well cell culture plate, add 40 μL of suspension containing 400 H358 or MIA PaCa-2 cells to each well, and continue to culture for 3 days in a 5% carbon dioxide cell incubator ; Add 3D CellTiter-Glo reagent to the cell culture plate at a rate of 20 μL per well, 100 rpm, 30 minutes later at room temperature for 2 hours, and use Envision 2104 to read the luminescence signal value.

The test results of some example compounds are shown in Table 3.

Table 3: Test results of compound cell proliferation inhibition

Example compound number	H358 IC ₅₀ (nM)	MIA PaCa-2 IC ₅₀ (nM)
1	179	87
2	1781	258
11	15	25
12	333	859
13	15	20
15	20	16
17	6	9
18	14	17
19	166	258
20	3	3
twenty one	17	14

.

The test results of some example compounds are shown in Table 6.

Table 6: Test results of compound cell proliferation inhibition

Note: A represents IC ₅₀ ≤50nM;

B represents 50nM＜IC ₅₀ ≤150nM;

C represents 150nM＜IC ₅₀ ≤500nM;

D represents 500nM＜IC ₅₀ ≤999nM;

——It means that the IC ₅₀ value is not detected.

Test Example 3 Metabolic stability test of liver microsomes

1. Prepare the reaction system according to the following table

2. Pre-incubate the reaction system in a 37°C water bath for 10 minutes. Add 40μL of 10mM NADPH solution to the reaction system, the final concentration of NADPH is 1mM respectively. Use 40μL ultrapure water instead of NADPH solution as a negative control. The role of the negative control is to exclude the influence of the chemical stability of the compound itself.

3. Add 4 μL of 200 μM test compound to the reaction system to start the reaction, and the final concentration of the drug is 2 μM.

4. Take out 50μL reaction samples at 0, 15, 30, 45 and 60 minutes, and use 4 times the cold containing internal standard (200nM alprazolam, 200nM labetalol, 2μM ketoprofen, 200nM caffeine). Acetonitrile quenched. The sample was centrifuged at 3,220g for 45 minutes. After centrifugation, take 90μL of supernatant and 90μL of ultrapure water and mix it for LC-MS/MS analysis and detection.

The test results of representative example compounds are shown in Table 7.

Table 7: Results of stability test of compound liver microsomes

Note:-means that the T _1/2 value has not been tested

Test Example 4 Whole blood stability test

1. Use the whole blood of healthy volunteers for the whole blood stability test.

2. Preparation of working fluid

Prepare a working solution of 1 mM DMSO for the test substance and a working solution of 1 mM acetonitrile for the reference drug propiamine bromide.

3. Test and sample analysis steps

Take 4μL of working solution and add 796μL of pre-incubated 50% whole blood (whole blood: pH 7.4 buffer salt solution = 1:1, V/V), and the final concentration of the analyte is 5μM. The final solvent concentration is 0.5%. The experiment is double parallel. For the test substance and the control drug, 50 μL aliquots of dosing whole blood were added to a new centrifuge tube as samples at 60, 120, 240 and 360 minutes, and cultured in a 37°C water bath with shaking at 60 rpm. At the end of each specified time point, take out the corresponding centrifuge tube, add 50μL of cold water to dissolve red blood cells, mix at 1500rpm for 1 minute, and then add 400μL of quencher (containing internal standard acetonitrile (IS, 500nM Labello) Er, 100 nM alprazolam and 2 μM ketoprofen)), vortex for 5 minutes. For zero-point samples, add 50 μL of medicated whole blood into a new centrifuge tube and then add 50 μL of cold water, mix at 1500 rpm for 1 minute, then add 400 μL of quencher, and vortex for 5 minutes. Centrifuge at 3,220g, 4°C for 60 minutes to precipitate protein. Transfer 100 μL of supernatant to a new plate. According to the liquid quality response signal and peak shape of the analyte, the supernatant was diluted with 100 μL of water. Mix well and analyze the samples by LC-MS/MS.

The test results of representative example compounds are shown in Table 8.

Table 8: Results of compound whole blood stability test

Claims

The compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers,

among them,

Part A is selected from
Wherein R is selected from H or C 1-6 alkyl;

Or, the AR 2 part is jointly selected from

Is a 4-10 membered heterocycloalkyl containing at least two N atoms,
Is a 4-7 membered heterocycloalkyl containing at least one N atom;

Each R 1 is substituted on the ring, which is independently selected from halogen, oxo, -OH, -NH 2 , -CN or the following groups optionally substituted with 1, 2 or 3 R 0 : C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or di-C 1-6 alkylamino;

Each R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylamino or di-C 1-4 alkylamino;

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

Each R 2 is independently selected from C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, -C(O)C≡CR b , -SO 2 C≡CR b , -C(O)C(R a )=C(R b ) 2 or -SO 2 C(R a )=C(R b ) 2 ;

Each R a is independently selected from H, deuterium, halo, C 1-4 alkyl or halogenated C 1-4 alkyl;

Each R b is independently selected from H, deuterium or the following groups optionally substituted with 1, 2, or 3 R c : C 1-6 alkyl, C 1-4 alkoxy C 1-3 alkyl , C 1-4 alkylamino C 1-3 alkyl, di C 1-4 alkylamino C 1-3 alkyl, 3-7 membered cycloalkyl C 1-3 alkyl, 4-7 membered heterocyclic ring Alkyl C 1-3 alkyl, phenyl C 1-3 alkyl or 5-6 membered heteroaryl C 1-3 alkyl;

Each R c is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, or halogenated C 1-6 Alkoxy;

X is selected from a single bond, -S-, -O-, -NH- or -N(C 1-3 alkyl)-;

R 3 is selected from H or the following groups optionally substituted with 1, 2 or 3 R d : C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, phenyl , Benzo 4-6 membered heterocyclyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl C 1-3 alkyl, Phenyl C 1-3 alkyl, benzo 4-6 membered heterocyclyl C 1-3 alkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclic C 1-3 alkyl or 5-10 Member heteroaryl C 1-3 alkyl;

Each R d is independently selected from deuterium, halogen, -OH, oxo, -NH 2 , -CN, deuterated C 1-4 alkylamino, deuterated di C 1-4 alkylamino, or optionally The following groups substituted by 1, 2 or 3 R d1 : C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1 -4 alkylamino, C 1-4 alkylaminomethyl, di-C 1-4 alkylaminomethyl, C 1-3 alkoxyimino, 3-7 membered cycloalkyl, 4-7 membered hetero Cycloalkyl, 4-7 membered heterocycloalkyl C 1-3 alkyl, phenyl or 5-6 membered heteroaryl;

Each R d1 is independently selected from halogen, -OH, oxo, -NH 2 , -CN, C 1-4 alkyl, or halo C 1-4 alkyl;

Y is selected from a single bond or -CH 2 -;

R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from H, halogen, -CN, -OH, -NH 2 , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, C 2-6 alkenyl amido or 3-7 membered cycloalkyl ；

Alternatively, R 4 and R 5 are joined together to form ring B; or, R 5 and R 6 are joined together to form ring B;

Ring B is selected from the following groups optionally substituted with 1, 2, 3 or 4 R e : phenyl, 5-6 membered cycloalkenyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl base;

Each R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino or 3-7 membered cycloalkyl;

R 9 is independently selected from H, halogen, C 1-6 alkyl or halo C 1-6 alkyl.
The compound of claim 1, wherein part A is selected from

Wherein R is selected from H or C 1-6 alkyl; or, AR 2 part is jointly selected from
The compound of claim 1, wherein said R 1 is independently selected from halogen, oxo, -OH, -NH 2 , -CN or optionally substituted with 1, 2 or 3 R 0 The following groups: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or di-C 1-4 alkylamino.
The compound of claim 1, wherein the R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-3 alkoxy, C 1-3 alkylamino, or two C 1-3 alkylamino.
The compound of claim 1, wherein the R 2 is independently selected from -C(O)C≡CR b , -SO 2 C≡CR b , -C(O)C(R a )= C(R b ) 2 or -SO 2 C(R a )=C(R b ) 2 .
The compound of claim 1 or 5, wherein each R a is independently selected from H, deuterium, fluorine, chlorine, methyl, ethyl, or halomethyl; each R b is independently selected from H, deuterium or the following groups optionally substituted with 1, 2 or 3 R c : C 1-4 alkyl, di-C 1-3 alkylamino C 1-2 alkyl or 4-6 membered heterocycle Alkyl C 1-2 alkyl.
The compound of claim 1, wherein the X is selected from a single bond, -S-, -O-, or -NH-.
The compound of claim 1, wherein the R 3 is selected from H or the following groups optionally substituted with 1, 2 or 3 R d : C 1-4 alkyl, 3-7 member Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, benzo4-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 4-9 membered heterocycloalkyl C 1-3 alkyl, phenyl C 1-3 alkyl, benzo 4-6 membered heterocyclyl C 1-3 alkyl, 5-6 membered heteroaryl C 1- 3 alkyl or 5-6 membered heteroaryl and 4-6 membered heterocyclyl C 1-3 alkyl.
The compound of claim 1 or 8, wherein the R d is independently selected from deuterium, halogen, -OH, oxo, -NH 2 , -CN, deuterated di-C 1-4 alkylamino Or the following groups optionally substituted by 1, 2 or 3 R d1 : C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , Two C 1-4 alkylamino, C 1-4 alkylaminomethyl, two C 1-4 alkylaminomethyl, C 1-3 alkoxyimino, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl.
The compound of claim 1 or 9, wherein the R d1 is independently selected from halogen, -OH, oxo, -NH 2 , -CN, C 1-4 alkyl, or halogenated C 1 -4 alkyl.
The compound of claim 1, wherein said R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from H, halogen, -CN, -OH, -NH 2 , C 1 -4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, C 2-4 alkenyl amido or 3-6 membered cycloalkyl.
The compound of claim 1, wherein R 4 and R 5 are joined together to form ring B.
The compound of claim 12, wherein the ring B is selected from the following groups optionally substituted with 1, 2, 3 or 4 R e : phenyl, 5-6 membered cycloalkenyl or 5 -6 membered heteroaryl; wherein each R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkane Oxy, C 1-4 alkylamino, di-C 1-4 alkylamino or 3-6 membered cycloalkyl.
The compound of claim 1, wherein the R 9 is selected from H, halogen, C 1-4 alkyl, or fluoro C 1-4 alkyl.
The compound of claim 1, selected from a compound of general formula (Ia), a compound of general formula (Ib), a compound of general formula (Ic), a compound of general formula (Id) or a compound of general formula (Ie),

Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, Y, m and A are as defined in any one of claims 1-14.
The compound of claim 1, selected from the following compounds:
A pharmaceutical composition comprising the compound according to any one of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.
The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers or the pharmaceutical composition of claim 17 is used in the preparation of the treatment of KRas G12C related diseases Use in medicine.